Journal articles on the topic 'Zhong guo hua'

We experimentally demonstrate a passively Q-switched erbium-doped fiber laser (EDFL) operation by using a saturable absorber (SA) based on tungsten disulfide (WS2). By depositing WS2 thin film layer at the end of optical fiber ferrule, we fabricated a SA device. The SA is incorporated into an Erbium-doped fiber laser (EDFL) cavity to generate a Q-switching pulses train operating at 1559.8 nm. As a result, stable passively Q-switched EDFL pulses with maximum output pulse energy of 123.2 nJ, repetition rate of 104.1 kHz, and pulse width of 9.61 us are achieved when the input pump power is 142.1 mW at the wavelength of 980 nm. Full Text: PDF ReferencesC. Gao, W. Zhao, Y. Wang, S. Zhu, G. Chen, and Y. Wang, "Passive Q-switched fiber laser with SESAM in ytterbium-doped double-clad fiber", in 27th International congress on High-Speed Photography and Photonics (International Society for Optics and Photonics, 2007). CrossRef M. Ahmed, N. Ali, Z. Salleh, A. Rahman, S. Harun, M. Manaf, et al., "Q-switched erbium doped fiber laser based on single and multiple walled carbon nanotubes embedded in polyethylene oxide film as saturable absorber", Optics & Laser Technology 65, 25 (2015). CrossRef M. A. Ismail, F. Ahmad, S. W. Harun, H. Arof and H. Ahmad, "A Q-switched erbium-doped fiber laser with a graphene saturable absorber", Laser Phys. Lett. 10, 025102 (2013). CrossRef G. Sobon, J. Sotor, J. Jagiello, R. Kozinski, K. Librant, M. Zdrojek, L. Lipinska, and K. M. Abramski, "Linearly polarized, Q-switched Er-doped fiber laser based on reduced graphene oxide saturable absorber", Appl. Phys. Lett. 101, 241106 (2012). CrossRef N. H. M. Apandi, F. Ahmad, S. N. F. Zuikafly, M. H. Ibrahim, S. W. Harun, "Bismuth (III) Telluride (Bi2Te3) topological insulator embed in PVA as passive Q-switcher at 2 micron region", Photon. Lett. of Poland 8, 101 (2016). CrossRef J. Bogusławski, G. Soboń, K. Tarnowski, R. Zybała, K. Mars, A. Mikuła, K. M. Abramski and J. Sotor, "All-polarization-maintaining-fiber laser Q-switched by evanescent field interaction with Sb2Te3 saturable absorber", Optical Engineering 55, 081316 (2016). CrossRef Z. Luo, Y. Huang, M. Zhong, Y. Li, J. Wu, B. Xu, H. Xu, Z. Cai, J. Peng, and J. Weng, "1-, 1.5-, and 2-um fiber lasers Q-switched by a broadband few-layer MoS2 saturable absorber", J. Lightwave Technol. 32, 4679 (2014). CrossRef N. N. Razak, A. A. Latiff, Z. Zakaria and S. W. Harun, "Q-switched Erbium-doped Fiber Laser with a Black Phosphorus Saturable Absorber", Photon. Lett. of Poland 9, 72 (2017). CrossRef D. Mao, Y. Wang, C. Ma, L. Han, B. Jiang, X. Gan, S. Hua, W. Zhang, T. Mei, and J. Zhao, "WS2 mode-locked ultrafast fiber laser", Sci Rep 5, 7965 (2015). CrossRef K. Wu, X. Zhang, J. Wang, X. Li, and J. Chen, "WS2 as a saturable absorber for ultrafast photonic applications of mode-locked and Q-switched lasers", Optics Express 23, 11453 (2015). CrossRef K. Lau, A. Latif, M. A. Bakar, F. Muhammad, M. Omar, and M. Mahdi, "Mechanically deposited tungsten disulfide saturable absorber for low-threshold Q-switched erbium-doped fiber laser", Applied Physics B 123, 221 (2017). CrossRef H. Chen, Y. Chen, J. Yin, X. Zhang, T. Guo, and P. Yan, "High-damage-resistant tungsten disulfide saturable absorber mirror for passively Q-switched fiber laser", Optics Express 24, 16287 (2016). CrossRef J. Lin, K. Yan, Y. Zhou, L. Xu, C. Gu, and Q. Zhan, "Tungsten disulphide based all fiber Q-switching cylindrical-vector beam generation", Applied Physics Letters 107, 191108 (2015). CrossRef H. Chen, Y. Chen, J. Yin, X. Zhang, T. Guo, and P. Yan, "High-damage-resistant tungsten disulfide saturable absorber mirror for passively Q-switched fiber laser", Optics Express 24, 16287 (2016). CrossRef K. Mohamed, B. Hamida, S. Khan, L. Hussein, M. Ahmat, E. Ismail, N. Kadir, A. Latif, S. Harun, "Q-switched erbium-doped fibre laser based on molybdenum disulfide and tungsten disulfide as saturable absorbers," Ukrainian Journal of Physical Optics, 18 (2017). CrossRef

Abstract Background: Morpho-physiological alternations of platelets provided a rationale to harness RNA sequencing of tumor-educated platelets (TEPs) for preoperative diagnosis of cancer. Timely, accurate, and non-invasive detection of ovarian cancer in women with adnexal masses presents a significant clinical challenge. Patients and Methods: This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n=3; Netherlands, n=5; Poland, n=1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. Results: The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. Analysis of public datasets suggested that TEPs had potential to detect multiple malignancies (Table 1). Conclusions: TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, early-stage ovarian cancer as well as other malignancies. However, these observations warrant prospective validations in a larger population before clinical utilities. Table 1. Performance for TEPs in public pan-cancer datasets. Disease n Healthy Control AUC, area under the curve (95% CI) Women NSCLC (non-small-cell lung cancer) 126 77 0.758 (0.691-0.825) Breast cancer 38 77 0.817 (0.726-0.909) Colorectal cancer 18 77 0.973 (0.945-1.000) Pancreatic cancer 16 77 0.993 (0.981-1.000) Glioblastoma 10 77 0.923 (0.831-1.000) Men NSCLC 119 82 0.746 (0.677-0.815) Colorectal cancer 25 82 0.933 (0.884-0.982) Pancreatic cancer 22 82 0.993 (0.984-1.000) Glioblastoma 19 82 0.981 (0.959-1.000) All NSCLC 245 159 0.774 (0.728-0.820) Colorectal cancer 40 159 0.978 (0.961-0.996) Breast cancer 38 159 0.821 (0.736-0.906) Pancreatic cancer 35 159 0.987 (0.974-0.999) Glioblastoma 35 159 0.931 (0.890-0.972) Hepatobiliary carcinomas 14 159 0.991 (0.978-1.000) Citation Format: Yue Gao, Chun-Jie Liu, Hua-Yi Li, Xiao-Ming Xiong, Sjors G.j.g. In ‘t Veld, Gui-Ling Li, Jia-Hao Liu, Guang-Yao Cai, Gui-Yan Xie, Shao-Qing Zeng, Yuan Wu, Jian-Hua Chi, Qiong Zhang, Xiao-Fei Jiao, Lin-Li Shi, Wan-Rong Lu, Wei-Guo Lv, Xing-Sheng Yang, Jurgen M.j. Piek, Cornelis D de Kroon, C.a.r. Lok, Anna Supernat, Sylwia Łapińska-Szumczyk, Anna Łojkowska, Anna J. Żaczek, Jacek Jassem, Bakhos A. Tannous, Nik Sol, Edward Post, Myron G. Best, Bei-Hua Kong, Xing Xie, Ding Ma, Thomas Wurdinger, An-Yuan Guo, Qing-Lei Gao. Platelet RNA signature enables early and accurate detection of ovarian cancer: An intercontinental, biomarker identification study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB168.

In recent years, many attempts have been made to improve the sensory properties of SnO2, including design of sensors based on one-dimensional nanostructures of this material, such as nanofibers, nanotubes or nanowires. One of the simpler methods of producing one-dimensional tin oxide nanomaterials is to combine the electrospinning method with a sol-gel process. The purpose of this work was to produce SnO2 nanowires using a hybrid electrospinning method combined with a heat treatment process at the temperature of 600 °C and to analyze the morphology and structure of the one-dimensional nanomaterial produced in this way. Analysis of the morphology of composite one-dimensional tin oxide nanostructures showed that smooth, homogeneous and crystalline nanowires were obtained. Full Text: PDF ReferencesN. Dharmaraj, C.H. Kim, K.W. Kim, H.Y. Kim, E.K. Suh, "Spectral studies of SnO2 nanofibres prepared by electrospinning method", Spectrochim. Acta - Part A Mol. Biomol. Spectrosc. 64, (2006) CrossRef N. Gao, H.Y. Li, W. Zhang, Y. Zhang, Y. Zeng, H. Zhixiang, ... & H. Liu, "QCM-based humidity sensor and sensing properties employing colloidal SnO2 nanowires", Sens. Actuators B Chem. 293, (2019), 129-135. CrossRef W. Ge, Y. Chang, V. Natarajan, Z. Feng, J. Zhan, X. Ma, "In2O3-SnO2 hybrid porous nanostructures delivering enhanced formaldehyde sensing performance", J.Alloys and Comp. 746, (2018) CrossRef M. Zhang, Y. Zhen, F. Sun, C. Xu, "Hydrothermally synthesized SnO2-graphene composites for H2 sensing at low operating temperature", Mater. Sci. Eng. B. 209, (2016), 37-44. CrossRef Y. Zhang, X. He, J. Li, Z. Miao, F. Huang, "Fabrication and ethanol-sensing properties of micro gas sensor based on electrospun SnO2 nanofibers", Sens. Actuators B Chem. 132, (2008), 67-73. CrossRef W.Q. Li, S.Y. Ma, J. Luo, Y.Z. Mao, L. Cheng, D.J. Gengzang, X.L. Xu, S H. Yan, "Synthesis of hollow SnO2 nanobelts and their application in acetone sensor", Mater. Lett. 132, (2014), 338-341. CrossRef E. Mudra, I. Shepa, O. Milkovic, Z. Dankova, A. Kovalcikova, A. Annusova, E. Majkova, J. Dusza, "Effect of iron doping on the properties of SnO2 nano/microfibers", Appl. Surf. Sci. 480, (2019), 876-881. CrossRef P. Mohanapriya, H. Segawa, K. Watanabe, K. Watanabe, S. Samitsu, T.S. Natarajan, N.V. Jaya, N. Ohashi, "Enhanced ethanol-gas sensing performance of Ce-doped SnO2 hollow nanofibers prepared by electrospinning", Sens. Actuators B Chem. 188, (2013), 872-878. CrossRef W.Q. Li, S.Y. Ma, Y.F. Li, X.B. Li, C.Y. Wang, X.H. Yang, L. Cheng, Y.Z. Mao, J. Luo, D.J. Gengzang, G.X. Wan, X.L. Xu, "Preparation of Pr-doped SnO2 hollow nanofibers by electrospinning method and their gas sensing properties", J.Alloys and Comp. 605, (2014), 80-88. CrossRef X.H. Xu, S.Y. Ma, X.L. Xu, T. Han, S.T. Pei, Y. Tie, P.F. Cao, W.W. Liu, B.J. Wang, R. Zhang, J.L. Zhang, "Ultra-sensitive glycol sensing performance with rapid-recovery based on heterostructured ZnO-SnO2 hollow nanotube", Mater. Lett, 273, (2020), 127967. CrossRef F. Li, X. Gao, R. Wang, T. Zhang, G. Lu, Sens. "Study on TiO2-SnO2 core-shell heterostructure nanofibers with different work function and its application in gas sensor", Actuators B Chem, 248, (2017), 812-819. CrossRef S. Bai, W. Guo, J. Sun, J. Li, Y. Tian, A. Chen, R. Luo, D. Li, "Synthesis of SnO2–CuO heterojunction using electrospinning and application in detecting of CO", Sens Actuators B Chem, 226, (2016), 96-103. CrossRef H. Du, P.J. Yao, Y. Sun, J. Wang, H. Wang, N. Yu, "Electrospinning Hetero-Nanofibers In2O3/SnO2 of Homotype Heterojunction with High Gas Sensing Activity", Sensors, 17, (2017), 1822. CrossRef X. Wang, H. Fan, P. Ren, "Electrospinning derived hollow SnO2 microtubes with highly photocatalytic property", Catal. Commun. 31, (2013), 37-41. CrossRef L. Cheng, S.Y. Ma, T.T. Wang, X.B. Li, J. Luo, W.Q. Li, Y.Z. Mao, D.J Gengzang, "Synthesis and characterization of SnO2 hollow nanofibers by electrospinning for ethanol sensing properties", Mater. Lett. 131, (2014), 23-26. CrossRef P.H. Phuoc, C.M. Hung, N.V. Toan, N.V. Duy, N.D. Hoa, N.V. Hieu, "One-step fabrication of SnO2 porous nanofiber gas sensors for sub-ppm H2S detection", Sens. Actuators A Phys. 303, (2020), 111722. CrossRef A.E. Deniz, H.A. Vural, B. Ortac, T. Uyar, "Gold nanoparticle/polymer nanofibrous composites by laser ablation and electrospinning", Matter. Lett. 65, (2011), 2941-2943. CrossRef S. Sagadevan, J. Podder, "Investigation on Structural, Surface Morphological and Dielectric Properties of Zn-doped SnO2 Nanoparticles", Mater. Res. 19, (2016), 420-425. CrossRef

Abstract TCR-engineered T (TCR-T) cells and TCR-anti-CD3 bispecific T-cell engagers (TCEs) are potent TCR-based therapeutic agents with distinct advantages and limitations in tumor treatment. TCR-T cells offer durable persistence within patients but necessitate personalized manufacturing and lack the capacity to harness bystander T cells. Conversely, TCEs are readily available as "off-the-shelf" products and can recruit bystander T cells, yet they exhibit a shorter lifespan. In our study, we sought to merge the merits of both approaches by engineering T cells to secrete a TCR-anti-CD3 TCE specific for alpha fetoprotein (AFP), a tumor-associated antigen abundantly expressed in hepatocellular carcinoma (HCC). We initially identified a TCR with specificity for the AFP158-166 peptide bound to HLA-A*02:01 and enhanced its affinity to picomolar via phage display. To facilitate efficient secretion by T cells, we adapted the high-affinity TCR to a single-chain format (scTCR) and fused it with a CD3-specific single-chain antibody fragment (scAFP-TCE). Our findings demonstrated that scAFP-TCE effectively redirected bystander T cells to engage in the lysis of HCC cells. Moreover, scAFP-TCE could be secreted by T cells transduced with lentiviral particles encoding the TCE gene. These transduced T cells exhibited potent antitumor activity both independently and by enlisting bystander T cells. This innovative T cell strategy, combining the bystander-recruiting ability of fusion proteins with the durable persistence seen in T cell therapy after a single infusion, presents a promising alternative to conventional TCR-based therapeutic agents. We anticipate that this novel approach may hold substantial potential for enhancing HCC treatment and expanding the scope of TCR-based immunotherapies. Citation Format: Hanli Sun, Jiao Huang, Kai Zhan, Wanli Wu, Xianqing Tang, Min Liu, Shanshan Guo, Hongjun Zheng, Yingjie Huang, Shi Zhong. A new strategy for T cell therapy: T cells secreting TCR anti-CD3 bispecific T-cell engager [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3598.

Abstract Mutated KRAS proteins are ideal cancer targets, as they are expressed frequently and specifically in certain solid tumors. A large proportion of human colorectal cancer and pancreatic ductal adenocarcinoma express the tumor driver KRAS gene mutations G12V/G12D, but drugs targeting G12V/G12D are not available, revealing a huge unmet clinical need. While small molecules often fail to target the KRAS mutation G12V/G12D, T cell receptor-mimic (TCR-mimic) antibodies can specifically recognize KRAS mutations presented by human leukocyte antigen (HLA), opening up possibilities for targeting such intracellular antigens. Here, we discovered novel antibodies highly specific to G12V/HLA and G12D/HLA complexes by immunizing our proprietary RenTCR-mimicTM mice and using high-throughput Beacon-based screening. These TCR-mimic antibodies have higher affinities compared to endogenous TCRs, which may effectively reduce the possibility of tumor escape. Germline distribution analysis indicated their high sequence diversity, which suggests diverse epitope targeting. Although pancreatic cancer is extremely difficult to treat and has an extremely low KRAS mutant peptide-HLA complex density on the cell surface, our TCR-mimic antibodies exhibited potent in vitro tumor lysis activity when assembled into CD3 T cell engagers. Furthermore, these antibodies demonstrated convincing off-target safety. Together, our results indicate promising therapeutic potential of these KRAS mutation-targeted TCR-mimic antibodies for the treatment of solid tumors. Citation Format: Jun Du, Wanbo Tang, Xin Jiao, Limin Zhao, Pengfei Du, Yuqi Zhang, Jian Bao, Han Chen, Chaoshe Guo, W. Frank An. Targeting mutant KRAS proteins with novel TCR-mimic fully human antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6717.

Abstract The widespread use of chest computed tomography in lung cancer screening has led to the detection of ground-glass opacity (GGO) nodules, which typically harbor pre-invasive or minimally invasive adenocarcinoma and 20-40% of GGO nodules progress to invasive lung adenocarcinoma within 4 years. Lack of approved treatments to intercept disease progression has imposed challenges in the clinical management of patients with GGOs. Previous studies showed that GGO nodules have substantially lower rates of HLA deletions than invasive/metastatic lung cancer, suggesting that GGO nodules constitute a critical window of vulnerability for immune interception. We therefore sought to identify the most immunogenic and cytotoxic neoantigens in patients with GGO nodules and to develop LNP-mRNA cancer vaccines to intercept the disease progression from pre-invasive to invasive adenocarcinoma. Whole exome and RNA sequencing of a large cohort (>300) patients identified potential neoantigen candidates, with KRAS-G12C, KRAS-G12D and EGFR-L858R as the most frequently predicted shared neoantigens consistent with >40% GGO patient population harboring either mutant KRAS or EGFR driver oncogenes. LNP-mRNA vaccines targeting KRAS-G12C and EGFR-L858R showed marked immunogenicity as determined by ELISPOT assays. Moreover, KRAS-G12C vaccination induced CD4+ T cell responses whereas EGFR-L858R vaccination triggered CD8+ T cell responses. Both these vaccines are being tested in GGO immunoprevention studies. Our data suggest the potential of KRAS and EGFR vaccines in the treatment of early disease, particularly in EGFR mutant patients who fail to respond to immunotherapy. Citation Format: Yongfeng He, Sijin Luo Zhong, Bhavneet Bhinder, Geoffrey Markowitz, Arshdeep Singh, Eric Gardner, Myung Soo Ko, Nasser K. Altorki, Shaoyi Jiang, Vivek Mittal. LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4097.

