In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

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In tumor bearing animals, the membrane phospholipid phosphatidylserine (PS) suppresses immune responses, suggesting that PS signaling could counteract the antitumor effect of antibody-driven immune checkpoint blockade. Here we show that treating melanoma-bearing mice with a PS-targeting antibody enhances the antitumor activity of downstream checkpoint inhibition. Combining PS-targeting antibodies with CTLA-4 or PD-1 blockade resulted in significantly greater inhibition of tumor growth than did single agent therapy. Moreover, combination therapy enhanced CD4+ and CD8+ tumor-infiltrating lymphocyte numbers; elevated the fraction of cells expressing the pro-inflammatory cytokines IL2, IFNγ, and TNFα; and increased the ratio of CD8 T cells to myeloid-derived suppressor cells and regulatory T cells in tumors. Similar changes in immune cell profiles were observed in splenocytes. Taken together, these data show that antibody-mediated PS blockade enhances the antitumor efficacy of immune checkpoint inhibition.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Prostate cancer (PCa) is an androgen-dependent disease. Nonetheless, the role of single nucleotide polymorphisms (SNPs) in genes encoding androgen metabolism remains an unexplored area.
To investigate the role of germline variations in cytochrome P450 17A1 (CYP17A1) and steroid-5α-reductase, α-polypeptides 1 and 2 (SRD5A1 and SRD5A2) genes in PCa.
In total, 494 consecutive Spanish patients diagnosed with nonmetastatic localized PCa were included in this multicenter study and were genotyped for 32 SNPs in SRD5A1, SRD5A2, and CYP17A1 genes using a Biotrove OpenArray NT Cycler. Clinical data were available. Genotypic and allelic frequencies, as well as haplotype analyses, were determined using the web-based environment SNPator. All additional statistical analyses comparing clinical data and SNPs were performed using PASW Statistics 15.
The call rate obtained (determined as the percentage of successful determinations) was 97.3% of detection. A total of 2 SNPs in SRD5A1-rs3822430 and rs1691053-were associated with prostate-specific antigen level at diagnosis. Moreover, G carriers for both SNPs were at higher risk of presenting initial prostate-specific antigen levels>20ng/ml (Exp(B) = 2.812, 95% CI: 1.397-5.657, P = 0.004) than those who are AA-AA carriers. Haplotype analyses showed that patients with PCa nonhomozygous for the haplotype GCTTGTAGTA were at an elevated risk of presenting bigger clinical tumor size (Exp(B) = 3.823, 95% CI: 1.280-11.416, P = 0.016), and higher Gleason score (Exp(B) = 2.808, 95% CI: 1.134-6.953, P = 0.026).
SNPs in SRD5A1 seem to affect the clinical characteristics of Spanish patients with PCa.
Copyright © 2015 Elsevier Inc. All rights reserved.

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On April 6, 2016 Pfizer Inc. (NYSE: PFE) reported that the merger agreement between Pfizer and Allergan plc (NYSE: AGN) has been terminated by mutual agreement of the companies (Press release, Pfizer, APR 6, 2016, View Source [SID:1234510532]). The decision was driven by the actions announced by the U.S. Department of Treasury on April 4, 2016, which the companies concluded qualified as an "Adverse Tax Law Change" under the merger agreement.

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"Pfizer approached this transaction from a position of strength and viewed the potential combination as an accelerator of existing strategies," stated Ian Read, Chairman and Chief Executive Officer, Pfizer. "We remain focused on continuing to enhance the value of our innovative and established businesses. Our most recent product launches, including Prevnar 13 in Adults, Ibrance, Eliquis and Xeljanz, have been well-received in the market, and we believe our late stage pipeline has several attractive commercial opportunities with high potential across several therapeutic areas. We also maintain the financial strength and flexibility to pursue attractive business development and other shareholder friendly capital allocation opportunities."

"We plan to make a decision about whether to pursue a potential separation of our innovative and established businesses by no later than the end of 2016, consistent with our original timeframe for the decision prior to the announcement of the potential Allergan transaction," continued Read. "As always, we remain committed to enhancing shareholder value."

In connection with the termination of the merger agreement, Pfizer has agreed to pay Allergan $150 million for reimbursement of expenses associated with the transaction.

As previously announced, Pfizer plans to report its First-Quarter 2016 financial results on May 3, 2016.

Recombinant factor VIII Fc fusion protein (rFVIIIFc) is a long-acting coagulation factor approved for the treatment of hemophilia A. Here, the rFVIIIFc manufacturing process and results of studies evaluating product quality and the capacity of the process to remove potential impurities and viruses are described. This manufacturing process utilized readily transferable and scalable unit operations and employed multi-step purification and viral clearance processing, including a novel affinity chromatography adsorbent and a 15 nm pore size virus removal nanofilter. A cell line derived from human embryonic kidney (HEK) 293H cells was used to produce rFVIIIFc. Validation studies evaluated identity, purity, activity, and safety. Process-related impurity clearance and viral clearance spiking studies demonstrate robust and reproducible removal of impurities and viruses, with total viral clearance >8-15 log10 for four model viruses (xenotropic murine leukemia virus, mice minute virus, reovirus type 3, and suid herpes virus 1). Terminal galactose-α-1,3-galactose and N-glycolylneuraminic acid, two non-human glycans, were undetectable in rFVIIIFc. Biochemical and in vitro biological analyses confirmed the purity, activity, and consistency of rFVIIIFc. In conclusion, this manufacturing process produces a highly pure product free of viruses, impurities, and non-human glycan structures, with scale capabilities to ensure a consistent and adequate supply of rFVIIIFc.
Copyright © 2015 Biogen. Published by Elsevier Ltd.. All rights reserved.

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