Journal articles on the topic 'Hu huan xing'

AbstractThis paper discusses some terminological consequences of the acceptance of a seemingly all-pervasive yin yang dualism by ancient Chinese naturalists, with a focus on the origin of certain technical terms introduced to designate morphological and functional items in the emerging Chinese medicine. These terms were selected from words not originally linked to morphological and physiological notions. They served as metaphors to illustrate both function and the yin yang nature of the items they were chosen to designate. How to translate these terms into Western languages is a complex issue not sufficiently discussed among philologists.In 79 CE, the historian Ban Gu (32‐92) published the Bai hu tong , based on contributions by an unknown number of participants in one of the first documented meetings of intellectuals in antiquity. Chapter 8 offers a discourse on the meaning of qing , ‘emotion’, and xing , ‘moral disposition’. Two terms were available that had been in long use in this arena of meanings, albeit without a clear-cut distinction along the lines of a Yin-Yang categorisation. No metaphors were required here. Rather, a redefinition of qing and xing was required to assign a yang nature to the former and a yin nature to the latter.The Bai hu tong is a telling example of a continuing heterogeneity of explanatory models in early Chinese life sciences. The following discussion offers an impression of the merger of what may originally have been a neutral attempt at a dualistic categorisation of all phenomena in terms of two natural categories of yin and yang with another doctrine. The second clearly valued yang phenomena more highly than yin phenomena and applied this distinction to more and less desirable moral categories. Also, the Bai hu tong offers evidence of different metaphorical usages of the term fu in physiological theory from as early as Han times. To the older meaning: ‘short-term storage facility’ a second meaning of ‘palace’ was added. The question of an adequate translation of such terms in modern languages is worth further thought.1

Abstract Abstract 4063 Intermittent PTH (iPTH) treatment is bone anabolic and has been successfully used for treatment of osteoporosis. The aims of the study were to investigate the effects of iPTH-induced bone formation on myeloma progression and unravel molecular mechanisms associated with these effects, using the SCID-rab and SCID-hu models. Using our reported procedure (Xin et al., BJH 2007), we established a novel myeloma cell line, Hg, capable of sequential passaging in experimental models. Hg cells have similar gene expression profiling (GEP) as the original patient's plasma cells, are classified in the MMSET subtype and express DKK1. SCID-hu or SCID-rab (8-10 hosts/group in each model) mice engrafted with Hg myeloma cells were subcutaneously treated with saline or iPTH (80 ug/kg/day) for 4 weeks. Overall, whereas BMD of the myelomatous bones in saline-treated hosts was similarly reduced in SCID-rab and SCID-hu mice by 14±5%, it was increased by 10±2% in iPTH-treated hosts (p<0.002 saline vs. iPTH-treated hosts). Histologic and histomorphometric analyses revealed increased bone formation parameters and no effect on number of osteoclasts. The bone anabolic effect of iPTH was associated with reduced myeloma growth by >50% (p<0.03) assessed by measurement of human immunoglobulin level in mice sera and histologically. Treatment with iPTH also increased BMD and attenuated myeloma growth in SCID-rab mice engrafted with myeloma cells from 10 patients. We found by qRT-PCR that type-1 PTH receptor was not expressed by myeloma cells and that PTH had no direct effect on in vitro growth of myeloma cells indicating that PTH anti-myeloma effect is indirectly mediated through modulation of the BM microenvironment. To shed light on molecular mechanisms associated with iPTH effects, human GEP and qRT-PCR validation of selected genes were preformed on whole myelomatous human bones from Hg-bearing SCID-hu mice treated with saline or iPTH for 4 weeks (5 hosts/group). Mice were sacrificed 2 hours after the last injection. Treatment with iPTH upregulated 343 genes and downregulated 410 genes ('2 folds, p<0.05) in myelomatous bones. There was a remarkable alteration in expression of genes associated with cAMP (e.g. RGS1/2 upregulation) and Wnt (e.g. LRP4 upregulation; DKK1 downregulation) signaling, upregulation of growth factors and receptors involved in bone remodeling (e.g. FGFR1/2, FDGFA, FDGFRA, TGFB, TGFBR1), and increased expression of osteoblast markers (e.g. osteocalcin, RUNX2). Interestingly, although iPTH induced upregulation of RANKL there was a reduction in expression of osteoclastic genes (e.g. ACP5/TRAP, NFATC1), probably due to increased osteoblast numbers, downregulation of inflammatory genes (e.g. AIF1) and upregulation of anti-inflammatory genes (e.g. TNFAIP6, CXCL14). Moreover, iPTH reduced expression of typical myeloma associated genes (e.g. CD38, WHSC1, IRF4) and had no effect on expression of myeloma growth factors such as IL6 and IGF1. Expression of certain documented anti-myeloma factors was upregulated by iPTH (e.g. decorin). We conclude that iPTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis, and attenuated bone resorption and myeloma growth through mechanisms involving increased production of anti-myeloma factors by osteoblasts and minimizing inflammatory conditions induced by myeloma. Treatment with iPTH may be a promising approach for myeloma bone disease and tumor progression. Disclosures: No relevant conflicts of interest to declare.

Abstract In higher eukaryotes, post-transcriptional regulation of gene expression, which is accomplished by an ensemble of RNA-binding proteins (RBPs), is critical for cellular homeostasis. Unkempt (UNK) is an evolutionarily conserved Zinc Finger/RING domain RNA-binding protein that was originally identified as a developmental regulator in Drosophila. Recent studies suggest that UNK targets specific mRNAs through its two compact zinc finger clusters and regulates their translation. However, the underlying molecular mechanisms by which UNK represses translation remain unclear. To examine UNK interactions, we purified Flag-tagged UNK and subjected the preparations to Mass spectrometry (MS) and identified an enriched protein Cytoplasmic poly(A)-binding protein(PABPC1), a key component of the translation machinery that binds to the poly(A) tail of mRNAs to promote translation and mRNA turnover. GST Pull down assay and reciprocal immunoprecipitations in HEK293 cells further confirmed the strong interaction between UNK and PABPC1 and showed that the interaction is RNA-dependent. Notably, the structural analysis, along with mutational studies proved that the interaction is mediated by the C-terminal MLLE domain of PABPC1 and the C-terminal Domain of UNK both in vitro and in vivo. Further MS2 tethering assay indicated that UNK inhibits PABPC1-stimulated translation activity. Our studies identified Unkempt as a novel partner of PABPC1 that functions to represses PABPC1-stimulated translation. The findings provide novel insight into the molecular function of Unkempt and PABPC1-mediated translational machinery. Citation Format: Naren Li, Liang Hu, Qinfang Liu, Yulan Xiong, Jianzhong Yu. Translational repression by a novel partner of human cytoplasmic poly(A) binding protein [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 866.

The common occurrence of cults of the dead in Neolithic and early Bronze Age societies around the world raises at least one major question about early Chinese religion: what factors account for the elaboration of ancestor worship in China and for the degree to which—compared to its role in other cultures—it endured? The study of Chinese religion in the Neolithic and Shang periods (ca. 4000–1050 B.C.E.) can contribute to our understanding of such matters, but the bulk of recent scholarship is inevitably and properly focused on technical analyses of sites, artifacts, rituals, and spiritual Powers. Many studies address problems of definition, such as the nature of Ti, the high god of the Shang, and his cult (Akatsuka 1977:471–537; Ikeda 1981:25–39; Eno 1990); images of T'ien (Heaven, Sky) (Hayashi 1989a); the nature of the Earth Power and its associated altar of the soil (Tai Chia-hsiang 1986); the role of sun, bird, and other totems in Neolithic and Shang belief (Hu Hou-hsüan 1977; Allan 1981; Tu Chin-p'eng 1992; Wu Hung 1985; Paper 1986; Ch'ien Chihch'iang 1988; Juyü 1991; Wang Chi-huai 1992; Xiong Chuanxin 1992; Chang Teshui 1993; Chang Wen 1994; Wang Lu-ch'ang 1994); methods and objects of sacrifice (Ikeda 1980; Ch'iu Hsi-kuei 1985; Childs-Johnson 1987; Lien Shao-ming 1989; Itō 1990; Hao Pen-hsing 1992); the religious dimensions of illness (Takashima 1980) and of settlement building (Akatsuka 1977:494–99).

AbstractBACKGROUND: Based on posturography parameters during sleep deprivation (SD), a mental fatigue index (MFI) was constructed for healthy male cadets.METHODS: There were 37 young male subjects who volunteered for two successive days of SD. Their posturography balance, profile of mood status (POMS), and heart rate variability (HRV) were measured at four different times (10:00 and 22:00 of day 1, 10:00 and 22:00 of day 2). According to the methods used in our previous research, similar MFIs based on posturography parameters were computed. Then, correlations of MFIs with POMS scores and HRV values were evaluated by linear and nonlinear methods including quadratic, S-curve, growth, and exponential analyses.RESULTS: MFI continued to increase during SD and MFI as the independent variable had quadratic relationships with fluster (R2 0.057), depression (R2 0.067), and anger (R2 0.05) scores of POMS. A linear correlation was found between MFI and the depression score (R2 0.045) and MFI correlated linearly (R2 0.029) and nonlinearly (R2 0.03) with heart rate. Similarly, MFI reflected changes in the time and frequency domain parameters of HRV, with linear (R2range: 0.0290.082) or nonlinear (R2range: 0.0300.082) relationships.DISCUSSION: The increase of MFI was linked with amplification of personal negative moods and an imbalance of autonomic nervous system activity. The findings suggest that MFI might be a potential indicator of mental fatigue and provide a method to prevent driving fatigue and human errors.Cheng S, Yang J, Su M, Sun J, Xiong K, Ma J, Hu W. Postural stability change under sleep deprivation and mental fatigue status. Aerosp Med Hum Perform. 2021; 92(8):627632.

Though widely used in the treatment of coronary heart disease (CHD), the mechanism of traditional Chinese medicine (TCM) is still unclear because of its complex prescription rules. This study prospectively collected 715 prescriptions of TCM for the treatment of CHD. The characteristics of TCM in prescriptions were described and analyzed, and the rules of prescriptions were analyzed by using association rules. Frequency statistics showed that the high-frequency herbs with a frequency of more than 60% were Gan-cao, Huang-qi, Dang-gui, Chuan-xiong, Yan-hu-suo, and San-qi. The high-frequency herb combinations were summarized by using association rules. By using the method of the “Top N groups” to excavate the empirical prescriptions, the basic prescriptions for treating CHD were summarized. We named the intersection herbs of the basic prescriptions and the high frequency herbs as the core herbal prescription. To explore the possible mechanisms underlying the anti-CHD effect of the core herbal prescription, the bioactive components of core herbal prescription and their targets were screened out by using network pharmacology. Molecular docking was performed between the bioactive components and core targets. A total of 28 potential active ingredients and 5 core targets were identified for the treatment of CHD with core herbal prescription. The enrichment analysis results indicated that the mechanism of action mainly involved neuroactive ligand-receptor interaction and calcium signaling pathway. The commonly used herbal pairs for CHD with qi deficiency and blood stasis syndrome were Huang-qi and Dang-gui. The mechanism of action of common herbal pairs was also studied by network pharmacology. This study summarized the prescription rule of TCM in the treatment of CHD and may provide a new idea for the treatment of CHD.

Abstract Urothelial cell carcinoma is the most common cancer of the renal pelvis or ureter in humans. Due to a lack of animal models, its pathogenic causes remain elusive. Here, we generated IkkαΔKsp mice lacking Ikkα specifically in epithelial cells of the developing kidney and genitourinary tract as well as renal tubules. The mutant mice developed invasive papillary urothelial cell carcinomas initiated from the pelvis, leading to hydronephrosis, and the animals eventually died. Depleting neutrophils or antibiotic treatment slowed down the development of phenotypes but did not rescue them, suggesting that epithelial-cell-autonomous aberrant alterations induced by Ikkα loss are critical for the initiation of urothelial cancer. Moreover, We found that the urothelial cell carcinomas in the mutant mice highly expressed cancer stem-cell markers such as Sox2, K15, p63, Nanog, and CD44, as well as FGFR3 and osteopontin (OPN). Thus, we hypothesize that Ikkα ablation-mediated OPN and FGFR3 overexpression regulates and amplifies CD44+ renal cancer-stem cells for tumor initiation. These alterations are shared with human papillary urothelial cell carcinomas. Citation Format: Xin Li, Feng Zhu, Chengfei Jiang, Yongmei Zhao, Bao Tran, Donna Butcher, Xiaolin Wu, Tross Debra, Yinling Hu. IIKKa deletion amplifies renal transitional epithelial stem cells and initiates lethal invasive papillary urothelial cell carcinoma development [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 926.