BackgroundImmune-mediated adverse events (imAE) commonly occur in patients treated with immune checkpoint inhibitors (ICI), and pneumonitis is known to occur in 3 -5 % of patients treated with anti-PD-1 / PD-L1 antibodies.1 Most cases are grade 1 or 2 events and can be treated with immunosuppression, but high-grade events occur in a minority of patients and can be fatal.2 Since lung inflammatory phenotypes, including fibrotic idiopathic interstitial pneumonias and infectious pneumonias, were associated with allelic variation in Human Leukocyte Antigen (HLA) genes,3 4 we hypothesized that HLA variants might also be a risk factor for ICI- associated pneumonitis.MethodsOut of 1761 atezolizumab (anti-PD-L1) treated patients across nine Genentech (GNE) clinical trials with available whole-genome sequencing data, 72 (4.1%) developed pneumonitis (table 1). We inferred HLA genotypes using HLA-HD5 and performed an association study including 87 alleles with a carrier frequency of >2%. In order to confirm our results, and to test whether the association is generalizable to different classes of ICI, we genotyped two additional cohorts using an Illumina genome-wide SNP array (GSA v3), followed by HLA imputation using HIBAG6: (1) 20 ICI-treated cancer patients with pneumonitis and 20 matched controls without from a pilot study on the AEROSMITH trial from Parker Institute for Cancer Immunotherapy (PICI); (2) 15 ICI-treated melanoma patients with pneumonitis and 149 without from Peter MacCallum Cancer Centre (PMC) (table 1).ResultsTwo HLA class II alleles that are part of a common haplotype showed significant associations with pneumonitis risk after multiple testing adjustment (HLA-DRB1*15:01, HLA-DQA1*01:02), with HLA-DRB1*15:01 showing the strongest association (p = 0.0002, odds ratio (OR) =2.51). No associations were identified in the control arms (N = 1192). In the PICI pilot cohort, HLA-DRB1*15:01 did not reach statistical significance in spite of a comparable OR (p = 0.26, OR = 2.75), but the allele was significantly associated with pneumonitis risk in the PMC cohort (p = 0.03, OR = 3.92). A meta-analysis across the three cohorts yielded a highly significant p-value of 1.2x10–5 (OR = 2.67, figure 1), suggesting that the association is generalizable across ICI. Importantly, the same class II haplotype was previously shown to be associated with diverse lung inflammatory, including fibrotic, phenotypes.3,4,7,8Abstract 811 Table 1Investigated cohortsAbstract 811 Figure 1Forest plot for HLA-DRB1*15:01 meta-analysis with ICI-associated pneumonitis. GNE, Genentech; PICI, Parker Institute for Cancer Immunotherapy; PMC, Peter MacCallum Cancer Centre; OR, odds ratio; CI, confidence interval; W, weight http://dx.doi.org/10.1136/jitc-2021-SITC2021.811ConclusionsIn summary, our findings establish HLA class II allelic variation as a potential risk factor in ICI-associated pneumonitis, and future research is warranted to determine whether this genetic association can be refined according to specific clinical presentations.ReferencesWang H, Guo X, Zhou J, Li Y, Duan L, Si X, et al. Clinical diagnosis and treatment of immune checkpoint inhibitor-associated pneumonitis. Thorac Cancer 2020;11:191–7.Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti–programmed death-1/Programmed death ligand 1 therapy. J Clin Oncol 2016;35:709–17.Tian C, Hromatka BS, Kiefer AK, Eriksson N, Noble SM, Tung JY, et al. Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nat Commun 2017;8:599.Fingerlin TE, Zhang W, Yang IV, Ainsworth HC, Russell PH, Blumhagen RZ, et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet 2016;17:74.Kawaguchi S, Higasa K, Shimizu M, Yamada R, Matsuda F. HLA-HD: An accurate HLA typing algorithm for next-generation sequencing data. Hum Mutat 2017;38:788–97.Zheng X, Shen J, Cox C, Wakefield JC, Ehm MG, Nelson MR, et al. HIBAG—HLA genotype imputation with attribute bagging. Pharmacogenomics J 2014;14:192–200.Voorter CEM, Drent M, Berg-Loonen EM van den. Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602–DRB1*150101. Hum Immunol 2005;66:826–35.Furukawa H, Oka S, Shimada K, Sugii S, Ohashi J, Matsui T, et al. Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. Plos One 2012;7:e33133.Ethics ApprovalPatients included in this study signed an optional Research Biosample Repository (RBR) Informed Consent Form (ICF) and provided whole blood samples. By signing the optional RBR ICF, patients provided informed consent for analysis of inherited and non-inherited genetic variation from whole blood samples. Ethics Committees (EC) and Institutional Review Boards (IRB) in each country and each study site for each clinical trial approved the clinical trial protocol, the main study ICF, and theRBR ICF.

Abstract Accurate monitoring of orthotopic tumors in oncological research is critical. While conventional surgical exposure method or imaging methods such as bioluminescence imaging (BLI), ultrasound imaging (US) and computed tomography (CT) have different advantages and limitations. Magnetic Resonance Imaging (MRI) offers a non-invasive modality with high sensitivity. This study compares BLI and MRI in tracking tumor progression, focusing on the human glioblastoma multiforme (GBM) orthotopic xenograft mouse model. To establish the GBM model, human glioblastoma cells U87 MG-luc, expressing firefly luciferase, were intracranially implanted in female BALB/c nude mice. In-life tumor growth was assessed longitudinally every 3-4 days using BLI (IVIS Lumina S5, PerkinElmer, US) and MRI (Bruker BioSpec 117/16, 11.7T ultra-high field scanner, Germany) with a T2-weighted sequence. Mice were randomized into two groups (n=8) based on the MRI-derived tumor volume and BLI signal on the 3rd day post inoculation. One day after grouping, each cohort received specific treatments: one with the standard vehicle control and the other with Temozolomide (TMZ) (10mg/kg, 5 days/week, oral gavage). This treatment lasted until day 21, after which whole brains were removed and tumors excised from surrounding normal tissue and weighed. The results from both BLI and MRI showed that the control group exhibited consistent tumor growth, while TMZ treatment significantly inhibited tumor growth by day 21. However, some differences were observed, particularly for small tumor size, with more accurate measurement with MRI compared to BLI. By day 7 (3 days post treatment), MRI indicated a Tumor Growth Inhibition (TGI) of 32.63%, whereas BLI indicated a 5.04% increase in the TMZ-treated group compared to the control group. From day 11 onwards, both methods demonstrated a TGI exceeding 70% with TMZ treatment. Moreover, there was a pronounced difference in tumor weight correlations: MRI assessments showed a strong correlation (R2=0.9967) with extracted tumor weights, whereas in contrast to BLI showed a weaker correlation (R2=0.5371). The lower correlation for BLI, could be explained by the hypoxia and necrosis commonly observed in larger tumors or after treatment leading to decrease of ATP and reduction of bioluminescence. BLI offers rapid 2D imaging but lacks precision in determining location and depth of GBM tumor. Moreover, it requires luciferase engineered cell lines. In contrast, MRI provides high-resolution 3D imaging without genetic modifications, providing precise anatomical evaluations. Our study highlights the advantages of MRI over BLI for longitudinal monitoring of orthotopic GBM models. MRI imaging modality opens the possibility to use more clinically relevant patient derived xenograft (PDX) models of GBM in an orthotopic manner, improving the clinical transability to evaluate new GBM treatment modalities. Citation Format: Mingrui Guo, Ruisong Su, Jeff W H Chor, Zheyan Zhang, Mandy Tan, Xing Qi Teo, Haosheng Feng, Kuan J. Lee, Li Hua, Longyun Zhang, Jie Cai, Guanping Mao, Jingjing Wang, Keefe Chng, Weiping Han, Colin Guo. Magnetic resonance imaging and bioluminescence imaging for evaluating tumor burden in orthotopic glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4179.

BackgroundPrevious studies have observed an increasing trend in the prevalence of hyperuricemia which is linked to the physiological prerequisite for gout in recent years. However, the prevalence of hyperuricemia varies across different populations and different areas.ObjectivesThe aim of this study was to explore the prevalence of hyperuricemia and influencing factors in Chinese adults.MethodsThe analysis was a part of a cross-sectional study in Guangdong Second Provincial General Hospital in Guangzhou City, China between January 2009 and December 2019. A total of 205922 participants (21401 with hyperuricemia) were included in this study. Hyperuricemia was defined as serum uric acid ≥416.0 µmol/L (7.0 mg/dl) for men and ≥357.0 µmol/L(6.0 mg/dl) for women. We calculated the prevalence of hyperuricemia and used the multivariate-adjusted logistic regression model to identify the risk factors associated with hyperuricemia.ResultsThe overall estimated prevalence of HUA was 10.4% in China. Our study showed the prevalence of hyperuricemia in male (10.7%) was higher than that in female (9.9%) (P<0.05). The prevalence of HUA in the age group(≥75) subjects (13.3%) was higher than others. Multivariate logistic regression analysis revealed that sex (OR=1.75), age (OR=1.68), blood urea nitrogen (BUN) (OR=1.051), creatinine (Cr) (OR=1.045), high-density lipoprotein cholesterol (HDL-C) (OR=1.225), low-density lipoprotein cholesterol (LDL-C) (OR=1.466), systolic blood pressure (SBP) (OR=1.012),triglycerides (TG) (OR=1.460) and Body Mass Index (BMI) (OR=1.080) could increase the risk of hyperuricemia, while diastolic blood pressure (DBP) (OR=0.998), fasting plasma glucose (FPG) (OR=0.902) and total cholesterol (TC) (OR=0.704) were associated with a lower risk of hyperuricemia in all adults.ConclusionThe latest prevalence of hyperuricemia is high in Chinese adults and is associated with multiple factors, indicating that prevention and control strategies for hyperuricemia are needed urgently.References[1]Han B, Wang N, Chen Y, Li Q, Zhu C, Chen Y, Lu Y. Prevalence of hyperuricaemia in an Eastern Chinese population: a cross-sectional study. BMJ Open. 2020 May 20;10(5):e035614.[2]Liu H, Zhang XM, Wang YL, Liu BC. Prevalence of hyperuricemia among Chinese adults: a national cross-sectional survey using multistage, stratified sampling. J Nephrol. 2014 Dec;27(6):653-8.[3]Song P, Wang H, Xia W, Chang X, Wang M, An L. Prevalence and correlates of hyperuricemia in the middle-aged and older adults in China. Sci Rep. 2018 Mar 12;8(1):4314.[4]Dong X, Zhang H, Wang F, Liu X, Yang K, Tu R, Wei M, Wang L, Mao Z, Zhang G,Wang C. Epidemiology and prevalence of hyperuricemia among men and women in Chinese rural population: The Henan Rural Cohort Study. Mod Rheumatol. 2020 Sep;30(5):910-920.[5]Shan R, Ning Y, Ma Y, Gao X, Zhou Z, Jin C, Wu J, Lv J, Li L. Incidence and Risk Factors of Hyperuricemia among 2.5 Million Chinese Adults during the Years 2017-2018. Int J Environ Res Public Health. 2021 Feb 28;18(5):2360.Table 1.The prevalence of hyperuricemia by gender and age groupsVariableNumberHyperuricemianPrevalence (%)GenderMale1242371333010.7Female8168580719.9Age group ＜3048437496510.3 30-4484331898910.7 45-595217549769.5 60-7414710164011.1 ≥75626983113.3Overall2059222140110.4Disclosure of InterestsNone declared

Abstract Pancreatic cancer is one of the most fatal human cancers, with an overall 5-year survival rate of 10.8%. Early detection is critical for improving pancreatic cancer prognosis, but biomarkers for early detection are lacking. We conducted a two-stage study to identify circulating miRNAs as biomarkers for pancreatic cancer early detection using pre-diagnostic plasma samples, collected within 5 years prior to cancer diagnosis, from case-control studies nested in five prospective studies. The discovery stage included 185 case-control pairs from the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. Replication stage samples comprised 277 case-control pairs from diverse cohorts: Shanghai Women’s and Men’s Health Studies, Southern Community Cohort Study (SCCS), and Multiethnic Cohort. Controls were individually matched on age at enrollment, sex, recruitment site (SCCS), race/ethnicity, and date of blood draw in each cohort. Cell-free small RNAs were extracted from plasma samples and miRNAs were measured by the NanoString nCounter Analysis System using the Human v3 miRNA Expression panel (a total of 798 miRNAs). Normalized miRNAs were categorized by decile. For miRNAs that have ≥10% samples with an undetectable level (0), the non-zero level was categorized by approximately 10% increment. Associations of circulating miRNAs with pancreatic cancer risk, measured in odds ratios (ORs) and 95% confidence intervals (CIs) per decile change, were calculated using conditional logistic regression analyses in discovery and replication studies, separately within each cohort, and results meta-analyzed. We identified three miRNAs, hsa-miR-199a-3p+/hsa-miR-199b-3p, hsa-miR-191-5p, hsa-miR-767-5p, being consistently associated with pancreatic risk in both discovery and replication sets, with combined ORs (95% CIs) of 0.89 (0.84-0.95), 0.90 (0.85-0.95), and 1.08 (1.02-1.13), and P of 9.09E-05, 6.95E-05 and 4.03E-03, respectively. Adjustment for age, BMI, smoking, diabetes and family history of pancreatic cancer did not change the associations. Stratified analyses by age at diagnosis found five additional replicated miRNAs: hsa-miR-640, hsa-miR-1299, hsa-miR-22-3p, hsa-miR-874-5p, and hsa-miR-449b-5p among those 65 years or older, with combined ORs (95% CIs) of 1.33 (1.16-1.52), 1.28 (1.12-1.46), 0.76 (0.65-0.89), 1.25 (1.09-1.43), and 1.22 (1.07-1.39), and P-value ranging from 4.75E-05 to 0.003. These results suggest that circulating miRNA biomarkers may be useful in identifying individuals with high risk of developing pancreatic cancer for close surveillance and/or a screening test. Citation Format: Cong Wang, Hui Cai, Qiuyin Cai, Jie Wu, Rachael Stolzenberg-Solomon, Clair Zhu, Yu-Tang Gao, Jordan Berlin, Fei Ye, Wei Zheng, Veronica W. Setiawan, Xiao-Ou Shu. Circulating miRNA as biomarkers for pancreatic cancer early detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB109.

Abstract Acute Myeloid Leukemia (AML) is a clonal hematopoietic neoplasm, accounting for ~80% of acute leukemia cases in adults. The poor clinical outcome of AML patients (~27% five-year overall survival) is largely due to the inefficiency and toxicity of standard therapies. In the past decade, immunotherapies or cellular therapies (CAR-T/TCR-T cells) have achieved FDA approvals in certain types of solid tumors and leukemia, but currently there is no approved immunotherapy in AML. One potential reason is that AML actively inhibits antigen presentation (AP) to reduce its immunogenicity, thus dampening the efficacies of immunotherapies. This growing consensus is supported by the clinical evidence that AML exhibits low levels of AP machinery at diagnosis and even lower when relapsed from conventional chemotherapies. Besides, better outcomes could be achieved when combining immune checkpoint blockade with neo-antigens-inducing hypomethylating agents, highlighting the importance of AP in AML. We thus hypothesize that targeting tumor-endogenous AP suppressors will enhance AML immunogenicity and benefit immunotherapies. Recent studies have suggested that autophagy or soluble protein PCSK9 can mediate MHC-I degradation or disrupt MHC-I recycling, respectively. Transcription/epigenetic repressors TRAF3 and EZH2, as well as thymidylate synthase, were identified as MHC-I inhibitors. However, their specificity in MHC-I modulation and precise roles in regulating tumor antigenic peptide-MHC-I complexes (pMHC-I) are still unclear. Hence, there is an increasing need to identify AML-specific AP regulation mechanisms. To map such mechanisms, we performed pMHC-I-guided CRISPR screens in both human and mouse AML cell lines. Through these screens, we constructed positive and negative regulatory networks of pMHC-I modulation and compared the role of these novel regulators in the simultaneous modulation of MHC-I expression. This is the first-in-class systematic identification of AP regulators in AML. Among these negative AP regulators, we are particularly interested in the interferon regulatory factor 2 binding protein 2 (IRF2BP2), an AML-specific transcriptional regulator that is highly expressed in AML compared with normal hematopoietic stem and progenitor cells (HSPCs). Notably, IRF2BP2 expression negatively correlates with major histocompatibility complex class I (MHC-I) expression, interferon (IFN) response signatures, and T cell activity in AML patients. Ablation of IRF2BP2 enhanced AP in AML and facilitated T cell-mediated elimination of AML. Moreover, IRF2BP2 depletion synergized with IFN treatment to further boost AP at both transcriptional and protein levels. Our findings reveal a new class of tumor-associated immune-evasion mechanisms that target AP, with potential application as therapeutic targets for next-generation cancer immunotherapies. Citation Format: Xufeng Chen, Qiao Lu, Hua Zhou, Jia Liu, Bettina Nadorp, Audrey Lasry, Zhengxi Sun, Jiangyan Zhang, Michael Cammer, Kun Wang, Zoe Ciantra, Jia You, Qianjin Guo, Hongbing Zhang, Debrup Sengupta, Ahmad Boukhris, Cheng Liu, Peter Cresswell, Patricia L. M. Dahia, Jun Wang, Iannis Aifantis. Targeting MHC-I antigen presentation for cancer immune evasion in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A10.

We present a surface plasmon resonance (SPR) structure based on Kretschmann configuration incorporating bimetallic layers of noble (Ag) and magnetic materials (Ni) over CaF2 prism. Extensive numerical analysis based on transfer matrix theory has been performed to characterize the sensor response considering sensitivity, full width at half maxima, and minimum reflection. Notably, the proposed structure, upon suitably optimizing the thickness of bimetallic layer provides consistent enhancement of sensitivity over other competitive SPR structures. Hence we believe that this proposed SPR sensor could find the new platform for the medical diagnosis, chemical examination and biological detection. Full Text: PDF ReferencesJ. Homola, S.S. Yee, G. Gauglitz, "Surface plasmon resonance sensor based on planar light pipe: theoretical optimization analysis", Sens. Actuators B Chem. 54, 3 (1999). CrossRef X.D. Hoa, A.G. Kirk, M. 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Abstract MYC is the most frequently amplified gene in human cancers and one of the most sought-after drug targets for cancer therapy. Its function as a transcription factor is essential for its oncogenic potential. However, development of small molecules that target oncogenic MYC function in cells has been intractable due to its lack of known ligand binding sites. To overcome these structural challenges, we leveraged Kronos Bio’s small molecule microarray (SMM) screening platform to identify small molecules that can bind to MYC transcriptional complexes in cell lysates from cancer cells with deregulated MYC function. Unbiased transcriptional signature-based profiling identified multiple SMM hits that modulated the MYC transcription regulatory network (TRN) in MYC-dependent cancer cell lines. One of the SMM hits mimicked signature changes due to MYC loss of function, which were also similar to signature changes effected by BET bromodomain inhibitors. Biochemical, biophysical, and structural analyses found that the SMM hit could directly engage with BET bromodomains in purified systems. Cell-based proximity labeling demonstrated binding to BET proteins in live cells, and comparative pharmacology approaches suggested that the BET protein engagement was likely driving the observed gene expression changes. These results demonstrate the utility of the SMM platform in identifying ligands that modulate transcription factor TRNs through binding to critical cofactors. Citation Format: Emily B Cohen, Zhihua Ma, Wayne L Glore, Oleg A Volkov, Tong Liang, Nikolaus D Obholzer, Andrew C Clay, Mulini Reddy Pingili, Yupeng Zheng, Jun Li, Shi Yun Wang, Tom Chen, David B Freeman, Hua Gao, Minyun Zhou, Priscilla Cheung, Tamara D Hopkins, Marius S Pop, Christopher J Dinsmore, B. Wesley Trotter, Charles Y Lin, Peter B Rahl. Small molecule microarray lysate screen identifies bromodomain ligands that target the MYC transcription regulatory network [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A059.

BackgroundSirolimus is a non-calcineurin immunosuppressant commonly used in patients with organ transplantation to prevent rejection. While various inflammatory syndromes have been described post-sirolimus use, it is uncommon to have inflammatory arthritis to sirolimus1. We present a patient who developed significant joint inflammation following sirolimus use.ResultsOur patient is a 39 year old gentleman who had a heart transplant in 1992 following dilated cardiomyopathy. He was switched to sirolimus after concerns about chronic kidney disease and graft vascular disease. Six weeks later, he developed bilateral foot pain and swelling which prevented him from weight bearing. He had an MRI which showed significant bone marrow oedema in the midfoot tarsal bone and basal metatarsals. He then had a nuclear scan which showed highly increased and symmetrical uptake in both mid feet affecting the cuneiform and second, third and fourth bases of the metatarsals. The appearances showed increased osteoblastic activity with increased vascularity which was more in keeping with bone inflammation/infection and no osteonecrosis. His C-reactive protein was elevated at 148. This improved to 30 after cessation of the sirolimus. Blood cultures were negative.Of significance in his history, he also suffers from gout and has had previous monoarthritic flares involving his wrist, elbow and index finger. However, he was placed on febuxostat 80 mg in 2018 with excellent response. His serology was negative for anti-CCP and Rheumatoid factor. His urate levels were controlled at 374. He was also found to be HLA-B27 positive, but there was no evidence of inflammatory back pain.He was placed on a tapering course of prednisolone and coupled with the cessation of the Sirolimus, his pain and swelling resolved. In follow-up clinic appointments, he remained in remission from his inflammatory arthritis and did not require any additional treatment but continued on Mycophenolate Mofetil and Ciclosporin for his cardiac transplant.ConclusionThere are many studies investigating the use of sirolimus as an anti-inflammatory agent in autoimmune conditions such as rheumatoid arthritis2 and inflammatory bowel disease3. The mechanisms include down regulation of IL-17 and IL-63.However, the induction of an inflammatory arthritis by sirolimus can paradoxically occur as sirolimus causes a reduction in the STAT 3 and the anti-inflammatory cytokine IL-103. There has been raised levels of IL-6 and TNFα in serum of patients with inflammatory sequelae post sirolimus therapy1. This disequilibrium of inflammatory cascade is related to the ability of Sirolimus to inhibit mammalian target of rapamycin (mTOR) which then subsequently modulates these effects4. In general, these pro-inflammatory sequelae are mild and tend to resolve after cessation of the drug1. Although our patient had severe arthritic manifestations which required steroid therapy, his symptoms were transient after removal of Sirolimus.References[1]Buron F, Malvezzi P, Villar E, Chauvet C, Janbon B, et al. (2013) Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study. PLOS ONE 8(1): e53078[2]Wang J, Zhang SX, Hu FY, Zheng XJ, Cheng T, Yu NN, Yang WX, Gao C, Wen HY, Li XF. Sirolimus Treatment in Patients with Refractory Rheumatoid Arthritis: A Double-Arm, Open-Label, phase 1/2 Trial. Arthritis Rheumatol, 2018:70 (suppl 10).[3]Yin H, Li X, Zhang B, et al. Sirolimus ameliorates inflammatory responses by switching the regulatory T/T helper type 17 profile in murine colitis. Immunology. 2013;139(4):494-502.[4]T Weichhart, G. Costantino, M. Poglitsch, M. Rosner, M. Zeyda, KM. Stuhlmeier, T Kolbe, TM. Stulnig, WH. Horl, M Hengstschlager, M. Muller, and MD. Saemann. The TSC-mTOR Signaling Pathway Regulates the Innate Inflammatory Response. Immunity Volume 29, Issue 4, 17 October 2008, Pages 565-577Disclosure of InterestsNone declared

