HIGHER ORDER SCHWARZIAN DERIVATIVES FOR CONVEX UNIVALENT FUNCTIOS

We observe that in contrast to the class S, the extremal functions for the bound of higher order Schwarzian derivatives for the class S c of convex univalent functions are different. We prove the sharp bound for three first consecutive derivatives

Tivozanib in the treatment of renal cell carcinoma

Mehmet Hepgur, Sarmad Sadeghi, Tanya B Dorff, David I Quinn Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA Abstract: Renal cell carcinoma (RCC) is an aggressive malignancy compared to other urological malignancies and has been associated with poor responses to conventional cytotoxic chemotherapy. Interferon-a and interleukin-2 were previously utilized in a limited number of patients with good performance status due to toxicity and safety issues. Over the last decade, through advances in the understanding of the biology and pathology of RCC, the important role of vascular endothelial growth factor (VEGF) in RCC has been identified. Data from randomized trials have led to the approval of first-generation tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib; however, these agents inhibit a wide variety of kinase targets and are associated with a range of adverse effects. More recently, a new generation TKI, axitinib, has been approved by the US Food and Drug Administration. Tivozanib is a novel TKI, which is a potent inhibitor of VEGF-1, VEGF-2, VEGF-3, c-kit, and PDGR kinases, with a more restricted target spectrum. Phase II and III studies have demonstrated significant activity and a favorable safety profile as an initial targeted treatment for advanced RCC. This review examines the emerging data with tivozanib for the treatment of advanced RCC. Preclinical investigations as well as Phase I, II, and III data are examined; data on the comparative benefits of tivozanib are reviewed. Finally, we discuss the future potential of tivozanib in combination, biomarkers associated with tivozanib response, and acquisition of resistance and nonkidney cancer indications. Keywords: targeted therapy, renal cell cancer, tyrosine kinase inhibitor, tivozani

Injectivity of sections of convex harmonic mappings and convolution theorems

In the article the authors consider the class ${\mathcal H}_0$ of sense-preserving harmonic functions $f=h+\overline{g}$ defined in the unit disk $|z|<1$ and normalized so that $h(0)=0=h'(0)-1$ and $g(0)=0=g'(0)$, where $h$ and $g$ are analytic in the unit disk. In the first part of the article we present two classes $\mathcal{P}_H^0(\alpha)$ and $\mathcal{G}_H^0(\beta)$ of functions from ${\mathcal H}_0$ and show that if $f\in \mathcal{P}_H^0(\alpha)$ and $F\in\mathcal{G}_H^0(\beta)$, then the harmonic convolution is a univalent and close-to-convex harmonic function in the unit disk provided certain conditions for parameters $\alpha$ and $\beta$ are satisfied. In the second part we study the harmonic sections (partial sums) $$s_{n, n}(f)(z)=s_n(h)(z)+\overline{s_n(g)(z)},$$ where $f=h+\overline{g}\in {\mathcal H}_0$, $s_n(h)$ and $s_n(g)$ denote the $n$-th partial sums of $h$ and $g$, respectively. We prove, among others, that if $f=h+\overline{g}\in{\mathcal H}_0$ is a univalent harmonic convex mapping, then $s_{n, n}(f)$ is univalent and close-to-convex in the disk $|z|< 1/4$ for $n\geq 2$, and $s_{n, n}(f)$ is also convex in the disk $|z|< 1/4$ for $n\geq2$ and $n\neq 3$. Moreover, we show that the section $s_{3,3}(f)$ of $f\in {\mathcal C}_H^0$ is not convex in the disk $|z|<1/4$ but is shown to be convex in a smaller disk.Comment: 16 pages, 3 figures; To appear in Czechoslovak Mathematical Journa

GPCR-OKB: the G protein coupled receptor oligomer knowledge base

Rapid expansion of available data about G Protein Coupled Receptor (GPCR) dimers/oligomers over the past few years requires an effective system to organize this information electronically. Based on an ontology derived from a community dialog involving colleagues using experimental and computational methodologies, we developed the GPCR-Oligomerization Knowledge Base (GPCR-OKB). GPCR-OKB is a system that supports browsing and searching for GPCR oligomer data. Such data were manually derived from the literature. While focused on GPCR oligomers, GPCR-OKB is seamlessly connected to GPCRDB, facilitating the correlation of information about GPCR protomers and oligomers

Learning from the past and stepping into the future : toward a new generation of conflict prediction

Developing political forecasting models not only increases the ability of political scientists to inform public policy decisions, but is also relevant for scientific advancement. This article argues for and demonstrates the utility of creating forecasting models for predicting political conflicts in a diverse range of country settings. Apart from the benefit of making actual predictions, we argue that predictive heuristics are one gold standard of model development in the field of conflict studies. As such, they shed light on an array of important components of the political science literature on conflict dynamics. We develop and present conflict predictions that have been highly accurate for past and subsequent events, exhibiting few false-negative and false-positive categorizations. Our predictions are made at the monthly level for 6-month periods into the future, taking into account the social–spatial context of each individual country. The model has a high degree of accuracy in reproducing historical data measured monthly over the past 10 years and has approximately equal accuracy in making forecasts. Thus, forecasting in political science is increasingly accurate. At the same time, by providing a gold standard that separates model construction from model evaluation, we can defeat observational research designs and use true prediction as a way to evaluate theories. We suggest that progress in the modeling of conflict research depends on the use of prediction as a gold standard of heuristic evaluation

Educating International Security Practitioners: Preparing to Face the Demands of the 21st Century International Security Environment

The authors examine the challenges of the 21st century international security environment to which future strategic leaders and policy practitioners will need to respond. More specifically, they offer the reader insights into security studies and leadership development at their respective levels (military undergraduate, civilian undergraduate, traditional and nontraditional graduate, and senior military officer) and institutions (including research centers and professional outreach programs). The goal is to inform a broader audience about what is currently being done in the way of educating strategic practitioners at these various institutions, and what might need to be done differently or better.https://press.armywarcollege.edu/monographs/1835/thumbnail.jp

Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression

Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration

Compression of Structured High-Throughput Sequencing Data

Large biological datasets are being produced at a rapid pace and create substantial storage challenges, particularly in the domain of high-throughput sequencing (HTS). Most approaches currently used to store HTS data are either unable to quickly adapt to the requirements of new sequencing or analysis methods (because they do not support schema evolution), or fail to provide state of the art compression of the datasets. We have devised new approaches to store HTS data that support seamless data schema evolution and compress datasets substantially better than existing approaches. Building on these new approaches, we discuss and demonstrate how a multi-tier data organization can dramatically reduce the storage, computational and network burden of collecting, analyzing, and archiving large sequencing datasets. For instance, we show that spliced RNA-Seq alignments can be stored in less than 4% the size of a BAM file with perfect data fidelity. Compared to the previous compression state of the art, these methods reduce dataset size more than 40% when storing exome, gene expression or DNA methylation datasets. The approaches have been integrated in a comprehensive suite of software tools (http://goby.campagnelab.org) that support common analyses for a range of high-throughput sequencing assays.National Center for Research Resources (U.S.) (Grant UL1 RR024996)Leukemia & Lymphoma Society of America (Translational Research Program Grant LLS 6304-11)National Institute of Mental Health (U.S.) (R01 MH086883

Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial

Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations. In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0-2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing. Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1-22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2-39·6). The most common grade 3-4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths. Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit-risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations. Pfizer/Medivation