Abstract Background: HER2-targeted agents combined with endocrine therapy (ET) has been recommended as an optional therapeutic strategy for hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) co-positive metastatic breast cancer (MBC). Pyrotinib is an oral irreversible pan-ErbB receptor tyrosine kinase inhibitor targeting EGFR, HER2 and HER4, with proven efficacy in combination with chemotherapy in HER2-positive MBC. This multicenter, single-arm phase 2 trial aimed to investigate the efficacy and safety of pyrotinib plus letrozole in patients with estrogen receptor (ER)-positive, HER2-positive MBC (NCT04407988). Methods: Pre-/perimenopausal or postmenopausal women with histologically confirmed HER2-positive (immunohistochemistry [IHC] 3+ or 2+ with fluorescence in situ hybridization positive) and ER-positive (the percentage of ER+ cells ≥ 10% by IHC) MBC were enrolled. Prior treatment for metastatic disease was not allowed. Eligible patients received pyrotinib (400 mg, po, qd) plus letrozole (2.5 mg, po, qd) until disease progression or unacceptable toxicity. For pre-/perimenopausal patients, additional treatment with ovarian function suppression (OFS) was required. The primary endpoint was clinical benefit rate (CBR), defined as the rate of patients with complete response (CR), partial response (PR), or stable disease (SD) for at least 24 weeks per RECIST 1.1. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between December 3, 2019 and April 2, 2021, 26 patients were enrolled. As of July 5, 2021, CBR was 76.9% (20 of 26; 95% CI 56.4% to 91.0%) and ORR was 57.7% (15 of 26; 95% CI 36.9% to 76.6%). One of the 26 patients (3.8%) had CR, 14 (53.8%) had PR, 5 (19.2%) had SD, 5 (19.2%) had progressive disease, and 1 (3.8%) had not evaluable disease. The benefits in CBR and ORR were observed across all subgroups. The most common any grade AEs were diarrhea (25 of 26, 96.2%), vomiting (8 of 26, 30.8%), nausea (6 of 26, 23.1%), and oral ulceration (6 of 26, 23.1%). Diarrhea was the only reported grade 3 AE that occurred in 5 patients (19.2%). No grade 4 or 5 AEs occurred during this study. Conclusions: Pyrotinib combined with letrozole showed an encouraging antitumor activity with good tolerance in patients with ER/HER2 co-positive MBC, promising as an alternative treatment option for this disease. The study is ongoing. Citation Format: Quchang Ouyang, Huihua Xiong, Min Yan, Jincai Zhong, Li Ran, Ting Luo, Liping Liu, Jing Li, Xiaohong Yang, Huawu Xiao, Ning Xie, Hui Wu, Jianxiang Gao, Jun Lu, Xuming Hu, Zheyu Hu, Can Tian, Zhengrong Shui, Min Cao. Pyrotinib in combination with letrozole for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: A multicenter, single-arm, phase II trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-32.

Abstract Background Camrelizumab and nab-paclitaxel demonstrated promising anti-tumour activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC) in FUTURE trial. Anti-angiogenic agents have been reported to facilitate immune infiltration. Famitinib is a tyrosine kinase inhibitor targeting VEGFR-2, PDGFR and c-kit. The FUTURE-C-PLUS trial (NCT04129996) which added famitinib to camrelizumab and nab-paclitaxel is a single-arm, phase 2 trial evaluating this novel triplet combinatorial strategy in patients with advanced immunomodulatory TNBC. Study design and the primary endpoint ORR has been reported previously (Zhi-ming Shao, et al. ASCO 2021, Abstract 1007). Here, we reported the updated results of this trial. Method Briefly, this study enrolled women aged 18-70 years, with previously untreated, histologically confirmed, unresectable, locally advanced, recurrent or metastatic immunomodulatory TNBC. Immunomodulatory TNBC was defined as CD8 expression on at least 10% of cells using immunohistochemistry analysis. Eligible patients received the triple therapy. Study design has been reported previously in ASCO 2021. Results Between Oct 2019 and Oct 2020, 48 patients were enrolled and treated. 39 (81.3%, 95% CI 70.2-92.3) patients had a confirmed objective response which has been reported in ASCO 2021. At this updating data cutoff (June 30, 2021), the median progression-free survival was 11.9 months (95% CI, 7.3-16.5) with the median follow-up was 14.0 months. While overall survival data were not mature yet, a promising overall survival rate was observed at 12 months (84•2%, 95% CI 73.4-95.0) and 18 months (73.6%, 95% CI 52.0-95.2). In the 39 responders, median duration of response was also not mature. The disease control rate was 95.8% (46/48). The most common treatment-related grade 3 or 4 adverse events were neutropenia (16 [33.3%]), anemia (5 [10.4%]), febrile neutropenia (5 [10.4%]), and thrombocytopenia (4 [8.3%]). No treatment-related deaths were reported. Conclusions These data, combined with those from our previous reports, provide further evidence for the triplet combination of famitinib, camrelizumab and nab-paclitaxel as an active therapy in advanced Immunomodulatory TNBC. To our knowledge, this is the best objective response rate reached in first-line treatment of advanced TNBC. A randomized controlled FUTURE-Super trial (NCT04395989) is keeping recruiting patients to further validate those findings. Citation Format: Li Chen, Yi-Zhou Jiang, Songyang Wu, Jiong Wu, Genhong Di, Guangyu Liu, Keda Yu, Lei Fan, Junjie Li, Yifeng Hou, Zhen Hu, Canming Chen, Xiaoyan Huang, Ayong Cao, Xin Hu, Shen Zhao, Xiaoyan Ma, Xiaoyu Zhu, Jianjun Zou, Wentao Yang, Zhonghua Wang, Zhi-ming Shao. Updated data from FUTURE-C-PLUS: Combination of famitinib with camrelizumab plus nab-paclitaxel as first-line treatment for advanced, immunomodulatory triple-negative breast cancer, an open-label, single-arm, phase 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-04.

Correction of Fragile X Syndrome in Mice. Dölen G, Osterweil E, Rao BSS, Smith GB, Auerbach BD, Chattarji S, Bear MF. Neuron 2007;56:955–962. Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders. Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome. Qiu LF, Lu TJ, Hu XL, Yi YH, Liao WP, Xiong ZQ. Cereb Cortex 2009 in press. (doi:10.1093/cercor/bhn163) Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabotropic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation.

Abstract Background: Renal cell carcinoma (RCC) is a highly heterogeneous and metastatic disease with a widely varying prognosis. RCC is the first solid tumor treated with immune checkpoint blockade and approved by the FDA for showing improvement of clinical outcomes. Immune checkpoints physiologically regulate immune response via appropriate signals to T cells and maintain homeostasis, while pathologically they can be co-opted by cancer cells to evade the immune system. Here we developed a humanized (Hu)-mice model with adaptive transferred human immune cells to test the role of ICB [anti-PD-1/PD-L1, or anti-CTLA-4 antibody (Ab)] in an orthotopic human RCC tumor-bearing xenograft mouse model and analyzed the correlation of innate immune cells with tumor burden. Methods: Luciferase-tagged RCC cell line 786-O were injected intra-kidney into immune-deficient Rag2 mice. After tumor formation, mice were humanized by intraperitoneal injection of donor PBMCs (20×106/per mouse). Treatment groups included control, anti-PD-1/PD-L1 Abs or anti-CTLA-4 Ab (all Abs 200 µg/mouse, iv) weekly for 4 weeks. Tumor growth was measured by weekly bioluminescent imaging (BLI) and tumor weight at necropsy. The presence of human immune cells and tumor infiltrating lymphocytes was confirmed by flow cytometry and immunohistochemistry staining. The significance of the differences between groups was determined by student t test. The Pearson correlation coefficient was obtained by analysis of correlation between different study parameters. Results: BLI level showed a steady xenograft tumor progression for nine weeks. Anti-PD-1/PD-L1 Abs treatment trended toward reducing tumor BLI level while anti-CTLA-4 Ab significantly decreased tumor BLI level (p&lt;0.01). Furthermore, anti-PD-1/PD-L1 Abs reduced lung metastasis with a significant decrease of BLI level compared to control group (p&lt;0.05). Meanwhile, humanization was evidenced by robust, elevated levels of human CD45+ lymphocytes in the peripheral blood compared to non-reconstituted Rag2 mice. Infiltrated human CD3+CD8+ cells were found in mouse blood and spleen. Granzyme B+ cells, CD31+ cells, and pan-cytokeratin+ cells were found in tumors. Interestingly, we observed inverse correlation between circulating human CD8+ T cells and mouse RCC tumor burden. Conclusion: We successfully generated a humanized RCC mouse model which allows the RCC xenograft to grow steadily within the human immune system reconstituted Rag2 mice. Circulating CD8+ T cells are inversely correlated to tumor growth in this model. The PD-1/PD-L1 or CTLA-4-targeted immunotherapies showed distinct therapeutic effects in our humanized orthotopic xenograft model, which may lead to personalized treatment targeting different immune checkpoints to reinvigorate anti-tumor responses in RCC patients. Citation Format: Xin Zhang, Amita Bhattarai, Ravan Moret, Grace Maresh, Alicia Nicole Ray, David Woods, Rachel Graham, Maria Latis, Stephen Bardot, Li Li. Inverse correlation of circulating CD8+ T cells with tumor burden from immune checkpoint treatment in humanized orthotopic model of renal cell carcinoma [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 3104.

Abstract Previously we reported that bone marrow-derived macrophages are required for lung squamous cell carcinoma development in kinase-dead Ikkα knockin (KA/KA) mice. The KA/KA lungs display strikingly enlarged sizes, sustained inflammation with increased expression of multiple cytokines and chemokines and marked infiltrating macrophages and T cells, and tissue damage, which look like a “burning hill”. To determine a critical event for the pathogenesis of the lung disease and SCC development, in this study, we found that these F4/80+CD11b+CSF1R+ monocyte-derived macrophages isolated from KA/KA lungs showed enlarged sizes carrying many lipid droplets and highly expressed the genes that encode proteins involved in lipid metabolism compared to WT. To determine whether the lung lipid concentrations regulate foamy macrophage development, we incubated Raw macrophages with WT or KA/KA lung extract, respectively, and found that KA/KA lung extracts induced lipid droplets and elevated lipid levels and pathways for lipid metabolism compared to WT lung extracts. Furthermore, we found that cytokines including IL-4, IL-6, IL-33, and IFNb, promoted lipid metabolism in Raw macrophages incubated with WT lung extracts, and also stimulated lipid metabolism in human lung SCC SW900 cells. These results suggest that these cytokines, which were highly expressed in KA/KA lungs, contribute to aberrant lipid metabolism. Because IL-4, which is produced by Th2 T cells, promoted lipid metabolism in macrophages and lung SCC cells, we further showed that KA/KA lung CD4 T cells stimulated lipid gene expression in Raw macrophages compared to WT lung CD4 T cells. Depleting CD4 T cells indeed significantly decreased foamy macrophage formation in the lungs of KA/KA mice. Importantly, treatment with a lipid inhibitor reduced IL-4-mediated lipid metabolism in Raw macrophages and human lung SCC SW900 cells, as well as this treatment attenuated lung foamy macrophage numbers and dampened lung SCC development in irradiated KA/KA mice with KA/KA bone marrow transplants. These findings highlight that the interplay between CD4 T cells, macrophages, cytokines, and epithelial cells contribute to a series of biological events in a landscape scale, which promote lung disease and lung SCC development through aberrant lipid metabolism. Citation Format: Gongping Shi, Sayantan Banerjee, Xin Li, Gajendra Jogdand, Yongmei Zhao, Kunio Nagashima, Thorkell Andresson, Jyoti Shetty, Bao Tran, Yinling Hu. Lipid-rich foamy macrophages along with CD4 T cell-derived signaling drive aberrant lipid metabolism and are a cause of lung cancer development [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 1355.

Citrus cultivation in China has increased since the late 1970s, with China now having the largest area of citrus in culture in the world that is spread in 22 provinces and municipalities. Hunan Province has undergone a program to become one of the major citrus producers in China. Poncirus trifoliata is the main rootstock, so citrus viroids are a limiting factor for further citriculture development. In mainland China, only the presence of Citrus exocortis viroid (CEVd) has been reported from Etrog citron indexing, sPAGE (sequential polyacrylamide gel electrophoresis) analysis (2), and reverse transcription (RT)-PCR (3). Three viroid-like RNAs, a1, b1, and d, based on sPAGE patterns were detected years ago in our laboratory in budsticks received from Sichuan Province. To identify different viroids and determine their distribution, a survey has been undertaken. Field trees showing stunting, bark scaling and cracking of the rootstock, and poor yield were tested using biological indexing and PCR for the most frequent citrus viroids. Samples from six trees of a local sweet orange variety and three of a Clementine variety introduced from abroad, both grafted on P. trifoliata and showing a variable degree of bark scaling and cracking, were collected near Changsha and in the County of Xin Ning at the end of summer 2006. Small pieces of bark were inserted in stems of young E. citron budwood grafted on rough lemon and maintained in a warm greenhouse (24 to 32°C). Indexing on E. citron showed mild epinasty and leaf roll typical of citrus viroid infections. To identify specific viroids, bark was ground to a fine powder with liquid nitrogen and total RNA was extracted with TRIZOL Reagent (Invitrogen, San Diego, CA) and tested by RT-PCR to detect CEVd, Hop Stunt viroid (HSVd), and Citrus viroid III (CVd-III), as well as to identify the cachexia variants of HSVd. Four primer pairs were used to test the RNA extracts by RT-PCR (1). All samples were infected by HSVd, eight with CVd-III, and six with CEVd. The cachexia variants of HSVd were detected in four of nine samples. Mixed infections were as follows: one sample had CEVd and HSVd, eight had HSVd and CVd-III, and five were infected by the three viroids. A second sampling 3 months after inoculation gave the same amplification patterns. The results show that at least three viroids are present in citrus orchards in Hunan Province. To our knowledge, this is the first report of cachexia variants of HSVd and CVd-III in China. The common occurrence of these viroids supports the need for proper indexing of mother trees and a specific shoot tip grafting program to create healthy budwood sources to provide healthy plants. References: (1) L. Bernard and N. Duran-Vila. Mol. Cell. Probes, 20:105, 2006. (2) L. Han et al. Viroids. CSIRO Publishing, Melbourne, 283, 2003. (3). Q. Hu et al. Acta Bot. Sin. 39:613, 1997.