Abstract Introduction: The FAST study ignited the hope of CLDN18.2 as a promising novel therapeutic target for gastric cancer (GC). However, the tumor immune-microenvironmental features of CLDN18.2-positive GC is still unclear, making it difficult to develop/optimize CLDN18.2-targeted treatments. Methods: Multiplex immunohistochemistry (mIHC) was used to decipher the density and spatial structure of T cells, B cells, macrophages, neutrophils in FFPE tumor tissues of 80 GC patients (60 of them received anti-PD-1/PD-L1 treatment). Tumor immune-microenvironmental features and survival distributions stratified by CLDN18.2 were analyzed with two independent-sample t-test and Log-rank test, respectively. Results: We considered mIHC-stained samples with moderate-to-strong CLDN18.2 expression ≥40% of tumor cells as the cutoff for positivity, which shared a high concordance with IHC-based CLDN18.2 staining. The density of CD8+PD-1-, CD8+LAG-3-, and CD8+TIM-3- T cells were significantly higher in CLDN18.2-positive compared with negative tumors (346.28 vs. 204.86/mm2, P=0.011; 436.83 vs. 278.64/mm2, P=0.024; 391.85 vs. 260.72/mm2, P=0.039). In addition, the density of neutrophils (CD66b+) was higher in CLDN18.2-positive than negative group (725.17 vs. 496.23/mm2, P=0.043), while the density of M1 (CD68+CD163-HLA-DR+), M2 macrophages (CD68+CD163+HLA-DR-) and B cells (CD20+) were comparable between CLDN18.2-positive and negative group. In view of spatial analysis, average numbers of CD8+PD1-, CD8+LAG3-, CD8+TIM3-T cells surrounding tumor cells within a 20 μm range were higher in CLDN18.2-positive tumors than in negative group (0.16 vs. 0.09, P=0.011; 0.20 vs. 0.12, P=0.029; 0.18 vs. 0.12, P=0.047). Also, in CLDN18.2-positive group, tumor cells surrounded by CD8+PD1-, CD8+LAG3- T cells or M1 macrophages within a 20 μm range accounted for a higher proportion of all tumor cells than CLDN18.2-negative group (10.79% vs. 6.60%, P=0.015; 12.68% vs. 8.70%, P=0.049; 9.08% vs. 6.56%, P=0.033). These findings suggested that CLDN18.2-positive GC harbored complex immune-microenvironmental features. Additionally, CLDN18.2-positive group had shorter OS/irOS than CLDN18.2-negative group (median OS: 23.33 vs.36.6 months, P<0.001; median irOS: 10.03 vs. 20.13 months, P=0.012). The impact of CLDN18.2-related microenvironmental features on prognosis deserved further investigation. Conclusion: CLDN18.2-positive GC displayed unique immune-microenvironmental characteristics, which provided a phenotypic view for the biological role of CLDN18.2 in GC, and is of great significance for the development of CLDN18.2-targeted therapies. Citation Format: Keren Jia, Yang Chen, Jiajia Yuan, Changsong Qi, Yanyan Li, Jifang Gong, Jing Gao, Xiaotian Zhang, Jian Li, Cheng Zhang, Lin Shen. Multiplex immunohistochemistry defined the tumor immune microenvironment and immunotherapeutic outcome in CLDN18.2-positive gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6107.

Abstract Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway plays critical roles in cell growth, differentiation, motility, survival, and intracellular trafficking, and is one of the most frequently dysregulated pathways in human cancers including B-cell malignancies. There are 3 classes of PI3K, among which Class I PI3Ks including PI3Kα, β, γ, and δ isoforms are the mostly studied and plays key roles in physiological functions. PI3Kα has a role in insulin-dependent signaling, PI3Kβ functions in platelet aggregation, thrombosis and insulin signaling, and PI3Kγ/δ are expressed mainly in leukocytes and regulate lymphocyte activation, mast cell degranulation, and chemotaxis. Early PI3K inhibitors such as idelalisib are effective against B-cell malignancies such as chronic lymphocytic leukemia, but their clinical use is largely limited due to intolerable toxicities. More selective PI3Kδ inhibitors such as umbralisib (TGR-1202) demonstrates improved clinical efficacy and safety profile compared to current standard of care and was recently approved as a monotherapy for follicular lymphoma and marginal zone lymphoma. However, there is still unmet medical need for novel PI3Kδ inhibitors with improved safety profile and better efficacy to be used as monotherapy and in suitable combination strategies. Here we introduce FCN-289, a novel and oral next-generation PI3Kδ inhibitor. FCN-289 demonstrates potent kinase activity against PI3Kδ with single-digit nanomolar IC50 and remarkably improved selectivity over other PI3K isoforms compared with TGR-1202. FCN-289 exhibits significant anti-proliferating activity against various human diffuse large B-cell lymphoma (DLBCL)-derived cancer cell lines (OCI-LY10, TMD-8 and WSU-NHL) with superior activity compared with TGR-1202. Consistently, FCN-289 shows dose-dependent anti-tumor growth activity superior to that of TGR-1202 at the same and higher dose in TMD-8 DLBCL xenograft models. FCN-289 shows significantly improved anti-tumor activity when combined with BTK inhibitor ibrutinib in TMD-8 and OCI-LY10 DLBCL xenograft models. In non-clinical settings, FCN-289 exhibits good pharmacokinetic (PK) and safety properties with shorter Tmax and higher bioavailability in both rats and dogs, higher exposure in rats, improved CYP450 inhibition profile, and less plasma protein bound ratio compared with TGR-1202.Together, FCN-289 is a novel PI3Kδ inhibitor that possesses more potent in vitro and in vivo anti-cancer activities in B-cell malignancies-derived models with improved selectivity against other PI3K isoforms compared with TGR-1202. Combination with ibrutinib further improves anti-tumor activity compared with monotherapy. FCN-289 shows favorable PK and safety profiles compared with TGR-1202. Our findings highlight the therapeutic potential of FCN-289 as a novel targeted approach as monotherapy or in combination for treating B-cell malignancies. Citation Format: Shu Lin, Zuwen Zhou, Rui Tan, Hua Xu, Huajie Zhang, Weipeng Zhang, Ling Chen, Lijun Yang, Xingdong Zhao, Yanxin Liu, Zongyao Zou, Yuwei Gao, Jiashu Zhou, Weibo Wang. FCN-289, a novel, potent and selective PI3Kδ inhibitor for the treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5453.

Abstract Auristatins represent an important class of anti-mitotic antibody-drug conjugate (ADC) payloads with potent cytotoxic effects on rapidly dividing cancer cells. Most notably, monomethyl auristatin E (MMAE) stands as the most extensively validated compound, laying the foundation for the vcMMAE (vedotin) linker-payload technology that has contributed to the approval of several ADCs, including brentuximab vedotin, polatuzumab vedotin-piiq, tisotumab vedotin-tftv, and enfortumab vedotin-ejfv. However, while these first-generation ADCs have paved the way for a paradigm shift in cancer treatment away from traditional chemotherapy, there remains a discernible opportunity for improvement in both efficacy and safety. In this context, we introduce the Adcentrx auristatin platform, which substantially expands the therapeutic window of auristatin-ADCs beyond the vedotin technology. Through systematic exploration, we have synthesized >100 proprietary auristatin analogues with a range of distinctive properties. We identified optimized linker-payloads by strategically pairing lead payload candidates with our proprietary i-ConjugationTM, an irreversible, stable cysteine conjugation technology, and fine-tuned linkers. The resulting ADCs with a drug-to-antibody ratio (DAR) of 8 were extremely hydrophilic with excellent in vivo pharmacokinetics, and sustained DAR retention for a period of 21-days. Comparative assessments against vedotin-ADCs revealed that Adcentrx-ADCs demonstrated superior efficacy across multiple targets and indications in various mouse xenograft models. In Sprague-Dawley rats, Adcentrx-ADCs exhibited remarkable tolerability, albeit their high drug loading of 8. In summary, our preclinical studies underscore the significant enhancement in the therapeutic index achieved by the Adcentrx auristatin platform. Furthermore, this technology presents a promising alternative mode of action to camptothecins, exhibiting tolerance to targets expressed in non-proliferative normal tissues but without the burden of severe dose-limiting toxicities such as interstitial lung disease. Citation Format: Dong Jun Lee, Sabine Rottmann, Anna Wang, Peter P. Challita, Andrew M. Hau, Wes Sisson, Mario M. Kuo, Kris Zhang, Monica Leung, Alexis Mahloch, Erin Nye, Paul Datta, Sam Janssen, Felipe Acosta, Oscar Betancourt, Maria Shahmoradgoli, Alexander Chu-Kung, MaoJun Guo, Pia M. Challita-Eid, Hui Li. Advancing a novel tubulin-inhibitor ADC technology: The Adcentrx auristatin platform offers enhanced efficacy and safety profiles compared to vedotin technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1909.

Abstract Background: AMG510, a novel KRAS G12C mutation-specific inhibitor approved in 2021 by FDA, was the first therapy to directly target the KRAS oncoprotein in KRAS-mutant cancers with other direct KRAS G12C inhibitors currently being investigated in multiple clinical trials. However, the emergence of resistance in patients who initially were responsive is a challenge. Uncovering the underlying mechanism of resistance would support the identification and development of novel therapies to overcome drug resistance. In this study, we generated a panel of KRAS G12C inhibitor-resistant tumor models by introducing a secondary KRAS mutation on top of G12C for use as in vitro and in vivo tools to develop possible strategies to overcome such resistance. Methods: First, by using CRISPR/Cas9, we introduced a secondary KRAS mutation, including Y96C, Y96D and Y96S in MIA PaCa, which harbours a homozygous KRAS G12C mutation. Point mutation knock-in was validated by sanger sequencing and cell identity was confirmed by SNP. Then cell viability was measured by CellTiter-Glo after 5 days incubation with AMG510 and MRTX849. RAS-MAPK pathway activity was assessed in the parental and mutant cell lines Y96D by Western blot. Xenograft of MIA PaCa KRAS G12C/Y96D cells l was also established. Results: Successful homozygous point mutation knock-in was achieved as confirmed by sanger sequencing. The double mutant cells displayed the similar growth rate as well as the morphology. In cell viability assays, relative to KRAS G12C parental cells, cells expressing the double-mutant alleles showed marked resistance to AMG510 and MRTX849. Consistent with the effects on cell viability, persistent phosphorylated ERK (pERK) and pRSK levels was also observed in KRAS G12C/Y96D expressing cells even at high concentrations of MRTX849, indicating sustained RAS-MAPK activity. In addition, MIA PaCa-KRAS G12C/Y96D was able to grow in vivo and will be used for pharmacological evaluation of KRAS inhibitors. Conclusion: These double-mutant cells can be used to assess preclinical in vitro/in vivo efficacy of KRAS-targeted therapeutics. Crown Bioscience is in the process of developing a series of KRAS G12C inhibitor-resistant cell lines to better facilitate efficacy testing of KRAS-targeted therapeutics. Citation Format: Jun Zhou, Zi Ye, Ning Bo, Dan Zhang, Li Hua, Chenpan Nie, Jingjing Wang, Rajendra Kumari, Leo Price, Xiaoxi Xu. Developing KRAS G12C inhibitor-resistant tumor models for efficacy evaluation of next-generation anticancer therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 401.

BackgroundEfficacy of cancer vaccines requires the induction of tumor antigen-specific cytotoxic T-lymphocytes (CTL) to effectively clear established tumors. Orchestration of antigen presentation, co-stimulatory signaling, and innate cytokine signals are necessary steps for tumor-specific T-cell activation. The ONM-500 nanovaccine platform1-2 utilizes a novel pH-sensitive polymer that forms an antigen-encapsulating nanoparticle and functions both as a carrier for antigen delivery of both peptide and protein antigens to dendritic cells and acts as an adjuvant, activating the stimulator on interferon genes (STING) pathway and generating a CD8+ CTL response. Peptide antigens have translational challenges due to complex formulations and/or HLA-type-specific antigen sequence recognition, processing and presentation. Full-length protein antigens alleviate HLA subtype limitation, allowing coverage of multi-immunogenic T cell epitopes in patients. Pairing ONM-500 adjuvant with the full-length E6 and E7 oncoproteins from human papillomavirus (HPV) cancers shows great potential to treat HPV-associated cancer in patients.MethodsBased on the previously demonstrated STING-dependent T cell activation by ONM-500 [1], the nanovaccine was formulated with full-length HPV16 E6 and E7 proteins (recombinant), and the nanoparticle properties and antigen loading were characterized. In vivo lymph node accumulation following subcutaneous administration was evaluated using fluorescent nanovaccines. Direct binding of ONM-500 to recombinant human STING (CTD) was evaluated using isothermal titration calorimetry (ITC) compared to the endogenous ligand 2’,3’-cGAMP. Antitumor efficacy was evaluated in multiple syngeneic tumor models, including the TC-1 model which overexpresses HPV16 E6 and E7 with the ONM-500 vaccine in combination with anti-PD-1 checkpoint inhibitor. Long-term anti-tumor memory was evaluated in a follow-up rechallenge study after 60 days in tumor-free animals.ResultsCharacterization of ONM-500 nanovaccine shows reproducible particle chemi-physical properties and antigen loading. The nanoparticle size substantiates the effective lymph node accumulation for antigen cross-presentation in dendritic cells following subcutaneous administration. ITC studies with human STING demonstrated effective binding by ONM-500 adjuvant. The nanovaccine anti-tumor efficacy was previously demonstrated in melanoma, colorectal, and HPV-associated syngeneic tumor models. In TC-1 tumors, ONM-500 nanovaccine containing full-length E6/E7 protein showed 100% overall survival at 55 days (figure 1). Tumor growth inhibition was also improved over E7 antigen peptide formulated nanovaccine. A rechallenge study demonstrated long-term antigen-specific anti-tumor memory response.Abstract P857 Figure 1ConclusionsONM-500 STING-activating nanovaccines effectively deliver antigens in vivo to lymph nodes to elicit antigen-specific CTL response. The anti-tumor efficacy in multiple tumor models demonstrates the potential of ONM-500 as a general STING agonist cancer vaccine platform, and full-length E6/E7 incorporated ONM-500 is being developed for HPV-associated cancers.Ethics ApprovalAll animal procedures were performed with ethical compliance and approval by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center (Protocol No. 2017-101954) and Pennsylvania State College of Medicine (Protocol No. 47682).ReferencesLuo M, Wang H, Wang Z, Cai H, Lu Z, Li Y, Du M, Huang G, Wang C, Chen X, Porembka MR, Lea J, Frankel AE, Fu YX, Chen ZJ, Gao J. A STING-activating nanovaccine for cancer immunotherapy. Nat Nanotechnol 2017; 12:648–654.Luo M, Liu Z, Zhang X, Han C, Samandi LZ, Dong C, Sumer BD, Lea J, Fu YX, Gao J. Synergistic STING activation by PC7A nanovaccine and ionizing radiation improves cancer immunotherapy. J Control Release 2019; 28:154–160.

Abstract Background: The advent of immune checkpoint inhibitors has improved morbidity and mortality for some cancers, and recent breakthroughs in gene & cell therapy have shed light on curing some types of blood cancers. However, many cancers remain intractable and the development of novel, effective and safe therapies continue to be a priority. Cancer vaccines as a cancer immunotherapy approach has seen a resurgence in recent years, due to the success of mRNA vaccines for the COVID-19. However, the accurate prediction of immunogenicity of cancer vaccines remains elusive. Methods: Our models predict the probability of a given peptide derived from the protein of interest to be presented by MHC-I or MHC-II. For MHC-I antigen presentation model development, over 17 million entries in the dataset were collected from published literature and available databases, e.g., IEDB, with peptide lengths ranging from 8 to 11. The peptides were restricted to 150 unique MHC-I alleles. Similarly, ~4 million entries with peptide lengths ranging from 13 to 21 were collected for MHC-II antigen presentation model development, and the peptides were restricted to 19 unique MHC-II alleles. To develop advanced antigen presentation models, a language model was chosen as the backbone network and contrast learning was used to better discriminate the peptide-MHC match versus mismatch. Overall, both MHC-I and MHC-II presentation models were constructed with about 30 million parameters. To validate the model prediction accuracy, automated peptide synthesis and surface plasmon resonance (SPR) technologies were applied. Results: Using open-sourced data, our developed AI models surpassed the performance of state-of-the-art prediction algorithms, the latest versions of NetMHCpan and MixMHCpred, for both MHC-I and MHC-II antigen presentation. Furthermore, to validate the algorithm accuracy and the peptide immunogenicity, 28 predicted patentable peptides derived from mutated TP53 protein were synthesized and their binding to respective common HLA alleles were validated using SPR. We found that greater than 80% of the peptides display binding affinities that are stronger than the positive control, suggesting that AI significantly improves neoantigen peptide vaccine design. Conclusions: We developed advanced AI algorithms to rapidly design shared neoantigen T cell epitopes with predicted strong binding affinity to MHC-I and MHC-II. We envision that the epitopes predicted and designed by our AI algorithms possess great potential in advancing the field of off-the-shelf cancer vaccine development and hold the promise of significantly benefiting patients, once translated into the clinic. Citation Format: Genwei Zhang, Jiewen Du, Xiangrui Gao, Tianyuan Wang, Zhenghui Wang, Qingxia Zhang, Tongren Liu, Dong Chen, Ruohan Zhu, Yalong Zhao, Chi Han Samson Li, Melvin Toh, Lipeng Lai. Towards the efficient design of shared neoantigen peptide cancer vaccines using artificial intelligence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3525.

BackgroundLittle is known about bridging clonal heterogeneity into the resistance of immune checkpoint inhibitors (ICI). Recent reports showed that excluded tumor-infiltrating lymphocytes (TIL) into stroma assessed by an artificial intelligence (AI)-powered spatial TIL analyzer, Lunit SCOPE IO, was related to loss-of-heterozygosity of HLA genes which would be one of crucial resistance pathways of ICI.1 In the current study, we hypothesized that Immune-excluded phenotype called by Lunit SCOPE IO would be related to clonal heterogeneity resulted from genome-wide accidents during early carcinogenesis which may cause an improper targeting of TIL for diverse clones with multiple genomic aberrations.MethodsFor spatial TIL analysis, we applied Lunit SCOPE IO1 which automatically detects TIL and segmentizes cancer area and stroma, then it classified Immune phenotype of 1 mm2-sized grid in H&E image. Inflamed score or Immune-excluded score were defined as the proportion of Inflamed phenotype, which is high intra-tumoral TIL density, or Immune-excluded phenotype, which is exclusively high TIL density only in stroma, within a whole-slide image, respectively. We evaluated the correlation of Immune phenotype with APOBEC mutational signature by single-base substitution (SBS) signature 2 and/or SBS13,2 whole-genome doubling, and subclonal genome fraction which reflects intra-tumoral heterogeneity,3 and clusters of T cell receptor (TCR) repertoire 4 derived from previous reports of The Cancer Genome Atlas (TCGA), consists of 7,467 tumor samples from 22 cancer types.Abstract 830 Table 1Correlation between immune phenotype and clonal evolution of cancer [* Median (95% confidence interval)]ResultsIn the TCGA pan-carcinoma database, APOBEC mutational signature was significantly correlated with increased ratio of cancer stroma to cancer epithelium (median 0.866 vs 1.19, fold change +37.4%), and increased TIL density in cancer stroma (median 558 vs 764 / mm2, fold change +36.9%), but it was not correlated with intra-tumoral TIL density (median 63 vs 59 / mm2, fold change -6.3%). Interestingly, Immune-excluded score (IES) called by Lunit SCOPE IO was positively correlated with APOBEC mutational signature as well as expression levels of APOBEC1, APOBEC3A, and APOBEC3B, whole-genome doubling, and subclonal genome fraction, respectively, while Inflamed score (IS) or immune cytolytic activity (GZMA and PRF1 expressions) was negatively or not significantly correlated to those variables (table 1). TCR repertoire was expanded in the tumor samples with high IS (spearman rho = 0.279), but it was not increased in those with high IES (spearman rho = -0.0595).ConclusionsThere is a significant correlation between distinct TIL deposition in stroma, or Immune-excluded phenotype, with APOBEC-attributed clonal expansion of cancer, without proper expansion of TCR repertoire.ReferencesOck CY, Park C, Paeng K, Yoo D, Kim S, Park S, Lee SH, Mok T, Bang YJ. Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes reveals distinct genomic profile of immune excluded phenotype in pan-carcinoma. Cancer Res 2021;81(Supp 13):1908.Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstrom EN, Islam SMA, Lopez-Bigas N, Klimczak LJ, McPherson JR, Morganella S, Sabarinathan R, Wheeler DA, Mustonen V, PCAWG Mutational Signatures Working Group, Getz G, Rozen SG, Stratton MR, PCAWG Consortium. The repertoire of mutational signatures in human cancer. Nature 2020;578(7793):94–101.Taylor AM, Shih J, Ha G, Gao GF, Zhang X, Berger AC, Schumacher SE, Wang C, Hu H, Liu J, Lazar AJ, Cancer Genome Atlas Research Network, Cherniack AD, Beroukhim R, Meyerson M. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 2018;33(4):676–689.e3.Zhang H, Liu L, Zhang J, Chen J, Ye J, Shukla S, Qiao J, Zhan X, Chen H, Wu CJ, Fu YX, Li B. Investigation of antigen-specific T-Cell receptor clusters in human cancers. Clin Cancer Res 2020;26(6):1359–1371.

Abstract Background: Immune checkpoint inhibitors (CPIs) targeting PD-(L)1 have become a standard of care for untreated, advanced melanoma, but demonstrated limited efficacy in mucosal melanoma. Tebotelimab, also known as MGD013, is a PD-1/LAG-3 bispecific tetravalent DART® molecule with synergistic antitumor activity shown in preclinical studies. We conducted an open-label, single-arm, multi-cohort phase 1 study (NCT04653038) to assess the efficacy and safety of tebotelimab in melanoma patients (pts) including those with CPI-naïve mucosal melanoma. Methods: The CPI-naïve cohort of this study enrolled pts with unresectable, recurrent or metastatic, mucosal or acral melanoma who had received no systemic therapy. Tebotelimab 600 mg was administered intravenously once every two weeks. The primary endpoint was overall response rate (ORR) assessed by independent radiologic review committee (IRC) per RECIST v1.1 in the efficacy analysis set consisting of pts who received ≥1 dose of tebotelimab. A post-hoc sensitivity analysis was conducted in the IRC-response evaluable set consisting of pts with IRC-assessed target lesions in the efficacy analysis set who received ≥1 post-baseline tumor assessment by IRC or died within 13 weeks after first dose. Results are reported for mucosal melanoma. Results: At data cut-off (January 19, 2022), 25 pts with mucosal melanoma were enrolled (median age, 61 years; male, 40%; ECOG 1, 40%; TNM Stage IV, 92%; metastatic, 80%). LAG-3 expression level was ≥1% in seven (28%), <1% in 15 (60%), and unknown in three (12%). PD-L1 expression was positive (CPS≥1) in three (12%), negative (CPS<1) in 19 (76%), and unknown in three (12%). All pts received ≥1 dose of tebotelimab. In the efficacy analysis set (n=25), three, three, and four pts achieved complete response (CR), partial response (PR), and stable disease (SD), respectively, leading to a confirmed ORR of 24% (95% confidence interval [CI], 9-45), with median duration of response (DOR) not reached, and a disease control rate (DCR) of 40% (95% CI, 21-61). In the IRC-response evaluable set (n=20), three, three, and four pts achieved CR, PR, and SD, respectively, leading to a confirmed ORR of 30% (95% CI, 12-54), with median DOR not reached, and a DCR of 50% (95% CI, 27-73). Immune-related treatment-emergent adverse events occurred in 11 (44%) pts, most commonly, hypothyroidism (20%), hyperthyroidism (16%), and white blood cell count decreased (12%). Grade ≥3 and serious treatment-related adverse events (TRAEs) were reported in three (12%) and four (16%) pts, respectively. TRAEs led to treatment discontinuation and death each in one (4%). Conclusions: Tebotelimab demonstrated preliminary but promising antitumor activity and a tolerable safety profile in pts with untreated, unresectable, recurrent or metastatic, mucosal melanoma. Citation Format: Si Lu, Yu Chen, Meiyu Fang, Zhengyun Zou, Di Wu, Zhiguo Luo, Jian Zhang, Jing Chen, Gang Huang, Hongming Pan, Xiubao Ren, Ying Cheng, Haichuan Su, Yuan Xin, Qiong Hua, Jianmei Hou, Jun Guo. Tebotelimab, a PD-1/LAG-3 bispecific antibody, in patients with untreated, unresectable, recurrent or metastatic, mucosal melanoma: An open-label, single-arm, Phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT208.

A preliminary study to determine the group of compound contained in the ethanolic extract of mahagony (Swietenia mahagoni L. Jacq.) seeds and its inhibitory activity to a-glucosidase enzyme has been done. The information from this study will be used in the further investigation about the specific constituents related to the bioactivity. The seed was grounded and then extracted with ethanol by maceration technique. The crude extract was separated with liquid-liquid extraction by using n-hexane, ethyl acetate, and methanol as the solvents. The best eluent for isolation, chloroform:ethanol (1:1), was determined by thin layer chromatography while alumina as stationary phase. The isolation step with column chromatography gave two types of isolates, yellow and colorless isolate. In order to get information about the compound, the crude extract was subjected to phytochemical assignment and the isolate with the better activity was analyzed by infrared spectroscopy. The inhibitory activity for the yellow isolate with IC50 as 19.345 ppm was better than the colorless isolate. Therefore, the IR spectroscopy assay was subjected to the yellow isolate. Based on the comparison IR spectra with literatures, it has suggested that the yellow isolate contains tetranortriterpenoid or limonoid group.Keywords: Swietenia mahagoni L. Jacq., diabetes type 2, a-glucosidase, tetranortriterpenoidREFERENCE World Health Organization. Global report on diabetes. http://www.who.int. Accessed on 18 July 2017.Kementerian Kesehatan Republik Indonesia. 2014. Situasi dan analisis diabetes. Jakarta: Pusat Data dan Informasi Kemenkes RI.Dutta, M., Raychaudhuri, U., Chakroborty, R., and Maji, D. 2011. Role of diet and plants on diabetic patients - a critical appraisal. Science and Culture. 77 (3–4).Eid, A.M.M., Elmarzugi, N.A., and El-Enshasy, H.A. 2013. 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The optical setup for holographic projection on the scatterings in fluorescent liquids is presented. Such media can be used as volumetric screens for near-eye holographic displays, solving the problem of speckle noise and very small exit pupils in existing setups. Three different oils (canola, olive and engine oil) with 532 nm laser and tonic water with 405 nm laser are used for projecting holographic fields, the quality of such images is investigated. The laser wavelength is cut out from acquisition on a camera and only filtered fluorescent light is observed. The best and brightest results are obtained with engine oil. Full Text: PDF ReferencesX. Li, C. P. Chen, H. Gao, et al. "Video-Rate Holographic Display Using Azo-Dye-Doped Liquid Crystal", Journal of display technology 10(6), 438-443 (2014). CrossRef X. Li, Z. Song, F. Li, X. Dong, W. Liu, "79‐3: Video‐rate Holographic Display in ZnSe layer‐assisted Quantum Dot Doped Liquid Crystal with High‐photorefractive Sensitivity", SID Symposium Digest of Technical Papers. Vol. 48. No. 1. 2017, CrossRef Sasaki, Takeo, et al. "Real-time dynamic hologram in photorefractive ferroelectric liquid crystal with two-beam coupling gain coefficient of over 800 cm–1 and response time of 8 ms", Applied Physics Letters 6(2) (2013) CrossRef N. Tsutsumi, K. Kinashi, A. Nomura, W. Sasaki, "Quickly Updatable Hologram Images Using Poly(N-vinyl Carbazole) (PVCz) Photorefractive Polymer Composite", Materials 5.8: 1477-1486 (2012) CrossRef M. Makowski, "Simple holographic projection in color", et al. Optics express 20.22: 25130-25136 (2012) CrossRef A. Yagi, M. Imura, Y, Kuroda, O. Oshiro, "360-degree fog projection interactive display", SIGGRAPH Asia 2011 Emerging Technologies. ACM, (2011) CrossRef C.H. Hsu, K. L. Hua, W. H. Cheng. "Omni-Tube: a low-cost portable omnidirectional interactive 3D display", SIGGRAPH Asia 2012 Posters. ACM, (2012) CrossRef Z. Zeng, H. Zheng, X. Lu, H. Gao, Y. Yu, "Dynamic holographic three-dimensional projection based on liquid crystal spatial light modulator and cylindrical fog screen", Opt Rev (2015) 22: 853 CrossRef I. Rakkolainen, "Feasible mid-air virtual reality with the immaterial projection screen technology", 3DTV-Conference, Tampere (2010) CrossRef S. Yanfeng, et al. "A multi-plane optical see-through holographic three-dimensional display for augmented reality applications", Optik 157: 190-196 (2018) CrossRef G. Li, D. Lee, Y. Jeong, J. Cho, B. Lee, "Holographic display for see-through augmented reality using mirror-lens holographic optical element", Opt. Lett. 41(11), 2486-2489 (2016) CrossRef C. L. Lin, Y. Z. Su, M. W. Hung, K. C. Huang "Augmented reality system", Proc. SPIE 7798, Applications of Digital Image Processing XXXIII, 779826 (2010) CrossRef A. Maimone, A. Georgiou, J. S. Kollin, "Holographic near-eye displays for virtual and augmented reality", ACM Trans. Graph. 36, 4, 1-16 (2017) CrossRef M. Quinten, Optical properties of nanoparticle systems: Mie and beyond (John Wiley & Sons 2010). CrossRef J.-W. Liaw, S.-W. Tsai, H.-H. Lin, T.-C. Yen, B.-R. Chen, "Wavelength-dependent Faraday–Tyndall effect on laser-induced microbubble in gold colloid", Journal of Quantitative Spectroscopy and Radiative Transfer 113(17), 2234-2242 (2012), CrossRef T. Mu et al. "Classification of edible oils using 532 nm laser-induced fluorescence combined with support vector machine", Anal. Methods 5, 6960 (2013) CrossRef T. Mu et al. "Classification of Motor Oil Using Laser-Induced Fluorescence and Phosphorescence", Analytical Letters 49:8, 1233-1239 (2015) CrossRef V. Rostampour, M. J. Lynch, "Quantitative Techniques To Discriminate Petroleum Oils Using LED-induced Fluorescence", WIT Transactions on Ecology and the Environment 95, 265 262 (2006) CrossRef F. Wyrowski and O. Bryngdahl, "Iterative Fourier-transform algorithm applied to computer holography", Opt. Soc. Am. A 5(7), 1058-1065 (1988) CrossRef

Environmental concerns lead to a continually growing demand for clean energy generation. Thus, alternative energy sources or green fuels attract attention. The anion exchange membrane fuel cell (AEMFC) emerged as an excellent alternative due to its air CO2-free emissions, low-cost electrocatalyst used at the cathode, and industrial-scale membrane production development [1-3]. Many efforts have been made to have AEMFC performances like those already shown by the proton exchange membrane fuel cell (PEMFC). Excellent results have been obtained for the lasted technology regarding power densities and operational cell life [4]. It should be recognized that due to the nature of the electrode reactions in AEMFC, Eqs. 1-2, the performance enhancement of the overall cell reaction, Eq. 3, depends not only on the selected catalysts and ionomers/membranes but also on the cell's water management. The complexity of water management relies on the simultaneous production and consumption of water in anode and cathode, respectively, where the production is two-fold higher than the consumption. This effect might lead to anode flooding during the hydrogen oxidation reaction (HRR), Eq. 1. In contrast, during oxygen reduction reaction (OER), Eq. 2, the risk of membrane drying is latent as long as a water imbalance arises between both anodic and cathodic sides. It has been confirmed quantitatively that water direction movement could go from anode to cathode in a hydrophilic membrane (diffusion transport mode); however, using a membrane with hydrophobic properties promotes the water to travel from cathode to anode (electro-osmotic drag, EOD mode). In this context, it is convenient to identify the water direction trend under variable selected operating conditions. In particular, achieving the anode-to-cathode water direction would improve the AEMFC performance by avoiding flooding on the anode by cathode hydration through water diffusion through the membrane. Therefore, this work tested the influence of symmetric and asymmetric flow rates and relative humidities within an AEMFC using a hydrophilic membrane. According to both modes of transport, the AEMFC performance was studied using polarization curves. The experimental procedure involved trapping water out of each half-cell during a chronoamperometry in steady-state conditions. Also, the water incoming was quantified independently for each selected operating condition in order to make a mass balance (Figure 1a). The variable operating conditions were the reactant flow rate, low (125 cm3 min-1) and high (250 cm3 min-1), and the reactant humidity level. In Figure 1b, the results demonstrated that the EOD predominance was promoted when low symmetric flow rates (125 cm3 min-1 for anode and cathode) were used in the AEMFC, suggesting membrane dehydration. On the contrary, the water diffusion dominance appears under high (250 cm3 min-1) symmetric and asymmetric flow rates between anode and cathode; under these conditions, the membrane dehydration might be suppressed by anode flooding alleviation. Once the flow conditions are given, no changes in water transport mode were detected for changes in the humidity level (Figure 1c-d). The AEMFC performance was affected by the water transport mechanism, giving lower peak power densities for EOD-dominated systems (35.2 mW cm-2 at 60°C, Figure 1e) than those obtained by diffusion (62.8 mW cm-2 at 60°C, Figure 1f). The most suitable operating condition is under water-diffusion at non-saturated streams (below 65%), where a decrease in performance is experienced as the humidifier temperature increases from 60°C to 80°C (supersaturated flow), with peak power densities of 62.8 and 3.7 mW cm-2, respectively. References: Zhang, J. Liu, Y. Wang, L. An, M. D. Guiver, N. Li, Highly Stable Anion Exchange Membranes Based on Quaternized Polypropylene, J. Mater. Chem. A 3 (2015) 12284-12296. https://doi.org/10.1039/C5TA01420D G. Wright, F. Jiantao, B. Britton, T. Weissbach, H. F. Lee, E. A. Kitching, T. J. Peckham, S. Holdcroft, Hexamethyl-p-terphenyl poly(benzimidazolium): A Universal Hydroxide-Conducting Polymer for Energy Conversion Devices, Energy Environ. Sci. 9 (2016) 2130-2142. https://doi.org/10.1039/c6ee00656f Zhang, Y. Hua, Z. Gao, Strategies to Optimize Water Management in Anion Exchange Membrane Fuel Cells, J. Power Sources 525 (2022) 231141. https://doi.org/10.1016/j.jpowsour.2022.231141 Gottesfeld, D. R. Dekel, M. Page, C. Bae, Y. Yan, P. Zelenay, Y. S. Kim, Anion Exchange Membrane Fuel Cells: Current Status and Remaining Challenges, J. Power Sources 375 (2018) 170-184. https://doi.org/10.1016/j.jpowsour.2017.08.010 Figure 1

Abstract Introduction: KRAS is one of the most frequent mutated oncogenes and has been recognized as undruggable for many years. AMG510, the first therapy to directly target KRAS, was approved by the FDA to treat non-small cell lung cancer (NSCLC) bearing KRAS G12C mutation. However, the emergence of resistance in patients remains a challenge and limits its clinical benefits, which calls for next-generation targeted therapy or combination strategies to overcome the resistance to KRAS G12C inhibitors. A variety of secondary mutations in KRAS attributing to the resistance have been identified, which requires robust in vitro and in vivo preclinical models to validate potential therapeutics targeting these mutations. Therefore, we generated a panel of KRAS G12C inhibitor-resistant tumor models to facilitate the development of possible strategies to overcome such resistance. Methods: First, a secondary KRAS mutation, including H95D, H95Q, H95R, Q61H and R68S, was introduced by using CRISPR/Cas9 technology in MIA PaCa cell line, which harbors a homozygous KRAS G12C mutation in addition to Y96D, Y96C and Y96S previously published by us. Point mutation knock-in was validated by sanger sequencing, and cell identity was confirmed by SNP assay. In vitro, the parental and mutated cells were treated with either AMG510 and MRTX849 and cell viability was measured by CellTiter-Glo. In vivo efficacy of KRAS G12C inhibitors, AMG510 and MRTX849, SOS1 inhibitor, BI-3406 and MEK inhibitor, Trametinib were evaluated in the Y96D mutated MIA PaCa subcutaneous xenograft. Results: Homozygous secondary point mutation knock-in in MIA PaCa cells was confirmed by sanger sequencing. Similar growth rate and morphology was observed in selected clones compared to the parental line. Similar to Y96D mutation previously published, R68S mutation was highly resistant to both KRAS G12C inhibitors, with IC50 increased more than 100 fold for both MRTX849 and AMG510, whereas H95D, H95Q and H95R mutation was more resistant to MRTX849, while Q61H had a minimal effect on either one of the inhibitors. In addition, cells expressing KRAS G12C/Y96D were also resistant to AMG510 and MRTX849 in in vivo study, whereas combination of BI-3406 (single treatment: TGI of 27%) and Trametinib (single treatment: TGI of 76%) suppressed tumor growth significantly with TGI of 93% on day 17 after randomization compared to control group (p<0.001). Also, the combination showed significant improvement compared to BI-3406 single treatment (p<0.001) whereas no significant improvement was observed compared to Trametinib single treatment (p>0.05). Conclusion: CRISPR/Cas9 engineered second site KRAS mutations in cells harboring KRAS G12C mutation displayed a differentially resistant profile to KRAS G12C inhibitors. Thus, H95D/Q/R, R68S and Y96D can be used as preclinical inhibitor-resistant models to evaluate clinical strategies to overcome resistance to KRAS-targeted therapies. Citation Format: Jun Zhou, Li Hua, Jian Feng, Ning Bao, Dan Zhang, Jingjing Wang, Marrit Putker, Ludovic Bourre. Characterization of a panel of CRISPR/Cas9 engineered KRAS G12C inhibitor-resistant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1942.

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Abstract Background: Current allogeneic CAR-T cell therapies face challenges with post-infusion expansion and efficacy. In response, we developed ThisCART, a non-genetic editing, allogeneic platform that significantly enhances CAR-T cell expansion and efficacy. This is achieved through a novel approach of intracellular retention of membrane proteins, reducing surface expression of TCRαβ/CD3 complexes and HLA-I molecules. Our lead product, ThisCART19, has demonstrated superior efficacy compared to conventional AutoCART19 in preclinical and early clinical studies for B-ALL. Methods: In the clinical trial NCT04384393, we assessed the safety and efficacy of ThisCART19 in patients with B-cell malignancies. Post-lymphodepletion, participants received infusions of ThisCART19 and AutoCART19, both personalized from the patient's own T cells, in equal proportions. Safety and efficacy were the primary endpoints, evaluated on Day 28 post-infusion and throughout extended follow-up. Mechanistic insights were gained through comprehensive multi-omics studies, including RNAseq, whole-cell proteomics, and phosphoproteomics. Results: ThisCART19 showed enhanced expansion and an improved safety profile in vivo. As of 01 January 2024, Two patients diagnosed as relapse/refractory acute B cell leukemia (R/R B-ALL) were enrolled in the clinical trial. Pt1 is a 55yo male with Ph-positive B-ALL (36% blasts) who relapsed after multiagent chemotherapy and TKIs. Pt2 is a 16yo male with CNS leukemia (78.5% blasts) after multiagent chemotherapy. No DLTs or ICANS were observed. Pt1 experienced Grade 1 CRS that resolved without treatment, and Pt2 experienced Grade 2 CRS that resolved after tocilizumab and corticosteroids. Complete remission with MRD-negative status was achieved by Day 28. Pharmacodynamic analysis indicated a significant expansion of CAR-T cells, predominantly in the CAR+TCR- subset, highlighting autonomous CAR signaling enhancement. Multi-omics analysis identified upregulation in JAK-STAT, PI3K-Akt, and NFKB pathways, suggesting improved cell proliferation, survival, anti-apoptotic activity, and effector function. This molecular profiling provides a mechanistic understanding of ThisCART19A's therapeutic efficacy. Conclusion: The ThisCART platform marks a transformative advancement in allogeneic CAR-T cell therapy. By enhancing CAR signaling autonomously through a unique intracellular retention of TCRαβ/CD3 complexes, ThisCART has shown promising safety and efficacy in early clinical trials. Its potential in reshaping the treatment landscape for hematological and autoimmune disorders positions ThisCART as a crucial development in cellular therapeutics. Citation Format: Jun Li, Lei Xue, Sujun Li, Ling He, Kaichun Liu, Rong Jin, Tao Wang, Yinhang Zhang, Shanshan Chen, Yulian Gao, Dan Liu, Liyun Yang, Xingbing Wang. Clinical validation and mechanistic insights of ThisCART: A novel allogeneic platform enhancing CAR-T signaling via intracellular TCRαβ/CD3 retention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB341.

