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Journal articles on the topic "907/.2"
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Sun, Kaiming, Ruzanna Atoyan, Mylissa A. Borek, et al. "The Combination of Venetoclax and CUDC-907 Exhibits Synergistic Activity in Venetoclax-Refractory DLBCL." Blood 128, no. 22 (2016): 4184. http://dx.doi.org/10.1182/blood.v128.22.4184.4184.
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Abstract CUDC-907 is a first-in-class, oral, dual inhibitor of Class I and II HDAC, as well as Class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6 and 10 and PI3K-alpha, delta and beta isoform. Preclinical studies demonstrate that CUDC-907 has potent effects on acetylated histone-regulated genes and PI3K signaling. CUDC-907 showed potent antitumor activity in multiple preclinical tumor models as well as in patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL), with objective responses reported in multiple patients, including complete responses. It is currently being investigated in a Phase 2 study in patients with RR DLBCL, including those with MYC-alterations. Preclinical studies of CUDC-907 in combination with chemotherapeutic and targeted agents are in progress. Venetoclax, a BH3 mimetic and selective BCL2 inhibitor, was recently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) whose tumors had a 17p deletion. Results from a Phase 1 study of venetoclax monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma showed that patients with DLBCL exhibited short-lived responses to venetoclax. Thus, combination approaches may be required to achieve durable responses to venetoclax in DLBCL. In our preclinical studies, we examined the combination of venetoclax and CUDC-907 in DLBCL cell lines. Interestingly, the combination exhibited the most synergy, as measured by fold-improvement over predicted additive effect, in cell lines insensitive to venetoclax. For example, OCI-Ly3 cells were insensitive to single agent venetoclax with an IC50 >10uM; however, in combination with a fixed dose (12nM) of CUDC-907, venetoclax resulted in >10000-fold improvement in potency with a combination IC50 of 0.001uM. Synergy was also observed in tumor growth inhibition studies in xenograft models. Western blot analysis showed that single-agent CUDC-907 simultaneously increased pro-apoptotic BIM protein and decreased anti-apoptotic BCL2 protein levels. Interestingly, the low nano-molar concentrations of CUDC-907 that were shown to regulate the BCL-2 family member proteins could also potentiate pro-apoptotic effects of venetoclax when used together in combination in WSU-DLCL2 cell line which carries MYC and BCL2 translocations. Thus, the effect of CUDC-907 on BCL2 family members appears to be the basis for the observed synergy with venetoclax, which functions to displace BIM from BCL2. These results provide a mechanistic rationale for the use of CUDC-907 in combination with venetoclax for the treatment of patients with DLBCL. Disclosures Sun: Curis: Employment, Equity Ownership. Atoyan:Curis: Employment, Equity Ownership. Borek:Curis: Employment, Equity Ownership. Dellarocca:Curis: Employment, Equity Ownership. Rhyasen:Curis: Employment, Equity Ownership. Fattaey:Curis: Employment, Equity Ownership. Tuck:Curis, Inc.: Employment, Equity Ownership.
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Knight, Tristan, Xinan Qiao, Jun Ma, et al. "The Combination of CUDC-907 and Gilteritinib Shows Promising Antileukemic Activity in Vitro and In Vivo in Preclinical Models of FLT3-ITD AML." Blood 134, Supplement_1 (2019): 1262. http://dx.doi.org/10.1182/blood-2019-123793.
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Introduction FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are found in approximately one quarter of acute myeloid leukemia (AML) cases. Its presence results in constitutive activation of the FLT3 receptor tyrosine kinase and its downstream growth/pro-survival pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT, and confers a poor prognosis. Gilteritinib is a selective inhibitor of FLT3 recently approved by the Food and Drug Administration for treatment of patients with relapsed/refractory AML and a FLT3 mutation. However, gilteritinib exposure induces upregulation of FLT3 - a mechanism of resistance. Previously, we showed that CUDC-907, a dual PI3K/histone deacetylase inhibitor, downregulates FLT3 expression (Li X, et al. Haematologica. 2019; epub ahead of print). We therefore hypothesized that combining CUDC-907 with gilteritinib would abrogate FLT3 upregulation and expression, resulting in synergistic antileukemic activities against FLT3-mutated AML. Methods FLT3-ITD AML cell lines and primary patient samples were treated with gilteritinib or CUDC-907, alone or in combination at clinically achievable concentrations, and subjected to annexin V/propidium iodide staining and flow cytometry analysis to quantify apoptosis. Protein levels of FLT3, Bcl-2 family proteins, and key components of the MAPK/ERK, PI3K/AKT, and JAK/STAT pathways were examined using western blotting. The impact of the observed alterations upon apoptosis were confirmed via overexpression, knockdown, and targeted inhibitor experiments. Real-time RT-PCR was used to determine FLT3 transcript levels. The FLT3-ITD AML cell line MV4-11 was used to generate a xenograft mouse model to assess in vivo efficacy of the two agents. Results CUDC-907 and gilteritinib demonstrated potent synergistic antileukemic effects in FLT3-ITD AML cell lines in vitro and patient samples ex vivo, with combined therapy. CUDC-907 abolished gilteritinib-induced expression of FLT3 in both cell lines and primary patient samples. Gilteritinib treatment reduced p-AKT, p-S6, and p-STAT5 and increased p-ERK, while CUDC-907 reduced p-AKT and p-ERK, and upregulated p-STAT5. The combination of gilteritinib and CUDC-907 decreased not only p-AKT and p-S6, but also p-ERK and p-STAT5. Targeted inhibition of ERK and JAK2/STAT5 signaling by SCH772984 and AZD1480, respectively, confirmed their roles in resistance to gilteritinib and CUDC-907 monotherapies, respectively. Combined gilteritinib and CUDC-907 treatment reduced expression of the anti-apoptotic BCL-2 family member Mcl-1 and increased expression of the pro-apoptotic protein Bim. MCL-1 overexpression and BIM knockdown partially rescued FLT3-ITD AML cells upon drug treatment, confirming their role in the antileukemic activity of combined gilteritinib and CUDC-907. To determine in vivo efficacy of the two agents, NSGS mice were injected with MV4-11 cells. Three days later, the mice were randomized into vehicle control (n=5), 40 mg/kg gilteritinib (oral gavage; n=5), 100 mg/kg CUDC-907 (oral gavage; n=5) or combination (40 mg/kg gilteritinib + 100 mg/kg CUDC-907; n=6) groups. CUDC-907 was given daily for 5 days on, 2 days off, for a total of 4 cycles. Gilteritinib was administered daily for 28 days. Both agents were well tolerated; maximal weight loss was 5.5%, 0.9%, and 6.7% in the CUDC-907, gilteritinib, and combination groups, respectively. Median survival of mice in the vehicle control group was 43 days. Median survival in the CUDC-907 monotherapy and gilteritinib monotherapy arm was 40.5 days and 104 days, respectively. One mouse in the combination therapy arm died on day 138, while the remaining 5 mice in the combination therapy arm continue to survive, as of time of writing (day 168), and are asymptomatic (Figure 1). Conclusion We confirmed that the combination of CUDC-907 plus gilteritinib synergistically induces apoptosis in both FLT3-ITD AML cell lines and primary patient samples, and that gilteritinib-induced FLT3 expression is abolished by CUDC-907. Cooperative inhibition of the PI3K-AKT, JAK-STAT, and RAS-RAF pathways, as well as upregulation of Bim/downregulation of Mcl-1 all appear to contribute to this observed antileukemic synergy. Our cell line-derived xenograft mouse model provides strong evidence of in vivo efficacy and robust grounds for clinical translation of this therapeutic combination. Disclosures No relevant conflicts of interest to declare.