With the increase in energy consumption with unprecedented rate, there is an urgent need for the development of independent, efficient and maintenance free power sources. With the growing emergence of flexible, wearable electronic devices in the current market, the requirement for portable and highly flexible power sources has also increased many folds. The electronic devices such as stretchable circuits [1], e-papers [2], bendable displays [3], e-skins [4], wearable electronic devices [5], etc. are receiving wide attention due to their applications in robotics, medical science, human machine interface, fitness trackers, smart watches and many more. The waste mechanical energy in the environment such as vibration, wind and human body motions can be converted into electricity by triboelectric energy harvesting technologies [6]. Energy is one of the essential requirements of the society and it is necessary to search newly and highly efficient technologies that harvest many forms of energy from the environment which is generally wasted. For the last two decades, the scientists and researchers have been focused on the synthesis and characterization of novel source of energy harvesting and self-powered devices useful for numerous energy applications without external inputs. In this paper, a novel triboelectric nanogenerator (TENG) based on Polymethyl methacrylate (PMMA) as transparent and flexible polymer materials with gold nanoparticles (AuNPs) has been synthesized and characterized. The SEM image clearly reveals the spherical shape of the synthesized AuNPs. The XRD pattern of the prepared material shows accurate diffraction peaks at 2theta values indicate the presence of mixed phases of fluorine tin oxide (SnO2), AuNPs, and metallic copper (Cu) which are in excellent agreement with the previously mentioned 2theta values in the literature. Further, the EDS analysis confirms the presence of Sn, Au, O, and Cu within the synthesized TENG. Finally, the proposed synthesize PMMA-based TENG produces maximum AC output voltage and current signal up to 5V and 10 μA, respectively with very high transmittance of 100 %. The electric energy in terms of AC voltage produced by synthesized PMMA-based TENG is further converted into DC voltage which is used to light up light - emitting diodes in future. The synthesized TENG consists of two parts such as lower part and upper part. The spacer (sponge or spring) is placed between the upper part as well as the lower part. The synthesized lower part of TENG consists of three layers such as (a) fluorine tin oxide (FTO), (b) copper (Cu), and (c) gold nanoparticles (AuNPs) whereas the upper part of the synthesized TENG consists of two layers such as (a) aluminum (Al) and (b) polymethyl methacrylate (PMMA) transparent and flexible polymer. By taking FTO substrate, we first deposit the copper layer with micrometer range of thickness on the top of FTO with the help of Magnetron Sputtering technique at 5.8 X 10-2 m bar base working pressure, 60 sccm gas-flow, 200 W power, 200˚C temperature for 5 minutes. Next, the freshly prepared AuNPs are prepared by using the following steps: (A) Seed solution preparation; (B) Growth solution preparation; and (C) Washing the gold nanoparticles:- By centrifugation process, only the gold nanoparticles remains and the other byproducts in the form of liquid is removed. The spherical shape of the synthesized AuNPs has been observed within the SEM image. The XRD pattern of the prepared sample indicates the diffraction peaks of SnO2, AuNPs, and metallic Cu at different 2theta values. The EDS analysis further confirms the presence of Sn, Au, O, and Cu materials within the synthesized lower part of TENG while the UV-Visible spectroscopy analysis clearly shows 100 % light transmission and ~0 % light absorption of transparent and flexible PMMA polymer material used for synthesis of TENG. References Hu, H. S. Kim, J. Y. Lee, P. Peumans, Y. Cui, ACS Nano 4 (2010) 2955-2963. Chen, J. Au, P. Kazlas, A. Ritenour, H. Gates, M. McCreary, Nature 423 (2003) 136-136. Yoon, D.Y Ham, O. Yarimaga, H. An, C.W. Lee, J.M. Kim, Advanced Materials 23 (2011) 5492-5497. Hu, R. Xiong, H. Guo, R. Ma, S. Zhang, Z. L. Wang, V. V. Tsukruk, Advanced Materials 28 (2016) 3549-3556. S. Rim, S. H. Bae, H. Chen, J. L. Yang, J. Kim, A. M. Andrews, P. S. Weiss, Y. Yang, H. R. Tseng, ACS Nano 9 (2015) 12174-12181. W. Kim, J. H. Lee, J. K. Kim, U. Jeong, NPG Asia Materials 12 (2020) 6. Figure 1

The radiation conversion phenomenon is used for UV sensing applications with rare earth doped phosphors. This paper presents the results of structural and optical measurements of undoped and europium doped LaPO4 phosphors. LaPO4 phosphors with 1% mol, 2% mol, and 5% mol of europium were fabricated by the co-precipitation method. The effect of Eu3+ concentrations on the luminescence characteristics under UV LED excitation was investigated. The maximum quantum efficiency of luminescence (c.a. 82%) was obtained in sampled doped with 5% of europium. Full Text: PDF ReferencesM. Runowski, "Nanotechnologia – nanomateriały, nanocząstki i wielofunkcyjne nanostruktury typu rdzeń/powłoka", Chemik 68, 9, 766-775 (2014). DirectLink J. Zhou, J.L. Leano Jr., Z. Liu, D. Jin, K.-L. Wong, R.S. Liu, et al., "Impact of Lanthanide Nanomaterials on Photonic Devices and Smart Applications", Small 14, 1801882 (2018). CrossRef Z. Li, Y. Zhang, G. Han, "Lanthanide-Doped Upconversion Nanoparticles for Imaging-Guided Drug Delivery and Therapy", Springer Series in Biomater. Sci. Eng. 6, 139-164, (2016). CrossRef M. Lin, Y. Zhao, S. Wang, M. Liu, Z. Duan, Y. Chen, et al., "Recent advances in synthesis and surface modification of lanthanide-doped upconversion nanoparticles for biomedical applications", Biotechnol. Adv. 30, 1551-1561 (2012). CrossRef H. Su, Y. Nie, H. Yang, D. Tang, K. Chen, T. Zhang, "Improving the thermal stability of phosphor in a white light-emitting diode (LED) by glass-ceramics: Effect of Al2O3 dopant", J. Eur. Ceram. Soc. 38, 2005-2009 (2018). CrossRef J. Huang, X. Hu, J. Shen, D. Wu, C. Yin, R. Xiang, et al., "Facile synthesis of a thermally stable Ce3+:Y3Al5O12 phosphor-in-glass for white LEDs", Cryst. Eng. Comm 17, 7079-7085 (2015). CrossRef R. Zhang, H. Lin, Y. Yu, D. Chen, J. Xu, Y. Wang, "A new-generation color converter for high-power white LED: transparent Ce3+:YAG phosphor-in-glass", Laser Photon. Rev. 8, 158-164 (2014). CrossRef B. Zheng, Y. Bai, H. Chen, H. Pan, W. Ji, X. Gong, et al., "Near-Infrared Light-Excited Upconverting Persistent Nanophosphors in Vivo for Imaging-Guided Cell Therapy", ACS Appl. Mater. Interfaces 10, 19514 (2018). CrossRef J. Qiao, G. Zhou, Y. Zhou, Q. Zhang, Z. Xia, "Divalent europium-doped near-infrared-emitting phosphor for light-emitting diodes", Nature Communications 10 (1), 5267 (2019). CrossRef V. Singh, A. Kumar, C. Mehare, H. Jeong, S. Dhoble, "UV/VUV excited photoluminescence of Tb3+ doped LaPO4 green emitting phosphors for PDP applications", Optik 206, 163733 (2020). CrossRef G. Han, Y. Wang, C. Wu, J. Zhang, "Hydrothermal synthesis and vacuum ultraviolet-excited luminescence properties of novel Dy3+-doped LaPO4 white light phosphors", Mat. Res. Bull. 44 (12), 2255-2257 (2009). CrossRef K. S. Gupta, P. S. Ghosh, M. Sahu, K. Bhattacharyya, R. Tewari, V. Natarajan, "Intense red emitting monoclinic LaPO4:Eu3+ nanoparticles: host–dopant energy transfer dynamics and photoluminescence properties", RSC Adv. 5, 58832-58842 (2015). CrossRef

Abstract KRAS mutations are frequently found in various types of cancers with an overall mutation frequency of 19.3%. G12C mutation of KRAS (KRASG12C) represents 11.4% of all KRAS mutations in cancer. Targeting KRAS mutations as a cancer treatment strategy has long been investigated for over 30 years already but still remains unconquered field. XNW14010 is a highly selective KRASG12C inhibitor that is rationally designed from AMG510, another proven covalent inhibitor of KRASG12C with potential antineoplastic activity. Compared to AMG510, XNW14010 demonstrated a better pharmaceutical potential and a better safety profile. XNW14010 does not have an axial chiral center shown in AMG510, thus the production cost of this agent could be vastly reduced. The in vitro efficacy of XNW14010 was tested in a variety of cancer cell lines with either wild type KRAS or different mutant KRAS, including lung cancer, colorectal cancer, and pancreatic cancer. The result shows that XNW14010 potently inhibits the activity of KRASG12C, but not wild type KRAS or KRAS bearing other mutations. Specifically, in a pancreatic cancer cell line MIA PaCa-2, which bears KRASG12C, the IC50 of XNW14010 is 26 nM. Furthermore, XNW14010 demonstrated a much less plasma protein binding (PPB) than AMG510 (50.4% versus 93.2%, respectively), suggesting much great potential to penetrating into tumor tissue for XNW14010 compared to AMG510. XNW14010 exhibited comparable or superior pharmacokinetic characteristics compared to AMG510 after oral administration in animal studies. More interestingly, XNW14010 has an improved brain penetration capability. The brain/plasma ratio of XNW14010 exposure is two folds as high as that of AMG510 and the Cmax of XNW14010 in brain tissue is also much higher. XNW14010 had a wider therapeutic window and good tolerance compared to AMG510, both in mouse and dog models, suggesting potentially better safety profile in humans. We also compared the antineoplastic activity of XNW14010 with that of AMG510 in vivo in Xenograft mouse models including lung cancer, colorectal cancer, and pancreatic cancer. The results demonstrated that XNW14010 has comparable antineoplastic activities to AMG510 when administered at the same doses. In pancreatic cancer, the total growth inhibition (TGI) is 90% when administered at the dose of 10 mg/kg QD. Given the better PPB, superior brain penetrating capacity, and similar antineoplastic activitie of XNW14010 compared to AMG510 in non-clinical studies, XNW14010 is expected to be a potent therapeutic candidate in treating cancers bearing KRASG12C, including pancreatic cancer. Citation Format: Yonghan Hu, Xin Li, Bin Huang, Liang Kong, Meijie Le, Yan Li, Cungang Liu, Xiaojun Liu, Bin Qian, Jing Qiang, Qifeng Shi, Wengui Wang, Yuchuan Wu, Zhenwei Wu, Linfeng Xu, Jinfeng Zhao. XNW14010:A highly selective KRASG12C inhibitor with potent efficacy in animal model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A071.

Abstract Background: The delta isoform of PI3K (PI3Kδ) plays an important role in B-cell development and function by mediating the signaling of key receptors on B cells. Aberrant activation of PI3Kδ signaling pathway promotes the survival and proliferation of malignant B cells, making selective inhibition of this isoform a promising therapeutic approach for the treatment of B cell malignances. Amdizalisib (HMPL-689, Amdiz), discovered and being currently developed in a pivotal phase II clinical trial (NCT04849351) by HUTCHMED, is a highly potent and selective PI3Kδ inhibitor. Based on encouraging clinical data from the phase Ib study (2021 ESMO, abstract# 8330), Amdiz is a designated breakthrough therapy in China for treatment of relapsed and refractory follicular lymphoma. Herein, we report the pre-clinical anti-tumor activity of Amdiz. Methods: Kinase activity was measured by Transcreener™ Fluorescence Polarization assay. The kinome selectivity profile of Amdiz was evaluated in Eurofins KinaseProfiler™ panel containing 323 kinases. Cell based phosphorylation of AKT was determined by using Acumen Explorer system. CD63 expression in basophils was evaluated by FACS assay. Inhibitory effects of Amdiz alone or in combination with other agents on cell viability were investigated in a panel of B cell lymphoma cell lines by CellTiter-Glo luminescent or CCK-8 assay. The ability of Amdiz to inhibit the activation of B cells in animals was evaluated in naïve rats using an ex vivo assay, and B cell activation was determined by evaluating CD86 expression using FACS analysis. Human B cell lymphoma cell line derived xenograft models were used to determine the anti-tumor activity of Amdiz in combination with other agents such as rituximab, BTK inhibitor, and venetoclax. Results: Amdiz is a highly selective inhibitor of PI3Kδ, showing more than 250-fold selectivity over other PI3K isoforms and no significant inhibition over other 319 protein kinases at the concentration of 1 µM. Amdiz potently inhibited PI3Kδ in biochemical, cellular and human whole blood assays with IC50s ranging from 0.8-3 nM. Its inhibitory effects on cell viability were also evaluated in a panel of B -cell lymphoma cell lines. Results showed that Amdiz potently inhibited cell survival with IC50s from 0.005 to 5 μM. Amdiz showed a long-lasting and strong inhibition on B cell activation in a rat pharmacodynamics (PD) study at a dose as low as 0.1 mg/kg. Moreover, Amdiz significantly improved anti-tumor activity of standard-of-care agents as well as targeted agents in multiple B-cell lymphoma models both in vitro and in vivo. Conclusion: Amdiz is a highly potent and selective PI3Kδ inhibitor with strong activity against B-cell lymphoma in pre-clinical studies, supporting clinical evaluation as either a single agent or in combination with other therapeutic agents for the treatment of B-cell malignancies. Citation Format: Jia Hu, Jianhan Wang, Xiaoming Dai, Jianlin He, Junqing Liang, Ying Yu, Juntao Yu, Na Yang, Linfang Wang, Yu Cai, Xiong Li, Weiguo Qing, Yongxin Ren, Weiguo Su. Amdizalisib (HMPL-689), a highly selective PI3Kδ inhibitor, exhibits potent anti-tumor activity in pre-clinical B-cell lymphoma models [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 5454.