Abstract Background: Molecularly targeted therapies are critical for improving cancer treatment. Since proteins are the targets of these therapies and functional effectors of genomic aberrations, proteogenomics data from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) provides an unprecedented opportunity to characterize existing and future therapeutic targets for cancer treatment. Approach: CPTAC proteogenomics data from >1000 cancer patients spanning 10 cancer types was used to evaluate current and potential therapeutic targets curated from four databases. Cell line data from DepMap was further integrated to distinguish causations from associations. Computational pipelines were deployed to identify synthetic lethality for targeting tumor suppressor loss and to prioritize tumor associated antigens as immunotherapy targets. Results: We systematically collected 3050 druggable proteins and classified them into 5 tiers to facilitate different applications such as companion diagnostics, drug repurposing, and new therapy development. Many druggable proteins showed poor mRNA-protein correlation, including secreted proteins and proteins whose abundance was correlated with their interaction partners instead of cognate mRNA, highlighting the necessity of direct proteomic quantification of drug targets. 618 druggable proteins showed both overexpression in tumors compared to normal and significant dependency in CRISPR-Cas9 screens of cell lines of the same lineage. Notably, PAK1, a kinase targeted by investigational drugs, demonstrated both overexpression and dependency in all cancer types. A similar analysis of phosphoproteomics data focusing on known activating sites of druggable proteins further revealed targetable dependencies driven by protein hyperactivation. The phosphosite pS50 on PTPN1, a phosphatase targeted by experimental drugs, was increased in 7 cancer types and PTPN1 demonstrated dependency in related cancer cell lines. Based on tumor proteogenomic data and cell line CRISPR-Cas9 screen data, we identified synthetic lethality for difficult to target tumor suppressor losses, revealing TP53 mutations as a candidate biomarker to select breast cancer patients for CHEK1 inhibition, and endometrial cancer patients for treatment with doxorubicin. We identified 140 proteins whose expression was restricted in normal tissues but abnormal in tumors. Experimental analysis of peptides predicted to have high binding affinity to the most common allotype HLA-A02 for 7 prioritized proteins identified 21 peptides from 5 proteins with both strong binding affinity and immunogenicity which could be further investigated as immunotherapy targets. Conclusion: We generate a comprehensive resource of protein and peptide targets that covers multiple therapeutic modalities. This unique resource will pave the way for repurposing of currently available drugs and developing new drugs for cancer treatment. Citation Format: Jonathan T. Lei, Sara R. Savage, Xinpei Yi, Bo Wen, Hongwei Zhao, Lauren K. Somes, Paul W. Shafer, Yongchao Dou, Qiang Gao, Valentina Hoyos, Bing Zhang. Pan-cancer proteogenomics expands the landscape of therapeutic targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5726.

