BRAF V600E is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting ''active'' protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf V600E with an IC50 of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf V600E kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf V600E -bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf V600E -positive cells. In B-Raf V600E -dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf V600E -driven tumors.cancer ͉ cell signaling ͉ melanoma ͉ phosphorylation ͉ protein kinases O ncogenic mutations in the BRAF gene (1) correlate with increased severity and decreased response to chemotherapy in a wide variety of human tumors (2-4). Hence, direct therapeutic inhibition of oncogenic B-Raf kinase activity affords an avenue to treat these tumors. The therapeutic approach of targeting oncogenic kinase activity has proved very valuable in oncology (5, 6). Recently, we have described the technique termed scaffold-based drug discovery, a strategy for identifying small molecule inhibitors of cyclic nucleotide phosphodiesterases (7). Here, we describe an expansion of this strategy to discover a scaffold targeting protein kinases, and we report the elaboration of this scaffold into the potent and selective B-Raf V600E inhibitor PLX4720. Because a majority of all melanomas harbor an activating missense mutation (V600E) in the B-Raf oncogene (1), targeted inhibition of the V600E gene product is a particularly rational therapeutic goal in this otherwise therapy-resistant tumor type. Previous generations of B-Raf inhibitors possess Raf inhibitory activity at low nanomolar concentrations (8-13); however, the relative therapeutic efficacy of such inhibitors has been hampered by the lack of bioavailability or by the number of nonspecific targets that are also affected (14, 15). The development of highly specific and effectual inhibitors of the BRAF V600E gene product would provide insight into the true therapeutic rele...

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OBJECTIVEWe estimated the prevalence and incidence of diabetes among specific subgroups of Asians and Pacific Islanders (APIs) in a multiethnic U.S. population with uniform access to care.RESEARCH DESIGN AND METHODSThis prospective cohort analysis included 2,123,548 adult members of Kaiser Permanente Northern California, including 1,704,363 with known race/ethnicity (white, 56.9%; Latino, 14.9%; African American, 8.0%; Filipino, 4.9%; Chinese, 4.0%; multiracial, 2.8%; Japanese, 0.9%; Native American, 0.6%; Pacific Islander, 0.5%; South Asian, 0.4%; and Southeast Asian, Korean, and Vietnamese, 0.1% each). We calculated age-standardized (to the 2010 U.S. population) and sex-adjusted diabetes prevalence at baseline and incidence (during the 2010 calendar year). Poisson models were used to estimate relative risks.RESULTSThere were 210,632 subjects with prevalent diabetes as of 1 January 2010 and 15,357 incident cases of diabetes identified during 2010. The crude diabetes prevalence was 9.9% and the incidence was 8.0 cases per 1,000 person-years and, after standardizing by age and sex to the 2010 U.S. Census, 8.9% and 7.7 cases per 1,000 person-years. There was considerable variation among the seven largest API subgroups. Pacific Islanders, South Asians, and Filipinos had the highest prevalence (18.3, 15.9, and 16.1%, respectively) and the highest incidence (19.9, 17.2, and 14.7 cases per 1,000 person-years, respectively) of diabetes among all racial/ethnic groups, including minorities traditionally considered high risk (e.g., African Americans, Latinos, and Native Americans).CONCLUSIONSHigh rates of diabetes among Pacific Islanders, South Asians, and Filipinos are obscured by much lower rates among the large population of Chinese and several smaller Asian subgroups.

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.

Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca concentrations, suggesting differences in the Ca sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca binding paralog of the β cell Ca sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca sensing plays in regulating β cell maturation.

Biosimilars are highly similar versions of approved branded biologics. Unlike generics, they are not exact replicas of reference products. Minor differences between biosimilars and reference products in some aspects are expected; likewise, biosimilar products will differ from each other. The objective of this review is to discuss the challenges associated with the development and approval of biosimilar products that are unique because of their complex structure and specialized manufacturing processes, which can impact not only efficacy but also immunogenicity and safety. Regulatory guidelines recommend a totality-of-evidence approach focused on stepwise development that involves demonstration of structural similarity and functional equivalence. Structural and functional characteristics of the proposed biosimilar are compared with the reference product; similarity of these functions forms the foundation of the biosimilar development program, including potential animal studies, a human pharmacokinetics/pharmacodynamics equivalence study, and a clinical study to confirm similar efficacy, safety, and immunogenicity. The clinical study should be performed in a sensitive population using appropriate endpoints to allow detection of any clinically meaningful differences between the biosimilar and the reference product if such differences exist. In conclusion, development of biosimilars is focused on the minimization of potential differences between the proposed biosimilar and reference product and the establishment of a robust manufacturing process to consistently produce a high-quality biosimilar product.

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