Background Emails have become an integral part of our daily life and work. Phishing emails are often disguised as trustworthy ones and attempt to obtain sensitive information for malicious reasons (Egelman, Cranor, Hong, 2008;). Anti-phishing tools have been designed to help users detect phishing emails or websites (Egelman, et al., 2008; Yang, Xiong, Chen, Proctor, & Li, 2017). However, like any other types of automation aids, these tools are not perfect. An anti-phishing system can make errors, such as labeling a legitimate email as phishing (i.e., a false alarm) or assuming a phishing email as legitimate (i.e., a miss). Human trust in automation has been widely studied as it affects how the human operator interacts with the automation system, which consequently influences the overall system performance (Dzindolet, Peterson, Pomranky, Pierce, & Beck, 2003; Lee & Moray, 1992; Muir, 1994; Sheridan & Parasuraman, 2006). With interacting with an automation system, the human operator should calibrate his or her trust level to trust a system that is capable but distrust a system that is incapable (i.e., trust calibration; Lee & Moray, 1994; Lee & See, 2004; McGuirl & Sarter, 2006). Among the various system capabilities, automation reliability is one of the most important factors that affect trust, and it is widely accepted that higher reliability levels lead to higher trust levels (Desai et al., 2013; Hoff & Bashir, 2015). How well these capabilities are conveyed to the operator is essential (Lee & See, 2004). There are two general ways of conveying the system capabilities: through an explicit description of the capabilities (i.e., description), or through experiencing the system (i.e., experience). These two ways of conveying information have been studied widely in human decision-making literature (Wulff, Mergenthaler-Canseco, & Hertwig, 2018). Yet, there has not been systematic investigation on these different methods of conveying information in the applied area of human-automation interaction (but see Chen, Mishler, Hu, Li, & Proctor, in press; Mishler et al., 2017). Furthermore, trust and reliance on automation is not only affected by the reliability of the automation, but also by the error types, false alarms and misses (Chancey, Bliss, Yamani, & Handley, 2017; Dixon & Wickens, 2006). False alarms and misses affect human performance in qualitatively different ways, with more serious damage being caused by false-alarmprone automation than by miss-prone automation (Dixon, Wickens, & Chang, 2004). In addition, false-alarm-prone automation reduces compliance (i.e., the operator’s reaction when the automation presents a warning); and miss-prone automation reduces reliance (i.e., the operator’s inaction when the automation remains silent; Chancey et al., 2017). Current Study The goal of the current study was to examine how the methods of conveying system reliability and automation error type affect human decision making and trust in automation. The automation system was a phishing-detection system, which provided recommendations to users as to whether an email was legitimate or phishing. The automation reliability was defined as the percentage of correct recommendations (60% vs. 90%). For each reliability level, there were a false-alarm condition, with all the automation errors being false alarms, and a miss condition, with all the errors being misses. The system reliability was conveyed through description (with an exact percentage described to the user) or experience (with immediate feedback to help the user learn; Barron, & Erev, 2003). A total of 510 participants were recruited and completed the experiment online through Amazon Mechanical Turk. The experimental task consisted of classifying 20 emails as phishing and legitimate, with a phishing-detection system providing recommendations. At the end of the experiment, participants rated their trust in this automated aid system. The measures included a performance measure (the decision accuracy made by the participants), as well as two trust measures (participants’ agreement rate with the phishing-detection system, and their self-reported trust in the system). Our results showed that higher system reliability and feedback increased accuracy significantly, but description or error type alone did not affect accuracy. In terms of the trust measures, false alarms led to lower agreement rates than did misses. With a less reliable system, though, the misses caused a problem of inappropriately higher agreement rates; this problem was reduced when feedback was provided for the unreliable system, indicating a trust-calibration role of feedback. Self-reported trust showed similar result patterns to agreement rates. Performance was improved with higher system reliability, feedback, and explicit description. Design implications of the results included that (1) both feedback and description of the system reliability should be presented in the interface of an automation aid whenever possible, provided that the aid is reliable, and (2) for systems that are unreliable, false alarms are more desirable than misses, if one has to choose between the two.

BackgroundCholangiocarcinoma (CCA) is an aggressive malignancy of the biliary tract that carries an unfavorable prognosis. Recurrent, hotspot mutations in the IDH1 gene are found in 10–20% of CCAs and can be targeted with mutant IDH1 inhibitors, though objective responses leading to a reduction in tumor size are rare.1 2 Mutant IDH1 has neomorphic enzymatic activity that results in the production of the oncometabolite D-2-hydroxyglutarate (D-2-HG).3 D-2-HG promotes biliary tumor formation through cancer cell-intrinsic effects,4–6 but D-2-HG can also act as a paracrine factor released by IDH1-mutant cancer cells into the tumor microenvironment to promote tumor growth through non-cell intrinsic mechanisms.7 8 We have performed studies to determine the paracrine effects of D-2-HG on fibroblasts to further examine the CCA tumor microenvironment.MethodsTo determine if fibroblasts are paracrine targets of D-2-HG in the CCA TME, we treated LX-2 hepatic stellate fibroblast cells with 0–50mM exogenous D-2-HG and utilized liquid chromatography-mass spectrometry to quantify the amount of intracellular D-2-HG. D-2-HG treated LX-2 fibroblasts and controls were then examined for changes in gene expression across 579 immune-related genes using the Nanostring platform. In partnership with Tempus, bulk RNA sequencing of IDH1-mutant (N=52) and wild type (N=403) CCA patient tumor samples was performed and CIBERSORT was used for deconvolution of gene expression data to define tumor-infiltrating immune cell populations.ResultsIntracellular D-2-HG was increased in LX-2 cells treated with exogenous D-2-HG compared to controls (figure 1A). D-2-HG treated fibroblasts showed significant changes in immune-related gene expression with significant increases in expression of genes involved in immunometabolism, TLR signaling, and inflammasome signaling—as indicated by unsupervised hierarchical clustering (figure 1B). The most upregulated gene in D-2-HG-conditioned LX-2 fibroblasts is SPP1 (figure 1C). We further identified that human IDH1-mutant CCA samples have a unique tumor immune microenvironment (figure 2A) and a significantly higher number of infiltrating M2 macrophages compared to wild-type controls (figure 2B).Abstract 944 Figure 1D-2-HG induces gene expression changes in fibroblasts. (A) Mass-spec analysis of intracellular D-2-HG levels in LX-2 fibroblasts treated with control or D-2-HG containing media. (B) Gene expression patterns for 579 immune-related genes in the Nanostring Human Immunology V2 panel for LX-2 cells treated with control media (pink) or 50mM D-2-HG (gray) for 48 hours. D-2-HG treated cells have a distinct gene expression pattern as indicated by unsupervised hierarchical clustering. (C) Normalized mRNA expression for selected genes in LX-2 cells treated with control (black) or 50mM D-2-HG (red) containing media reveal upregulation of multiple genes that may alter the tumor immune microenvironment in CCA (*P<0.05, **P≤0.01).Abstract 944 Figure 2The infiltrating immune cell populations in IDH1-mutant CCA. (A) RNA sequencing data from IDH1-mutant and wild-type CCA tumor samples was deconvoluted with CIBERSORT to define tumor-infiltrating immune cell populations. Cell populations with significant increases or decreases (Mann-Whitney U test, p<0.01) are plotted in a color spectrum to represent Log2FC in IDH1-mutant vs. wild-type tumors. (B) Box plot of the proportion of tumor-infiltrating immune cells identified as M2 macrophages in IDH1 wild-type (turquoise) and IDH1-mutant (gold) patient tumor samples (***P<0.001)ConclusionsD-2-HG significantly alters gene expression in hepatic stellate cells, precursors to cancer-associated fibroblasts in CCA.9 The most upregulated gene in D-2-HG conditioned fibroblasts was SPP1, which has been implicated in the recruitment and polarization of immunosuppressive M2 macrophages leading to decreased antitumor immunity.10–12 Interestingly, our analyses of resected human CCA samples showed that the IDH1-mutant CCA tumor immune microenvironment is characterized by an increase in M2 macrophages. Further study of how D-2-HG dysregulates fibroblast gene expression and affects tumor-infiltrating immune cell populations is warranted.ReferencesCrispo F, Pietrafesa M, Condelli V, Maddalena F, Bruno G, Piscazzi A, et al. IDH1 targeting as a new potential option for intrahepatic cholangiocarcinoma treatment-current state and future perspectives. Molecules 2020;25. doi:10.3390/molecules25163754.Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:796–807.Waitkus MS, Diplas BH, Yan H. Biological role and therapeutic potential of IDH mutations in cancer. Cancer Cell 2018;34:186–195.Du X, Hu H. The roles of 2-Hydroxyglutarate. Front Cell Dev Biol 2021;9:651317.Ma S, Jiang B, Deng W, Gu Z-K, Wu F-Z, Li T, et al. D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth. Oncotarget 2015;6:8606–8620.Saha SK, Parachoniak CA, Bardeesy N. IDH mutations in liver cell plasticity and biliary cancer. Cell Cycle 2014;13:3176–3182.Böttcher M, Mougiakakos D. Immunometabolic regulation of anti-tumor T-cell responses by the oncometabolite d-2-Hydroxyglutarate. Immunometabolism 2019;1. doi:10.20900/immunometab20190007.Friedrich M, Bunse L, Wick W, Platten M. Perspectives of immunotherapy in isocitrate dehydrogenase-mutant gliomas. Curr Opin Oncol 2018;30:368–374.Ma L, Wang L, Khatib SA, Chang C-W, Heinrich S, Dominguez DA, et al. Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Hepatol 2021. doi:10.1016/j.jhep.2021.06.028Zhang Y, Du W, Chen Z, Xiang C. Upregulation of PD-L1 by SPP1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma. Exp Cell Res 2017;359:449–457.Psallidas I, Stathopoulos GT, Maniatis NA, Magkouta S, Moschos C, Karabela SP, et al. Secreted phosphoprotein-1 directly provokes vascular leakage to foster malignant pleural effusion. Oncogene 2013;32:528–535.Wei J, Marisetty A, Schrand B, Gabrusiewicz K, Hashimoto Y, Ott M, et al. Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. J Clin Invest 2019;129:137–149.Ethics ApprovalThis study was approved by the Johns Hopkins Hospital IRB: IRB approval number CR00023377.