This paper presents some results of rainfall forecast in the monsoon onset period in South Vietnam, with the use of ensemble Kalman filter to assimilate observation data into the initial field of the model. The study of rainfall forecasts are experimented at the time of Southern monsoon outbreaks for 3 years (2005, 2008 and 2009), corresponding to 18 cases. In each case, there are five trials, including satellite wind data assimilation, upper-air sounding data assimilation, mixed data (satellite wind+upper-air sounding data) assimilation and two controlled trials (one single predictive test and one multi-physical ensemble prediction), which is equivalent to 85 forecasts for one trial. Based on the statistical evaluation of 36 samples (18 meteorological stations and 18 trials), the results show that Kalman filter assimilates satellite wind data to forecast well rainfall at 48 hours and 72 hours ranges. With 24 hour forecasting period, upper-air sounding data assimilation and mixed data assimilation experiments predicted better rainfall than non-assimilation tests. The results of the assessment based on the phase prediction indicators also show that the ensemble Kalman filter assimilating satellite wind data and mixed data sets improve the rain forecasting capability of the model at 48 hours and 72 hour ranges, while the upper-air sounding data assimilation test produces satisfactory results at the 72 hour forecast range, and the multi-physical ensemble test predicted good rainfall at 24 hour and 48 hour forecasts. The results of this research initially lead to a new research approach, Kalman Filter Application that assimilates the existing observation data into input data of the model that can improve the quality of rainfall forecast in Southern Vietnam and overall country in general.References Bui Minh Tuan, Nguyen Minh Truong, 2013. 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BackgroundReports suggest that cancer patients may be more vulnerable to COVID-19, with increased disease severity and higher mortality rate.1–3 Although this is likely multifactorial, the exact pathogenesis has not been clearly elucidated. Studies have shown increased ACE2 expression in tumours as compared to normal tissues,4 5 thereby providing increased viral binding. Moreover, other mechanisms of cancer immunotherapy including treatment- and disease-related immunosuppression and functional exhaustion have been reported in patients with concomitant cancer and COVID-19; contributing to greater COVID-19 disease severity.6–8 There is still much to be revealed about the interplay between COVID-19, cancer and the immune system. These insights will give us greater understanding of the immunopathological processes underlying COVID-19 in cancer patients and their clinical relevance.MethodsA 45-year-old South Asian male diagnosed with COVID-19, with incidental discovery of stage II T3N0 caecal adenocarcinoma was consented for our study. The patient had experienced mild symptoms throughout the course of the disease, and underwent laparoscopic right hemicolectomy 10 days after recovery from COVID-19. His blood, lymph nodes, normal tissue and tumour samples were obtained for further analysis (figure 1). Multiplex immunohistochemistry was performed to understand SARS-CoV-2-associated tumour immune microenvironment. Moreover, to simulate ex vivo SARS-CoV-2 infection, dissociated cells from blood, lymph nodes, and tissue samples were stimulated with SARS-CoV-2 peptides or control for 16 hours. This was followed by 25-colour flow cytometry analysis for immune markers and cytokines. We then compared unstimulated with stimulated cells to study SARS-CoV-2-elicited immune response.ResultsMultiplex immunohistochemistry demonstrated upregulated expression of ACE2 in the tumour as compared to adjacent normal tissue, whilst SARS-CoV-2 was detected only in adjacent normal tissue but not within the tumour (figure 2). We also observed SARS-CoV-2 in other organs such as appendix and lymph nodes; and the presence of tertiary lymphoid structure, abundant T cells and NK cells within the proximity of the tumour (figure 2). Additionally, upon stimulation with SARS-CoV-2 peptides, we successfully elicited SARS-CoV-2-specific CD4+ T cells expressing immune markers such as granzyme B, TNF-α and IFN-γ (figure 3). Deep profiling of the samples is on-going with single-cell sequencing and digital spatial profiling.Abstract 475 Figure 1Study design, methodology and brief summary of the findingsBlood, lymph nodes, normal tissue and tumour samples were obtained from a 45-year-old South Asian male who was diagnosed with COVID-19 and caecal adenocarcinoma. Lymph nodes, normal tissue and tumour samples were analysed with multiplex immunohistochemistry, while dissociated cells from blood, lymph nodes and tissue samples were subjected to SARS-CoV-2 peptide stimulation and analysed with 25-colour flow cytometry. Multiplex immunohistochemistry detected SARS-CoV-2 proteins only in adjacent normal tissue but not within the tumour. Exhausted tumour-infiltrating T cells were also detected. Flow cytometry revealed CD4+ T cells expressing IFN-γ and granzyme BAbstract 475 Figure 2Multiplex immunohistochemistry of tissue samples(A) Multiplex immunohistochemistry of normal colon tissue. From left to right: SARS-CoV-2 nucleocapsid (green), CD3 (red), CD56 (cyan) and FOXP3 (white), representative of SARS-CoV-2 virus, T cells, NK cells and regulatory T cells respectively. (B) Multiplex immunohistochemistry of tertiary lymphoid structure. First row from left to right: PD-L1 (green), CD3 (orange), CD68 (red) and DAPI (blue). Second row from left to right: CD8 (magenta), cytokeratin (white), FOXP3 (cyan) and compositeAbstract 475 Figure 3Cytokine profiling with 25-colour flow cytometry panelBlood cells were incubated with SARS-CoV-2 peptides or control for 16 hours. This was followed by 25-colour flow cytometry panel with immune markers and cytokines. Both gated populations were observed to be increased after stimulation with SARS-CoV-2 peptides, suggesting that they might be SARS-CoV-2-specific T cells. Further gating on the populations showed that they were CD4+ T cells expressing granzyme B, with high (population 2) or moderate (population 1) TNF-α and IFN-γ expressionsConclusionsWe believe this is the first report of immune profiling of in situ tumour microenvironment in a cancer patient with COVID-19. Our findings showed the presence of viral proteins in several tissues despite negative swab test result, and the ability to elicit ex vivo SARS-CoV-2-specific T cell responses through peptide stimulation experiments.Ethics ApprovalThis study was approved by Centralised Institutional Review Board of SingHealth; approval number 2019/2653.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferencesLiang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. 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BackgroundHyperprogressive disease (HPD) is a distinct pattern of rapid tumor progression observed in patients with cancer who are undergoing immune checkpoint inhibitor therapy. Despite the growing evidence, a universal definition of HPD remains to be established, and incidence rates vary based on the defining criteria. Therefore, a refinement of currently existing criteria is warranted to better characterize this phenomenon and evaluate its incidence.MethodsTwo independent investigators performed a systematic literature search in EMBASE and MEDLINE using keywords selected in Park et al.1: checkpoint, immunotherapy, pd1, pdl1, ctla4, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab and hyperprogress. Studies published from March 3, 2020 to April 20, 2020 that included the incidence and definition of HPD in patients receiving immunotherapy were included for analysis. Selected studies were then combined with those included in the meta-analysis by Park et al.1 Duplicates were removed, and the study with a larger cohort was selected in instances of overlap between two cohorts. In total, 50 studies were included for meta-analysis.2–51 Pooled incidence rates of HPD and prespecified subgroup analyses based on four categories defining HPD (tumor growth rate ratio, tumor growth kinetics ratio, early tumor burden increase, and combination) were obtained with 95% confidence intervals (CI) using a random effects model performed on R.ResultsA total of 6009 patients from 50 studies were included in the meta-analysis. Incidences varied from 0.0% to 43.1% (figure 1), and the overall pooled incidence of HPD was 12.9% (95%CI, 11.1%–14.7%). Significant heterogeneity was observed (I2= 77%; p<0.01). Studies were also grouped into one of 4 categories (table 1) based on the definition of HPD used to calculate the tumor growth acceleration: tumor growth rate ratio (pooled incidence of HPD 10.5%; 95% CI, 7.9%–13.0%), tumor growth kinetics ratio (pooled incidence, 14.8%; 95% CI, 12.0%–17.5%), early tumor burden increase (pooled incidence, 17.2%; 95% CI, 9.7%–24.7%), and combinations of the above (pooled incidence, 12.2%; 95% CI, 9.2%–15.2%).Abstract 238 Table 1Subgroup analyses based on definitions of HPDAbbreviationTGR, tumor growth rate; TGK, tumor growth kinetics.Abstact 238 Figure 1Overall pooled incidence of HPD. The overall pooled incidence of HPD was 12.9% (95% CI, 11.1%–14.7%). Significant heterogeneity was observed (I2 = 77%; p<0.01).ConclusionsThe overall incidence of HPD from 50 studies was 12.9% (95%CI, 11.1%–14.7%). HPD incidence varied from 0% to 43.1% depending on the definition each investigator chose. There is a growing need for a more uniform definition of HPD that does not underestimate or overestimate its incidence.ReferencesPark HJ, Kim KW, Won SE, et al. Definition, incidence, and challenges for assessment of hyperprogressive disease during cancer treatment with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Netw Open 2021;4(3):1–16. doi:10.1001/jamanetworkopen.2021.1136Champiat S, Dercle L, Ammari S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res 2017;23(8):1920–1928. doi:10.1158/1078-0432.CCR-16-1741Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res 2017;23(15):4242–4250. doi:10.1158/1078-0432.CCR-16-3133Saâda-Bouzid E, Defaucheux C, Karabajakian A, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 2017;28(7):1605–1611. doi:10.1093/annonc/mdx178Ferrara R, Mezquita L, Texier M, et al. Comparison of fast-progression, hyperprogressive disease, and early deaths in advanced non–small-cell lung cancer treated with PD-1/PD-L1 inhibitors or chemotherapy. JCO Precis Oncol 2020;(4):829–840. doi:10.1200/po.20.00021Abbas W, Rao RR, Popli S. Hyperprogression after immunotherapy. South Asian J Cancer 2019;08(04):244–246. doi:10.4103/sajc.sajc_389_18Aoki M, Shoji H, Nagashima K, et al. Hyperprogressive disease during nivolumab or irinotecan treatment in patients with advanced gastric cancer. ESMO Open 2019;4(3):1–10. doi:10.1136/esmoopen-2019-000488Hwang I, Park I, Yoon S kyo, Lee JL. Hyperprogressive disease in patients with urothelial carcinoma or renal cell carcinoma treated with PD-1/PD-L1 inhibitors. Clin Genitourin Cancer 2020;18(2):e122-e133. doi:10.1016/j.clgc.2019.09.009Kamada T, Togashi Y, Tay C, et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A 2019;116(20):9999–10008. doi:10.1073/pnas.1822001116Kanjanapan Y, Day D, Wang L, et al. Hyperprogressive disease in early-phase immunotherapy trials: clinical predictors and association with immune-related toxicities. Cancer 2019;125(8):1341–1349. doi:10.1002/cncr.31999Kim CG, Kim KH, Pyo KH, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol 2019;30(7):1104–1113. doi:10.1093/annonc/mdz123Kim Y, Kim CH, Lee HY, et al. Comprehensive clinical and genetic characterization of hyperprogression based on volumetry in advanced non–small cell lung cancer treated with immune checkpoint inhibitor. J Thorac Oncol 2019;14(9):1608–1618. doi:10.1016/j.jtho.2019.05.033Russo G Lo, Moro M, Sommariva M, et al. 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Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort. Aliment Pharmacol Ther 2019;49(10):1323–1333. doi:10.1111/apt.15245Ten Berge DMHJ, Hurkmans DP, den Besten I, et al. Tumour growth rate as a tool for response evaluation during PD-1 treatment for non-small cell lung cancer: a retrospective analysis. ERJ Open Res 2019;5(4):00179–02019. doi:10.1183/23120541.00179-2019Tunali I, Gray JE, Qi J, et al. Novel clinical and radiomic predictors of rapid disease progression phenotypes among lung cancer patients treated with immunotherapy: an early report. Lung Cancer 2019;129:75–79. doi:10.1016/j.lungcan.2019.01.010Arasanz H, Zuazo M, Bocanegra A, et al. Early detection of hyperprogressive disease in non-small cell lung cancer by monitoring of systemic T cell dynamics. Cancers (Basel) 2020;12(2):1–14. doi:10.3390/cancers12020344Forschner A, Hilke FJ, Bonzheim I, et al. 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Introducción: La enfermedad renal crónica asociada a la obesidad (ERC-AO) es una enfermedad con aumento en la prevalencia en las últimas décadas. Se caracteriza por un exceso de desequilibrios hormonales adipocíticos (adipoquinas), desregulación del sistema de equilibrio energético y desequilibrios en la homeostasis metabólica. Propósito de la revisión: El objetivo de la revisión es delinear el papel de los diferentes mecanismos fisiopatológicos para el desarrollo de enfermedad renal funcional o anatómica en pacientes con obesidad. Buscamos reportes actualizados en donde se incluye los resultados de mejor supervivencia para los pacientes con ERC-AO. Recientes hallazgos: Actualmente sabemos la ERC-AO tiene un comportamiento pro inflamatorio crónico. La obesidad y sobrepeso se asocian alteraciones hemodinámicas, estructurales e histopatológicas en el riñón, así como alteraciones metabólicas y bioquímicas que predisponen a la enfermedad renal, aun cuando la función renal y las pruebas convencionales sean normales. Conclusiones: Clasificamos a la ERC-AO en Tipo 1: Obesidad y alteraciones funcionales potencialmente reversibles. Tipo 2: Obesidad y alteraciones estructurales histopatológicas potencialmente no reversibles (Incluye la Glomerulopatía asociada a obesidad y glomeruloesclerosis focal y segmentaria). Tipo 3: Obesidad en relacionada con enfermedades crónicas (Diabetes, Hipertensión, Hipertensión pulmonar. Insuficiencia Cardíaca). Tipo 4: Obesidad en el paciente con terapia sustitutiva de la función renal. Recibido: Agosto 03, 2022 Aceptado: Septiembre 30, 2022 Publicado: Septiembre 30, 2022 Editor: Dr. Franklin Mora Bravo. Introducción La obesidad es una enfermedad en crecimiento con un aumento en su prevalencia en las últimas décadas, asociándose a un elevada carga asistencial y económica para los sistemas sanitaros derivado de su relación con enfermedades cardiovasculares, endocrinas, psicológicas, renales entre otras [1, 2]. El incremento en las tasas de obesidad en distintos grupos etarios, desde niños hasta adultos jóvenes conlleva a asumir que en el futuro veremos más enfermedad renal relacionada con la obesidad (ERC-AO) en la población general, con implicaciones relevantes para los sistemas de atención [3]. Por ello el conocimiento y comprensión de esta interacción podría tener implicaciones en la prevención y tratamiento de las enfermedades renales. Dentro de la población general la obesidad se asocia a incremento en el riesgo de diversas condiciones patológicas, como la hipertensión arterial crónica (HTA), enfermedad renal crónica (ERC), artrosis, infecciones, síndrome de apnea hipopnea obstructiva del sueño (SAHOS) y diabetes mellitus (DM) entre otras [3]. No obstante, en el escenario de la ERC, la obesidad juega un rol dual y paralelo en el desarrollo de la enfermedad, tradicionalmente se ha denominado “paradoja de la obesidad”, donde por un lado actúa como un factor de riesgo modificable para el desarrollo de la enfermedad renal crónica (ERC) y por otro se ha asocia de manera consistente con mejores resultados de supervivencia en pacientes con enfermedad renal terminal [1]. Por lo anterior, en las próximas páginas describimos aspectos fisiopatológicos que involucran la obesidad en el desarrollo de la ERC. Definición y epidemiología La obesidad es una condición que se caracteriza por la acumulación anormal o excesiva de tejido adiposo con consecuencias patológicas adversas e incremento del riesgo cardiovascular [4]. Utilizando para su definición y diagnostico un indicador simple como es la relación entre el peso y la talla denominado índice de masa corporal (IMC), se calcula dividiendo el peso de una persona en kilos por el cuadrado de su talla en metros (kg/m2). Un IMC entre 18.5 y 25 kg/m2 es considerado por la Organización Mundial de la Salud (OMS) como peso normal, un IMC entre 25 y 30 kg/m2 como sobrepeso y un IMC > 30 kg/m2, como obesidad [5-7]. Además, la obesidad puede ser clasificada en tres niveles de severidad: clase I (IMC 30.0 – 34.9), clase II (IMC 35.0 – 39.9) y clase III (IMC > 40) [8]. Durante las últimas tres décadas, la prevalencia de adultos con sobrepeso y obesidad (IMC ≥ 25 kg/m2) en todo el mundo ha aumentado sustancialmente, convirtiendo a la obesidad en una epidemia y se prevé que su prevalencia crezca un 40% en la próxima década [6]. Actualmente, el problema de obesidad se ha visto en mayor aumento debido al incremento en la afectación en niños, lo que ocasiona una mayor prevalencia de patologías a edad temprana. En 2016, según las estimaciones de la OMS unos 41 millones de niños menores de cinco años tenían sobrepeso o eran obesos [7]. Esto afectando a todos los países, independiente de su nivel de ingresos [7]. La prevalencia del sobrepeso y la obesidad en niños y adolescentes (de 5 a 19 años) ha aumentado de forma espectacular, del 4% en 1975 a más del 18% en 2016. Este aumento ha sido similar en ambos sexos: un 18% de niñas y un 19% de niños con sobrepeso en 2016. Mientras que en 1975 había menos de un 1% de niños y adolescentes de 5 a 19 años con obesidad, en 2016 eran 124 millones (un 6% de las niñas y un 8% de los niños) [7]. La creciente prevalencia de la obesidad tiene implicaciones para las enfermedades cardiovasculares (ECV) y también para la ERC. Un IMC alto es uno de los factores de riesgo más fuertes para la ERC de nueva aparición [6]. Epidemiología de la enfermedad renal crónica asociada a obesidad (ERC-AO) La enfermedad renal crónica (ERC) es una condición de interés en salud pública, asociada a una elevada morbilidad y mortalidad a nivel mundial. Las guías KDIGO (Kidney Disease: Improving Global Outcomes), definen la ERC como la presencia de alteraciones en la estructura o función renal durante al menos tres meses y con implicaciones para la salud [9, 10]. Los principales elementos clasificatorios para definir la presencia de ERC son la tasa de filtración glomerular (TFG) estimada (G1 a G5) utilizando como umbral definitorio una TFG 60 ml/min/1,73m2 y la tasa de excreción de albúmina en orina (A1 a A3) según el cociente albúmina/creatinina en una muestra aislada de orina sea < 30, 30-300 o > 300 mg/g, respectivamente [9, 10]. Si bien inicialmente existía cierta controversia sobre el uso de la TFG para el diagnóstico de la ERC en fases iniciales, trabajos recientes han puesto en evidencia que tanto una TFG< 60 ml/min/1.73 m2 como un cociente albúmina/creatinina (CAC) ≥ 1.1 mg/mmol (10 mg/g) son predictores independientes del riesgo de mortalidad e insuficiencia renal terminal (IRT) en población general [11, 12]. En consecuencia, debido a estas categorías podemos determinar el pronóstico de cada paciente. Los datos globales sugieren que la prevalencia de la ERC se encuentra entre el 10 y el 16 %, pero la información sobre la prevalencia de la población por categoría de TFG y ACR es escasa [13]. La ERC es una afección asociada a una elevada carga de morbilidad, mortalidad y enfermedad cardiovascular (ECV). A medida que disminuye la función renal, surgen trastornos metabólicos y hemodinámicos que aumentan las tasas de hospitalización, ECV y muerte [4]. El conjunto de factores de riesgo conocidos para la progresión de la ERC es relativamente pequeño, y las terapias y estrategias efectivas para retrasar la progresión de la ERC son limitadas [14]. Por lo cual resulta necesario conocer y entender los diferentes factores de riesgo y su impacto en el daño renal, en aras de lograr minimizar la progresión del mismo, sobre todo en aquellos en los cuales se puede realizar intervenciones activas, evaluables, controlables y con seguimiento continuo como es la obesidad. A la fecha existe suficiente evidencia para asociar la obesidad con el desarrollo y progresión de la enfermedad renal crónica. Los datos granulares sobre la prevalencia de la obesidad en personas con ERC son limitados pero consistentes en todo el espectro de la enfermedad renal. En la Encuesta Nacional de Examen de Salud y Nutrición de 2011–2014, el 44.1 % de los pacientes con ERC en los Estados Unidos también tenían obesidad (21.9 % con obesidad de clase 1 y 11.1 % con clase 2 y obesidad clase 3, habiéndose incrementado el porcentaje global un 5% en los últimos 12 años [15]. La glomeruloesclerosis focal y segmentaria (GEFS) es el tipo de glomerulonefritis que se asocia con mayor frecuencia a la obesidad [16]. La enfermedad glomerular habitualmente asociada a la obesidad se denomina glomerulopatía relacionada con la obesidad (GRO). Esta condición suele presentarse con síndrome nefrótico y pérdida progresiva de la función renal. Con la epidemia mundial de obesidad, se produjo un aumento progresivo de la GRO del 0.2% entre 1986 y 1990 al 2% entre 1996 y 2000, y se ha convertido en un tema emergente en el ámbito de la nefrología [15]. Etiología y patogénesis de la ERC-AO La obesidad se caracteriza por un exceso de desequilibrios hormonales adipocíticos (adipoquinas), desregulación del sistema de equilibrio energético y desequilibrios en la homeostasis metabólica [12]. Hay dos tipos de tejido adiposo presentes en los humanos: tejido adiposo blanco (WAT) y tejido adiposo marrón (BAT) [17-19]. El depósito de grasa ectópica primariamente ocurre en lugares donde no se almacena fisiológicamente, como el hígado, el páncreas, el corazón y el músculo esquelético; secundariamente hay un cambio en la distribución del tejido adiposo visceral con almacenamiento de tejido adiposo en los espacios intraperitoneal y retroperitoneal; luego se presenta la desregulación inflamatoria y de adipoquinas; y por último la resistencia a la insulina [20]. Tejido adiposo blanco (WAT) El tejido adiposo blanco (WAT) se caracteriza por ser un tejido blanco o amarillo con menor vascularización e inervación que el tejido marrón. Las células grasas tienen un tamaño que oscila entre 20 y 200 µm y contienen una única vacuola lipídica (uniloculares). En dicha vacuola se almacenan lípidos para su uso cuando hay demanda energética. De la totalidad de los lípidos que abarca la vacuola lipídica del adipocito blanco, del 90 al 99% son triacilgliceroles. El tejido adiposo blanco genera una gran cantidad de adipocinas y lipocinas. Las adipocinas son péptidos que actúan como hormonas o mensajeros que regulan el metabolismo. El tejido adiposo blanco se localiza en el tejido omental, mesentérico, retroperitoneal, perirrenal, gonadal y pericárdico [19]. Este tejido al igual que el tejido adiposo de otros sitios, está compuesto por una variedad de células que incluyen macrófagos, neutrófilos, células T CD4 y CD8, células B, neutrófilos, mastocitos, células T reguladoras y células T asesinas naturales (NK) [21, 22]. El tejido adiposo es responsable de la secreción de muchas moléculas de señalización, incluidas adipocinas, hormonas, citocinas y factores de crecimiento, como leptina, adiponectina, resistina, factor de necrosis tumoral-α (TNF-α), interleucina 6 (IL-6), monocito, proteína quimioatrayente-1 (MCP-1), factor de crecimiento transformante-β (TGF-β) y angiotensina II [23]. Tejido adiposo marrón o pardo (BAT) La coloración marrón del tejido adiposo se debe a que está más vascularizado y tiene un alto contenido de mitocondrias, las células grasas que componen el tejido adiposo pardo son multiloculares o tienen varias vacuolas lipídicas. Estas células tienen forma poligonal y miden de 15 a 50 µm. A diferencia del tejido adiposo blanco, el tejido marrón no tiene la función de almacenar energía, sino que la disipa a través de la termogénesis. Para lograr la regulación de la temperatura corporal, el tejido adiposo pardo se localiza en sitios superficiales y profundos [18]. Clasificación de la ERC-AO Se ha establecido que la obesidad es una enfermedad con un comportamiento pro inflamatorio crónico con múltiples comorbilidades asociadas [19]. El tejido adiposo como se describió previamente funciona como un órgano con actividad endocrina y esta infiltrado por diferentes poblaciones celulares que incluyen macrófagos y otras células con actividad inmune como linfocitos T, B y células dendríticas [19]. La mayor parte de la grasa corporal total, se considera como un sistema de órganos endocrinos, la perturbación de este tejido tiene como resultado una respuesta patológica al balance calórico positivo en individuos susceptibles que directa e indirectamente contribuye a la enfermedad cardiovascular y metabólica, se tiene conocimiento de tres principales mecanismos de disfunción del tejido adiposo “adiposopatía” [20]. Estos mecanismos incluyen alteraciones hemodinámicas, metabólicas e inflamatorias, lo que es la base de la clasificación de la ERC-AO propuesta en esta revisión (Tabla 1). ERC-AO tipo 1 La obesidad produce un daño renal de forma directa a través de alteraciones hemodinámicas, inflamatorias, y desregulación de factores de crecimiento y adipocitoquinas, además de aumento de leptina y disminución de adiponectina, aun cuando la función renal y las pruebas convencionales sean normales [16]. La obesidad desencadena una serie de eventos, que incluyen resistencia a la insulina, intolerancia a la glucosa, hiperlipidemia, aterosclerosis e hipertensión, todos los cuales están asociados con un mayor riesgo cardiovascular [4, 16] (Figura 1). La obesidad conduce a un incremento en la reabsorción tubular de sodio, alterando la natriuresis y provocando una expansión de volumen extracelular debido a la activación del sistema nervioso simpático (SNS) y el sistema renina-angiotensina-aldosterona (SRAA)(16). El aumento en la reabsorción tubular de sodio y la consiguiente expansión de volumen extracelular es un evento central en el desarrollo de HTA en la obesidad [4, 16]. Algunos estudios sugieren que se produce un aumento de la reabsorción de sodio en algunos segmentos además del túbulo proximal, posiblemente en el asa de Henle. Además, hay un aumento del flujo sanguíneo renal, la tasa de filtración glomerular (TFG) y la fracción de filtración [16]. La hiperfiltración glomerular, asociada con el aumento de la presión arterial y otras alteraciones metabólicas como la resistencia a la insulina y la DM, finalmente resultan en daño renal y disminución del filtrado glomerular [16]. Por otro lado, la activación del SNS también contribuye a la hipertensión relacionada con la obesidad [4]. Hay evidencia de que la denervación renal reduce la retención de sodio y la hipertensión en la obesidad, lo que sugiere que la activación del SNS inducida por la obesidad aumenta la presión arterial principalmente debido al estímulo de retención de sodio, más que a la vasoconstricción [16]. Los mecanismos que conducen a la activación del SNS en la obesidad aún no se conocen por completo, pero se han propuesto varios factores como desencadenantes de este estímulo, entre ellos la hiperinsulinemia, la hiperleptinemia, el aumento de los niveles de ácidos grasos, los niveles de angiotensina II y las alteraciones del reflejo barorreceptor. El aumento de los niveles de leptina está asociado a la activación del SNS y su efecto sobre el aumento de los niveles de presión arterial incluye también la inhibición de la síntesis de óxido nítrico (potente vasodilatador) [16, 24, 25].También se ha descrito un aumento de la producción de endotelina-1 en sujetos obesos, lo que contribuye aún más a la elevación de los niveles de presión arterial y, en consecuencia, a la disfunción renal. Estudios recientes han demostrado que la endotelina-1 está aumentada en pacientes con hipertensión intradiálisis, lo que sugiere que esta sustancia juega un papel clave en la génesis de la hipertensión en pacientes con ERC y posiblemente esté asociada con la hipertensión en pacientes obesos [16, 25]. Por lo anterior, las alteraciones hemodinámicas en los pacientes con obesidad conllevan a progresión de la ERC e incremento del riesgo cardiovascular derivado del desarrollo de enfermedades adicionales como la HTA, potencialmente estos cambios son reversibles con el control de la obesidad. ERC-AO Tipo 2 Mantener el estado de obesidad más allá de los efectos renales funcionales produce cambios estructurales irreversibles a nivel glomerular [25]. El estudio de pacientes con ERC y obesidad ha permitido identificar la presencia de enfermedad glomerular asociada a la obesidad, denominada glomerulopatía relacionada con la obesidad (GRO). En esta condición la hipertrofia glomerular parece ser la lesión inicial que estimula el borramiento de los podocitos y desencadena la respuesta inflamatoria local [25, 26]. Es relevante mencionar que las señales profibrogénicas inducen la formación de depósitos en la matriz extracelular de las nefronas, que conduce al engrosamiento de la membrana basal glomeruloesclerosis y fibrosis tubulointersticial [26]. Dentro del curso patogénico de la enfermedad la expansión de la superficie glomerular conduce a que los podocitos sean incapaces de cubrirla, esto lleva a disfunción y borramiento de los mismos, generando ruptura de la barrera de filtración glomerular con sobrecarga de las células restantes, lo que finalmente conduce a hiperfiltración y proteinuria [25, 26]. No obstante, no todos los pacientes con obesidad o IMC aumentado desarrollan ERC, lo cual sugiere que el incremento del IMC por sí solo no genera aumento en la incidencia o progresión de la ERC, ameritando alteraciones metabólicas adicionales. En los siguientes apartados se describen algunas de estas vías fisiopatológicas comunes a todos los tipos de ERC-AO. ERC-AO Tipo 3 La obesidad produce daño renal de forma secundaria ya que aumenta el riesgo de diabetes mellitus, hipertensión y daño cardiovascular, estas patologías causan enfermedad renal diabética (ERD), nefroangioesclerosis, y glomerulopatía asociada a hipertensión pulmonar e insuficiencia cardíaca. La mortalidad no solo se ve afectada por la presencia de la obesidad sino por la presencia de diabetes tipo 2, hipertensión arterial, hipertensión pulmonar e insuficiencia cardíaca. Los peores resultados en supervivencia lo padecen los pacientes con falla cardíaca, obesidad e insuficiencia renal. ERC-AO Tipo 4 En pacientes en hemodiálisis los niveles más elevados de adiponectina se asocian paradójicamente con tres veces más riesgo de muerte [24]. La obesidad se asocia a niveles muy bajos adiponectina por lo que la obesidad en el grupo poblacional que se realiza hemodiálisis es un fuerte factor protector con mejores resultados de supervivencia a 3 años comparados con pacientes con índice de masa corporal normal o baja. Mecanismos fisiopatológicos comunes en la ERC-AO Lipotoxicidad derivada del tejido adiposo En pacientes obesos el exceso de energía conduce a un microambiente sometido a estrés crónico, lo cual resulta en hipertrofia del tejido adiposo hasta que los adipocitos alcanzan su límite de crecimiento [25]. En ese momento, el exceso de especies toxicas lipídicas se acumula ectópicamente en diferentes órganos, induciendo un efecto nocivo conocido como lipotoxicidad; especialmente a nivel renal [27]. La lipotoxicidad se asocia a cambios estructurales y funcionales de las células mesangiales, podocitos y células tubulares proximales [28]. En los podocitos, esto interferiría con la vía de la insulina, crítica para la supervivencia y el mantenimiento de la estructura de los podocitos, lo que conduciría a la apoptosis de los podocitos e induciría una respuesta hipertrófica compensatoria en los podocitos restantes [25]. En el riñón, los depósitos de lípidos ectópicos contribuyen tanto a la inflamación local como al estrés oxidativo [27]. En modelos de ERD, la dislipidemia puede favorecer la acumulación de lípidos ectópicos e intermediarios lipídicos, no solo en el riñón sino también en tejidos extrarrenales como hígado, páncreas y corazón [27]. La acumulación de lípidos en el parénquima renal, genera daño en varias poblaciones celulares, incluídos podocitos, células epiteliales tubulares proximales y el tejido tubulointersticial a través de distintos mecanismos descritos en las siguientes apartados, pudiendo general compromiso a largo plazo de la función renal [27]. El tejido adiposo es una fuente importante de producción de diferentes factores proteicos activos, conocidos como adipocitocinas, las cuales participan en diferentes procesos metabólicos. Alteraciones en la secreción y señalización de moléculas derivadas del tejido adiposo durante la obesidad en gran medida puede mediar en la patogenia de los trastornos metabólicos [25]. A continuaciones se describe el rol de las adipocinas en la patogenia de la ERC y obesidad. Adiponectina La adiponectina es una proteína secretada principalmente por los adipocitos WAT, las principales funciones biológicas de la adiponectina incluyen una mayor biosíntesis de ácidos grasos y la inhibición de la gluconeogénesis hepática [17]. Es probablemente la adipocina secretada más abundantemente, forma alrededor del 0.05 % de las proteínas séricas y mide de 3 a 30 mg/ml en humanos, para su activación utiliza dos isoformas del receptor (AdipoR1 y AdipoR2) son receptores de siete transmembranas y tienen una homología del 66.7 % en su estructura [17]. Sin embargo, AdipoR1 y AdipoR2 son estructural y funcionalmente distintos de los receptores acoplados a proteína G porque su terminal N es intracelular, mientras que el terminal C es extracelular [29, 30]. La señalización de adiponectina se basa principalmente en interacciones de tipo receptor-ligando, en las que la adiponectina se une a sus receptores afines e inicia la activación de varias cascadas de señalización intracelular a través de las vías AMPK, mTOR, NF-κB, STAT3 y JNK [17]. La adiponectina inicia la activación de la señalización de AMPK mediada por la proteína adaptadora APPL1, que se une al dominio intracelular de AdipoR. Eso produce la activación de la biosíntesis de moléculas, otras proteínas reguladoras e importantes factores de transcripción. AMPK es un regulador que participa principalmente en la proliferación celular [17]. Hay dos tipos de macrófagos, M1 participan en la estimulación de los factores pro inflamatorios e induce la resistencia a la insulina y M2 bloquean una respuesta inflamatoria y promueve el metabolismo oxidativo; En los macrófagos, la adiponectina promueve la diferenciación celular de monocitos a macrófagos M2 y suprime su diferenciación a macrófagos M1, lo que muestra efectos pro inflamatorios y antiinflamatorios. Además, también activa los factores antiinflamatorios IL-10 pero reduce las citoquinas pro inflamatorias como IFN-γ, IL-6 y TNF-α en los macrófagos humanos [17]. Los pacientes con ERC muestran niveles elevados de proteína C reactiva (PCR), IL-6 y TNF-α y tienen una activación aberrante de receptor tipo toll (TLR)-4 [25]; en un estudio realizado en el año 2005 en 29 pacientes con ERC no diabéticos en etapa 5 y 14 controles sanos, se identificó que los pacientes con ERC tenían una expresión elevada del gen y la proteína TLR4, la estimulación de TLR-4 in vitro indujo la activación de TNF-α y NF-κB en células C2C12. Esto sugiere indirectamente que la activación de TLR-4 podría promover la inflamación muscular de los pacientes con ERC [31]. Los niveles de adiponectina se consideran predictivos de ERC, dado que estos se encuentran aumentados en pacientes con etapa pre diálisis [17, 29, 32]. Adicionalmente, en un estudio prospectivo realizado en el año 2008 en pacientes con ERC primaria no diabética identificó niveles elevados de adiponectina como un predictor novedoso de progresión de la ERC en hombres [33]. En estudios realizados en animales (ratones) muestran que la deficiencia de adiponectina se relaciona con varias alteraciones histológicas, incluida la fusión segmentaria procesos podocitarios, albuminuria y aumento del estrés oxidativo en los riñones [34]. Por otro lado, en pacientes obesos la producción de adiponectina se encuentra disminuida por lo que se cree que puede generar una función protectora sobre el riñón [29]. No obstante, paradójicamente, algunos estudios muestran que los pacientes con ERC y enfermedad renal crónica en diálisis (ERCT) tienen altos niveles de adipocinas, las explicaciones a esta situación son controversiales, se ha planteado podrían corresponder a un mecanismo compensatorio, otras consideraciones sugieren una disminución de la sensibilidad a la adiponectina o una reducción en el aclaramiento de la misma [35]. Leptina En pacientes con ERC independiente de la presencia de obesidad o no, se asocian a niveles elevados de leptina sérica. La leptina es una proteína de 167 aminoácidos, con una masa molecular de aproximadamente 16 kDa que está codificada por el gen LEP [23] secretada principalmente por los adipocitos, es una adipocina pleiotrópica. La leptina circulante llega a los órganos diana, donde se une a receptores específicos (conocidos como ObR, LR o LEPR), se conocen cinco isoformas del receptor de leptina en humanos (ObRa, ObRb, ObRc, ObRd y ObRe), de estas solo la isoforma ObRb (isoforma larga) se considera un receptor completamente activo, ya que es capaz de transducir completamente una señal de activación en la célula. Esta isoforma se encuentra altamente expresada en el sistema nervioso central (SNC), especialmente en el hipotálamo, donde participa en la regulación de la actividad secretora de este órgano. Los efectos de la leptina están mediados por cinco vías principales de señalización. Estas vías incluyen las vías de señalización JAK-STAT, PI3K, MAPK, AMPK y mTOR [23]. Por esta razón la principal función fisiológica de la leptina es transmitir información al hipotálamo sobre la cantidad de energía almacenada, como la masa de tejido adiposo, e influir en el gasto de energía al reducir el apetito. Regula el metabolismo energético, tiene efecto sobre la ingesta de alimentos, procesos de coagulación, angiogénesis, funciones relacionadas con la insulina y la remodelación vascular, además funciona como un pro inflamatorio molecular [36]. La leptina tiene efectos sobre el apetito y se ha demostrado que la hiperleptinemia contribuye a la hipertensión asociada a la obesidad por sobre activación del sistema nervioso simpático [37]. En cuanto al curso de la ERC, la leptina puede modular diferentes vías de señalización en el riñón, debido a que las células endoteliales glomerulares y mesangiales expresan abundantes receptores de leptina [25]. La leptina inducirá un incremento en la expresión de genes profibróticos, como TGF-β1 y citocinas pro inflamatorias [25]. El aumento en la expresión de TGF-β1, también contribuirá al desarrollarlo de la fibrosis renal, al unirse a receptores específicos a nivel renal, estimulara la expresión de factores profibróticos en un ciclo de retroalimentación positiva. Además, TGF-β1 es un potente iniciador de proliferación de células mesangiales renales [25]. Debido a su tamaño relativamente pequeño, la leptina atraviesa libremente el filtro glomerular de los riñones y luego se reabsorbe en la parte proximal de los túbulos contorneados [23]. Por lo que el estado elevado de leptina puede indicar una función renal deficiente [36]. Promueve la inflamación y trastorno de los lípidos, que contribuyen al riesgo de ERC [36]; se considera como “toxina urémica”, estando implicada tanto en la progresión de la enfermedad renal a través de efectos pro-hipertensivos y profibróticos, como en el desarrollo de complicaciones relacionadas con la ERC (inflamación crónica, pérdida de proteínas) [38]. Como se mencionó previamente, la leptina estimula la proliferación de células endoteliales glomerulares renales y aumenta la expresión de TGF-β1, un mediador clave de la hidrogénesis en estas células, el aumento de los niveles de leptina también contribuye al aumento de la expresión de colágeno tipo IV en el riñón, induce la proliferación de células mesangiales glomerulares mediante la activación de la vía PI3K, la hipertrofia de las células mesangiales aumenta la cantidad de proteína filtrada y albúmina que llega a las células del túbulo proximal y, como resultado, activa las vías inflamatorias y la fibrosis [23]. Puede presentarse un aumento en la síntesis del receptor TGFβ-1 secretado por las células endoteliales, este actúa de manera parácrina sobre el mesangio uniéndose a su receptor y activando la síntesis de proteínas de la matriz extracelular (ECM), incluyendo colágeno, fibronectina, tenazina y proteoglicanos; consiguientemente, un aumento en el nivel de TGFβ-1 conduce a la acumulación de MEC y, en consecuencia, a fibrosis glomerular y glomeruloesclerosis. En los podocitos, la leptina contribuye a la disminución de la expresión de las proteínas responsables de la filtración glomerular adecuada, incluidas la podocina, la nefrina, la podoplanina y la podocalixina. En las células del túbulo contorneado proximal (PTC), la leptina reduce la actividad metabólica de las células al activar la vía de señalización de mTOR [23]. Por otro lado, la leptina inhibe el apetito y aumenta el gasto de energía conduciendo a anorexia y desnutrición en pacientes con ERC, particularmente en casos de hemodiálisis de mantenimiento [36]. Por ende, una elevación de la leptina no solo nos indicaría daño renal, sino que además nos indica mayor progresión de complicaciones secundarias [39]. La obesidad aumenta la carga sobre los riñones y es un factor de riesgo de lesión renal, además de contribuir en los trastornos metabólicos asociados. Por lo que, teniendo en cuenta los efectos inhibitorios de la leptina sobre la obesidad, se puede considerar que puede proteger contra la lesión renal [39, 40]. Un estudio experimental publicado en el año 2017 demostró que la leptina disminuyó la ingesta calórica y los niveles de glucosa en ratas diabéticas [41], ese mismo año se publicó un estudio retrospectivo donde demostraron que la metreleptina, una metionil leptina humana recombinante, reduce el peso corporal y la dosis diaria de insulina en la diabetes mellitus tipo 1 [42]. La metreleptina ejerce efectos terapéuticos en la lipodistrofia [43], lo que indica que es probable que la leptina se aplique en los trastornos metabólicos [36]. Otras adipocinas Las principales adipocinas corresponden a la adiponectina y leptina como se ha descrito previamente. Además de estas, se distinguen la actividad de la visfatina y resistina, las cuales muestran propiedades pro-inflamatorias y efectos aterogénicos [25]. La visfatina estimula la expresión de TGF-β1, inhibidor del activador del plasminógeno-1 (PAI-1) y colágeno tipo I, los cuales han demostrado un rol importante como agentes profibróticos. Por otro lado, la resistina estimula la producción de las moléculas de adhesión como la molécula de adhesión intracelular 1 (ICAM-1) y la proteína de adhesión celular vascular 1 (VCAM-1) y promueve la activación del sistema renal simpático. Los niveles de estas adipocinas están marcadamente elevados en la obesidad y ERC correlacionándose con parámetros proinflamatorios y disminución de la tasa de filtración glomerular (TFG) [25, 37]. Durante el curso de la obesidad se presenta una sobre activación del SRAA, el tejido adiposo también estaría involucrado en la producción o estimulación de algunos de los componentes del RAS. Por ello la sobre estimulación del SRAA en obesos, asociado a la glomerulomegalia y desregulación de la reabsorción de sodio/glucosa, generalmente conlleva a hipertensión glomerular e hiperfiltración [25]. Otra adipocina a considerar, es la actividad de la adipocina proinflamatoria lipocalina 2 (LCN2), también denominada lipocalina asociada con la gelatinasa de neutrófilo (NGAL), estudiada como biomarcador funcional tanto para la enfermedad renal aguda como ERC(25). LCN2 es conocido por su papel en la respuesta inmune innata a través de su unión a sideróforos derivados de una infección bacteriana. Sin embargo, LCN2 no es secretada únicamente por neutrófilos sino también por otros tejidos como hígado, pulmones y de interés para este artículo, a nivel renal [25]. Se han informado niveles elevados de LCN2 en suero y orina en la lesión renal, debido a una expresión aumentada de LCN2 en el túbulo distal renal y una reabsorción alterada en el túbulo proximal [44]. El tejido adiposo, también puede producir factores angiogénicos como el factor de crecimiento del endotelio vascular (VEGF). Este elemento podría inducir la formación de novo de capilares glomerulares en gran parte defectuosos dentro del riñón, lo que contribuye a la hipertrofia glomerular característica de GRO [25] (Figura 2). Conclusiones La obesidad y el sobrepeso se asocian a alteraciones hemodinámicas, estructurales e histopatológicas en el riñón, así como alteraciones metabólicas y bioquímicas que predisponen a la enfermedad renal, aun cuando la función renal y las pruebas convencionales sean normales. Por lo tanto, los efectos renales de la obesidad son estructurales y funcionales. Hay varios mecanismos actualmente descritos que involucran a la obesidad como generador de alteraciones renales. Teniendo en cuenta las bases fisiopatológicas, proponemos una clasificación de la ERC-AO basadas en 4 tipos. Abreviaturas ERC: enfermedad renal crónica. ERC-AO: enfermedad renal crónica-asociada a enfermedad. VEGF: factor de crecimiento del endotelio vascular. OR: Odds ratio. Información suplementaria Materiales suplementarios no han sido declarados. Agradecimientos No aplica. Contribuciones de los autores Jorge Rico-Fontalvo: Conceptualización, Curación de datos, Análisis formal, Adquisición de fondos, Investigación, Metodología, Administración de proyecto, Recursos, Software, Escritura – borrador original. Rodrigo Daza-Arnedo: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Tomás Rodríguez-Yanez: Metodología, validación, supervisión, redacción: Revisión y edición. Washington Osorio: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Beatriz Suarez-Romero: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Oscar Soto: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Juan Montejo-Hernandez: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. María Cardona-Blanco: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Juan Camilo Gutiérrez: Conceptualización, Supervisión, Validación, Visualización, Redacción: revisión y edición. Todos los autores leyeron y aprobaron la versión final del manuscrito. Financiamiento Los autores proveyeron los gastos de la investigación. Disponibilidad de datos o materiales Los conjuntos de datos generados y analizados durante el estudio actual no están disponibles públicamente debido a la confidencialidad de los participantes, pero están disponibles a través del autor correspondiente a pedido académico razonable. Declaraciones Aprobación del comité de ética y consentimiento para participar No aplica para revisiones narrativas. Consentimiento para publicación No aplica cuando no se publican imágenes o fotografías del examen físico o radiografías/tomografías/resonancias de pacientes. Conflictos de interés Los autores reportan no tener conflictos de interés. 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Graphene-based composites have received a great deal of attention in recent year because the presence of graphene can enhance the conductivity, strength of bulk materials and help create composites with superior qualities. Moreover, the incorporation of metal oxide nanoparticles such as Fe3O4 can improve the catalytic efficiency of composite material. In this work, we have synthesized a composite material with the combination of reduced graphene oxide (rGO), and Fe3O4 modified tissue-paper (mGO-PP) via a simple hydrothermal method, which improved the removal efficiency of the of methylene blue (MB) in water. MB blue is used as the model of contaminant to evaluate the catalytic efficiency of synthesized material by using a Fenton-like reaction. The obtained materials were characterized by SEM, XRD. The removal of materials with methylene blue is investigated by UV-VIS spectroscopy, and the result shows that mGO-PP composite is the potential composite for the color removed which has the removal efficiency reaching 65% in acetate buffer pH = 3 with the optimal time is 7 h.
 Keywords
 Graphene-based composite, methylene blue, Fenton-like reaction.
 References
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Retraction: ‘’ by Jian‐Li Zhao , Le Zhang, Xu Guo , Jing‐Hua Wang , Wen Zhou , Min Liu , Xin Li and Hua Tang , IUBMB Life 2015, 67, 380–394 : The above article, published online on 15 May 2015 on Wiley Online Library (https://doi.org/10.1002/iub.1381) has been retracted by agreement between the journal's Editor in Chief, Dr. Efstathios S. Gonos, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by a third party. Several flaws and inconsistencies were found, including image manipulation in Figures 3C, 4C, 5B, 6B, 7C, 7D, 8B, 8C and 8D, and the editors consider the conclusions of this article to be invalid. The authors were contacted regarding the findings and the proposed retraction, but we did not receive a response.