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Younes, Anas, Jesus G. Berdeja, Manish R. Patel, et al. "Phase 1 Trial Testing Single Agent CUDC-907, a Novel, Oral Dual Inhibitor of Histone Deacetylase (HDAC) and PI3K: Initial Assessment of Patients with Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL), Including Double Expressor (DE) Lymphoma." Blood 126, no. 23 (2015): 257. http://dx.doi.org/10.1182/blood.v126.23.257.257.
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Abstract DLBCL, the most common lymphoid malignancy in adults, is an aggressive form of non-Hodgkin lymphoma (NHL) with significant heterogeneity in terms of gene expression, prognosis and response to treatment. Certain histone modifications and HDAC expression patterns have been implicated in the pathobiology of DLBCL and other cancers. Aberrant PTEN/PI3K/AKT signaling is also frequently observed in a variety of human cancers including DLBCL, where loss of PTEN activity and/or activating mutations in PI3K and AKT have been shown to reduce apoptosis and promote cell proliferation. Synergistic anti-tumor effects achieved with HDAC and PI3K inhibitor combinations in various DLBCL xenograft models have provided a strong rationale for testing a highly potent dual HDAC and PI3K inhibitor, CUDC-907. Significant anti-tumor effects have been observed across a wide range of DLBCL models exposed to CUDC-907, including the U2932 ABC DLBCL model that harbors BCL2 translocation and over-expresses cMYC and BCL6, and the WSU-DLCL-2 GCB DLBCL model that harbors EZH2 mutation. These disease mechanisms and preclinical data have led to testing of CUDC-907 in an ongoing Phase 1 trial in patients (pts) with various hematologic cancers. Sixty-three heavily pre-treated pts with lymphoma or multiple myeloma have received CUDC-907 in 21-day cycles according to once daily (QD), intermittent (BIW or TIW), or five days on/two days off (5/2) dosing schedules. CUDC-907 was escalated in 30 mg increments such that pts received 30-60 mg QD, 60-150 mg intermittently, or 60 mg 5/2. A dose expansion using the 60 mg 5/2 dose and schedule is ongoing. Thus far, CUDC-907 has demonstrated a manageable side effect profile and sustained clinical efficacy, particularly in the subset of pts with RR DLBCL. The most common treatment-related adverse events (AEs) were diarrhea (54%; 5% Grade ≥3), fatigue (37%; 3% Grade ≥3), nausea (22%) and thrombocytopenia (18%; 14% Grade ≥3), with dose limiting toxicities of hyperglycemia (QD and BIW schedules) and diarrhea (QD and TIW schedules). Side effects were reversible and manageable. Among 11/18 subjects with RR DLBCL who were evaluable for disease response, 6/11 (55%) achieved objective responses (2 CRs and 4 PRs); lasting a median of 119 days (range: 48 - 354+). Of 7 pts with sufficient tissue, 3 response-evaluable pts were found to over-express MYC and BCL2 by IHC, meeting criteria applied to "double-expressor" (DE) DLBCL. On CUDC-907 monotherapy, 2/3 confirmed pts with DE DLBCL have attained objective responses: 1 ongoing CR (followed by autologous stem cell transplant) and 1PR (lasting 132 days). The third response-evaluable pt with DE DLBCL has experienced lengthy stabilization of disease (171+ days). Signals emerging from preclinical and clinical studies suggest that pts with DLBCL, including those with particularly aggressive disease, may derive benefit from treatment with CUDC-907. Enrollment of pts with RR DLBCL is ongoing into the expansion phase of the Phase 1 trial that is testing CUDC-907 on the 60 mg 5/2 RP2D as monotherapy and in combination with rituximab. Tissue obtained from pts with RR DLBCL treated with CUDC-907 will be assessed for MYC, BCL2, and other genetic aberrations that will be correlated with clinical outcomes observed in the trial. A Phase 2 trial of CUDC-907 in RR NHL is currently being planned, with emphasis on MYC aberrations. Disclosures Younes: Celgene: Honoraria; Incyte: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Novartis: Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding; Curis: Research Funding; Takeda Millenium: Honoraria. Berdeja:Acetylon: Research Funding; Onyx: Research Funding; Abbvie: Research Funding; Curis: Research Funding; Celgene: Research Funding; Takeda: Research Funding; MEI: Research Funding; Novartis: Research Funding; Janssen: Research Funding; BMS: Research Funding; Array: Research Funding. Flinn:Celgene Corporation: Research Funding. Clancy:Curis: Employment, Equity Ownership. Ma:Curis: Employment, Equity Ownership. Sun:Curis: Employment, Equity Ownership. Tian:Curis: Employment, Equity Ownership. Wang:Curis: Employment, Equity Ownership. Viner:Curis: Employment, Equity Ownership.
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Shulman, David Stephen, Clay Gustafson, Kieuhoa Tran Vo, et al. "Phase 1 multicenter trial of CUDC-907 in children and young adults with relapsed or refractory solid tumors, CNS tumors, and lymphoma." Journal of Clinical Oncology 35, no. 15_suppl (2017): TPS10576. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps10576.
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TPS10576 Background: CUDC-907 is an oral first-in-class small molecule inhibitor of histone deacetylases (HDACs) and phosphatidylinositol-3-kinases (PI3Ks), two enzyme classes commonly implicated in pediatric malignancies. Preclinical data demonstrate that inhibition of these enzymes decreases tumor growth across a range of histologies. Data from preclinical and clinical studies suggest that down-regulation of Myc or Mycn signaling may be important in the antineoplastic effects of CUDC-907. Myc or Mycn signaling appears to drive a number of pediatric cancers, heralds a poor prognosis in many of these diseases and has proven difficult to target. CUDC-907 has completed adult phase I testing in patients with hematologic malignancies. The drug was tolerable using a 5 days on/2 days off (5/2) dosing strategy, with a recommended phase II dose of 60 mg. Diarrhea, fatigue, nausea and thrombocytopenia were the most commonly reported side effects. Partial and complete responses were observed in patients with Myc-altered diffuse large B cell lymphoma. Methods: This study is a phase I, open-label, multicenter trial of CUDC-907 in patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). The primary objectives are to determine the recommended phase II dose, describe toxicities, and describe pharmacokinetic parameters of CUDC-907 in this population. Other objectives include evaluation of disease response and exploration of the pharmacodynamic effects of CUDC-907. Patients receive CUDC-907 orally on a 5/2 schedule in 28-day cycles, with a pediatric mini-tab formulation available for younger children. Part A consists of a standard 3+3 design evaluating up to three dose levels. Following dose escalation, Part B consists of two expansion cohorts for patients with Mycn/Myc-driven neuroblastoma or mature B-cell lymphoma. Up to 44 patients may be enrolled across Parts A and B. Detailed pharmacokinetic testing is required in the first two cycles. Optional pharmacodynamic testing will quantify histone acetylation, Myc protein, and phospho-S6 in serial blood samples. Enrollment began in October 2016 and is ongoing. Clinical trial information: NCT02909777.
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Zhang, Dongyun, Robert Damoiseaux, Lilit Babayan, et al. "Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease." Journal of Clinical Endocrinology & Metabolism 106, no. 1 (2020): e232-e246. http://dx.doi.org/10.1210/clinem/dgaa699.
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Abstract Context Cushing disease (CD) is a life-threatening disorder. Therapeutic goals include symptom relief, biochemical control, and tumor growth inhibition. Current medical therapies for CD by and large exert no action on tumor growth. Objective To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth. Design High throughput screen employing a novel “gain of signal” ACTH AlphaLISA assay. Setting Academic medical center. Patients Corticotroph tumor tissues from patients with CD. Interventions None. Main outcome measures Potent inhibitors of corticotroph tumor ACTH secretion and growth. Results From a kinase inhibitor library, we identified the dual PI3K/HDAC inhibitor CUDC-907 as a potent inhibitor of murine and human corticotroph tumor ACTH secretion (median effective concentration 1-5 nM), and cell proliferation (median inhibitory concentration 5 nM). In an in vivo murine corticotroph tumor xenograft model, orally administered CUDC-907 (300 mg/kg) reduced corticotroph tumor volume (TV [cm3], control 0.17 ± 0.05 vs CUDC-907 0.07 ± 0.02, P < .05) by 65% and suppressed plasma ACTH (ACTH [pg/mL] control 206 ± 27 vs CUDC-907 47 ± 7, P < .05) and corticosterone (corticosterone [ng/mL] control 180 ± 87 vs CUDC-907 27 ± 5, P < .05) levels by 77% and 85% respectively compared with controls. We also demonstrated that CUDC-907 acts through HDAC1/2 inhibition at the proopiomelanocortin transcriptional level combined with its PI3K-mediated inhibition of corticotroph cell viability to reduce ACTH secretion. Conclusions Given its potent efficacy in in vitro and in vivo models of CD, combined with proven safety and tolerance in clinical trials, we propose CUDC-907 may be a promising therapy for CD.
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Soosainathan, Arany, Joanna Nikitorowicz-Buniak, Sunil Pancholi, et al. "Abstract P4-02-05: Exploiting novel models of endocrine-resistant breast cancer to identify new therapeutic targets." Cancer Research 82, no. 4_Supplement (2022): P4–02–05—P4–02–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-02-05.
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Abstract Introduction: While endocrine therapy is an effective, well-tolerated treatment for estrogen receptor positive breast cancer (ER+BC), a large proportion of initial responders will develop hormone therapy resistance, and relapse. A major challenge in determining the mechanisms underlying endocrine therapy resistance is our limited ability to recapitulate inter- and intra-tumour heterogeneity in vitro. In this study we developed ER+BC cells resistant to estrogen deprivation, and to palbociclib treatment, and subjected these to 2D and 3D high-throughput drug and siRNA screens, in order to elucidate the pathways underpinning the development of endocrine resistance. Methods: ER+BC cell lines modelling relapse on aromatase inhibitor therapy were derived by long-term culture in the absence of exogenous estrogen, and were termed long-term estrogen deprived (LTED). Two of these lines were then used to generate additional resistance to palbociclib, thus modelling endocrine-resistant, palbociclib-resistant disease. These lines were then subjected to screens performed in 2D and 3D. Effects of the siRNAs and drug compounds were assessed by measuring cell viability, with a robust Z score of -2 taken as a threshold of significance. Table 1 outlines the key characteristics of the cell lines, the details of the drug screens performed, and the top 3 drugs with their corresponding targets. The siRNA screens were performed in 2D and 3D with a 709 kinome library. Results: The siRNA screens highlighted PI3K-AKT-mTOR signalling as being dysregulated in multiple 3D and 2D models, while the drug screens showed that compounds targeting phosphoinositide 3-kinase alpha (PI3Kα) were significant common hits. This is consistent with the recent success of the BYLieve trial in targeting PI3Kα. A second key area of dependency was in cell cycle regulation, with CDK7 and CDK9 found to be significant hits in multiple models. The 709 kinase screens in 2D and 3D demonstrated broadly similar results (43 vs 37 median number of significant hits 2D vs 3D; Z-score <-2), while drug screening in 3D (Table 1) provided increased discrimination in identifying key vulnerabilities. CDK7 and CDK9 were selected for further study. siRNA-mediated knockdown of CDK9 had a significant effect on cell viability in endocrine-sensitive, endocrine-resistant, and palbociclib-resistant settings, whereas CDK7 knockdown did not. However, the CDK7 inhibitors THZ1 and ICEC0942, and the CDK9 inhibitors NVP-2 and AZD4573, were equally effective in endocrine-sensitive, endocrine-resistant, and palbociclib-resistant settings. Importantly, presence of a PIK3CA mutation was required for entry into the BYLieve trial, while CDK7 and CDK9 inhibitors were effective in the PIK3CA wild-type and mutant setting. Furthermore, while the presence of the ESR1 mutation is associated with poorer PFS with certain therapies, such as exemestane, the CDK7 and CDK9 inhibitors were equally effective in the ESR1 mutant and wild-type setting. Finally, combination treatment of palbociclib with CDK7 and CDK9 inhibitors showed synergism in palbociclib-resistant models. Conclusions: Targeted inhibition of CDK7 and/or CDK9 is effective in the LTED palbociclib-resistant setting, thus opening future avenues for the treatment of advanced, endocrine-resistant, palbociclib-resistant breast cancer. Table 1.Cell line characteristics and drug screen findingsCell line and key characteristics2D drug screen of 396 compounds, at 3 concentrations*3D drug screen of 70 compounds at 1 concentrationNumber of significant drug screen hits (Z score <-2). The top 3 hits and their targets are shownMCF7 LTEDWT6812PIK3CA mutantDinaciclib (CDKs 2/5/1/9)CUDC-907 (PI3Kα/HDAC)ESR1 wild typeTHZ1 (CDK7)PIK-75 HCl (PI3K)PIK-75 HCl (PI3Kα)Flavopiridol (CDKs 1/2/4/6)MCF7 LTEDY537C849PIK3CA mutantCUDC-907 (PI3Kα/HDAC)CUDC-907 (PI3Kα/HDAC)Activating ESR1 mutation (Y537C)THZ1 (CDK7)BGT226 (PI3K/mTOR)PIK-75 HCl (PI3Kα)NVP-2 (CDK9)MCF7 LTEDY537C-PalboR(n/a)8As MCF7 LTEDY537CCUDC-907 (PI3Kα/HDAC)Palbociclib resistantPIK-75 HCl (PI3Kα)NVP-2 (CDK9)SUM44 LTEDY537S6717PIK3CA mutantDinaciclib (CDKs 2/5/1/9)NVP-2 (CDK9)Activating ESR1 mutation (Y537S)CUDC-907 (PI3Kα/HDAC)WYE-125132 (mTOR)E-cadherin nullBGT226 (PI3K/mTOR)CUDC-907 (PI3Kα/HDAC)HCC1428 LTED5114PIK3CA wild typeCUDC-907 (PI3Kα/HDAC)CUDC-907 (PI3Kα/HDAC)ESR1 wild typeBGT226 (PI3K/mTOR)BGT226 (PI3K/mTOR)Torin-2 (mTOR)Sapanisertib (mTOR)HCC1428 LTEDPalboR(n/a)11As HCC1428 LTEDCUDC-907 (PI3Kα/HDAC)Palbociclib resistantCUDC-101 (EGFR)BGT226 (PI3K/mTOR)T47D LTED5712PIK3CA mutantCUDC-907 (PI3Kα/HDAC)CUDC-907 (PI3Kα/HDAC)Loss of ER expression in adapting to LTEDDinaciclib (CDKs 2/1/5/9)PIK-75 HCl (PI3Kα)THZ1 (CDK7)CUDC-101 (EGFR)ZR75.1 LTED29(n/a)PTEN nullDinaciclib (CDKs 2/5/1/9)Loss of ER expression in adapting to LTEDTHZ1 (CDK7)Omipalisib (PI3K/mTOR)LTED: long-term estrogen deprived*Number of significant hits at 100 nM dose are shown Citation Format: Arany Soosainathan, Joanna Nikitorowicz-Buniak, Sunil Pancholi, Marjan Iravani, John Alexander, Syed Haider, Stephen R Johnston, Mitchell Dowsett, Lesley A Martin, Clare M Isacke. Exploiting novel models of endocrine-resistant breast cancer to identify new therapeutic targets [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 P4-02-05.