Abstract Myelofibrosis (MF) is associated with splenomegaly, cytopenias, constitutional symptoms, and bone marrow fibrosis, with limited therapeutic options. Currently only two Janus kinase inhibitors (JAKi) are approved for MF worldwide. Jaktinib, an oral novel JAKi is under investigations. We present the results from a Phase 2 open-label and multi-center study, evaluated two different regimens of Jaktinib in patients (pts) with MF. Aims: To investigate the efficacy, safety and pharmacokinetics (PK) of Jaktinib in MF pts. Methods: Eligibility: MF pts included primary per WHO criteria (2016) or post-essential thrombocythemia / polycythemia vera MF according to IWG-MRT criteria; DIPSS-PLUS ≥ int-2 (int-1 with symptomatic splenomegaly/hepatomegaly required a treatment). From 21 study sites, 104 pts were randomized by 1:1 ratio to Jaktinib 100mg BID or 200mg QD during the first stage, then 14 additional were enrolled to Jaktinib 100mg BID in the second stage, total 118 pts participated in the study. The primary endpoint: the proportion of pts with spleen volume reduction from baseline ≥ 35% (SVR35) at week 24 (W24), assessed by Independent Review Committee based on MRI/CT images. Secondary endpoints: at W24 compared to baseline, the proportion of pts with ≥ 50% reduction on MPN-SAF TSS, improvements in RBC transfusion and hemoglobin (Hgb), safety profiles as well as the PK characteristics, etc. Results: 118 pts who completed treatments of 24 weeks or planned visits were summarized. Baseline characteristics were generally balanced between the two groups, and shown in Table 1. At W24, the SVR35 were 51.5% (34/66) in the 100mg BID and 28.8% (15/52) in the 200mg QD (p=0.0151), the median duration of response has not reached yet for the 100mg BID and 11.0 months for the 200mg QD. The median time to achieve a first SVR35 was 5.5 months and 11.0months, respectively. The proportion of pts achieved ≥50% improvement in TSS at W24 from baseline for BID and QD arms were 63.6% (42/66) and 53.8% (28/52), respectively. The mean percent of TSS change from baseline was -62.00 and -42.01, respectively. Approximately 35.6% (21 /59) of combined 59 pts whose baseline's Hgb ≤100g/L had elevated ≥20g/L at W24. Of the 6 pts who were transfusion-dependent at baseline, 2 pts became transfusion-independent after treatment. In addition, 5 (71.4%) out of 7 pts had a RBC infusion decreased ≥50%. The most common Grade ≥3 hematological TEAEs (≥ 5%) were anemia (100mg BID 24.2%, 200mg QD 28.8%), thrombocytopenia (16.7%, 11.5%), neutropenia (3.0%, 11.5%), and leukopenia (0, 7.7%). Most common non-hematological (of any grade) TEAEs (≥10%) were upper respiratory tract infection (24.2%, 30.8%), elevated creatinine (19.7%, 30.8%), elevated ALT (24.2%, 21.2%) and elevated bilirubin (24.2%, 13.5%), predominantly in Grade 1 or 2. A total 64 (54.2%) of the combined 118 pts had ≥ 1 dose adjustment/interruption, mostly due to thrombocytopenia (31.4%), anemia (22.0%), and neutropenia (8.5%), while 10 (10.2%) pts discontinued the treatment because of adverse events (thrombocytopenia[n=3], anemia[n=2，with 1 pts occurring pneumonia at the same time], pneumonia[n=1], tuberculosis[n=2], upper gastrointestinal bleeding[n=1], chronic kidney disease[n=1]). Total 23 (100mg BID 12 and 200mg QD 11) pts had their blood PK samples collected per protocol schedule. After single oral administration, the median T max is 2h and the average t 1/2 is 3~4 h in both groups. The AUC 0-24 of Jaktinib and its metabolites on the first day were comparable in both groups. After multiple doses, in comparison to 200mg QD, 100mg BID had a decreased C max and an increased C trough, resulting in less fluctuation between the peak and trough concentrations, which indicated that continual inhibitions of JAK-STAT pathway may result in better clinical outcomes. Summary/Conclusion: Jaktinib as a novel JAKi is generally well-tolerated and safe in Chinese MF pts. Significant reductions in spleen volume and constitutional symptom burden were observed in the 100mg BID, and also a sign of improvement was shown in RBC transfusion dependency and Hgb levels after Jaktinib treatment. Follow-up study is on-going and will provide long-term efficacy and safety data of Jaktinib. Figure 1 Figure 1. Disclosures Zhou: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Jiang: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Wu: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Zhuang: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Li: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Wang: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Huang: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Zhu: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Zhang: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Du: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Xiang: I agree not to accept honoraria or reimbursement, including travel support, from ineligible companies for my role as a chair/moderator/presenter in the accredited portions of this activity: Honoraria. Zhang: The content I am responsible for will be free of logos or other corporate identifiers of healthcare industry companies, specifically those whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or : Honoraria. Hu: Astellas Pharma, Inc.: Research Funding. Liu: The content I am responsible for will be free of logos or other corporate identifiers of healthcare industry companies, specifically those whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or : Honoraria. Jin: The content I am responsible for will be free of logos or other corporate identifiers of healthcare industry companies, specifically those whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or : Honoraria. Sun: The content I am responsible for will be free of logos or other corporate identifiers of healthcare industry companies, specifically those whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or : Honoraria. Zhou: The content I am responsible for will be free of logos or other corporate identifiers of healthcare industry companies, specifically those whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or : Honoraria.

