Mesenchymal gene expression subtyping analysis for early-stage human papillomavirus-negative head and neck squamous cell carcinoma reveals prognostic and predictive applications

Patients with oral cavity squamous cell carcinoma (OCSCC) are predominantly human papillomavirus (HPV)(-), and treatment typically involves surgical resection ± neck dissection, followed by radiation ± chemotherapy. We previously described four mRNA expression patterns (classical, atypical, basal, and mesenchymal), each with unique genomic features and prognosis. Here, we examine the clinical utility of gene expression subtyping in head and neck squamous cell carcinoma (HNSCC) and introduce potentially predictive applications in HPV(-) OCSCC. A retrospective genomic database analysis was performed including 562 HNSCC patients from MD Anderson (MDA-GSE41116) and The Cancer Genome Atlas (TCGA). Samples were assigned molecular subtypes (classical, atypical, basal, and mesenchymal) using an 88-gene classifier. HPV status was determined by gene expression. The clinical endpoint was overall survival censured at 36 months. The Kaplan-Meier plots and log-rank tests were used to investigate associations between clinical variables and survival. Of the 418 TCGA training patients who met analysis criteria, nearly 20% presented as stage I/II. Among node(-) OCSCC patients, the mesenchymal subtype is associated with worse survival (hazard ratio (HR) = 2.4, p = 0.021), offering a potentially actionable biomarker in otherwise early-stage, low-risk disease. This was confirmed in the MDA validation cohort. Node(-) non-mesenchymal OCSCC patients had far better survival compared to node(-) mesenchymal, and all node(+) patients had similarly poor survival. These findings suggest that the mesenchymal subtype is associated with poor survival in surgically resected, early-stage, node(-) OCSCC otherwise expected to have favorable outcomes. These findings highlight the potential value of gene expression subtyping as a pathology adjunct for prognostication and treatment decision-making in OCSCC patients

Do nudges reduce borrowing and consumer confusion in the credit card market?

We study nudges that turn out to have precise null effects in reducing long-run credit card debt. We test nudges across two field experiments covering 183,441 UK cardholders. Our first experiment studies nudges added to monthly credit card statements. Our second experiment studies letters and email nudges (separate from monthly statements) sent to cardholders who signed up to automatically pay the minimum required payment.In a follow-up survey to our second experiment, we find that 96% of respondents underestimate the time it would take to fully repay a debt if the cardholder made only the minimum required payment. The nudges reduce this confusion, but underestimation remains overwhelmingly common

Molecular Biology of Head & Neck Cancer: Risks and Pathways

Patients present with a differential baseline risk of cancer based on normal and expected variations in genes associated with cancer. The baseline risk of developing cancer is acted on throughout life as the genome of different cells interacts with the environment in the form of exposures (eg, toxins, infections). As genetic damage is incurred throughout a lifetime (directly to DNA sequences or to the epigenome), events are set in motion to progressively disrupt normal cellular pathways toward tumorigenesis. This article attempts to characterize broad categories of genetic aberrations and pathways in a manner that might be useful for the clinician to understand the risk of developing cancer, the pathways that are disrupted, and the potential for molecular-based diagnostics

Identification of Human Papillomavirus Infection in Cancer Tissue by Targeted Next-generation Sequencing

Human papillomaviruses (HPV) are oncogenic DNA viruses implicated in squamous cell carcinomas of several anatomic sites, as well as endocervical adenocarcinomas. Identification of HPV is an actionable finding in some carcinomas, potentially influencing tumor classification, prognosis, and management. We incorporated capture probes for oncogenic HPV strains 16 and 18 into a broader next-generation sequencing (NGS) panel designed to identify actionable mutations in solid malignancies. A total of 21 head and neck, genitourinary and gynecological squamous cell carcinomas and endocervical adenocarcinomas were sequenced as part of the UNCSeq project. Using p16 immunohistochemical results as the gold standard, we set a cutoff for proportion of aligned HPV reads that maximized performance of our NGS assay (92% sensitive, 100% specific for HPV). These results suggest that sequencing of oncogenic pathogens can be incorporated into targeted NGS panels, extending the clinical utility of genomic assays

Biochemical sensor based on a novel all-fibre cavity ring down spectroscopy technique incorporating a tilted fibre Bragg grating

A novel all-fibre cavity ring down spectroscopy technique is proposed where a tilt fibre Bragg grating (TFBG) or long-period grating (LPG) in the cavity provides sensitivity to surrounding medium. Such configuration with an LPG as the representative was theoretically analyzed. Two spectral bands were identified employable for sensing of surrounding refractive index for a weak LPG while only one band existed for a strong LPG. A TFBG, with enhanced sensitivity compared to usual LPGs, was used in a ring down cavity of 1 m constructed with 2 fibre Bragg gratings as the reflectors and the decay time changed from 220 to 450 ns when the TFBG was immersed into water from air

A circular economy framework for seafood waste valorisation to meet challenges and opportunities for intensive production and sustainability

