A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol.

Introduction: Taxanes are a class of chemotherapeutics commonly used to treat various solid tumors, including breast and ovarian cancers. Taxane-induced peripheral neuropathy (TIPN) occurs in up to 70% of patients, impacting quality of life both during and after treatment. TIPN typically manifests as tingling and numbness in the hands and feet and can cause irreversible loss of function of peripheral nerves. TIPN can be dose-limiting, potentially impacting clinical outcomes. The mechanisms underlying TIPN are poorly understood. As such, there are limited treatment options and no tools to provide early detection of those who will develop TIPN. Although some patients may have a genetic predisposition, genetic biomarkers have been inconsistent in predicting chemotherapy-induced peripheral neuropathy (CIPN). Moreover, other molecular markers (eg, metabolites, mRNA, miRNA, proteins) may be informative for predicting CIPN, but remain largely unexplored. We anticipate that combinations of multiple biomarkers will be required to consistently predict those who will develop TIPN. Methods: To address this clinical gap of identifying patients at risk of TIPN, we initiated the Genetics and Inflammatory Markers for CIPN (GENIE) study. This longitudinal multicenter observational study uses a novel, multimodal approach to evaluate genomic variation, metabolites, DNA methylation, gene expression, and circulating cytokines/chemokines prior to, during, and after taxane treatment in 400 patients with breast cancer. Molecular and patient reported data will be collected prior to, during, and after taxane therapy. Multi-modal data will be used to develop a set of comprehensive predictive biomarker signatures of TIPN. Conclusion: The goal of this study is to enable early detection of patients at risk of developing TIPN, provide a tool to modify taxane treatment to minimize morbidity from TIPN, and improved patient quality of life. Here we provide a brief review of the current state of research into CIPN and TIPN and introduce the GENIE study design.

Repositioning Fenofibrate to Reactivate p53 and Reprogram the Tumor-Immune Microenvironment in HPV+ Head and Neck Squamous Cell Carcinoma.

Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV- HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.

Examination of exclusion criteria in total knee arthroplasty rehabilitation trials: influence on the application of evidence in day-to-day practice.

OBJECTIVE: Total knee arthroplasty (TKA) rehabilitation trials use exclusion criteria, which may limit their generalizability in practice. We investigated whether patients seen in routine practice who meet common exclusion criteria recover differently from TKA compared to research-eligible patients. We hypothesized that research-ineligible patients would demonstrate poorer average postoperative function and slower rate of functional recovery compared to research-eligible patients. METHODS: Patient characteristics and exclusion criteria were extracted and summarized from trials included in the three most recent systematic reviews of TKA rehabilitation. Trial participant characteristics were compared to a clinical dataset of patient outcomes collected in routine TKA rehabilitation. Where possible, individual exclusion criterion from the trials were applied to the clinical dataset to determine "eligible" and "ineligible" groups for research participation. Postoperative functional outcomes including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Timed Up and Go (TUG) were compared between "eligible" and "ineligible" groups using mixed effects models. RESULTS: 2,528 participants from 27 trials were compared to 474 patients from the clinical dataset. Research participants were older, with lower Body Mass Index than patients in the clinical dataset. Many patients in the clinical dataset would be "ineligible" for research participation based upon common exclusion criteria from the trials. Differences were observed in average postoperative functioning between some "eligible" and "ineligible" groups in the clinical dataset. However, no differences were observed in functional recovery rate between groups, except for patients with diabetes whose TUG recovered more slowly than their "eligible" counterparts. CONCLUSIONS: Many patients in the clinical dataset were "ineligible" for research participation based upon common TKA rehabilitation trial exclusion criteria. However, the postoperative recovery rate did not differ between "eligible" and "ineligible" groups based on individual exclusion criterion-except for individuals with diabetes. This suggests that both clinical and research populations may recover similarly from TKA.

CoA Synthase (COASY) Mediates Radiation Resistance via PI3K Signaling in Rectal Cancer.

Neoadjuvant radiation is standard of care for locally advanced rectal cancer. Response to radiation is highly variable and directly linked with survival. However, there currently are no validated biomarkers or molecular targets to predict or improve radiation response, which would help develop personalized treatment and ideally targeted therapies. Here, we identified a novel biomarker, coenzyme A synthase (COASY), whose mRNA expression was consistently elevated in radioresistant human rectal cancers. This observation was validated in independent patient cohorts and further confirmed in colorectal cancer cell lines. Importantly, genetic overexpression and knockdown yielded radioresistant and sensitive phenotypes, respectively, in vitro and in vivo. COASY-knockdown xenografts were more vulnerable to radiation, showing delayed tumor growth, decreased proliferation, and increased apoptosis. Mechanistically, COASY protein directly interacted with the PI3K regulatory subunit PI3K-P85α, which increased AKT and mTOR phosphorylation, enhancing cell survival. Furthermore, shRNA COASY knockdown disrupted downstream PI3K pathway activation and also hindered DNA double-strand break repair, which both led to improved radiosensitivity. Collectively, this work reveals for the first time the biological relevance of COASY as a predictive rectal cancer biomarker for radiation response and offers mechanistic evidence to support COASY as a potential therapeutic target. SIGNIFICANCE: COASY is a novel radiotherapy response modulator in rectal cancer that regulates PI3K activation and DNA repair. Furthermore, COASY levels directly correlate with radiation response and serve as a predictive biomarker.

The theatrical stage as accident site in professional dance.

OBJECTIVE: Reducing work-related health hazards at the different theatre workplaces is one aspect of preventive options in professional dance. This also applies to hazards on the highly variable theatrical stage areas. However, detailed information on these stages and their risks is not available. The aim of this study was to analyze and evaluate work-related traumatic injuries in the stage area. METHODS: The basis for the evaluation was accident reports, from the German National Statutory Insurance, of work-related traumatic injuries occurring on stage in professional dancers (n=790: 407 males, 383 females) over a 17-year period (1995-2011). RESULTS: Most (79.4%) of the accidents on stage occurred during an ongoing performance (frequency: 10.1/100 performances), with only 19.7% occurring during rehearsals on stage (p<0.001). Due to the sustained injury, 30.2% of the dancers sustained a time-loss injury. Most (57.7%) of the injured dancers were older than 25 years. Of the accidents, 59.3% were initiated by a definably extrinsic cause, with 40.7% caused by intrinsic factors (p<0.001). Injuries were most commonly caused by the "partner" (21.7%) or "floor" (21.0%). The lower extremity was the most commonly affected body region (63.6%) (p<0.001). CONCLUSION: Stage performances seem to carry an increased injury risk compared to rehearsals. The "risk" of on-stage work is spread across various factors that seem to be stage-specific. There is a need for further qualitative and quantitative research to be able to classify the stage as workplace more precisely.