В последние годы высокими темпами проводятся исследования, связанные с поиском и изучением механизма действия новых и применяющихся в медицине ноотропных средств. Представляют интерес исследования, связанные с поиском новых комбинированных лекарственных средств ноотропного действия на основе субстанций D-гамма-пантотената кальция и янтарной кислоты, обладающих нейрометаболическими, атигипоксическими и адаптогенными свойствами. Целью настоящего исследования являлись разработка и обоснование оптимальных составов и технологий изготовления таблеток, обладающих ноотропным действием, и стандартизация предложенных лекарственных форм, содержащих пантогам и янтарную кислоту.Способ приготовления таблеточной смеси: все компоненты отвешивали в необходимом количестве, в ступку вносили пантогам, затем янтарную кислоту и растирали до однородного белого порошка. Прессование таблеток проводили на ручном прессе при давлении 120 мн/м2. Нанесение покрытия осуществлялось на лабораторной установке псевдоожиженного слоя с одной форсункой в перфорированном барабане объёмом 1000 мл. Полученные таблетки оценивали согласно требованиям по Государственной Фармакопее XIII, XIV. Сравнение таблеток пантогама сянтарной кислотой, полученных методом прямого прессования и влажного гранулирования, показало, что метод прямого прессования позволяет получать таблетки с хорошими физико-механическими показателями и биодоступностью. Для количественного определения пантогама в таблетках разработаны методики, основанные на кислотно-основном титровании, спектрофотометрическом определении. Проведена валидация методики количественного определения янтарной кислоты в лекарственных формах.На основании изучения физико-химических, технологических свойств субстанций и вспомогательных веществ обоснованы и разработаны составы и технология получения таблеток, содержащих пантогам и янтарную кислоту. 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The pandemic of COVID-19 has afflicted every individual and has initiated a cascade of directly or indirectly involved events in precipitating mental health issues. The human species is a wanderer and hunter-gatherer by nature, and physical social distancing and nationwide lockdown have confined an individual to physical isolation. The present review article was conceived to address psychosocial and other issues and their aetiology related to the current pandemic of COVID-19. The elderly age group has most suffered the wrath of SARS-CoV-2, and social isolation as a preventive measure may further induce mental health issues. Animal model studies have demonstrated an inappropriate interacting endogenous neurotransmitter milieu of dopamine, serotonin, glutamate, and opioids, induced by social isolation that could probably lead to observable phenomena of deviant psychosocial behavior. Conflicting and manipulated information related to COVID-19 on social media has also been recognized as a global threat. Psychological stress during the current pandemic in frontline health care workers, migrant workers, children, and adolescents is also a serious concern. Mental health issues in the current situation could also be induced by being quarantined, uncertainty in business, jobs, economy, hampered academic activities, increased screen time on social media, and domestic violence incidences. The gravity of mental health issues associated with the pandemic of COVID-19 should be identified at the earliest. Mental health organization dedicated to current and future pandemics should be established along with Government policies addressing psychological issues to prevent and treat mental health issues need to be developed. References World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard. 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Nitrogen is a paramount important essential element for all living organisms. It has been found to bea crucial structural component of proteins, nucleic acids, enzymes and other cellular constituents which are inevitable for all forms of life. In the atmosphere, the percentage of nitrogen is very high (N2, 78%) compared to other inorganic gases. However, most organisms have practically no direct access to this nitrogen. While plants can not directly uptake nitrogen from atmosphere, they are capable of assimilating other forms of nitrogen, for example ammonium (NH4+) and nitrate (NO3-). For agricultural crop production, artificial fixation of nitrogen is heavily utilized and it is an expensive process that requires high temperatures (at least 400 °C) and pressures (around 200 atm). It has been conspicuously demonstrated that indiscriminate use of fertilizer hampers soil physical, chemical and micro biological properties and also a potential risk to environment e.g. water quality. Besides, chemically manufactured fertilizers are depleted from soils in various ways, for instance; denitrifying bacteria, volatilization, and leaching. Consequently, it results relatively poor availability of nitrogen to get into plants. On the flipside, only 1-2% of the nitrogen fixation in the world occurs through the natural process of lightening. Notably, microbial fixation is well characterized in diazotrophs for example; Rhizobia and Frankia, and blue-green algae. Against the backdrop, we are accentuated on an environmentally friendlyand themost sustainable approach to increase productivity for legume and non-legume crops. Till today, the term biological nitrogen fixation (BNF) has received much attention as a sustainable alternative; this process facilitates atmospheric nitrogen to convert into ammonia by rhizobia in specialized plan organs termed “root nodules”. This review article seeks to better understand plant mechanisms involved in the development of root nodules in soybean. Soybean (Glycine max) is one of the most important oil crops and a source of animal feed protein in the world. It has a salient feature to fix atmospheric nitrogen through symbioses with compatible rhizobia that yields to determinate type nodule (Oldroyd, Murray et al. 2011). Biological nitrogen fixation in soybean nodules reduces the use of chemical nitrogen fertilizers resulting in cost-savings to producers and minimizes environmental damage due to nitrogen run-off. A better understanding of how nodules form and function is important for selection or generation of soybean genotypes with better nitrogen fixation capacity. Soybean nodules originate from root cortex via de novo cell differentiation (Oldroyd 2013). Consequently, two major nodule development zones are formed for instance; the nodule primordium (Npr) in the middle and it is encircled by nodule parenchyma (Npa). At later time point, the Npr gives rise to N-fixation zone and the Npa holds vascular bundles. It is not clear what early signaling pathways driving the conspicuous development of the nodule zones. My research is aimed at filling this knowledge gap by illustrating the molecular signatures that paves the way to cellular differentiation in root nodule development in soybean. Based on initial evidence obtained by the Subramanian lab, we hypothesize that microRNAs (miRNAs) play important regulatory roles in spatio-temporal expression of their target genes during nodule developmental in soybean. For instance, the regulation of auxin sensitivity by miR160 has been found to be crucial for formation of nodule primordia and vasculature in the parenchyma (Marie Turner 2013). Against this backdrop, this review article focused on nuclear and cytoplasmic transcriptome as well as miRNA profiles of parenchyma and primordial tissues and determine the relative abundance and differentially expressed mRNAs and regulatory role of miRNAs in cell differentiation and nodule development. Root nodule a sustainable alternative to fix atmospheric nitrogen Atmospheric nitrogen percentage is very high (N2, 78%) compared to other inorganic gases (Mary Elvira 1932). However, most of the organisms have practically no direct access to this nitrogen. Nevertheless, plants can not directly uptake nitrogen from atmosphere but they are capable of assimilating only very specific forms of nitrogen, for example ammonium (NH4+) and nitrate (NO3-) (Bytnerowicz and Fenn 1996, Peter M. Vitousek 1997) (Sponseller, Gundale et al. 2016). Virtually, nitrogen has been found to be a crucial structural component of proteins, nucleic acids, enzymes, and other cellular constituents which are inevitable for all forms of life (O'Brien, Vega et al. 2016). For agricultural crop production, artificial fixation of nitrogen is heavily utilized. It is an expensive process that requires high temperatures (approx. 400 °C) and pressures (approx. 200 atm) (Witschi 2000). It has been conspicuously demonstrated that indiscriminate use of N fertilizer hampers the diversity of the bacterial community and decreases soil C and N concentrations (Verzeaux, Alahmad et al. 2016). Notably, it has been demonstrated as a potential risk to environment e.g. water quality (Zhao, Sha et al. 2016) (Sponseller, Gundale et al. 2016). Besides, chemically manufactured fertilizers are depleted from soils in various ways, for instance; denitrifying bacteria, volatilization, and leaching (Johnson 1996, Peter M. Vitousek 1997). Consequently, it results relatively poor availability of nitrogen to get into plants. On the flipside, over 90 % of the nitrogen fixation in the world occurs through the natural process of lightening and microorganisms. Furthermore, microbial fixation is well characterized in diazotrophs for example; Rhizobia and Frankia, and blue-green algae (Cheng 2008). It has been demonstrated that Bradyrhizobium strains substantially escalated soybean grain yield, and protein content up to 57% and 26%, respectively (Zimmer, Messmer et al. 2016). Against the backdrop, we are accentuated on an environmentally friendly and a sustainable approach to increase the productivity for legume and non-legume crops. Literature mining depicted that biological nitrogen fixation in soybean nodules reduces the use of chemical nitrogen fertilizers resulting in cost-savings to producers and minimizes environmental damage due to nitrogen run-off. Rhizobia infection leads to the root nodule development In the natural environment, plants are continuously confronted with pathogenic and symbiotic microbes. Symbioses involves mutual exchange of diffusible signal molecules, first endophytic bacteria (rhizobia) are attracted by the plant root exudates flavonoids which are perceived and triggered the bacterial nodulation (nod) genes. Consequently, the bacteria synthesize specific lipochito-oligosaccharides, called nodulation (Nod) factors. This signal is perceived by the LysM receptor like kinase of host plant, it induces the root hair curling, and bacteria get access into the host epidermis through infection threads (ITs) and initiate cell division within the root cortex, leading to the progression of the root nodule meristem. In later stages of the interaction, bacteria are released from the infection threads into the plant cells, surrounded by membrane of plant origin. These bacteria multiply within the host cells and differentiate into the nitrogen fixing bacteroids (Udvardi and Day 1997) (Oldroyd 2013). Till now, integration of genetic and genomic approaches has revealed twenty-six genes to be involved in nodule development of Medicago truncatualaand Lotus japonicum (Kouchi, Imaizumi-Anraku et al. 2010). In addition, deep sequencing of the Medicago truncatularoot transcriptome has uncovered thousands of genes to be induced during Nod factor signaling and its resulting ethylene (ET) biosynthesis throughout the multiple development stages of indeterminate nodule (Larrainzar, Riely et al. 2015). Albeit the molecular mechanism of such regulation is not well understood. There has been a large-scale transcriptome analysis of B. japonicum-inoculated and mock-inoculated soybean root hairs. It has showed that a total of 1,973 soybean genes differentially expressed during root hair infection, particularly NFR5 and NIN genes (Libault, Farmer et al. 2010). Nevertheless, the signaling mechanisms directing the cellular differentiation of nodule are not known. Soybean root nodule organogenesis Soybean (Glycine max) has a genome size of 1.1 to1.5 Gb, it is partially diploidized tetraploid. It is one of the most important oil crops and a source of animal feed protein in the world (soybase.org/sb_about.php). It has a salient feature to fix atmospheric nitrogen through symbioses with compatible rhizobia that yields to determinate type nodule (Udvardi and Day 1997) (Oldroyd, Murray et al. 2011). Notwithstanding of the economic and environmental importance, there has been very few studies about quantitative trait loci (QTL) that controlling BNF traits, for instance nodule number, ration of nodule dry weight with nodule number, and shoot dry weight (SDW). It has been reported via composite interval mapping that approximately six QTLs bears very small effect on BNF traits (Santos, Geraldi et al. 2013). Besides, it has been demonstrated in earlier studies that nodules originate from root cortex via de novo cell differentiation into two different cell types, parenchymal and primordium (Celine Charon 1997) (Oldroyd&Downie 2008; Oldroyd 2013). In addition, early nodulin genes in legume for instance; Enod 40 gene reported to be expressed in root pericycle during the rhizobia infection and later it occupied in the dividing cortical cells (H. Kouchi and S. Hata 1993). Among the two major nodule development zones, the nodule primordium (Npr) in the middle which is encircled by nodule parenchyma (Npa). At later time point, the Npr gives rise to N-fixation zone and the Npa holds vascular bundles. Lately, a β- expansin gene, GmEXPB2 fused with GUS reporter gene which was observed to be preferentially expressed in nodule vascular trace and nodule vascular bundles. It indicated that GmEXPB2 might be crucial for nodule organogenesis. Over expression of GmEXPB2 contrast to suppressed GmEXPB2 transgenic lines found to be escalated nodule number, nodule mass and nitrogenase activity. It further suggested that GmEXPB2 might have influenced over root architecture, nodule formation and development, and profoundly yielding to biological N2 fixation (Li, Zhao et al. 2015). Even though, it is not clear what early signaling pathways driving the conspicuous development of the nodule zones. Against the back drop, to understand the regulation of auxin sensitivity by miR160 which is believed to be crucial for the formation of nodule primordia (Marie Turner 2013). Figure 1 a. Illustrating the progression of root nodule development through Rhizobial bacterial infection in the plant root leading to the determinate nodule (Oldroyd 2013). b. Nodule development zones A. Nodule primordial zone (Enod 40 gene) in the middle B. surrounding parenchyma (Enod 2 gene), differentiated from cortex (collected from Sen Subramanian lab). Regulatory small RNAs biogenesis and its molecular functions Regulatory small RNAs are ranged between 20 to 24 nucleotides which are ubiquitous elements of endogenous plant transcriptomics, a common response to exogenous viral infections and introduced double-stranded RNA (Axtell 2013). Three core enzymes families, for instance; RNAdependent RNA polymerase (RDR), Dicer like (DCL), and Argonaute (AGO) proteins paves the way of small RNA biogenesis and function in plants. Firstly, ribonuclease type III or DICERLIKE1 involves in the yield of a fold-back precursor RNA or primary miRNA (primiRNA) transcripts using an RNA templates in the nuclei. Later, the resulting miRNA-miRNA duplex which is originated in nucleus then translocated into cytoplasm. The guided miRNAmolecule is incorporated into ARGONAUTE (AGO) to form an active RISC complex to specific target RNAs that are complementary to the miRNA, and this process eventually follows up mRNA cleavage, represses the translation of the mRNAs or Chromatin modification. This phenomenon accentuated as an inhibition or silencing of the gene expression, which play a crucial role in the developmental process in plant and animal (Chapman and Carrington 2007) (Axtell 2013). Fig. 2 Regulation of gene expression events via RISC complex (modified from https://www.google.com/?gws_rd=ssl#q=mirna+picture+in+plants accessed on 7th February, 2016) Fig. 3 Gene expression events occurring in typical plant cell (modified https://www.google.com/search?q=transcription+and+translation accessed on 7th February, 2016) It has been found in several studies that most plant miRNAs are non-coding RNA, and small 21-24 nucleotide long (Cuperus, Fahlgren et al. 2011). It requires DCL1-clade DCL for their biogenesis and AGO1-clade AGO for their function (Wu, Zhou et al. 2010, Manavella, Koenig et al. 2012). In rice (Oryza sativa), DCL3 has been reported in the biogenesis of 24nt long miRNA that incorporated in AGO4 to regulate the target gene expression primarily through mRNA cleavage (Wu, Zhou et al. 2010). Argonaute proteins (AGO) form RNA inducing silencing complexes (RISC) with small RNAswhich is known as post-transcriptional gene silencing. It has typically four domains, for instance:N-terminal, PAZ, MID and PIWI domains. The MID-PIWI lobes are belongs to the C-terminus. It has been studied that MID-domains contains the specificity loop to recognize and bind to the 5’-phosphate of smRNAs. The PIWI domains contained the catalytic active site D-E-D-H/D. PAZ domain anchored the 2-nt overhang at the 3’ end of miRNAs. The N-terminal domain involved in the separation of miRNA-miRNA duplex and the slicer activity of the mRNA (Song, Smith et al.2004). There has been an expansion and duplications of AGO family members during plantevolution (Singh, Gase et al. 2015). The functional diversification of AGOs is indicating sRNAdirected regulatory pathways. The binding preference of AGO and sRNA is mainly assigned by the sequence of sRNA. In Arabidopsis, 10 AGO have been extensively studied (Liu et al. 2014). It has been demonstrated that AtAGO10 like AtAGO1, it recognized distinct structural features in miR165/miR166 duplex than involved by AtGO1. AtAGO10 found to regulate shoot apical meristem by decoying miR165/miR166 and subsequent repression of homeodomain-leucinezipper (HD-ZIP) gene expression (Zhu, Hu et al. 2011). Notably, 22 AGO proteins have been reported in Soybean (Glycine max). It has been found that genome duplication in Soybean resulted such a proliferation of AGOs. For example: its genome encodes two copies of AGO1, AGO2, AGO5, AGO4/9, AGO6 and AGO7 (Xiang Liu 2014). However, the molecular function of the plant AGO genes yet not very clear. There are several miRNA families that are conserved across the vast evolutionary distances from flowering plants to mosses (Cuperus, Fahlgren et al. 2011). It has been observed in another study that miRNA, and its target pairing found to be stable for a prolonged periods of plant evolution. On the flip side, another group demonstrated that conserved plant miRNAs and their targets are to somehow flexible. For instance; miR159 is a highly conserved miRNA that targets not only a subset of MYB mRNAs but also observed to target a non MYB mRNA, SGN-U567133 (Buxdorf, Hendelman et al. 2010). A mutant tomato transgenic line (miR159-resistant line) showed higher level of the SGN-U567133 transcript and exhibited defects in leaf and flower development. This result suggests that miR159 involves in a post-transcriptional regulation. Additionally, it is found to be crucial for the normal tomato development. Recently, the identification of miRNAs in the regulation of photoperiodic pathways in soybean have been reported through high throughput sequencing and qRT-PCR. Six libraries were constructed using Illumina Solexa, for instance; 0, 8, and 16 h under short day treatment, similar time points considered for the long the long day treatment. A total of 163 miRNAs families were reported which covered 318 plant miRNAs, and unclassified 81 novel predicted miRNAs. As expected, significant differences in abundance between short day and long day treatment was observed (Wenbin Li 2015). These findings provided evidence of miRNA in the regulation of flowering time that ultimately affects the seed yield and quality of soybean. The complex regulatory network of miRNA-mRNA interactions during viral infection has been revealed via small RNA seq (sRNA), degradome seq, and genome-wide transcriptome analysis. There has been a total of 253 soybean miRNAs found to be two-folds abundance compared with mock-inoculated control demonstrated through sRNA seq analysis. Among them 105 miRNAs were identified as potential targets of 125 transcripts that has been validated by degradome seq analyses. In addition, 2679 genes were detected via genome wide transcriptomic analysis. These genes have been differentially expressed during infection of soybean mosaic virus and among them 71 genes projected to induce in defense response (Hui Chen 2016). These findings suggested the regulatory role miRNA that governed the target gene expression during viral infection. Furthermore, the regulatory role of microRNAs (miRNAs) during Soybean- Bradyrhizobium japonicum mutualistic association was studied first by Subramanian et al. 2008. They sequenced approximately 350000 small RNAs of soybean root sample which were inoculated with B. japonicum. It helps to detect 20 conserved miRNAs loci based on the similarity to miRNAs in another plant species. In addition, 35 novel miRNAs were identified based on potential hairpin forming precursors in Soybean EST as well as shotgun genomic sequences (Subramanian, Fu et al. 2008). These findings advocated the potential role of miRNAs in the regulation of legumerhizobiumsymbiosis. In another study, 120 hairpin-forming precursor genes have been identified in soybean by Turner et al. In addition, they reported three novel miRNAs for instance; miR160, miR164 and miR393 found to be involved in auxin signaling (Turner, Yu et al. 2012). Moreover, the plant hormone auxin is thought to have a pivotal role in nodule organogenesis in determinate and indeterminate type of nodule. It indicates a redundancy and diversity of miRNAs family members that governs the formation of root nodule. It has been illustrated that auxin receptor gene family hushed by over expressed microRNA393. These plant roots found to be hypersensitive to auxin and yielded normal nodule. This observation advocated that only minimal/reduced auxin signaling is required for determinate nodule development. Likewise, overexpressed microRNA160 hushed a set of repressor auxin response transcription factor. These plant roots were hypersensitive to auxin and observed not to be reluctant in epidermal responses to rhizobia. Notably, it yielded to lower sized nodule primordium (Marie Turner 2013). This observation indicated that auxin hypersensitivity inhibits nodule organogenesis Organ specific expression of profile of miRNA and the potential targets were also studied. Two genes (Glyma10g10240 and Glyma17g05920) which were the target of miR169 but detected to be highly expressed in soybean nodule. Likewise, three potential targets of gma-new-miR13587 demonstrated to be highly expressed in the nodules than in the roots. As expected, gma-newmiR13587 found to be poorly expressed in the nodules than in the roots (Turner, Yu et al. 2012). There was an inverse expression pattern observed in between roots and nodules. Li et al., studied the transgene expression of three novel miRNAs namely, miR482, miR1512, and miR1515 in Soybean. They noticed a significant increase of nodule numbers while root length and later root density were normal in all tested miRNA lines. As expected, there were differential expression of these miRNAs in supernodulating and nonnodulating soybean mutants. They reported that 6 novel miRNAs decoyed 22 predicted target genes. And it was estimated via real time polymerase chain reaction and qRT-PCR (Li, Deng et al. 2010). It advocates that miRNAs have the signatory roles in soybean nodule development. Sequencing of small RNAs and Parallel analysis of RNA ends (PARE) libraries revealed to identify 284 nodule miRNAs, more than 500 target genes, and including 178 novel soybean miRNAs. It has been reported that ENOD93 only found to be expressed in nodule tissue not in other plant parts of Soybean. Ectopic expression of miR393j-3p and RNAi silencing approach to ENOD93 expression showed a significant reduction in nodule formation (Zhe Yan 2015). Therefore, this study showed a list of miRNAs and their potential target of nodulation genes. In the model legume (Medicago truncatula), 25 conserved miRNA families and 100 novel miRNA reads were detected by high-throughput sequencing. The expression of MtHAP2-1 (encodes a CCAAT binding transcription factor) to meristematic zones was restricted by miR169a which is found to be critical for the development of indeterminate type of nodule (Combier, Frugier et al. 2006). In another study, HDZIPIII transcripts were inhibited by overexpression of miR166, it dropped the number of symbiotic nodule and lateral root (Boualem, Laporte et al. 2008). To get insights into key genes of nodule zones, transcript profiles of specific cells/tissues were investigated at different time points from indeterminate nodules of M. truncatulausing laser capture micro dissection. It has been demonstrated from the comprehensive gene expression map that selected genes enriched in different cell/tissue types (Limpens, Moling et al. 2013). These findings indicated that organ specific gene expression could be controlled by the presence or absence of miRNAs. Recently, Agrobacterium rhizogenesmediated hairy root transformation has been applied as tool for exploring cell type specific gene expression in tomato. Cell type or tissue specific promoter introduced into INTACT and TRAP constructs via gateway cloning technology to develop binary vectors. INTACT method used to capture biotin tagged nuceli from specific cell types and TRAP method used for profiling of mRNAs or foot printing of individual ribosomes (Ron 2014). TRAP methodology is not required tissue fixation or single cell suspension. It has been successfully used to date in organisms ranging from D. melanogaster to mice and human cultured cells. Multiple ribosomes or Polyribosomes (polysomes) are engaged in translation on a single mRNA. To evaluate the translation state of an mRNA, ribosomal subunits, ribosomes, and polysomes can be isolated from detergent-treated cell extracts (Heiman, Kulicke et al. 2014). In this study, we would perform polysome isolation deploying gene cassettes ENOD40p:HF-GFP-RPL18 for primordial tissues, and ENOD2p:HF-GFP-RPL18 for parenchymal tissues in Glycine max root nodules that express an epitope tagged version of ribosomal protein L18. Over the last one decade, there has been several microarrays-based studies which characterized transcriptional variations deployed in nodule formation. It has been embedded with couple of shortcomings, for instance; relative late time points study, incomplete representation of plant genes,discrimination of close paralogs, and reduced sensitivity. Lately, next generation sequencingtechnology have widened the horizon of transcription analyses in different legume species to detectsymbiosis induced changes in late nodule developmental stages. Against this backdrop, we areaccentuated to reveal early transcriptional changes induced in determinate type of soybean noduleby Bradyrhizobium japonicum. In determinate type of nodule, two major nodule development zones are formed for instance, the nodule primordium (Npr) in the middle and it is encircled by nodule parenchyma (Npa). At later time point, the Npr converted to N-fixation zone and the Npa contained vascular bundles. Of these facts, it is not clear what early signaling pathways driving the conspicuous development of thenodule zones. In this context, mechanisms regulate the distinct gene expression profiles in Npr andNpa cell types has not understood clearly. The proposed research study is aimed at filling this knowledge gap byillustrating the molecular signatures that paves the way to cellular differentiation in root noduledevelopment in soybean considering four different time points (5 dai, 7 dai, 10 dai& 14 dai). The hypothesisis microRNAs(miRNAs) play important regulatory roles in spatio-temporal expression of their target genesduring nodule developmental in soybean. For example, a gradient of microRNA localizationbetween nodule primordium and parenchyma cells could result in distinct differentiation of thesecell types. To test this hypothesis, one has to obtain both cell type-specific miRNA andtranscriptome (miRNA target) profiles. Since, the majority of miRNA regulation occurs in thecytoplasm, we reasoned that comparison of nuclear and ribosomal transcriptome profiles wouldreveal genes whose expression is potentially regulated by post transcriptional mechanisms such asmiRNA cleavage. Combining this information with cell type-specific miRNA profiles, andto test the above hypothesis and identify key miRNA-target pairs important for nodule celldifferentiation. The use of translating ribosome affinity purification (TRAP) of nodule zonecells, namely from parenchyma and primordial tissues, to obtain cytoplasmic transcriptomes data. Techniques to determine cell type specific expression profiles: TRAP methods TRAP is termed translating ribosome affinity purification, combines cell-type-specific transgene expression with affinity purification of translating ribosomes. It supersedes the need for tissue fixation, and facilitates to study the cell type-specific mRNA profiles of any genetically defined cell type. It has been successfully used to date in organisms ranging from D. melanogaster to mice, and human cultured cells. Multiple ribosomes or Polyribosomes (polysomes) are engaged in translation on a single mRNA. To evaluate the translation state of an mRNA, ribosomal subunits, ribosomes, and polysomes can be isolated from detergent-treated cell extracts. In this study, the polysome isolation using gene cassettes ENOD40p:HF-GFP-RPL18 for primordial tissues, and ENOD2p:HF-GFP-RPL18 for parenchymal tissues in Glycine max root nodules that express an epitope tagged version of ribosomal protein L18 RPL18(Heiman, Kulicke et al. 2014, Ron 2014). Relative abundance and differentially expressed mRNAs profile in two different tissue specific zones would help to understand the effect of regulatory role of miRNAs in cell differentiation and nodule development. References: Axtell, M. J. (2013). "Classification and comparison of small RNAs from plants." Annu Rev PlantBiol 64: 137-159. 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AbstractThe global spread of English has made it the dominant language in academic publishing (Hyland, Ken. 2015. Academic Publishing: Issues and Challenges in the Construction of Knowledge. Oxford: Oxford University Press). Influenced by enterprise culture, scholars from peripheral non-Western countries face mounting pressure to publish in English (Curry, Marry Jane & Theresa Lillis (eds.). 2017. Global academic publishing: Policies, perspectives and pedagogies. Bristol, UK: Multilingual matters). The English academic publishing industry has also ballooned in China (Tian, Mei, Yan Su & Xin Ru. 2016. Perish or publish in China: Pressures on young Chinese scholars to publish in internationally indexed journals. Publications 4(2). 9.). In response to the Chinese government’s commitment to developing world-class universities and disciplines to enhance the internationalization of its higher education system, local Chinese scholars are increasingly encouraged to produce research that has international impact, as well as to engage in international academic exchange and cooperation arrangements (Li, Yongyan & Guangwei Hu. 2018. Collaborating with management academics in a new economy: Benefits and challenges. Publications 6. 1–17). In seeking academic collaboration, a growing number of Chinese academics have participated in visiting scholar programs offered by western-based universities. In light of this emergent phenomenon, this study explores how Chinese visiting scholars, driven by an ethical imperative to enhance human capital at “neoliberal universities” (Holborow, Marnie. 2013. Applied linguistics in the neoliberal university: Ideological keywords and social agency. Applied Linguistics Review 4(2). 229–257), exploited language-related resources available to them to succeed in English academic publishing. Data, which include in-depth interviews, social media posts, journals, resumes and manuscripts that were in press at academic journals, were collected from two Chinese professors who took part in a one-year visiting scholar program in the U.S. university. Our findings revealed that under the mounting expectations to publish in English-dominated SSCI journals, our focal participants enacted linguistic entrepreneurial practices.

