Genomic and Transcriptomic Alterations Associated with STAT3 Activation in Head and Neck Cancer.

BackgroundHyperactivation of STAT3 via constitutive phosphorylation of tyrosine 705 (Y705) is common in most human cancers, including head and neck squamous carcinoma (HNSCC). STAT3 is rarely mutated in cancer and the (epi)genetic alterations that lead to STAT3 activation are incompletely understood. Here we used an unbiased approach to identify genomic and epigenomic changes associated with pSTAT3(Y705) expression using data generated by The Cancer Genome Atlas (TCGA).Methods and findingsMutation, mRNA expression, promoter methylation, and copy number alteration data were extracted from TCGA and examined in the context of pSTAT3(Y705) protein expression. mRNA expression levels of 1279 genes were found to be associated with pSTAT3(705) expression. Association of pSTAT3(Y705) expression with caspase-8 mRNA expression was validated by immunoblot analysis in HNSCC cells. Mutation, promoter hypermethylation, and copy number alteration of any gene were not significantly associated with increased pSTAT3(Y705) protein expression.ConclusionsThese cumulative results suggest that unbiased approaches may be useful in identifying the molecular underpinnings of oncogenic signaling, including STAT3 activation, in HNSCC. Larger datasets will likely be necessary to elucidate signaling consequences of infrequent alterations

The impact of ocean acidification on the functional morphology of foraminifera

This work was supported by the NERC UK Ocean Acidification Research Programme grant NE/H017445/1. WENA acknowledges NERC support (NE/G018502/1). DMP received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland). MASTS is funded by the Scottish Funding Council (grant reference HR09011) and contributing institutions.Culturing experiments were performed on sediment samples from the Ythan Estuary, N. E. Scotland, to assess the impacts of ocean acidification on test surface ornamentation in the benthic foraminifer Haynesina germanica. Specimens were cultured for 36 weeks at either 380, 750 or 1000 ppm atmospheric CO2. Analysis of the test surface using SEM imaging reveals sensitivity of functionally important ornamentation associated with feeding to changing seawater CO2 levels. Specimens incubated at high CO2 levels displayed evidence of shell dissolution, a significant reduction and deformation of ornamentation. It is clear that these calcifying organisms are likely to be vulnerable to ocean acidification. A reduction in functionally important ornamentation could lead to a reduction in feeding efficiency with consequent impacts on this organism’s survival and fitness.Publisher PDFPeer reviewe

Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer

etuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9–11.4) and 8.9 (90% CI = 2.7–15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6–40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8+ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC

MGP Panel is a comprehensive targeted genomics panel for molecular profiling of multiple myeloma patients

PURPOSE: We designed a comprehensive multiple myeloma (MM) targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. EXPERIMENTAL DESIGN: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNAs). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical fluorescence in situ hybridization (FISH) (translocations), multiplex ligation probe analysis (MLPA) (CNAs), whole genome sequencing (WGS) (CNAs, mutations, translocations) or droplet digital PCR (ddPCR) of known standards (mutations). RESULTS: Canonical IgH translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for one patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2=0.969. VAFs for 74 mutations were compared between sequencing and ddPCR with concordance of R2=0.9849. CONCLUSIONS: In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost effective, comprehensive, clinically actionable and can be routinely deployed to assist risk stratification at diagnosis or post-treatment to guide sequencing of therapies

Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma:a paradigm shift to reduce overtreatment of indolent tumors

Although growing evidence points to highly indolent behavior of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), most patients with EFVPTC are treated as having conventional thyroid cancer

Experience of Pleasure and Emotional Expression in Individuals with Schizotypal Personality Features

Difficulties in feeling pleasure and expressing emotions are one of the key features of schizophrenia spectrum conditions, and are significant contributors to constricted interpersonal interactions. The current study examined the experience of pleasure and emotional expression in college students who demonstrated high and low levels of schizotypal personality disorder (SPD) traits on self-report questionnaires. One hundred and seventeen subjects with SPD traits and 116 comparison controls were recruited to participate. Cluster analyses conducted in the SPD group identified negative SPD and positive SPD subgroups. The negative SPD group exhibited deficient emotional expression and anticipatory pleasure, but showed intact consummatory pleasure. The positive SPD group reported significantly greater levels of anticipatory, consummatory and total pleasure compared to the control group. Both SPD groups reported significantly more problems in everyday memory and greater levels of depressive and anxiety-related symptoms

Electric dipole moments and the search for new physics

Static electric dipole moments of nondegenerate systems probe mass scales for physics beyond the Standard Model well beyond those reached directly at high energy colliders. Discrimination between different physics models, however, requires complementary searches in atomic-molecular-and-optical, nuclear and particle physics. In this report, we discuss the current status and prospects in the near future for a compelling suite of such experiments, along with developments needed in the encompassing theoretical framework.Comment: Contribution to Snowmass 2021; updated with community edits and endorsement

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe