Canopy Homolog 2 contributes to liver oncogenesis by promoting unfolded protein response-dependent destabilization of tumor protein P53.

BACKGROUD AND AIMS: Abnormalities in the tumor protein P53 (p53) gene and overexpression of mouse double minute 2 homolog (MDM2), a negative regulator of p53, are commonly observed in cancers. p53 destabilization is regulated by endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in cancer. However, the mechanisms remain enigmatic. Canopy homolog 2 (CNPY2) is a key UPR initiator that primarily involved in ER stress and is highly expressed in the liver, but its functional role in regulating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of CNPY2 in hepartocarcinogenesis through URP-dependent p53 destabilization. APPROACH AND RESULTS: Here, we showed that CNPY2 expression is up-regulated in HCC and negatively correlated with survival rate in liver cancer patients. Deletion of Cnpy2 obliterates diethylnitrosamine (DEN)-induced HCC in mice. Mechanistic studies demonstrated that CNPY2 binds and prevents ribosome proteins from inhibiting MDM2 and enhances the UPR activity of protein kinase RNA-like endoplasmic reticulum kinase and inositol-requiring transmembrane kinase endoribonuclease-1α, leading to p53 destabilization and cell-cycle progression. In addition, transcriptome analyses uncovered that CNPY2 is also required for DEN-induced expression of oncogenes, including c-Jun and fibroblast growth factor 21. Intratumoral injection of nanoparticle-based CRISPR single-guide RNA/CRISPR-associated protein 9 mRNA against Cnpy2 has antitumor effects in HCC. CONCLUSIONS: These findings demonstrate that CNPY2 is crucial for liver oncogenesis through UPR-dependent repression of p53 and activation of oncogenes, providing insights into the design of a therapeutic target for HCC.

Clinical Utility of Olaparib in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Review of Current Evidence and Patient Selection.

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive and fatal disease with a median survival of 36 months. With the advent of genetic sequencing to identify individual genomic profiles and acquired tumor-specific pathways, targeted therapies have revolutionized cancer treatment, including the treatment strategy in mCRPC. Poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPi) are oral drugs that target mutations in the homologous recombination repair (HRR) pathway, which are found in approximately 27% of prostate cancer patients. In May 2020, the first PARP inhibitor, olaparib, was approved by the US Food and Drug Administration for men with mCRPC with HHR gene mutations based on the findings of the Phase III PROfound trial that showed improved overall survival in men with mCRPC who received olaparib and whose disease had progressed on a novel hormonal agent. This review summarizes the current evidence and clinical utility of olaparib as treatment in men with mCRPC. We describe the mechanism of action of PARPi, key clinical trials of olaparib in men with mCRPC, and ongoing Phase II and III clinical trials investigating olaparib in combination therapy and as front-line therapy in mCRPC.

Complete response to neoadjuvant pembrolizumab and capecitabine in microsatellite stable, Epstein-Barr virus-positive, locally advanced gastric adenocarcinoma: case report.

Immunotherapy has been established as a standard in select molecular subgroups of treatment-refractory advanced gastric cancer. However, its role in resectable gastric cancer where perioperative systemic therapy is the standard remains unclear. We present a case of a man who was diagnosed with resectable gastric cancer that was microsatellite stable but programmed death-ligand 1 (PD-L1) and Epstein-Barr Virus (EBV)-positive. Given extenuating circumstances of the SARS-CoV-2 pandemic, preferences to limit exposure to the healthcare setting, and the unique tumor molecular features, neoadjuvant pembrolizumab and capecitabine was pursued after multidisciplinary discussion. He was able to achieve a complete response to this neoadjuvant regimen with no further signs of radiographic or pathologic disease on follow-up. We highlight a dramatic response to this novel approach that represents among the first cases to support a potentially viable neoadjuvant chemoimmunotherapy strategy to resectable gastric cancer. In select patients, perioperative immunotherapy-based therapy may constitute a promising strategy in resectable gastric cancer and warrants further investigation.

Sex Differences in Using Systemic Inflammatory Markers to Prognosticate Patients with Head and Neck Squamous Cell Carcinoma.

Background: Remarkable discrepancy exists in outcomes between men and women for multiple malignancies. We sought to expose sex differences in using platelet count and neutrophil-to-lymphocyte ratio (NLR) to predict overall survival for select cancer types with focus on head and neck squamous cell carcinoma (HNSCC).Methods: Peripheral blood samples from 9,365 patients seen in a tertiary teaching hospital with nine different primary tumors were retrospectively examined. HNSCC RNA-sequencing data from The Cancer Genome Atlas were analyzed by two computational means [Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE)] to extend our observations to the tumor microenvironment.Results: For HNSCC, platelet count was more predictive of overall survival for males [log-rank test: HR = 1.809; 95% confidence interval (CI), 1.461-2.239 vs. HR = 1.287; 95% CI, 0.8901-1.861], whereas NLR was more predictive for females (HR = 2.627; 95% CI, 1.716-4.02 vs. HR = 1.261; 95% CI, 0.998-1.593). For females, lymphocyte count was more associated with survival than neutrophil count (multivariate Cox regression: P = 0.0015 vs. P = 0.7476). Both CIBERSORT (P = 0.0061) and ESTIMATE (P = 0.022) revealed greater immune infiltration in females. High tumor infiltration by T lymphocytes was more strikingly associated with survival in females (HR = 0.20, P = 0.0281) than in males (HR = 0.49, P = 0.0147).Conclusions: This is the first study to comprehensively demonstrate sex bias in the clinical utility of platelet, granulocyte, and lymphocyte counts as biomarkers to prognosticate HNSCC patients.Impact: This work emphasizes the necessity to consider sex in appraising inflammatory markers for cancer risk stratification. Cancer Epidemiol Biomarkers Prev; 27(10); 1176-85. ©2018 AACR.

Can we accredit hospital ethics? A tentative proposal.

OBJECTIVES: The objective of this research was to develop ethics accreditation standards for hospitals. RESEARCH DESIGN: Our research methods included a literature review, an expert focus group, the Delphi technique and a hospital survey. The entire process was separated into two stages: (1) the development of a draft of hospital ethics accreditation standards; and (2) conducting a nationwide hospital survey of the proposed standards. RESULTS: This study produced a tentative draft of hospital ethics accreditation standards comprised of six chapters and 62 standards based on the expert focus group and Delphi technique. The six chapters are: Medical ethics policies, regulations and leadership; The establishment and operation of a medical ethics committee; The establishment and operation of research-related ethics committees; Medical ethics education; Organisational ethical climate; and Respect for patients' rights and establishment of good hospital-patient relationships. The hospital survey indicated that the concept of an organisational ethical climate was new to most hospital managers, most hospitals disliked the idea of having a separate hospital ethics accreditation system, and small hospitals were concerned about their ability to comply with all of the standards. CONCLUSIONS: Regardless of whether hospital ethics accreditation can be a stand-alone accreditation or just part of existing hospital accreditation programmes, we hope this draft can serve as a good reference for future endeavours by hospital accreditation authorities.