A doença mão-pé-boca é uma infecção viral, normalmente benigna que afeta comumente crianças até 10 anos, causada pelos enterovírus humano. O propósito deste estudo foi revisar os aspectos da doença que se faz presente nos dias atuais abordando a etiologia, epidemiologia, surtos, sintomatologia e comorbidades, diagnóstico, prevenção e tratamento. Foram selecionadas publicações em periódicos referenciados nas fontes de dados do Google Acadêmico, Pubmed e Periódicos Capes com as palavras chaves relacionadas ao tema desse trabalho como doença mão-pé-boca e crianças, sendo selecionados artigos produzidos até 2017. Apesar de diagnóstico clínico aparentemente simples, a doença pode ser confundida com outras enfermidades por suas características semelhantes, que podem induzir o colega odontólogo ao equívoco de diagnóstico.Descritores: Doença de Mão, Pé e Boca; Diagnóstico, Odontopediatria.ReferênciasSarkar PK, Sarker NK, Tayab A. Hand, foot and mouth disease (hfmd):an update. 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Int J Infect Dis. 2010;14:e1076-81.Wang J, Hu T, Sun D, Ding S, Carr M, Xin W, et al. Epidemiological characteristics of hand, foot, and mouth disease in Shandong, China, 2009-2016. Sci Rep.2017;7(1):1-9.He SZ, Chen MY, Xu XR, Yan Q, Niu JJ, Wu WH et al. Epidemics and aetiology of hand, foot and mouth disease in Xiamen, China, from 2008 to 2015. Epidemiol Infect. 2017;145:1865-74.Dantas A, Oliveira MJ, Lourenço O, Coelho PB. Doença mão-pé-boca no adulto - a propósito de um caso clínico. Rev Port Med Geral Farm. 2013;29:62-5.Chatproedprai S, Theanboonlers A, Korkong S, Thongmee C, Wananukul S, Poovorawan. Clinical and molecular characterization of hand-foot-and-mouth disease in thailand, 2008-2009. J Infect Dis. 2010;63:229-233.Zhang W, Du Z, Zhang D, Yu S, Hao Y. Quantifying the adverse effect of excessive heat on children: an elevated risk of hand, foot and mouth disease in hot days. Sci Total Environ. 2016;541:194-99.Koh WM, Bogich T, Siegel K, Jin J, Chong EY, Tan CY et al. The epidemiology of hand, foot and mouth disease in Asia: a systematic review and analysis. Pediatr Infect Dis J. 2016;35(10):e285-300.Pham HV, Hoang TNA, Duong HT, Phan LT, Phan UTN, Ho NX et al. Clinical characteristics of hand, foot and mouth disease in Daklak Province, Vietnam and associated factors of severe cases. Virus Dis.2017;28(4):430-33.Lam JM. Characterizing viral exanthems. Ped Health. 2010;4(6):623-35.World Health Organization: western Pacific Region. A guide to clinical management and public health response for hand, foot, and mouth disease (HFMD).Ganga N. Hand foot and mouth disease like illness in office practice. Indian J Pediatr. 2017; 84(3):216-18.Chang LY, Lin TY, Hung K, Huang YC, Lin KL, Hsueh C et al.Clinical features and risk factors of pulmonary oedema after en terovi rus-71-related hand, foot, and mouth disease. Lancet. 1999;354(9191):1682-86.Cabrol Y, Peah P, Mey C, Duong V, Richner B, Laurent D et al. A prospective, comparative study of severe neurological and uncomplicated hand, foot and mouth forms of paediatric enterovirus 71 infections. Int J Infect Dis. 2017;59:69-76.Alter SJ, Bennett JS, Koranyi K, Kreppel A, Simon R. Common childhood viral infections. Curr Probl Pediatr Adolesc Health Care. 2015;45:21-53.Li Y, Deng H, Li M, Wang W, Jia X, Gao N et al. Prolonged breastfeeding is associated with lower risk of severe hand, foot and mouth disease in chinese childre. Pediatr Infect Dis J. 2016;35(3):353-55.Wolf D, Otto J. Efficacy and safety of lidocaine gel in patients from 6 months up 8 years with acute painful sites in the oral cavity: a randomized, placebo-contolled, double-blind, comparative study. Int J Pediatr. 2015.2015:146717.