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Younes, Anas, Ian W. Flinn, Yasuhiro Oki, et al. "A First-In-Man Phase 1 Study Of CUDC-907, a First-In-Class Chemically-Designed Dual Inhibitor Of PI3K and HDAC In Patients With Refractory Or Relapsed Lymphoma and Multiple Myeloma." Blood 122, no. 21 (2013): 4363. http://dx.doi.org/10.1182/blood.v122.21.4363.4363.
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Abstract Background PI3K and HDAC inhibitors have demonstrated single agent clinical activity in patients (pts) with a variety of B-cell malignancies, including lymphoma and multiple myeloma (MM). Preclinical experiments indicated synergistic effects between HDAC and PI3K pathway inhibitors. CUDC-907 is a chemically-designed small molecule that combines the active hydroxamate moiety of HDAC inhibitors with a PI3K inhibitor morpholinopyrimidine pharmacophore. CUDC-907 potently inhibits class I PI3K (alpha, beta, and delta) as well as HDACs class I and II enzymes. Preclinical experiments demonstrated that CUDC-907 inhibits the PI3K-AKT-mTOR pathway and compensatory MEK/ERK and STAT3 signaling pathways. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells, including human B-cell tumor xenograft models. Here we present the preliminary results of a First-In-Human Phase 1 study of CUDC-907. Methods This is a Phase 1 study using a standard 3+3 dose escalation design. CUDC-907 was orally administered to pts with lymphoma and MM. Patients were eligible if they had relapsed or refractory disease after at least 2 prior regimens and adequate bone marrow and organ functions. The starting dose was 30mg given continuously once daily in 21-day cycles without rest, with planned escalations until the maximum tolerated dose was reached. In the absence of dose limiting toxicities (DLTs), pts were allowed to continue treatment until disease progression. DLTs were defined so as to include ≥ Grade 3 adverse events (AE) or any Grade AE resulting in dose delay ≥7 days. Tumor response was assessed every 2 cycles using standard criteria appropriate for the disease type. Blood samples for pharmacokinetic (PK) and pharmacodynamic analyses were collected during Cycle 1. Results At the time of this abstract, 6 pts were treated on study: 3 each at 30 and 60 mg/day dose. The median age was 70 years (range 61-77) and 2 pts had MM, 3 Non-Hodgkin’s lymphoma and 1 Hodgkin's lymphoma. The median number of prior regimens was 3 (range 2-8) and 3 pts had prior bone marrow transplant. The most common treatment-related AEs were diarrhea (6 pts, Grade 1-3) and thrombocytopenia (5 pts, Grade 1-4). The severity and time to onset of these events appear to be dose-related. In general, thrombocytopenia recovered quickly by withholding treatment and diarrhea was well controlled with loperamide co-administration. However, 1 pt at the 60 mg/day dose level with a history of diabetes and poor co-medication compliance (i.e., loperamide and insulin) developed multiple DLTs including diarrhea (Grade 3), thrombocytopenia (Grade 4) and hyperglycemia (Grade 4). Of the 6 pts, 2 remain on treatment at ≥ 5 cycles with stable disease. CUDC-907 was rapidly transformed to 2 metabolites, M1 and M2, with M2 retaining potent PI3K inhibition activity. While CUDC-907 had low plasma exposure and a short half-life, M2 levels increased during the 24 hour PK sampling period. Conclusion To address AEs and further dose escalate, with consideration of the PK profile of the parent and M2 metabolite, the protocol was modified to include 2 additional dosing schedules: 2x/week and 3x/week administration. In addition, the 30mg continuous daily dose cohort was expanded to further assess the tolerability of this schedule. Updated results from pts treated with the 3 schedules will be presented. Disclosures: Younes: Gilead: Honoraria; Seattle Genetics: Honoraria; Millenium: Honoraria; Celgene: Honoraria; Johnson & Johnson: Honoraria; Pharmacyclics: Honoraria. Fattaey:Curis, Inc.: Employment. Lai:Curis, Inc.: Employment. Laliberte:Curis, Inc.: Employment. Voi:Curis, Inc.: Employment.
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Li, Xinyu, Jun Ma, Yongwei Su, et al. "Combination of Venetoclax and CUDC-907 Shows Superior Antileukemic Activity Against Acute Myeloid Leukemia Ex Vivo." Blood 128, no. 22 (2016): 1571. http://dx.doi.org/10.1182/blood.v128.22.1571.1571.
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Abstract Overall survival rates for adults and children with acute myeloid leukemia (AML) remain unacceptably low. Resistance to chemotherapy is the major factor contributing to such dismal overall survival rates. Chemoresistance in leukemia cell line models has been associated with overexpression of the anti-apoptotic Bcl-2 family members. As such, small molecule Bcl-2 inhibitors represent a promising strategy for treating AML. Venetoclax (ABT-199) is a Bcl-2-selective inhibitor that has demonstrated promising antileukemic activity against AML. However, initial resistance to ABT-199 remains a concern. In our most recent study, we identified a novel Mcl-1-mediated intrinsic mechanism of resistance to ABT-199 in AML cells: ABT-199 treatment results in increased sequestration of Bim by Mcl-1, preventing Bim from inducing apoptosis (Niu X, et al. Clinical Cancer Research. 2016; epub ahead of print). We also found that ABT-199 in combination with DNA damaging agents results in enhanced DNA damage and synergistic antileukemic activity against AML cells. Based on these findings, we hypothesized that simultaneously downregulating Mcl-1, upregulating Bim, and enhancing DNA replication stress and/or DNA damage would maximally enhance ABT-199-induced cell death, leading to potent synergistic antileukemic activity against AML. CUDC-907, a dual histone deacetylase inhibitor (HDACI) and PI3K inhibitor, is currently being tested in Phase I and Phase II clinical trials for the treatment of lymphoma, multiple myeloma, and advanced/relapsed solid tumors (www.clinicaltrials.gov). It inactivates both PI3K/AKT and MEK/ERK signaling pathways in different cancer cell types. Inhibition of these pathways has been shown to cause downregulation of Mcl-1 and upregulation of Bim and HDACIs have been demonstrated to downregulate CHK1 and Wee1, as well as upregulate Bim, leading to DNA damage and cell death. Furthermore, CHK1 and Wee1 inhibitors have been shown to cause DNA replication stress through downregulation of ribonucleotide reductase (RNR). Therefore, CUDC-907 would be an ideal compound to combine with ABT-199 to enhance its antileukemic activity against AML. In this study, we investigated the antileukemic activity of CUDC-907 alone and in combination with ABT-199 in both AML cell lines and primary patient samples. CUDC-907 treatment resulted in increased Bim expression and decreased Mcl-1, CHK-1, Wee1, and RRM1 (the regulatory subunit of RNR) expression in both AML cell lines and primary patient samples. Ectopic overexpression of Mcl-1 and shRNA knockdown of Bim demonstrated that both were at least partially involved in CUDC-907-induced apoptosis. Treatment with a CHK1-selective inhibitor LY2603618, the Wee1-selective inhibitor MK-1775, or hydroxyurea (RNR inhibitor) enhanced CUDC-907-induced apoptosis in a synergistic fashion, demonstrating that downregulation of Wee1, CHK1, and RRM1 was also an important contributor to CUDC-907-induced apoptosis. Consistent with our hypothesis, the combination of CUDC-907 and ABT-199 resulted in significantly increased apoptosis compared to single drug treatment and excellent synergy in both AML cell lines (n=6) and primary patient samples (n=18), regardless of their sensitivities to ABT-199. Synergy was also detected when AML cells were treated with CUDC-907 first for 16 h and then followed by ABT-199 treatment for another 8 h. Western blots revealed that combined treatment caused further decrease of Mcl-1, CHK1, and Wee1, while comet assays revealed that the combination caused significantly increased DNA strand breaks in both AML cell lines and primary patient samples. Our results demonstrate that CUDC-907 synergizes with ABT-199 in AML cells, and support the clinical development of the combination of CUDC-907 and ABT-199 in the treatment of AML. Disclosures Yang: Seattle Genetics: Research Funding.