Introduction & Objective: Type 1 diabetes (T1D) is a heterogeneous disorder; however, the extent to which genetic and clinical factors distinguish T1D patient’s subgroups remains uncertain. We aimed to incorporate HLA alleles and their interactions and then develop a novel T1D Genetic Risk Score (GRS). Also, we utilized a phenome-wide association study (PheWAS) to refine T1D subtype classification. Methods: Among 1,352 Chinese T1D cases and 1,602 healthy controls, we used logistic regression to identify HLA class I and II alleles associated with T1D risk and combined significant loci to create the GRS. We modeled interactions between alleles marking strongly associated HLA haplotypes. Then, we employed PheWAS to assess the associations between 43 phenotypes and risk genotypes. Results: T1D patients had reduced polymorphisms in HLA alleles and attenuated linkage disequilibrium between alleles compared to controls. The HLA-DRB1*09:01-HLA-DQA1*03:02 loci were significantly associated with the risk of T1D. Additionally, HLA-B*58:01 and HLA-C*3:02 exhibited associations with T1D and linkage with the DR3 haplotype. We observed a stronger genetic risk associated with an earlier onset age, especially in childhood-onset patients (p<0.001) based on the PheWAS and GRS. A significant association was found between lower ALT (p<0.01) and higher GAD antibody titers (p<0.001) and increased genetic risk in adult-onset patients. Conclusion: Our study characterized the HLA type and the association of genetic risk in Chinese T1D patients with different ages of onset and autoantibody titers. We translated the T1D genetic and clinical subtypes to further our understanding of the etiology of these subtypes. Disclosure Y. Shi: None. T. Yue: None. H. Tan: None. Y. Ding: None. L. Pan: None. C. Guo: None. S. Luo: None. X. Zheng: None. J. Weng: None.

Introduction: It was reported that the complex, formed between acylated insulin and human serum albumin (HSA), enters an essentially inactive albumin-bound depot, leading to a dramatically decreased potency. Objectives: This study was performed to develop a more potent once-weekly insulin analog GZR4 and investigate its molecular and pharmacological properties. Methods: In vitro assays were employed to characterize the biological attributes of GZR4 through its interactions with HSA and insulin receptor (IR), intracellular signaling, and cellular metabolic responses. In vivo efficacy was evaluated in T1DM STZ treated rats and db/db mice, with Icodec (once-weekly insulin under development) as positive control. Results: GZR4 was designed by introducing C22 fatty acid to B29 lysine of insulin backbone (A14E, B16H, B25H, desB30 human insulin) through 12×OEG linker. GZR4 displayed 2-fold increase in HSA binding, while 1.5-fold decrease in IR-A binding, 2.5-fold decrease in IR-B binding compared with insulin Icodec. In the presence of HSA, a sandwich binding model showed GZR4 retained IR binding response with 10.2 RU while Icodec essentially displayed no binding, IR phosphorylation activity relative to human insulin was 0.233%±0.012% and 0.034%±0.002% for GZR4 and Icodec respectively. In adipocytes, GZR4 stimulated lipogenesis in a similar dose-dependent manner as human insulin. HbA1c-lowering capability of GZR4 was 3 times higher than that of Icodec in TIDM STZ treated rats and db/db mice. Conclusions: Current studies demonstrate that the length of the OEG linker between insulin and fatty acid plays an essential role on the potency of the acylated insulins. In the presence of HSA, GZR4 retains partially in vitro bioactivity while Icodec entered an essentially inactive state. Accordingly, GZR4 showed higher in vivo hypoglycemia efficacy than Icodec. Pharmacological evaluation revealed that GZR4 has the potential to be a novel once-weekly basal insulin with lower dosing compared to Icodec. Disclosure W. Xing: None. W. Chen: None. Y. Zhang: None. J. Gao: None. A. He: None. J. Zhang: None. Y. Deng: None. F. Xue: None. Y. Wang: None. H. Fu: None. R. Zhang: None. J. Huang: None. Z. Gan: None.

Introduction: Combining two mechanisms (GLP-1 and FGF21) can deliver synergistic and complementary functions. ZT003 is a novel long-acting GLP-1/FGF21 dual agonist, and in this study, its therapeutic potential has been explored in animal models. Methods: In vitro GLP-1 and FGF21 activities of the fusion protein were measured using a BHK cell line overexpressing human GLP-1 receptor and a HEK293 cell line overexpressing human beta-Klotho. In vivo tests were carried out in DIO mice, db/db mice and NASH mice to demonstrate the pharmacological efficacy of ZT003 on body weight, food intake, plasma glucose, circulating lipids, liver fat content, NAS score and other metabolic parameters as compared to the benchmark molecules. The pharmacokinetic parameters were measured in non-human primates. Results: ZT003 is an engineered dual agonist fusion protein comprising GLP-1, anti-HSA nanobody (for half-life extension) and FGF21 conjugated with a small molecule to prevent C-terminal degradation. In cell-based assays, ZT003 showed an optimal GLP-1/FGF21 activity ratio. When tested in DIO obese mice and db/db diabetic mice, ZT003 demonstrated synergistic, sustained, and superior body weight reduction and glucose-lowering effect versus semaglutide, tirzepatide and YH25724. When tested in DIO NASH mice, ZT003 significantly improved lipid metabolism, hepatic steatosis, and liver histology, all of these effects being greater than semaglutide. The pharmacokinetic study in cynomolgus monkeys demonstrated the half-life of ZT003 is comparable to that of semaglutide, indicative that ZT003 is likely to be amenable for once-weekly dosing in humans. Conclusion: In conclusion, this novel GLP-1/FGF21 fusion protein in animals reveals therapeutically efficacious to treat obesity, diabetes, NASH and related co-morbidities, thus demonstrating the promise of the poly-pharmaceutical approach in metabolic drug discovery and development. Disclosure Y. Zhang: Employee; QL Biopharmaceutical Co. Ltd. Y. Zhang: None. C. Zhao: Employee; Beijing QL Biopharmaceutical Co., Ltd. S. Lin: None. W. Guo: Employee; Beijing QL Biopharmaceutical Co., Ltd. B. Wu: Employee; Beijing QL Biopharmaceutical Co. Ltd.

Introduction: Inadequate glycemic control in patients with premix insulin regimen is often due to the short half-life and pronounced peak-to-trough ratio of basal insulin. This necessitates the development of a premix insulin containing basal insulins with an extended half-life and steady pharmacokinetic (PK) profile. Objective: This study evaluated and characterized GZR33, an ultra-long half-life basal insulin, and GZR101 which is composed by GZR33 and insulin aspart. Methods: The binding affinity of GZR33 to the human insulin receptor (hIR) was analyzed in vitro using surface plasmon resonance. IR activation was examined in CHO cells in the presence and absence of human serum albumin (HSA). Adipogenesis was measured in 3T3L1 MBX cells. Potency was tested in vivo in streptozotocin-induced T1DM rats and db/db T2DM mice, using insulin degludec (iDeg) and iDegAsp as controls. PK studies were assessed in Sprague-Dawley rats. Results: GZR33 was constructed by linking a C22 fatty diacid side chain to desB30 human insulin via a 6×OEG linker. GZR33 exhibited strong hIRA and hIRB binding (dissociation constants: 2.86E-6 M and 1.28E-6 M). It activated IRA and IRB with EC50 of 370.13 ± 94.86 nM and 477.48 ± 64.28 nM, respectively, in 0.5% HSA, and induced adipogenesis with an EC50 of 2.45 ± 0.81 nM. PK studies showed a dose-dependent increase in maximum concentration and exposure, with a T½ of 5.45 h for GZR33 (2.3 h for iDeg). In T1DM rats and T2DM mice, GZR33 outperformed iDeg in reducing HbA1c and FBG, demonstrating a potency at least three-fold higher than iDeg. Additionally, GZR101's glucose-lowering effect was proportional to the GZR33 dosage in diabetic models. Conclusion: Traditional basal insulins display a 24-hour glucose-lowering effect with noticeable peaks, leading to fluctuating blood glucose in patients. However, a basal insulin with over 3-day longevity and once-daily dosing, like GZR33, can achieve a nearly peak-less PK profile at steady-state. Consequently, GZR101 emerges as a promising once-daily premix insulin candidate. Disclosure W. Chen: None. W. Xing: None. Y. Zhang: None. A. He: None. J. Gao: None. Q. Shi: None. F. Xue: None. Y. Wang: None. J. Zhang: None. D. Yu: None. C. Cui: None. T. Xie: None. Z. Gan: None.