Cellular senescence is a state in wich cells can not longer divide. The dysregulation of the cell senescence signaling pathway could lead to uncontrolled cell proliferation and formation of malignant cells. Intervening in cell senessence signaling pathway to bring cancer cells back to cell senessence state is a potential way in cancertreatment. Recent studies show that tumor cells can undergo celluar senessencestate by using special chemotherapy. In this study, we indicatedthat All trans retinoic acid (ATRA) is able to influence the expression of genes involved in cell senessence signaling pathway in gastric cancer cells MKN45. ATRA down-regulatesthe expression of important genes controlling cell growth. On the other hand, ATRA up-regulate the expression of GADD45A, P21 and P53 genes that play an important role in the signaling pathway of cells.This finding suggestes that ATRA could inhibite MKN45 cells through activating cell senescence signaling pathway. Keywords: All trans retinoic acid, gastric cancer stem cell, cell senescence. References [1] L. Hayflick, P.S. Moorhead, The serial cultivation of human diploid cell strains, Exp. Cell Res. 25 (1961) 585-621. https://doi.org/10.1016/0014-4827 (61)90192-6.[2] V. Dupé, N.B.Ghyselinck, V. Thomazy, L. Nagy, P.J. Davies, P. Chambon and M. Mark, Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods, Development Biology. 208 (1999) 30-34. https://doi.org/10.1006/dbio.1998. 9176.[3] López-Otín Carlos, et al, The hallmarks of aging, Cell. 153 (2013) 1194-1217. https://doi.org/ 10.1016/j.cell.2013.05.039.[4] Kuilman Thomas, et al, The essence of senescence, Genes & development. 24 (2010) 2463-2479. https://doi.org/10.1101/gad.1971610.[5] Collado Manuel and Manuel Serrano, Senescence in tumours: vidence from mice and humans, Nature Reviews Cancer. 10 (2010) 51-57. https:// doi.org/10.1038/nrc2772.[6] Hofmann, L. Sandra, Retinoids:"differentiation" agents for cancer treatment and prevention, Am J Med Sci. 304 (1992) 202-213. https://doi.org/10. 1097/00000441-199209000-00010.[7] Heo Shin-Hee, Juri Kwak and Kyung Lib Jang, All-trans retinoic acid induces p53-depenent apoptosis in human hepatocytes by activating p14 expression via promoter hypomethylation, Cancer letters. 362 (2015) 139-148 https://doi.org/10. 1016/j.canlet.2015.03.036.[8] P.H. Nguyen, J. Giraud, C. Staedel, L. Chambonnier, P. Dubus, E. Chevret, H. Bœuf, X. Gauthereau X, Rousseau B, Fevre M, Soubeyran I, Belleannée, S. Evrard, D. Collet, F. Mégraud, C. Varon, Knudsen, S. Erik, All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth, Oncogene. 35 (2016) 5619-5628. https://doi.org 10.1038/onc.2016. 87.[9] SherrCharles, Frank McCormick, The RB and p53 pathways in cancer, Cancer cell. 2(2002) 103-112. https://doi.org/10.1016/S1535-6108(02)00102-2.[10] Ngo Thu Ha, Luu Thi Binh, Le Thi Thanh Huong, Mai Van Linh, Nguyen Đac Trung, Nguyen Phu Hung, All-trans Retinoic Acid Effect on the Apoptosis Gene Expression of Gastric Cancer Cell (in Vietnamese), Journal of Sciences. 33 (2017) 138-143. https://doi.org/10.25073/2588-1140/vnunst. 4540.[11] K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method, Method. 25 (2001) 402-408. https://doi.org/10. 1006/meth.2001.1262.[12] E.Nelson Brown., Rinath Jeselsohn., Teeru Bihani., Miaofen G. Hu., Parthena Foltopoulou.,Charlotte Kuperwasser and Philip W. Hinds, Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium,Cancer Res. 72 (2012) 6477-6489. https://doi.org/10.1158/0008-5472.CAN-11-4139.[13] M. Trimarchi Jeffrey, Jacqueline A. Lees, Sibling rivalry in the E2F family, Nat Rev Mol Cell Biol. 3 (2002) 11-12. https://doi.org/10.1038/ nrm714.[14] Stevaux Olivier, Nicholas J. Dyson, A revised picture of the E2F transcriptional network and RB function, Current opinion in cell biology. 14 (2002) 684-691. https://doi.org/10.1016/S0955-0674(02)00388-5.[15] Wu Kou-Juey, Muh-Hwa Yang, Epithelial-mesenchymal transition and cancer stemness: the Twist1-Bmi1connection, Bioscience reports. 31 (2011) 449-455. https://doi.org/10.1042/BSR20 100114.[16] J.J.L. Jacobs, K. Kieboom, S. Marino, R.A. DePinho, M. van Lohuizen, The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus, Nature. 397(1999) 164-168. https://doi.org/ 10.1038/16476[17] R. Maestro, A.P. Dei Tos, Y. 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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 [1] Ma Joshi, Rue Bansal, Reng Purwar, Colour removal from textile effluents, Indian Journal of Fibre & Textile Research, 29 (2004) 239-259 http://nopr.niscair.res.in/handle/123456789/24631.[2] Kannan Nagar, Sundaram Mariappan, Kinetics and mechanism of removal of methylene blue by adsorption on various carbons-a comparative study, Dyes and pigments, 51 (2001) 25-40 https://doi.org/10.1016/S0143-7208(01)00056-0.[3] K Rastogi, J. N Sahu, B. C Meikap, M. N Biswas, Removal of methylene blue from wastewater using fly ash as an adsorbent by hydrocyclone, Journal of hazardous materials, 158 (2008) 531-540.https://doi.org/10.1016/j.jhazmat.2008.01. 105.[4] Qin Qingdong, Ma Jun, Liu Ke, Adsorption of anionic dyes on ammonium-functionalized MCM-41, Journal of Hazardous Materials, 162 (2009) 133-139 https://doi.org/10.1016/j.jhazmat. 2008.05.016.[5] Mui Muruganandham, Rps Suri, Sh Jafari, Mao Sillanpää, Lee Gang-Juan, Jaj Wu, Muo Swaminathan, Recent developments in homogeneous advanced oxidation processes for water and wastewater treatment, International Journal of Photoenergy, 2014 (2014). http://dx. doi.org/10.1155/2014/821674.[6] Herney Ramirez, Vicente Miguel , Madeira Luis Heterogeneous photo-Fenton oxidation with pillared clay-based catalysts for wastewater treatment: a review, Applied Catalysis B: Environmental, 98 (2010) 10-26 https://doi.org/ 10.1016/j.apcatb.2010.05.004.[7] Guo Rong, Jiao Tifeng, Li Ruifei, Chen Yan, Guo Wanchun, Zhang Lexin, Zhou Jingxin, Zhang Qingrui, Peng Qiuming, Sandwiched Fe3O4/carboxylate graphene oxide nanostructures constructed by layer-by-layer assembly for highly efficient and magnetically recyclable dye removal, ACS Sustainable Chemistry & Engineering, 6 (2017) 1279-1288 https://doi.org/10.1021/acssuschemeng.7b03635.[8] Sun Chao, Yang Sheng-Tao, Gao Zhenjie, Yang Shengnan, Yilihamu Ailimire, Ma Qiang, Zhao Ru-Song, Xue Fumin, Fe3O4/TiO2/reduced graphene oxide composites as highly efficient Fenton-like catalyst for the decoloration of methylene blue, Materials Chemistry and Physics, 223 (2019) 751-757 https://doi.org/ 10.1016/j.matchemphys.2018.11.056.[9] Guo Hui, Ma Xinfeng, Wang Chubei, Zhou Jianwei, Huang Jianxin, Wang Zijin, Sulfhydryl-Functionalized Reduced Graphene Oxide and Adsorption of Methylene Blue, Environmental Engineering Science, 36 (2019) 81-89 https://doi. org/10.1089/ees.2018.0157.[10] Zhao Lianqin, Yang Sheng-Tao, Feng Shicheng, Ma Qiang, Peng Xiaoling, Wu Deyi, Preparation and application of carboxylated graphene oxide sponge in dye removal, International journal of environmental research and public health, 14 (2017) 1301 https://doi.org/10.3390/ijerph14111301.[11] Yu Dandan, Wang Hua, Yang Jie, Niu Zhiqiang, Lu Huiting, Yang Yun, Cheng Liwei, Guo Lin, Dye wastewater cleanup by graphene composite paper for tailorable supercapacitors, ACS applied materials & interfaces, 9 (2017) 21298-21306 https://doi.org/10.1021/acsami.7b05318.[12] Wang Hou, Yuan Xingzhong, Wu Yan, Huang Huajun, Peng Xin, Zeng Guangming, Zhong Hua, Liang Jie, Ren MiaoMiao, Graphene-based materials: fabrication, characterization and application for the decontamination of wastewater and wastegas and hydrogen storage/generation, Advances in Colloid and Interface Science, 195 (2013) 19-40 https://doi. org/10.1016/j.cis.2013.03.009.[13] Marcano Daniela C, Kosynkin Dmitry V, Berlin Jacob M, Sinitskii Alexander, Sun Zhengzong, Slesarev Alexander, Alemany Lawrence B, Lu Wei, Tour James M, Improved synthesis of graphene oxide, ACS nano, 4 (2010) 4806-4814 https://doi.org/10.1021/nn1006368.[14] Zhang Jiali, Yang Haijun, Shen Guangxia, Cheng Ping, Zhang Jingyan, Guo Shouwu, Reduction of graphene oxide via L-ascorbic acid, Chemical Communications, 46 (2010) 1112-1114 http://doi. org/10.1039/B917705A [15] Gong Ming, Zhou Wu, Tsai Mon-Che, Zhou Jigang, Guan Mingyun, Lin Meng-Chang, Zhang Bo, Hu Yongfeng, Wang Di-Yan, Yang Jiang, Nanoscale nickel oxide/nickel heterostructures for active hydrogen evolution electrocatalysis, Nature communications, 5 (2014) 4695 https:// doi.org/10.1038/ncomms5695.[16] Wu Zhong-Shuai, Yang Shubin, Sun Yi, Parvez Khaled, Feng Xinliang, Müllen Klaus, 3D nitrogen-doped graphene aerogel-supported Fe3O4 nanoparticles as efficient electrocatalysts for the oxygen reduction reaction, Journal of the American Chemical Society, 134 (2012) 9082-9085 https://doi.org/10.1021/ja3030565.[17] Nguyen Son Truong, Nguyen Hoa Tien, Rinaldi Ali, Nguyen Nam Van, Fan Zeng, Duong Hai Minh, Morphology control and thermal stability of binderless-graphene aerogels from graphite for energy storage applications, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 414 (2012) 352-358 https://doi.org/ 10.1016/j.colsurfa.2012.08.048.[18] Deng Yang, Englehardt James D, Treatment of landfill leachate by the Fenton process, Water research, 40 (2006) 3683-3694 https://doi.org/ 10.1016/j.watres.2006.08.009.

Introdução: Com a evolução da microcirurgia ao longo dos anos o Retalho Anterolateral da Coxa vem se tornando uma das principais opções para reconstruções na cabeça, pescoço, tronco e extremidades devido sua versatilidade e confiabilidade. Objetivo: Descrever dados de um hospital terciário referência em trauma na reconstrução de extremidades com o Retalho Anterolateral da Coxa. Método: Este é um estudo retrospectivo de 18 retalhos Anterolateral da Coxa microcirúrgicos realizados entre Março de 2016 e Outubro de 2019 em pacientes de todas as idades, na reconstrução de membros, onde se observou dados referentes ao paciente: idade, sexo, membro acometido, tempo entre a lesão e a confecção do retalho; ao intraoperatório: anatomia dos vasos perfurantes, tempo cirúrgico total, vasos receptores utilizados; e informações do pós-operatório: número de cirurgias relacionadas ao retalho, necessidade de reabordagem e número de perdas. Foram excluídos pacientes que perderam seguimento ou que apresentaram dados do prontuário incompletos. Realizou-se estatística descritiva e cruzamento de algumas variáveis utilizando o teste t-Student. Resultados: Nas reconstruções houve predomínio de pacientes do sexo masculino (72%), em idade produtiva, de etiologia traumática e nos membros inferiores. O tempo médio até a reconstrução foi de 21 dias e o tempo cirúrgico foi de 384 minutos. O paciente permaneceu, em média, 39 dias internado. Dos 18 retalhos, 3 evoluíram com necrose, 2 por trombose arterial e 1 por infecção. 6 retalhos necessitaram de reaborgadem de emergência, 3 por sangramento, 2 por congestão e 1 por infecção. Foram realizadas uma média de 3 cirurgias até a alta. Foram identificadas 15 perfurantes miocutâneas (83%) e 3 septocutâneas (17%). A análise do sucesso do retalho em relação ao tempo cirúrgico e dos dias até a cirurgia não mostrou significância estatística, assim como a necessidade de reabordagem em relação ao tempo cirúrgico. Conclusão: O retalho Anterolateral da Coxa mostrou-se confiável, além de apresentar diversas vantagens como: por ser retirado com uma grande ilha de pele, apresentar pedículo longo, vasos de bom calibre, não necessitar de mudança de decúbito e apresentar baixa morbidade da área doadora.Descritores: Retalho Miocutâneo; Microcirurgia; Hospitais Especializados.ReferênciasDaniel RK, Taylor GI. Distant transfer of an island flap by microvascular anastomoses. A clinical technique. Plast Reconstr Surg. 1973;52(2):111-17.Ninkovic M, Voigt S, Dornseifer U, Lorenz S, Ninkovic M. Microsurgical advances in extremity salvage. Clin Plast Surg. 2012;39(4):491-505.Tamimy MS, Rashid M, Ehtesham-ul-Haq, Aman S, Aslam A, Ahmed RS. 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Object segmentation is an important task which is widely employed in many computer vision applications such as object detection, tracking, recognition, and retrieval. It can be seen as a two-phase process: object detection and segmentation. Object segmentation becomes more challenging in case there is no prior knowledge about the object in the scene. In such conditions, visual attention analysis via saliency mapping may offer a mean to predict the object location by using visual contrast, local or global, to identify regions that draw strong attention in the image. However, in such situations as clutter background, highly varied object surface, or shadow, regular and salient object segmentation approaches based on a single image feature such as color or brightness have shown to be insufficient for the task. This work proposes a new salient object segmentation method which uses a depth map obtained from the input image for enhancing the accuracy of saliency mapping. A deep learning-based method is employed for depth map estimation. Our experiments showed that the proposed method outperforms other state-of-the-art object segmentation algorithms in terms of recall and precision. KeywordsSaliency map, Depth map, deep learning, object segmentation References[1] Itti, C. Koch, E. Niebur, A model of saliency-based visual attention for rapid scene analysis, IEEE Transactions on pattern analysis and machine intelligence 20(11) (1998) 1254-1259.[2] Goferman, L. Zelnik-Manor, A. Tal, Context-aware saliency detection, IEEE transactions on pattern analysis and machine intelligence 34(10) (2012) 1915-1926.[3] Kanan, M.H. Tong, L. Zhang, G.W. Cottrell, Sun: Top-down saliency using natural statistics, Visual cognition 17(6-7) (2009) 979-1003.[4] Liu, Z. Yuan, J. Sun, J. Wang, N. Zheng, X. Tang, H.-Y. Shum, Learning to detect a salient object, IEEE Transactions on Pattern analysis and machine intelligence 33(2) (2011) 353-367.[5] Perazzi, P. Krähenbühl, Y. Pritch, A. Hornung, Saliency filters: Contrast based filtering for salient region detection, in: Computer Vision and Pattern Recognition (CVPR), 2012 IEEE Conference on, IEEE, 2012, pp. 733-740.[6] M. Cheng, N.J. Mitra, X. Huang, P.H. Torr, S.M. Hu, Global contrast based salient region detection, IEEE Transactions on Pattern Analysis and Machine Intelligence 37(3) (2015) 569-582.[7] Borji, L. Itti, State-of-the-art in visual attention modeling, IEEE transactions on pattern analysis and machine intelligence 35(1) (2013) 185-207.[8] Simonyan, A. Vedaldi, A. Zisserman, Deep inside convolutional networks: Visualising image classification models and saliency maps, arXiv preprint arXiv:1312.6034.[9] Li, Y. Yu, Visual saliency based on multiscale deep features, in: Proceedings of the IEEE conference on computer vision and pattern recognition, 2015, pp. 5455-5463.[10] Liu, J. 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