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Ruz-Maldonado, Inmaculada, Patricio Atanes, Guo Cai Huang, Bo Liu, and Shanta J. Persaud. "Direct Stimulatory Effects of the CB2 Ligand JTE 907 in Human and Mouse Islets." Cells 10, no. 3 (2021): 700. http://dx.doi.org/10.3390/cells10030700.
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Aims: The endocannabinoid system is a complex cell-signaling network through which endogenous cannabinoid ligands regulate cell function by interaction with CB1 and CB2 cannabinoid receptors, and with the novel cannabinoid receptor GPR55. CB1, CB2, and GPR55 are expressed by islet β-cells where they modulate insulin secretion. We have previously shown that administration of the putative CB2 antagonist/inverse agonist JTE 907 to human islets did not affect the insulinotropic actions of CB2 agonists and it unexpectedly stimulated insulin secretion on its own. In this study, we evaluated whether the lack of antagonism could be related to the ability of JTE 907 to act as a GPR55 agonist. Materials and Methods: We used islets isolated from human donors and from Gpr55+/+ and Gpr55−/− mice and quantified the effects of incubation with 10 μM JTE 907 on dynamic insulin secretion, apoptosis, and β-cell proliferation by radioimmunoassay, luminescence caspase 3/7 activity, and immunofluorescence, respectively. We also measured islet IP1 and cAMP accumulation using fluorescence assays, and monitored [Ca2+]i elevations by Fura-2 single cell microfluorometry. Results: JTE 907 significantly stimulated insulin secretion from islets isolated from human donors and islets from Gpr55+/+ and Gpr55−/− mice. These stimulatory effects were accompanied by significant elevations of IP1 and [Ca2+]i, but there were no changes in cAMP generation. JTE 907 also significantly reduced cytokine-induced apoptosis in human and mouse islets and promoted human β-cell proliferation. Conclusion: Our observations show for the first time that JTE 907 acts as a Gq-coupled agonist in islets to stimulate insulin secretion and maintain β-cell mass in a GPR55-independent fashion.
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Nayak, Satyaprakash, Dooyoung Lee, Steven Arkin, et al. "A Quantitative Systems Pharmacology Model for the Coagulation Network Describes Biomarker Changes Observed in a Clinical Study with FXa Variant and Predicts Age-Associated Biomarker Variations." Blood 126, no. 23 (2015): 3502. http://dx.doi.org/10.1182/blood.v126.23.3502.3502.
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Abstract It is known that the coagulation factor levels change with age. In this work, we have applied a quantitative systems pharmacology (QSP) model of the coagulation network to predict whether age related changes in coagulation factor levels will impact dose response for PF-05320907 on various pharmacodynamic endpoints. PF-05230907 (PF-907) is a variant of FXa, in which the conformational transition from zymogen to active protease is impaired. Binding to activated factor V facilitates its transition to the active conformation, rescues procoagulant activity and is hypothesized to localize PF-907 hemostatic effect to sites of hemorrhage. It is currently in development for the indication of intracerebral hemorrhage (ICH). Pharmacokinetic (PK) and pharmacodynamic (PD) data are available from the healthy subjects phase 1 study of single dose escalation of intravenous bolus infusion of PF-907. The next study for PF-907 will be conducted in ICH patients, who will have a much higher median age than the median age in the healthy subjects in the Phase 1 study. Our group has implemented a QSP model for the coagulation network to enable integrated understanding of all the data and underlying pharmacology1. The model has been optimized to describe in vitro biomarker changes including; thrombin generation assay (TGA), activated partial thromboplastin time (aPTT) and prothrombin time (PT) as well as in vivo biomarker changes including prothrombin fragment 1+2 (PF1+2), thrombin-anti-thrombin III complex (TAT) and D-dimer. In this simulation study, we used the model to first describe biomarker changes with treatment of FXa variant in hemostatic normal subjects and then used model simulations to predict the behavior of important biomarkers in an older ICH population. A single compartment PK model for PF-907 was first established to describe the PK data obtained from the phase 1 study. The PK model was then combined with the QSP model to predict biomarker changes following PF-907 treatment. Comparison with observed clinical data showed that the model adequately predicted dose-dependent change in TGA parameters, aPTT, PF1+2, TAT and D-dimer. In addition, the model also predicted that there would be no change in PT, which was consistent with observed first in human results with the PF-907 treatment. After model validation using FIH data, the model was then used to predict biomarker changes for older subjects using literature reported changes in baseline levels of coagulation factors for subjects over a period of 40 years. The simulation predicted minimal shifts in the PD responses suggesting that the dose-response to PF-907 may not change significantly between young and older populations. The model, however, did not consider other characteristics beyond coagulation factor level changes in older populations, which may impact the safety profile of PF-907 treatment. In summary, this study indicates that it is possible to predict the response of a hemostatic agent with a QSP model. Following validation, the model can also extrapolate from a standard subject to new patient populations and indicates that no dose adjustment due to age is required. Reference 1. Nayak, S., Lee, D., Patel-Hett, S., Pittman, D., Martin, S., Heatherington, A., Vicini, P. and Hua, F. (2015), Using a Systems Pharmacology Model of the Blood Coagulation Network to Predict the Effects of Various Therapies on Biomarkers. CPT: Pharmacometrics & Systems Pharmacology. doi:10.1002/psp4.50 Disclosures Nayak: Pfizer Inc: Employment. Lee:Pfizer Inc.: Employment. Arkin:Pfizer Inc: Employment. Martin:Pfizer Inc: Employment. Heatherington:Pfizer Inc.: Employment. Denney:Pfizer Inc.: Employment. Vicini:Pfizer Inc.: Employment. Hua:Pfizer Inc: Employment.
Dissertations / Theses on the topic "907/.2"
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Gertow, Karl. "Fatty acid transport proteins : candidate genes for the insulin resistance syndrome /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-907-2.