Introdução: A transmissão SARS-CoV-2 de humano para humano pode ocorrer e o risco de propagação no ar durante os procedimentos odontológicos geradores de aerossóis permanece uma preocupação. Acredita-se que um enxaguatório bucal antimicrobiano pré-operacional reduza o número de micróbios orais. No entanto, a eficácia do enxaguatório bucal pré-procedimento na redução do número de microrganismos disseminados por meio do aerossol gerado por procedimentos odontológicos ainda não está clara. Objetivo: avaliar através de uma revisão de literatura o uso de enxaguantes bucais na redução da carga viral do SARS-CoV-2. Materiais e Método: O levantamento literário para esta pesquisa foi realizado no período de dezembro de 2019 a 10 de agosto de 2020 nas bases de dados Scielo e Medline/PubMed. Na estratégia de busca, foram utilizadas as palavras “SARS-CoV-2”, “2019-nCoV”, “COVID-19”, “Dentistry”, “Odontologia”, “Odontología”, “Mouthwashes”, “Antissépticos Bucais” e “Antisépticos Bucales”. Resultados: Uma busca sistematizada foi realizada, foram encontrados 661 artigos, após a realização da leitura criteriosa dos artigos completos foram selecionados 42 artigos. 88% dos estudos indicavam o uso de Peróxido de hidrogênio a 1%, 76% indicavam Povidine 0,2% e apenas 19% o uso da Clorexidina a 0,12%. Conclusão: Os estudos presentes na literatura apresentam divergências nas indicações e porcentagens dos enxaguantes indicados. Os protocolos clínicos devem ser avaliados para reduzir o risco de transmissão e proteger pacientes e profissionais.Descritores: Infecções por Coronavírus; Betacoronavirus; Odontologia; Antissépticos Bucais.ReferênciasGe ZY, Yang LM, Xia JJ, Fu XH, Zhang YZ. Possible aerosol transmission of COVID-19 and special precautions in dentistry. J Zhejiang Univ Sci B. 2020;21(5):361-68. Peng X, Xu X, Li Y, Cheng L, Zhou X, Ren B. Transmission routes of 2019-nCoV and controls in dental practice. Int J Oral Sci. 2020;12(1):9.Fallahi HR, Keyhan SO, Zandian D, Kim SG, Cheshmi B. Being a front-line dentist during the Covid-19 pandemic: a literature review. Maxillofac Plast Reconstr Surg. 2020;42(1):12.Yoon JG, Yoon J, Song JY, Yoon SY, Lim CS, Seong H, et al. Clinical Significance of a High SARS-CoV-2 Viral Load in the Saliva. J Korean Med Sci. 2020;35(20):e195.Alharbi A, Alharbi S, Alqaidi S. Guidelines for dental care provision during the COVID-19 pandemic. Saudi Dent J. 2020;32(4):181-86.Amato A, Caggiano M, Amato M, Moccia G, Capunzo M, De Caro F. Infection Control in Dental Practice During the COVID-19 Pandemic. Int J Environ Res Public Health. 2020;17(13):4769.Amorim, LM, Maske TT, Ferreira SH, Santos RB, Feldens CA, Kramer PF. New Post-COVID-19 Biosafety Protocols in Pediatric Dentistry. Pesqui Bras Odontopediatria Clín. Integr. 2020; 20(Suppl 1): e0117.Araya-Salas,C. 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This study uses an in silico screening docking model to evaluate the ACE2 inhibitory activity of natural compounds and drugs. The study collected 49 compounds and evaluated the ACE2 inhibitory effect in silico. The study results show that 11 out of the 49 compounds had stronger inhibitory activity on ACE2 than MLN-4760. Lipinski’s rule of five criteria and predictive pharmacokinetic-toxicity analysis show that eight compounds including quercetin, galangin, quisinostat, fluprofylline, spirofylline, RS 504393, TNP and GNF-5 had drug-likeness. These compounds could be potential drug for the Covid-19 treatment.
 Keywords
 SARS-CoV-2S, Covid-19, ACE2, molecular docking, in silico.
 References
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Cobalt dopping Fe-MIL-88B were successfully synthesized -in solvothermal procedure using DMF as solvent and with/without NaOH. The samples were characterized using SEM, BET and TGA techniques. The partly substitution of Fe by Co does not change the octahedral shape of their parent Fe-MIL-88B. Crystallizations conducted in NaOH medium, however, results in rod like with 2-end octahedral shape crystals. The BET specific surface area is 139cm2/g. The TGA data indicated that the presence of Co resulted in an increase in thermal stability of synthesized samples compared to parent Fe-MIL-88B. The CO2 adsorption isotherms in Fe-MIL-88B-Co samples were measured volumetrically at five temperatures:278K, 288K, 298K, 308K, 318K. The obtained results showed that Fe-MIL-88B-Co is a potential adsorbent with a maximum adsortption capacity of 1.2312 mmol/g (at T= 278K). The sample synthesized in alkali medium exhibited a better adsorbent for CO2 storage.
 Keywords
 MIL, adsorption, CO2
 References
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus , is causing a serious worldwide COVID-19 pandemic. The emergence of strains with rapid spread and unpredictable changes is the cause of the increase in morbidity and mortality rates. A number of drugs as well as vaccines are currently being used to relieve symptoms, prevent and treat the disease caused by this virus. However, the number of approved drugs is still very limited due to their effectiveness and side effects. In such a situation, medicinal plants and bioactive compounds are considered a highly valuable source in the development of new antiviral drugs against SARS-CoV-2. This review summarizes medicinal plants and bioactive compounds that have been shown to act on molecular targets involved in the infection and replication of SARS-CoV-2.
 Keywords: Medicinal plants, bioactive compounds, antivirus, SARS-CoV-2, COVID-19
 References
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The curtain rose. The howling of desert wind filled the performance hall in the Shanghai Grand Theatre. Into the center stage, where a scenic construction of a mountain cliff and a desert landscape was dimly lit, entered the character of the Daoist priest Wang Yuanlu (1849–1931), performed by Chen Yizong. Dressed in a worn and dusty outfit of dark blue cotton, characteristic of Daoist priests, Wang began to sweep the floor. After a few moments, he discovered a hidden chambre sealed inside one of the rock sanctuaries carved into the cliff.Signaled by the quick, crystalline, stirring wave of sound from the chimes, a melodious Chinese ocarina solo joined in slowly from the background. Astonished by thousands of Buddhist sūtra scrolls, wall paintings, and sculptures he had just accidentally discovered in the caves, Priest Wang set his broom aside and began to examine these treasures. Dawn had not yet arrived, and the desert sky was pitch-black. Priest Wang held his oil lamp high, strode rhythmically in excitement, sat crossed-legged in a meditative pose, and unfolded a scroll. The sound of the ocarina became fuller and richer and the texture of the music more complex, as several other instruments joined in.Below is the opening scene of the award-winning, theatrical dance-drama Dunhuang, My Dreamland, created by China’s state-sponsored Lanzhou Song and Dance Theatre in 2000. Figure 1a: Poster Side A of Dunhuang, My Dreamland Figure 1b: Poster Side B of Dunhuang, My DreamlandThe scene locates the dance-drama in the rock sanctuaries that today are known as the Dunhuang Mogao Caves, housing Buddhist art accumulated over a period of a thousand years, one of the best well-known UNESCO heritages on the Silk Road. Historically a frontier metropolis, Dunhuang was a strategic site along the Silk Road in northwestern China, a crossroads of trade, and a locus for religious, cultural, and intellectual influences since the Han dynasty (206 B.C.E.–220 C.E.). Travellers, especially Buddhist monks from India and central Asia, passing through Dunhuang on their way to Chang’an (present day Xi’an), China’s ancient capital, would stop to meditate in the Mogao Caves and consult manuscripts in the monastery's library. At the same time, Chinese pilgrims would travel by foot from China through central Asia to Pakistan, India, Nepal, Bangladesh, and Sri Lanka, playing a key role in the exchanges between ancient China and the outside world. Travellers from China would stop to acquire provisions at Dunhuang before crossing the Gobi Desert to continue on their long journey abroad. Figure 2: Dunhuang Mogao CavesThis article approaches the idea of “abroad” by examining the present-day imagination of journeys along the Silk Road—specifically, staged performances of the various Silk Road journey-themed dance-dramas sponsored by the Chinese state for enhancing its cultural and foreign policies since the 1970s (Kuang).As ethnomusicologists have demonstrated, musicians, choreographers, and playwrights often utilise historical materials in their performances to construct connections between the past and the present (Bohlman; Herzfeld; Lam; Rees; Shelemay; Tuohy; Wade; Yung: Rawski; Watson). The ancient Silk Road, which linked the Mediterranean coast with central China and beyond, via oasis towns such as Samarkand, has long been associated with the concept of “journeying abroad.” Journeys to distant, foreign lands and encounters of unknown, mysterious cultures along the Silk Road have been documented in historical records, such as A Record of Buddhist Kingdoms (Faxian) and The Great Tang Records on the Western Regions (Xuanzang), and illustrated in classical literature, such as The Travels of Marco Polo (Polo) and the 16th century Chinese novel Journey to the West (Wu). These journeys—coming and going from multiple directions and to different destinations—have inspired contemporary staged performance for audiences around the globe.Home and Abroad: Dunhuang and the Silk RoadDunhuang, My Dreamland (2000), the contemporary dance-drama, staged the journey of a young pilgrim painter travelling from Chang’an to a land of the unfamiliar and beyond borders, in search for the arts that have inspired him. Figure 3: A scene from Dunhuang, My Dreamland showing the young pilgrim painter in the Gobi Desert on the ancient Silk RoadFar from his home, he ended his journey in Dunhuang, historically considered the northwestern periphery of China, well beyond Yangguan and Yumenguan, the bordering passes that separate China and foreign lands. Later scenes in Dunhuang, My Dreamland, portrayed through multiethnic music and dances, the dynamic interactions among merchants, cultural and religious envoys, warriors, and politicians that were making their own journey from abroad to China. The theatrical dance-drama presents a historically inspired, re-imagined vision of both “home” and “abroad” to its audiences as they watch the young painter travel along the Silk Road, across the Gobi Desert, arriving at his own ideal, artistic “homeland”, the Dunhuang Mogao Caves. Since his journey is ultimately a spiritual one, the conceptualisation of travelling “abroad” could also be perceived as “a journey home.”Staged more than four hundred times since it premiered in Beijing in April 2000, Dunhuang, My Dreamland is one of the top ten titles in China’s National Stage Project and one of the most successful theatrical dance-dramas ever produced in China. With revenue of more than thirty million renminbi (RMB), it ranks as the most profitable theatrical dance-drama ever produced in China, with a preproduction cost of six million RMB. The production team receives financial support from China’s Ministry of Culture for its “distinctive ethnic features,” and its “aim to promote traditional Chinese culture,” according to Xu Rong, an official in the Cultural Industry Department of the Ministry. Labeled an outstanding dance-drama of the Chinese nation, it aims to present domestic and international audiences with a vision of China as a historically multifaceted and cosmopolitan nation that has been in close contact with the outside world through the ancient Silk Road. Its production company has been on tour in selected cities throughout China and in countries abroad, including Austria, Spain, and France, literarily making the young pilgrim painter’s “journey along the Silk Road” a new journey abroad, off stage and in reality.Dunhuang, My Dreamland was not the first, nor is it the last, staged performances that portrays the Chinese re-imagination of “journeying abroad” along the ancient Silk Road. It was created as one of many versions of Dunhuang bihua yuewu, a genre of music, dance, and dramatic performances created in the early twentieth century and based primarily on artifacts excavated from the Mogao Caves (Kuang). “The Mogao Caves are the greatest repository of early Chinese art,” states Mimi Gates, who works to increase public awareness of the UNESCO site and raise funds toward its conservation. “Located on the Chinese end of the Silk Road, it also is the place where many cultures of the world intersected with one another, so you have Greek and Roman, Persian and Middle Eastern, Indian and Chinese cultures, all interacting. Given the nature of our world today, it is all very relevant” (Pollack). As an expressive art form, this genre has been thriving since the late 1970s contributing to the global imagination of China’s “Silk Road journeys abroad” long before Dunhuang, My Dreamland achieved its domestic and international fame. For instance, in 2004, The Thousand-Handed and Thousand-Eyed Avalokiteśvara—one of the most representative (and well-known) Dunhuang bihua yuewu programs—was staged as a part of the cultural program during the Paralympic Games in Athens, Greece. This performance, as well as other Dunhuang bihua yuewu dance programs was the perfect embodiment of a foreign religion that arrived in China from abroad and became Sinicized (Kuang). Figure 4: Mural from Dunhuang Mogao Cave No. 45A Brief History of Staging the Silk Road JourneysThe staging of the Silk Road journeys abroad began in the late 1970s. Historically, the Silk Road signifies a multiethnic, cosmopolitan frontier, which underwent incessant conflicts between Chinese sovereigns and nomadic peoples (as well as between other groups), but was strongly imbued with the customs and institutions of central China (Duan, Mair, Shi, Sima). In the twentieth century, when China was no longer an empire, but had become what the early 20th-century reformer Liang Qichao (1873–1929) called “a nation among nations,” the long history of the Silk Road and the colourful, legendary journeys abroad became instrumental in the formation of a modern Chinese nation of unified diversity rooted in an ancient cosmopolitan past. The staged Silk Road theme dance-dramas thus participate in this formation of the Chinese imagination of “nation” and “abroad,” as they aestheticise Chinese history and geography. History and geography—aspects commonly considered constituents of a nation as well as our conceptualisations of “abroad”—are “invariably aestheticized to a certain degree” (Bakhtin 208). Diverse historical and cultural elements from along the Silk Road come together in this performance genre, which can be considered the most representative of various possible stagings of the history and culture of the Silk Road journeys.In 1979, the Chinese state officials in Gansu Province commissioned the benchmark dance-drama Rain of Flowers along the Silk Road, a spectacular theatrical dance-drama praising the pure and noble friendship which existed between the peoples of China and other countries in the Tang dynasty (618-907 C.E.). While its plot also revolves around the Dunhuang Caves and the life of a painter, staged at one of the most critical turning points in modern Chinese history, the work as a whole aims to present the state’s intention of re-establishing diplomatic ties with the outside world after the Cultural Revolution. Unlike Dunhuang, My Dreamland, it presents a nation’s journey abroad and home. To accomplish this goal, Rain of Flowers along the Silk Road introduces the fictional character Yunus, a wealthy Persian merchant who provides the audiences a vision of the historical figure of Peroz III, the last Sassanian prince, who after the Arab conquest of Iran in 651 C.E., found refuge in China. By incorporating scenes of ethnic and folk dances, the drama then stages the journey of painter Zhang’s daughter Yingniang to Persia (present-day Iran) and later, Yunus’s journey abroad to the Tang dynasty imperial court as the Persian Empire’s envoy.Rain of Flowers along the Silk Road, since its debut at Beijing’s Great Hall of the People on the first of October 1979 and shortly after at the Theatre La Scala in Milan, has been staged in more than twenty countries and districts, including France, Italy, Japan, Thailand, Russia, Latvia, Hong Kong, Macao, Taiwan, and recently, in 2013, at the Lincoln Center for the Performing Arts in New York.“The Road”: Staging the Journey TodayWithin the contemporary context of global interdependencies, performing arts have been used as strategic devices for social mobilisation and as a means to represent and perform modern national histories and foreign policies (Davis, Rees, Tian, Tuohy, Wong, David Y. H. Wu). The Silk Road has been chosen as the basis for these state-sponsored, extravagantly produced, and internationally staged contemporary dance programs. In 2008, the welcoming ceremony and artistic presentation at the Olympic Games in Beijing featured twenty apsara dancers and a Dunhuang bihua yuewu dancer with long ribbons, whose body was suspended in mid-air on a rectangular LED extension held by hundreds of performers; on the giant LED screen was a depiction of the ancient Silk Road.In March 2013, Chinese president Xi Jinping introduced the initiatives “Silk Road Economic Belt” and “21st Century Maritime Silk Road” during his journeys abroad in Kazakhstan and Indonesia. These initiatives are now referred to as “One Belt, One Road.” The State Council lists in details the policies and implementation plans for this initiative on its official web page, www.gov.cn. In April 2013, the China Institute in New York launched a yearlong celebration, starting with "Dunhuang: Buddhist Art and the Gateway of the Silk Road" with a re-creation of one of the caves and a selection of artifacts from the site. In March 2015, the National Development and Reform Commission (NDRC), China’s top economic planning agency, released a new action plan outlining key details of the “One Belt, One Road” initiative. Xi Jinping has made the program a centrepiece of both his foreign and domestic economic policies. One of the central economic strategies is to promote cultural industry that could enhance trades along the Silk Road.Encouraged by the “One Belt, One Road” policies, in March 2016, The Silk Princess premiered in Xi’an and was staged at the National Centre for the Performing Arts in Beijing the following July. While Dunhuang, My Dreamland and Rain of Flowers along the Silk Road were inspired by the Buddhist art found in Dunhuang, The Silk Princess, based on a story about a princess bringing silk and silkworm-breeding skills to the western regions of China in the Tang Dynasty (618-907) has a different historical origin. The princess's story was portrayed in a woodblock from the Tang Dynasty discovered by Sir Marc Aurel Stein, a British archaeologist during his expedition to Xinjiang (now Xinjiang Uygur autonomous region) in the early 19th century, and in a temple mural discovered during a 2002 Chinese-Japanese expedition in the Dandanwulike region. Figure 5: Poster of The Silk PrincessIn January 2016, the Shannxi Provincial Song and Dance Troupe staged The Silk Road, a new theatrical dance-drama. Unlike Dunhuang, My Dreamland, the newly staged dance-drama “centers around the ‘road’ and the deepening relationship merchants and travellers developed with it as they traveled along its course,” said Director Yang Wei during an interview with the author. According to her, the show uses seven archetypes—a traveler, a guard, a messenger, and so on—to present the stories that took place along this historic route. Unbounded by specific space or time, each of these archetypes embodies the foreign-travel experience of a different group of individuals, in a manner that may well be related to the social actors of globalised culture and of transnationalism today. Figure 6: Poster of The Silk RoadConclusionAs seen in Rain of Flowers along the Silk Road and Dunhuang, My Dreamland, staging the processes of Silk Road journeys has become a way of connecting the Chinese imagination of “home” with the Chinese imagination of “abroad.” Staging a nation’s heritage abroad on contemporary stages invites a new imagination of homeland, borders, and transnationalism. Once aestheticised through staged performances, such as that of the Dunhuang bihua yuewu, the historical and topological landscape of Dunhuang becomes a performed narrative, embodying the national heritage.The staging of Silk Road journeys continues, and is being developed into various forms, from theatrical dance-drama to digital exhibitions such as the Smithsonian’s Pure Land: Inside the Mogao Grottes at Dunhuang (Stromberg) and the Getty’s Cave Temples of Dunhuang: Buddhist Art on China's Silk Road (Sivak and Hood). 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Abstract INTRODUCTION Immune Checkpoint Inhibitors (ICIs) have become a revolutionary milestone in the immune-oncology field and have shown a significant improvement in survival rates and outcomes of advanced malignancies. ICIs including: Ipilimumab (1) - monoclonal antibody that inhibits Cytotoxic T Lymphocyte associated Antigen 4 (CTLA4) - Nivolumab (2) - monoclonal antibody that blocks Programmed Cell Death Ligand 1 (PDL1) - and others turn off the tumor mediated immune system inhibition and boost the immune response against tumor cells resulting in decreased tumor growth. However, targeted immunotherapy has a wide spectrum of immune related side effects (3) that can affect various body organs ranging from mild skin rash to a critical immunotherapy induced pneumonitis and severe colitis. We present a case report of Ipilimumab/Nivolumab induced fulminant DKA in a non-diabetic patient. CASE PRESENTATION We present a case of a 71 year old male with a history of hypertension, hyperlipidemia, hemorrhagic stroke and stage 4 renal cancer with metastasis to the lungs who presented to the Emergency Department with altered mental status for 1 day and respiratory depression. He was accompanied by his wife who provided most of the history and denied any head trauma, seizure, uncontrolled hypertension, recent infections, arrhythmias, endocrine diseases or alcohol/drug use. Initial blood glucose was 1052, pH 7.11, bicarbonate 6, potassium 6.7, CO2 20.1, anion gap of 29 and WBCs 19.3 without any source of infections. Diabetic ketoacidosis (DKA) protocol was started and patient was intubated for worsening respiratory depression. Patient’s wife denied any personal or family history of diabetes mellitus and stated that his Hemoglobin A1c (HbA1c) has always been below 6% during his follow ups. Upon further questioning about any new medications, she stated that 15 years ago he had renal cell carcinoma treated with left radical nephrectomy and was recently discovered to have pulmonary nodules that were biopsy positive for renal cell carcinoma, to which he recently started Ipilimumab and Nivolumab immunotherapy about 2 month and last received doses was 3 days prior to presentation. She also reported one-month history of lethargy, polyuria and polydipsia. HbA1c was found to be 8.0% and lipase enzyme > 4000 u/L without any pancreatic changes or inflammation on Computed Tomography (CT) scan of the abdomen. Insulin autoantibodies, islet cells antibodies and serum C-peptide were undetectable. During the admission DKA and respiratory depression resolved but the patient continued to have hyperglycemia with blood glucose level of 300-400 and was treated with correctional insulin scale. Patient was discharged on long acting and regular insulin after appropriate education. DISCUSSION Ipilimumab and Nivolumab; the novel revolutionary targeted immunotherapy have been approved by the United States Food and Drug Administration in 2011 (4) and 2014 (5) respectively. They enhance the immune response against tumor cells through blocking the immune checkpoints CTLA4 and PDL1 which are activated by the tumor cells as an inhibitory mechanism to interrupt the T lymphocyte - tumor cell destruction pathway (6-7). Ipilimumab and Nivolumab are used in combination for inoperable or metastatic melanoma (8-9), advanced renal cell carcinoma (10), metastatic squamous non-small cell lung cancer (11) and currently in trials for recurrent small cell lung cancer treatment (12-13). They are also used for primary or metastatic urothelial carcinoma and prostate cancer (14). As ICIs enhance T lymphocytes immunity by disrupting the inhibitory signaling, they also decrease immune tolerance and, thereby; cause autoimmune toxicities. Yet, ICIs are usually not stopped since their beneficial outcomes seem to outweigh the adverse events. Immunotherapy related adverse events (irAEs) includes: systemic symptoms of fatigue, weakness, muscle and joint pain, dermatological: rash and itchy skin - reported in 10% of patients in trials for melanoma and lung cancer (15) - pneumonitis (16) (4%), gastrointestinal: decreased appetite, abdominal pain, nausea and vomiting, colitis (17) (10%), hepatic toxicity (18) (1-17%), and endocrinopathies: hypothyroidism and hyperthyroidism (19) (8.5% and 3.7% respectively). Severe neurologic disorders including acute demyelination polyneuropathy, ascending motor paralysis and myasthenia gravis have been reported (20). Although there are no guidelines for managing irEAs, most of them are managed with high-dose corticosteroids. Several cases of autoimmune diabetes mellitus have been reported (2% of cases) as endocrinologic irEAs, most of them were genetically susceptible to type 1 diabetes mellitus. Less than 1% of cases had diabetes mellitus of rapid onset and complete insulin insufficiency leading to fulminant DKA (19). However, the clinical course of their insulin secretion disruption was not well studied. To our knowledge, the case that we are presenting here is one of a few cases described in literature of fulminant diabetes/DKA caused by immunotherapy. In fulminant diabetes, patients present with severely elevated blood glucose or DKA; however, their HbA1c is unexpectedly low (7-8%) due to the abrupt onset of presentation. C-peptide and Islet cell autoantibodies levels are low or even undetectable which suggest that pancreatic B-cells are totally destroyed via a process that is not completely understood and not similar to the one causing classic autoimmune type 1 diabetes mellitus. In fulminant diabetes/DKA pancreatic islet cells are attacked by autoreactive T lymphocytes. Thiswas initially thought to be a cell-mediated phenomenon; however, some reported cases had 1 or more islet cell autoantibodies which suggests the implication of a humoral immune response component as well. Diagnosis of such an endocrinopathy should be proper and prompt due to the increased risk of death within the first 24 hours. CONCLUSION Identification of rare but serious irAEs like DKA, is very important. This requires a multi-dimensional approach involving effective education about the symptoms of DKA and hyperglycemia in patients receiving immunotherapy along with close monitoring of these patients. More research is needed in this area to clarify the frequency of this entity and its mechanism. DISCLAIMER This research was supported (in whole or in part) by HCA Healthcare and/or HCA Healthcare affiliated entity. The views expressed in this publication represent those of author(s) and do not necessarily the official views if HCA Healthcare or any of its affiliated entities. REFRENCES 1-Tarhini A., Lo E., Minor D.R. Releasing the brake on the immune system: Ipilimumab in melanoma and other tumors. Cancer Biother. Radiopharm. 2010;25:601-613. doi: 10.1089/cbr.2010.0865. 2-Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer. 2017;8(3):410-416. doi: 10.7150/jca.17144. 3-Kadono T. Immune-related adverse events by immune checkpoint inhibitors. Nihon Rinsho Meneki Gakkai Kaishi. (2017) 40:83-9. 10.2177/jsci.40.83 4-Lacroix, Marc (2014). Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7. 5-“Nivolumab Monograph for Professionals”. Drugs.com. Retrieved 14 November 2019. 6-Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. 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