Sequestsome-1/p62-targeted small molecules for pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by heightened autophagy and systemic immune dysfunction. Modest improvements in clinical outcomes have been demonstrated in completed clinical trials targeting autophagy with combination hydroxychloroquine (HCQ) and chemotherapy. Recent mechanistic insights into the role of autophagy-dependent immune evasion have prompted the need for more precise and druggable targets of autophagy inhibition. Sequestosome-1 (SQSTM-1) is a multidomain scaffold protein with well-established roles in autophagy, tumor necrosis factor alpha (TNFα)- and NF-κB-related signaling pathways. SQSTM1 overexpression is frequently observed in PDAC, correlating with clinical stage and outcome. Given the unique molecular structure of SQSTM-1 and its diverse activity, identifying means of limiting SQSTM-1-dependent autophagy to promote an effective immune response in PDAC could be a promising treatment strategy.

Changes in Disparities in Stage of Breast Cancer Diagnosis in Pennsylvania After the Affordable Care Act.

Background: This study sought to determine if increased access to health insurance following the Affordable Care Act (ACA) resulted in an increased proportion of early-stage breast cancer diagnosis among women in Pennsylvania, particularly minorities, rural residents, and those of lower socioeconomic status. Materials and Methods: Data on 35,735 breast cancer cases among women 50-64 and 68-74 years of age in Pennsylvania between 2010 and 2016 were extracted from the Pennsylvania Cancer Registry and analyzed in 2019. Women 50-64 years of age were subdivided by race/ethnicity, area of residence, and socioeconomic status as measured by area deprivation index (ADI). We compared the proportions of early-stage breast cancer diagnosis pre-ACA (2010-2013) and post-ACA (2014-2016) for all women 50-64 years of age to all women 68-74 years of age. This comparison was also made between paired sociodemographic subgroups for women 50-64 years of age. Multivariable logistic regression models were constructed to assess how race, area of residence, ADI, and primary care physician (PCP) density interacted to impact breast cancer diagnosis post-ACA. Results: The proportion of early-stage breast cancer diagnosis increased by 1.71% post-ACA among women 50-64 years of age (p < 0.01), whereas women 68-74 years of age saw no change. Multivariable logistic regression analysis demonstrated that minority women had lower odds of early-stage breast cancer diagnosis pre-ACA, but not post-ACA, when controlling for ADI. Meanwhile, increased area-level socioeconomic advantage was associated with higher odds of being diagnosed with early-stage breast cancer pre- and post-ACA irrespective of controlling for race, area of residence, or PCP density. Conclusions: Enhanced access to health insurance under the ACA was associated with an increased proportion of early-stage breast cancer diagnosis in Pennsylvanian women 50-64 years of age and may have reduced racial, but not socioeconomic, disparities in breast cancer diagnosis.

Extreme chromosome 17 copy number instability is a prognostic factor in patients with gastroesophageal adenocarcinoma: A retrospective cohort study.

Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell-to-cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN-17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN-17 and clinical outcome after surgical and nonsurgical treatment. CIN-17 was detected in 45.4% (158/348) and extreme CIN-17 in 28.4% (99/348). Extreme CIN-17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN-17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263-0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN-17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated nonoperatively.