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Fiedorow, Pawel. "Etude et optimisation de structures intégrées analogiques en vue de l'amélioration du facteur de mérite des amplificateurs opérationnels." Thesis, Lyon, INSA, 2012. http://www.theses.fr/2012ISAL0061.
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Rail à rail entrée - sortie, classe AB, faible consommation sont autant de critères que le concepteur d'amplificateur opérationnel (AOP) intègre pour réaliser une cellule analogique performante. Pour un AOP standard, l'accent n'est pas porté sur une caractéristique particulière mais sur l’ensemble de celle-ci. Dans le but d'augmenter le nombre de fonction par circuit intégré, la tension d'alimentation des AOPs ainsi que leur consommation en courant tendent à diminuer. L'objectif des circuits réalisés est de doubler le facteur de mérite des circuits déjà présents dans le portefeuille de STMicroelectronics. Le facteur de mérite est un indice qui compare des circuits équivalents. Il est défini par le rapport entre le produit capacité de charge x produit gain bande-passante et le produit courant de consommation x tension d'alimentation. L'état de l'art des structures d'AOPs a orienté l'étude vers des structures analogiques possédant au moins trois étages de gain. Un niveau de gain statique supérieur à la centaine de décibel est nécessaire pour utiliser ces amplificateurs dans des systèmes contre-réactionnés. Puisque chaque étage de gain introduit un noeud haute impédance et que chaque noeud haute impédance est à l'origine d'un pôle, l'étude de la compensation fréquentielle s'est avérée indispensable pour obtenir des structures optimisées. Pour simplifier l'étude de ces AOPs, le développement d'outils d'aide à la conception analogique a contribué à l'automatisation de plusieurs tâches.. Ces différents travaux ont été ponctués par la réalisation et la caractérisation de six circuits. Les compensations fréquentielles utilisées dans ces circuits sont la compensation nested miller , la compensation reversed nested miller et la compensation multipath nested miller . Parmi les six circuits, une moitié a été réalisée uniquement dans le but de valider des concepts de compensation fréquentielle et l'autre moitié avec toutes les contraintes d'une documentation technique propre à la famille d'AOP standard<br>To be in line with the standard of operational amplifier (opamp), designer integrates in his circuit several functionalities like a Rail to rail input and output, class AB output stage and low power consumption. For standard products, there is no outstanding performance but the average of all of them has to be good. In order to increase the number of functions on an integrated circuit, the power supply and current consumption are permanently decreasing. The aim of the designed circuits is to double the figure of merit (FOM) of the actual ST portfolio products. The FOM allows the comparison of similar opamps. It is defined by the ratio of the product of capacitive load x gain-bandwith product over the power consumption. The opamps’ state of the art has led this study to three stages analog cells. A DC gain higher than hundreds of decibel is required to use opamps in feedback configuration. As each stage of the structure introduces a high impedance node and as each high impedance node introduces a pole, the study of frequency compensation technics became essential for well optimized structures. To simplify the study of the opamps, three tools have been developed to help in the design of the frequency compensation network and to automate some tasks. This work has been followed by the realization of six cells. Three of them were designed to validate frequency compensation structure and the other three to satisfy a standard opamp datasheet. Nested Miller, Reversed Nested Miller and Multipath Nested Miller compensations were used in these circuits
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Fritsche, Louise [Verfasser]. "Identification and functional studies of two novel serine phosphorylation sites of insulin receptor substrate (IRS)-2: Ser 675 and Ser 907 / vorgelegt von Louise Fritsche." 2010. http://d-nb.info/1009929062/34.
Full textBooks on the topic "907/.2"
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1912-, Terkel Studs, ed. Envelopes of sound: The art of oral history. 2nd ed. Precedent Pub., 1985.
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1912-, Terkel Studs, ed. Envelopes of sound: The art of oral history. 2nd ed. Praeger, 1990.
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1912-, Terkel Studs, ed. Envelopes of sound: The art of oral history. 2nd ed. Praeger, 1991.
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Merlini, Stefano, ed. Il potere e le libertà. Il percorso di un costituzionalista. Firenze University Press, 2019. http://dx.doi.org/10.36253/978-88-6453-907-2.
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Il volume raccoglie le relazioni e gli scritti presentati in occasione del Convegno svoltosi a Firenze il 1° dicembre 2017, organizzato dal Centro di studi politici e costituzionali Piero Calamandrei - Paolo Barile nel centenario della nascita di Paolo Barile. Gli interventi raccolti ricostruiscono il percorso della vita e del pensiero di Paolo Barile, dagli anni giovanili della sua formazione culturale e scientifica, all’ingresso nella magistratura, l’adesione al Partito d’Azione, la Resistenza, l’incontro con Piero Calamandrei, gli studi e l’insegnamento universitario. Insegnamento mai disgiunto da un forte impegno civile e culturale, dall’esercizio della sua amata professione di avvocato e da un costante impegno politico che lo portò ad essere Ministro nel Governo Ciampi del 1993.
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Schubnell, Markus. Validation in Thermal Analysis. Carl Hanser Verlag GmbH & Co. KG, 2022. http://dx.doi.org/10.1007/978-1-56990-907-2.
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Popkin, Jeremy D. History, historians, & autobiography. University of Chicago Press, 2005.
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Pavel, Georgiev, ed. Khristii︠a︡nskata kultura v srednovekovna Bŭlgarii︠a︡: Materiali ot nat︠s︡ionalna nauchna konferent︠s︡ii︠a︡, Shumen 2-4 maĭ 2007 godina po sluchaĭ 1100 godini ot smŭrtta na Sv. kni︠a︡z Boris-Mikhail (ok. 835-907). Faber, 2008.
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A, Delle James, Mrozowski Stephen A, and Paynter Robert, eds. Lines that divide: Historical archaeologies of race, class, and gender. University of Tennessee Press, 2000.
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Jamichael, Henterly, ed. Good King Wenceslas. Pan Macmillan Children's Books, 1991.
Find full textBook chapters on the topic "907/.2"
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Gröpl, Christoph, Kay Windthorst, and Christian Coelln. "Art. 115c Erweiterte Kompetenz des Bundes." In Grundgesetz. Verlag C.H.BECK oHG, 2022. http://dx.doi.org/10.17104/9783406777219-907-2.
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Walker, Nehemiah. "907 Nehemiah Walker Annamaboe, 2 June 1686." In The Local Correspondence of the Royal African Company of England, 1681–1699, Vol. 2: The English in West Africa, 1685–1688, edited by Robin Law. British Academy, 2001. http://dx.doi.org/10.1093/oseo/instance.00104803.
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Santos, Maria Carolina, Cíntia Maria Rodrigues, and Vanessa Alves Ferreira. "EDUCAÇÃO EM SAÚDE E SUAS APLICAÇÕES NA CONSTRUÇÃO DO CONHECIMENTO DE GESTANTES." In PESQUISAS E DEBATES SOBRE A SAÚDE COLETIVA: UM INTERCÂMBIO ENTRE BRASIL E PORTUGAL. Editora Omnis Scientia, 2023. http://dx.doi.org/10.47094/978-65-81609-96-2/907-914.
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Andrade, Drielly Silva, Débora Conceição Santos de Oliveira, Alisson Maia de Almeida, et al. "IMPLEMENTAÇÃO DE UM PROGRAMA DE CAPACITAÇÃO PARA RASTREIO DE PERDA AUDITIVA EM IDOSOS NA ATENÇÃO BÁSICA: Um relato de experiência." In PESQUISAS E DEBATES SOBRE A SAÚDE COLETIVA: UM INTERCÂMBIO ENTRE BRASIL E PORTUGAL. Editora Omnis Scientia, 2023. http://dx.doi.org/10.47094/978-65-81609-96-2/896-907.