There is a growing concern among societies and consumers over food security and the sustainability of food production systems. For seafood, it has been highly advocated as a healthy food source and its sustainability credentials. However, the increasing global demand for seafood and the need to supply the quantities are creating sustainability issues, e.g., the importation of plant and marine proteins for aquafeed production. Consequently, there is a necessary need to analyse the supply chain and life cycle of these systems to determine their sustainability merits and how to enhance them. The circular economy (CE) aims to reduce processing by-product underutilisation, increase the rate of reuse, and reduce pressure on natural resources and systems. For seafood, there are large quantities of biomass that are being lost through bycatch/discards, waste from aquaculture (e.g., sludge and wastewater), and by-products generated through processing (e.g., trimmings and offal). These can all be valorised for the generation of feeds, value-added products, or further food production. This review will focus on seafood by-products generated during the processing into consumer products, and the current methods that could be used to manage or treat these waste streams. The review presents a stepwise framework that outlines valorisation opportunities for seafood by-products. This framework can enable producers, operators, regulators, and investors to integrate with the principles of the CE with the consideration of achieving economic viability. The challenges of seafood loss due to climate change and emerging recycling strategies will also need to be considered and integrated into the valorisation pathways. Communication, education, and engagement with stakeholders are key to transitioning to a circular economy. Where increase awareness and acceptance will create drivers and demand for seafood by-product valorisation. Overall, the impact of such a circular production system will potentially lead to higher production efficiency, reduce demand for natural resources, and greater seafood production. All of which addresses many of the United Nation's Sustainable Development Goals by contributing towards future food security and sustainability.This work was supported by the EAPA_576/2018 NEPTUNUS project. The authors would like to acknowledge the financial support of Interreg Atlantic Area. A.H.L Wan was co-funded under the HYDROfish project (2019–2022) which was funded under the Disruptive Technologies Innovation Fund (DTIF), established under Project Ireland 2040, run by the Department of Enterprise Trade and Employment with administrative support from Enterprise Ireland. His opinions expressed are his own. The authors would also like to thank Matt Bell for his editorial assistance

Induction Chemotherapy with Carboplatin, Irinotecan, and Paclitaxel Followed by High Dose Three-Dimension Conformal Thoracic Radiotherapy (74 Gy) with Concurrent Carboplatin, Paclitaxel, and Gefitinib in Unresectable Stage IIIA and Stage IIIB Non-small Cell Lung Cancer

Combined modality therapy is a standard therapy for patients with unresectable stage III non-small cell lung cancer (NSCLC). Gefitinib is active in advanced NSCLC, and in preclinical models, it potentiates the activity of radiation therapy. We investigate the tolerability of gefitinib in combined modality therapy in combination with three-dimensional thoracic conformal radiation therapy (3-dimensional TCRT).Stage III patients with a good performance status were treated with induction chemotherapy (carboplatin area under the curve [AUC] of 5, irinotecan 100 mg/m2, and paclitaxel 175 mg/m2 days 1 and 22) with pegfilgrastim support followed by concurrent chemotherapy (carboplatin AUC 2, and paclitaxel 45 mg/m2 weekly) and gefitinib 250 mg daily beginning on day 43 with 3-dimensional TCRT to 74 Gy.Between March 2004 and January 2006, 23 patients received treatment on the trial: median age 62 years (range 44–82), 52% female, 61% stage IIIA, 61% performance status 0, 17% ≥5% weight loss, and 91% underwent positron emission tomography staging. Induction chemotherapy with pegfilgrastim support was well tolerated and active (partial response rate, 24%; stable disease, 76%; and early progression, 0%). Twenty-one patients initiated the concurrent chemoradiation, and 20 patients completed therapy to 74 Gy. The primary toxicities of concurrent chemoradiation were grade 3 esophagitis (19.5%) and cardiac arrhythmia (atrial fibrillation) (9.5%). The median progression-free survival and overall survival were 9 months (95% confidence intervals [CI]: 7–13 months) and 16 months (95% CI: 10–20 months), respectively.Treatment with induction chemotherapy and gefitinib concurrent with 3-dimensional TCRT has an acceptable toxicity and tolerability, but the survival results were disappointing

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Correlative studies from checkpoint inhibitor trials have indicated that better understanding of human leukocytic trafficking into the human tumor microenvironment can expedite the translation of future immune-oncologic agents. In order to directly characterize signaling pathways that can regulate human leukocytic trafficking into the tumor, we have developed a completely autologous xenotransplantation method to reconstitute the human tumor immune microenvironment in vivo. We were able to genetically mark the engrafted CD34+ bone marrow cells as well as the tumor cells, and follow the endogenous leukocytic infiltration into the autologous tumor. To investigate human tumor intrinsic factors that can potentially regulate the immune cells in our system, we silenced STAT3 signaling in the tumor compartment. As expected, STAT3 signaling suppression in the tumor compartment in these autologously reconstituted humanized mice showed increased tumor infiltrating lymphocytes and reduction of arginase-1 in the stroma, which were associated with slower tumor growth rate. We also used this novel system to characterize human myeloid suppressor cells as well as to screen novel agents that can alter endogenous leukocytic infiltration into the tumor. Taken together, we present a valuable method to study individualized human tumor microenvironments in vivo without confounding allogeneic responses

Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.Integration of miRNA and gene patterns yielded evidence that proximal pairs of miRNAs are processed from polycistronic primary transcripts, and that intronic miRNAs and their host gene mRNAs derive from common transcripts. Patterns of miRNA expression revealed multiple tumor subtypes and a set of 34 miRNAs predictive of overall patient survival. In a global analysis, miRNA:mRNA pairs anti-correlated in expression across tumors showed a higher frequency of in silico predicted target sites in the mRNA 3'-untranslated region (with less frequency observed for coding sequence and 5'-untranslated regions). The miR-29 family and predicted target genes were among the most strongly anti-correlated miRNA:mRNA pairs; over-expression of miR-29a in vitro repressed several anti-correlated genes (including DNMT3A and DNMT3B) and substantially decreased ovarian cancer cell viability.This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers