The transmembrane tyrosine kinase receptor HER2 is overexpressed in 20% of invasive breast cancers and is associated with more aggressive disease. Until the advent of targeted agents, HER2 was associated with worse outcome. Trastuzumab, a recombinant humanized anti-HER2 monoclonal antibody, combined with chemotherapy improves disease-free and overall survival in both primary and metastatic tumors and represents a foundation of care for patients with HER2-positive breast cancers. However, a sizeable number of patients do not respond to this reagent, indicating the need for a biomarker able to recognize resistant tumors. Here, we review various studies on mechanisms of action and resistance to trastuzumab that have proven relevant in understanding how tumor care can be tailored to all HER2-positive patients.

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Intestinal immune homeostasis requires dynamic crosstalk between innate and adaptive immune cells. Dendritic cells (DCs) exist as multiple phenotypically and functionally distinct sub-populations within tissues, where they initiate immune responses and promote homeostasis. In the gut, there exists a minor DC subset defined as CD103(+)CD11b(-) that also expresses the chemokine receptor XCR1. In other tissues, XCR1(+) DCs cross-present antigen and contribute to immunity against viruses and cancer, however the roles of XCR1(+) DCs and XCR1 in the intestine are unknown. We showed that mice lacking XCR1(+) DCs are specifically deficient in intraepithelial and lamina propria (LP) T cell populations, with remaining T cells exhibiting an atypical phenotype and being prone to death, and are also more susceptible to chemically-induced colitis. Mice deficient in either XCR1 or its ligand, XCL1, similarly possess diminished intestinal T cell populations, and an accumulation of XCR1(+) DCs in the gut. Combined with transcriptome and surface marker expression analysis, these observations lead us to hypothesise that T cell-derived XCL1 facilitates intestinal XCR1(+) DC activation and migration, and that XCR1(+) DCs in turn provide support for T cell survival and function. Thus XCR1(+) DCs and the XCR1/XCL1 chemokine axis have previously-unappreciated roles in intestinal immune homeostasis.

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Available clinical human papilloma virus (HPV) diagnostics for head and neck cancer have limited sensitivity and/or fail to define the HPV genotype. Common HPV genotyping assays are costly and labor intensive. We sought to develop a next-generation sequencing (NGS)-based HPV genotyping assay that was sensitive enough to work on formalin-fixed paraffin-embedded (FFPE) samples. We developed an ion torrent NGS HPV genotyping assay using barcoded HPV PCR broad-spectrum general primers 5(+)/6(+) (BSGP)5(+)/6(+). To validate genotype specificity and use in archived clinical FFPE tumor samples, we compared NGS HPV genotyping at 2 sequencing centers with typing by Roche Linear Array assay in 42 oropharyngeal and cervical cancer specimens representing 10 HPV genotypes, as well as HPV-negative cases. To demonstrate the detection of a broad range of HPV genotypes, we genotyped a cohort of 266 cervical cancers. A comparison of NGS genotyping of FFPE cancer specimens with genotyping by Linear Array showed concordant results in 34/37 samples (92%) at sequencing site 1 and 39/42 samples (93%) at sequencing site 2. Concordance between sites was 92%. Designed for use with 10 ng genomic DNA, the assay detected HPV using as little as 1.25 ng FFPE-derived genomic DNA. In 266 cervical cancer specimens, the NGS assay identified 20 different HPV genotypes, including all 13 carcinogenic genotypes. This novel NGS assay provides a sensitive and specific high-throughput method to detect and genotype HPV in a range of clinical specimens derived from FFPE with low per-sample cost.

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Farletuzumab is a humanized monoclonal antibody that binds to folate receptor-α, which is highly expressed in ovarian carcinoma and largely absent from normal tissue. Farletuzumab was investigated in a double-blind, randomized phase III study in platinum-sensitive ovarian cancer.
Eligible patients had first recurrent ovarian cancer 6-24 months following completion of platinum-taxane chemotherapy. All patients received carboplatin plus paclitaxel or docetaxel (for six cycles combined with randomly assigned test products in a 1:1:1 ratio: farletuzumab 1.25 mg/kg, farletuzumab 2.5 mg/kg, or placebo). The single-agent test product was continued weekly until disease progression. The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors. Additional analyses not outlined in the original protocol were prespecified in the final statistical analysis plan, including a subgroup analysis by baseline CA-125 and farletuzumab exposure levels.
A total of 1,100 women were randomly assigned to treatment dose or placebo. PFS from the primary analysis was 9.0, 9.5, and 9.7 months for the placebo, farletuzumab 1.25 mg/kg, and farletuzumab 2.5 mg/kg groups, respectively. Neither farletuzumab group was statistically different from the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.81 to 1.21] and 0.86 [95% CI, 0.70 to 1.06] for farletuzumab 1.25 mg/kg and 2.5 mg/kg group v placebo, respectively). In the prespecified subgroup, baseline CA-125 levels not more than three times the upper limit of normal (ULN) correlated with longer PFS (HR, 0.49; P = .0028) and overall survival (OS) (HR, 0.44; P = .0108) for farletuzumab 2.5 mg/kg versus placebo. Subgroup analysis of farletuzumab exposure above the median, regardless of dose, showed significantly better PFS versus placebo. The most common adverse events were those associated with chemotherapy.
Neither farletuzumab dose met the study’s primary PFS end point. Prespecified subgroup analyses demonstrated that patients with CA-125 levels not more than three times the ULN and patients with higher farletuzumab exposure showed superior PFS and OS compared with placebo.
© 2016 by American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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A relationship has been reported between blood concentrations of coagulation factor VII (FVII) and obesity. In addition to its role in coagulation, FVII has been shown to inhibit insulin signals in adipocytes. However, the production of FVII by adipocytes remains unclear.
We herein investigated the production and secretion of FVII by adipocytes, especially in relation to obesity-related conditions including adipose inflammation and sympathetic nerve activation.
C57Bl/6J mice were fed a low- or high-fat diet and the expression of FVII messenger RNA (mRNA) was then examined in adipose tissue. 3T3-L1 cells were used as an adipocyte model for in vitro experiments in which these cells were treated with tumor necrosis factor-α (TNF-α) or isoproterenol. The expression and secretion of FVII were assessed by quantitative real-time PCR, Western blotting and enzyme-linked immunosorbent assays.
The expression of FVII mRNA in the adipose tissue of mice fed with high-fat diet was significantly higher than that in mice fed with low-fat diet. Expression of the FVII gene and protein was induced during adipogenesis and maintained in mature adipocytes. The expression and secretion of FVII mRNA were increased in the culture medium of 3T3-L1 adipocytes treated with TNF-α, and these effects were blocked when these cells were exposed to inhibitors of mitogen-activated kinases or NF-κB activation. The β-adrenoceptor agonist isoproterenol stimulated the secretion of FVII from mature adipocytes via the cyclic AMP/protein kinase A pathway. Blockade of secreted FVII with the anti-FVII antibody did not affect the phosphorylation of Akt in the isoproterenol-stimulated adipocytes.
Obese adipose tissue produced FVII. The production and secretion of FVII by adipocytes was enhanced by TNF-α or isoproterenol via different mechanisms. These results indicate that FVII is an adipokine that plays an important role in the pathogenesis of obesity.

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