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Henry II. "907. Faversham Abbey." In The Letters and Charters of Henry II, King of England 1154–1189, Vol. 2: Nos. 741–1341, Beneficiaries D–H, edited by Nicholas Vincent. Oxford University Press, 2020. http://dx.doi.org/10.1093/oseo/instance.00276356.
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Baxter, Richard. "907 To Francis Tallents?" In Calendar of the Correspondence of Richard Baxter, Vol. 2: 1660–1696, edited by N. H. Keeble and Geoffrey F. Nuttall. Oxford University Press, 1991. http://dx.doi.org/10.1093/oseo/instance.00009908.
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"CHAPTER 2: The new macro-environment for food, agribusiness and biofuels chains." In Food and agribusiness in 2030: a roadmap. Wageningen Academic Publishers, 2020. http://dx.doi.org/10.3920/978-90-8686-907-7_2.
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Chuang, Hui-Ping. "2. Erste Phase: Wiederbeginn (1027–1056)." In Das Steininschriftenprojekt des Wolkenheimklosters während der Liao-Dynastie (907–1125). De Gruyter, 2017. http://dx.doi.org/10.1515/9783110534849-002.
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Feng-shueh, Liu. "A Study of Banquet Music and Dance at the Táng Court (618–907 ce)." In Identity and Diversity. Routledge India, 2020. http://dx.doi.org/10.4324/9780367818425-2.
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"Table of Contents". У Qāsim Beg Ḥayātī Tabrīzī : A CHRONICLE OF THE EARLY SAFAVIDS AND THE REIGN OF SHAH ISMĀʿĪL (907–930/1501–1524). American Oriental Society, 2018. http://dx.doi.org/10.2307/j.ctv9b2vrs.2.
Full textConference papers on the topic "907/.2"
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Amoozgar, Zohreh, Jun Ren, Nancy Wang, et al. "907 Blockade of VEGF, angiopoietin-2, and PD1 reprograms dysfunctional endothelial cells in glioblastoma to quasi-antigen-presenting cells." In SITC 37th Annual Meeting (SITC 2022) Abstracts. BMJ Publishing Group Ltd, 2022. http://dx.doi.org/10.1136/jitc-2022-sitc2022.0907.
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Menezes de Faria Pereira, Igor, Júlia de Vasconcellos Sales Pizelli, Maria Fernanda Escocard Santiago, Mariah Barreto Vieira, Mila Queiroga Ramos, and Luiz José de Souza. "Análise do perfil clínico dos pacientes com dengue em Campos dos Goytacazes - RJ." In Semana Científica da Faculdade de Medicina de Campos. Faculdade de Medicina de Campos, 2023. http://dx.doi.org/10.29184/anaisscfmc.v22023p25.
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Introdução: A dengue é uma arbovirose transmitida pela fêmea do mosquito Aedes aegypti e possui quatro sorotipos distintos (DENV-1, DENV-2, DENV-3 e DENV-4). Em 2022 foram notificados 1,4 milhões de casos no Brasil, com picos registrados em períodos chuvosos. O quadro clínico cursa principalmente com febre alta, cefaleia, mialgia, dor retro-orbitária e exantema. Dentre os sinais de alarme, pode-se citar: dor abdominal intensa, hemorragias, hipotensão e hepatomegalia. A confirmação diagnóstica é laboratorial, através do isolamento do vírus ou sorologia. O tratamento consiste em reposição volêmica adequada e manejo dos sintomas. O controle do vetor é o principal método para prevenção da doença. Recentemente, uma nova vacina contra a dengue foi disponibilizada e mostra-se promissora no controle da doença. Objetivo: Detectar os sinais e sintomas predominantes entre os pacientes com diagnóstico confirmado para dengue no município de Campos dos Goytacazes (RJ) no período de janeiro a junho de 2023. Material e método: Foram analisados 907 prontuários de pacientes atendidos no município de Campos dos Goytacazes que tiveram antígeno ou sorologia reagentes para dengue. As variáveis observadas foram idade, sexo, mês em que o paciente teve a doença, sinais e sintomas e exame confirmatório, que foram contabilizados por meio do preenchimento de um formulário. Discussão e resultados: Dos 907 casos analisados, a faixa etária prevalente foi de 20-29 anos (21,9%). Pacientes do sexo feminino representaram 60,1%, enquanto o sexo masculino correspondeu a 39,9%. O pico de incidência foi no mês de março, com 26,7% dos casos, totalizando 242 casos positivos. Em relação aos sinais e sintomas, identificou-se febre (85,6%), mialgia (81,6%) e cefaleia (81,1%) como os de maior prevalência. Em seguida, pôde-se observar dor retro-orbitária (59%), náusea (45,5%), prurido (38,8%), gosto amargo (37,1%), exantema (36,1%), diarreia (24,8%), artralgia (24,4%), prostração (22,7%), vômitos (19,6%), fotofobia (12,8%); além de sintomas que indicam gravidade, mas pouco prevalentes, como dor abdominal forte (4%), gengivorragia (0,7%) e epistaxe (0,4%). Conclusão: Tendo em vista os casos positivos analisados, observou-se que os sintomas predominantes foram febre, mialgia e cefaleia. Outros sintomas como dor retro-orbitária, náuseas, prurido, gosto amargo e exantema também foram citados, em proporções menores. Além disso, notou-se que há uma prevalência do sexo feminino em detrimento do masculino. Sintomas de alarme e gravidade estiveram pouco presentes, assim como o número de internações.
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"907 MEP129 – Player-level tackle training interventions in tackle-collision sports – a scoping review." In 7th IOC World Conference on Prevention of Injury and Illness in Sport, Monaco, 29 February–2 March 2024. BMJ Publishing Group Ltd and British Association of Sport and Exercise Medicine, 2024. http://dx.doi.org/10.1136/bjsports-2024-ioc.342.
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Queiroz, Aline Lima, Isadora Morelli Lopes Yabagata, and Rosângela do Socorro Pereira Ribeiro. "INCIDÊNCIAS DE CASOS DE DENGUE E SEUS SOROTIPOS NOS ANOS DE 2015 A 2019 E SUA CORRELAÇÃO COM A MÉDIA PLUVIAL NO ESTADO DO TOCANTINS." In I Congresso Brasileiro de Parasitologia Humana On-line. Revista Multidisciplinar em Saúde, 2021. http://dx.doi.org/10.51161/rems/907.
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Introdução: A dengue é uma patologia de etiologia viral transmitido pela fêmea hematófaga Aedes aegypti, principal mosquito vetor. Sabe-se da existência do vírus RNA com 4 sorotipos (DENV - 1, 2, 3, 4) que se apresenta desde uma evolução benigna na forma clássica até uma evolução grave. No Brasil, essa patologia está diretamente relacionada ao ciclo pluvial, ocasionando criadouros do mosquito. Objetivo: Analisar a incidência dos casos de dengue nos anos 2015 a 2019. Investigar a precipitação com o aumento do número de casos. Identificar o sorotipo mais prevalente. Material e Métodos A pesquisa de caráter descritivo, elegeu dados de informática do SUS– DataSUS, artigos relacionados ao departamento e portais de instituições de pesquisa, uma análise simples, com informações de notificação pública de pacientes infectados pelo vírus, e monitoramento epidemiológico da Secretaria Estadual de Saúde dos 139 municípios tocantinenses, em conjunto com dados do Instituto Nacional de Meteorologia – INMET.Resultados: Conforme os boletins epidemiológicos do Ministério de Saúde em 2015 a 2019, a dengue acometeu o Brasil com aproximadamente 5,5 milhões de notificações, desses, 37 mil no estado do Tocantins, contando 9 mil casos do tipo DENV - 2, evoluindo com mil internações. Em 2019, ocorreram 14.088 casos, resultando um acréscimo de 390%, registrando o maior número de casos da última década. Em 2017 e 2018, o estado do Tocantins notificou uma queda na média pluviométrica de 256,7 mm e concomitante foi registrado uma baixa nas notificações de dengue. Conclusão: A associação significativa entre média pluviométrica e a incidência da doença. Ações em conjunto do estado do Tocantins com o Ministério da Saúde, em foco do crescimento de casos por consequência das chuvas, para serem potencialmente capazes de produzir mudanças efetivas na redução do número de notificações, inclusive em suas formas graves e no número de óbitos.
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Jameel, Abood. "Using Linear Programming Technique to Measure Minimum Costs: Ready-to-Wear Factory." In 4th International Conference on Administrative & Financial Sciences. Cihan University-Erbil, 2023. http://dx.doi.org/10.24086/icafs2023/paper.907.
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We suggest, in this paper, linear programming model that consists of ten variables and eighteen constraints to calculate the minimum total cost and minimum cost for each product in one of the ready-to-wear factories. This factory is producing 10 different types of products (5 types of Pants, 2 types of shirts, 1type of long Jacket, 1 type of suit and 1 type of premium suit). This model usually used to solve more complicated problems in different fields by formulating or changing the form of the problem to Linear Programming model and then solve this model by using Simplex Method. We will use Simplex method which is a simple and powerful tool for solving linear programming Model to calculate the Minimum Cost, because calculating cost is not easy problem. The present study ascertained that there is a significant powerful technique in quantitative methods called Linear Programming Method that can be used in Optimization cases. This study will provide this Factory and other Factories, particularly in Iraq, an exposure of linear programming Technique in making decisions to determine the minimum total cost and minimum cost for different products. The result of Statistical analysis exhibited or shows that: The Minimum total cost Z = 3249745000 IQD.
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Ковалева, Е. В., А. Р. Елфимова, А. К. Еремкина та ін. "КЛИНИЧЕСКИЕ ОСОБЕННОСТИ ТЕЧЕНИЯ ХРОНИЧЕСКОГО ГИПОПАРАТИРЕОЗА ПО ДАННЫМ ВСЕРОССИЙСКОГО РЕГИСТРА". У X (XXIX) НАЦИОНАЛЬНЫЙ КОНГРЕСС ЭНДОКРИНОЛОГОВ с международным участием «Персонализированная медицина и практическое здравоохранение». ФГБУ «НМИЦ эндокринологии» Минздрава России, 2023. http://dx.doi.org/10.14341/cong23-26.05.23-25.
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ЦЕЛЬ: изучить особенности клинического течения хронического гипопаратиреоза в российской по-
 пуляции.
 МАТЕРИАЛЫ И МЕТОДЫ: исследование проведено на основе данных Всероссийского регистра паци-
 ентов с хроническим послеоперационным (п/о) и нехирургическим (н/х) гипопаратиреозом, основанного
 в 2020 году под эгидой ГНЦ ФГБУ «НМИЦ эндокринологии» Минздрава России (http://gipopt.clin-reg.ru/).
 Электронная информационно-аналитическая платформа регистра позволяет в режиме онлайн вводить
 информацию по пациентам с данной патологией в различных регионах Российской Федерации (РФ), а также
 обладает динамической системой аналитики. Выгрузка базы данных проведена 18.01.2023 г.
 РЕЗУЛЬТАТЫ: общее число включенных в исследование пациентов составило 1039 человек (мужчин/
 женщин – 131/907, жив/умер – 1036/3) из 68 регионов РФ. Хронический п/о гипопаратиреоз наблюдался
 в 87,4% случаев (909/1039), н/х – в 12,6% (130/1039). П/о гипопаратиреоз в 43% случаев (391/909) развил-
 ся после хирургического лечения рака щитовидной железы, узлового и диффузного токсического зоба
 в 24% (218/909) и 14% (131/909), соответственно, после паратиреоидэктомии в 5% (43/909), в том числе
 селективной – в 35% (15/43). В структуре н/х гипопаратиреоза преобладал идиопатический вариант – 65%
 (60/92); реже – аутоиммунный (24%, 22/92) и другие наследственные формы (11%, 10/92). Медиана возраста
 на момент постановки диагноза н/х гипопаратиреоза была ожидаемо меньше, чем в группе п/о гипопара-
 тиреоза – 13 [5; 20] против 47 [36; 57] лет (р<0,0001, U-тест, поправка Бонферрони Р0=0,0036).
 Выявлена статистическая тенденция к более низким уровням кальциемии (медиана ионизированного
 кальция 0,98 ммоль/л [0,85; 1,08] против 1,04 [0,94; 1,12], р=0,018, U-тест, поправка Бонферрони Р0=0,0036)
 и магниемии (0,75 ммоль/л [0,70; 0,80] против 0,71 [0,65; 0,76], р=0,005), более высокому уровню фосфора
 крови (1,58 ммоль/л [1,21; 2,09] против 1,48 [1,31; 1,67]) у пациентов с н/х гипопаратиреозом по сравнению
 с п/о формой. По уровню суточной кальциурии группы не различались (р>0,05), однако пациенты с п/о ги-
 попаратиреозом имели значимо более низкие показатели рСКФ – 75,0 мл/мин/1,73 м2 [60,3; 91,1] против
 91,3 [68,7; 112,2] (р<0,0001, U-тест, поправка Бонферрони Р0=0,0036).
 В терапии гипопаратиреоза чаще всего, в 75% случаев, использовалась стандартная комбинация в виде
 сочетания активных форм витамина D и препаратов кальция. Дозы лекарственных препаратов (альфа-
 кальцидола, кальцитриола, карбоната кальция) в группах с п/о и н/х гипопаратиреозом не различались:
 1,50 мкг/сут [1,00; 2,00] против 1,25 [1,00; 2,25], 1,0 мкг/сут [0,5; 1,5] против 1,00 [0,50; 1,75] и 1500 мг/сут
 [1000; 2000] против 1200 [1000; 2000] соответственно (р>0,05).
 ВЫВОДЫ: самой частой причиной гипопаратиреоза в РФ является повреждение или удаление око-
 лощитовидных желез в ходе хирургического лечения по поводу различных заболеваний щитовидной
 железы, что согласуется с результатами мировых данных. Пациенты с н/х гипопаратиреозом имеют более
 раннюю манифестацию заболевания и тенденцию к более выраженным нарушениям минерального об-
 мена по сравнению с лицами с п/о патологией. Большинство пациентов получают стандартную терапию
 с умеренными суточными дозами препаратов, что соответствует позициям федеральных клинический
 рекомендаций по гипопаратиреозу.
 Источник финансирования: государственное задание «Всероссийский реестр пациентов
 с хроническим гипопаратиреозом как основа оптимизации и внедрения персонализированного под-
 хода для улучшения качества оказания медицинской помощи населению Российской Федерации»,
 НИОКТРАААА-А20-120011790168-2.