Recent studies of unconventional resource development (URD) and adverse health effects have been limited by distance-based exposure surrogates. Our study compared exposure classifications between air ...pollutant concentrations and "well activity" (WA) metrics, which are distance-based exposure proxies used in Marcellus-area studies to reflect variation in time and space of residential URD activity. We compiled Pennsylvania air monitoring data for benzene, carbon monoxide, nitrogen dioxide, ozone, fine particulates and sulfur dioxide, and combined this with data on nearly 9000 Pennsylvania wells. We replicated WA calculations using geo-coordinates of monitors to represent residences and compared exposure categories from air measurements and WA at the site of each monitor. There was little agreement between the two methods for the pollutants included in the analysis, with most weighted kappa coefficients between -0.1 and 0.1. The exposure categories agreed for about 25% of the observations and assigned inverse categories 16%-29% of the time, depending on the pollutant. Our results indicate that WA measures did not adequately distinguish categories of air pollutant exposures and employing them in epidemiology studies can result in misclassification of exposure. This underscores the need for more robust exposure assessment in future analyses and cautious interpretation of these existing studies.
A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise ...de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes.
The Prince George’s County Health Department encountered several challenges to increasing access to cardiac rehabilitation (CR) services among disadvantaged populations. They include excessive ...patient out-of-pocket costs; requirements that CR orders must be signed by a physician; provider reluctance to refer patients to CR, with most primary care providers preferring to refer clients to cardiologists for the latter to determine whether the patient needs CR referral; limited availability of CR programs; and difficulty identifying patients eligible for CR services. Discussions with other local health departments and public health practitioners indicate that these challenges are not unique to Maryland but are indicative of policy and system barriers that prevent the optimal delivery of cardiovascular health services. This case study documents the challenges and the Prince George’s County Health Department’s efforts to resolve them and provides recommendations for decision-makers seeking to make CR programs more accessible to disadvantaged populations.
Expression of the DNA/RNA helicase schlafen family member 11 (SLFN11) has been identified as a sensitizer of tumor cells to DNA-damaging agents including platinum chemotherapy. We assessed the impact ...of SLFN11 expression on response to platinum chemotherapy and outcomes in patients with metastatic castration-resistant prostate cancer (CRPC). Tumor expression of SLFN11 was assessed in 41 patients with CRPC treated with platinum chemotherapy by RNA sequencing (RNA-seq) of metastatic biopsy tissue (
= 27) and/or immunofluorescence in circulating tumor cells (CTC;
= 20). Cox regression and Kaplan-Meier methods were used to evaluate the association of SLFN11 expression with radiographic progression-free survival (rPFS) and overall survival (OS). Multivariate analysis included tumor histology (i.e., adenocarcinoma or neuroendocrine) and the presence or absence of DNA repair aberrations. Patient-derived organoids with SLFN11 expression and after knockout by CRISPR-Cas9 were treated with platinum and assessed for changes in dose response. Patients were treated with platinum combination (
= 38) or platinum monotherapy (
= 3). Median lines of prior therapy for CRPC was two. Median OS was 8.7 months. Overexpression of SLFN11 in metastatic tumors by RNA-seq was associated with longer rPFS compared with those without overexpression (6.9 vs. 2.8 months, HR = 3.72; 95% confidence interval (CI), 1.56-8.87;
< 0.001); similar results were observed for patients with SLFN11-positive versus SLFN11-negative CTCs (rPFS 6.0 vs. 2.2 months, HR = 4.02; 95% CI, 0.77-20.86;
= 0.002). A prostate-specific antigen (PSA) decline of ≥50% was observed in all patients with SLFN11 overexpression. No association was observed between SLFN11 expression and OS. On multivariable analysis, SLFN11 was an independent factor associated with rPFS on platinum therapy. Platinum response of organoids expressing SLFN11 was reduced after SLFN11 knockout. Our data suggest that SLFN11 expression might identify patients with CRPC with a better response to platinum chemotherapy independent of histology or other genomic alterations. Additional studies, also in the context of PARP inhibitors, are warranted.
Pregnant women may be vulnerable to changes in ambient temperature and warming climates. Recent evidence suggests that temperature increases are associated with placental abruption, a risk factor for ...stillbirth.
We investigated the effect of acute exposures to apparent temperature on stillbirths in Harris County, Texas, 2008–2013.
We conducted a case-crossover study to investigate the association between temperature and stillbirth among 708 women. We used data from the National Climatic Data Center to estimate maternal exposure to daily average apparent temperature over the days (lag days 1 through 6) preceding the stillbirth event. We employed symmetric bidirectional sampling to select six control periods one to three weeks before and after each event and applied conditional logistic regression to examine associations between increases of apparent temperature and stillbirths during the warm season (May–September). We adjusted for fine particulate matter (PM2.5), nitrogen dioxide (NO2) and ozone (O3) and used stratified analysis to examine differences in risk by maternal race/ethnicity. We also examined the association among stillbirths with and without placental abruptions.
Independent of air pollutant exposures, a 10 °F increase in apparent temperature in the week preceding delivery (lag days 1 to 6) was positively associated with a 45% (adjusted OR = 1.45, 95% confidence interval (CI): 1.18, 1.77) increase in risk for stillbirth. Risks were elevated for stillbirths occurring in June through August, for Hispanic and non-Hispanic Black women, but not for non-Hispanic Whites. We also observed elevated risks associated with temperature increases in the few days preceding delivery among stillbirths caused by placental abruption, with the risk being highest on lag day 1 (OR = 1.93, 95% CI: 1.15, 3.23).
Independent of maternal ambient air pollutant exposure, we found evidence of an association between apparent temperature increases in the week preceding an event and risk of stillbirth. Risks for stillbirth varied by race/ethnicity. Further, in the first study to evaluate the impact of temperature on a specific complication during pregnancy, the risks were higher among mothers with placental abruption.
•Increased temperature in the week preceding delivery was associated with stillbirth risk.•Stillbirth risk varied by maternal race/ethnicity.•Increased temperature was associated with risk of stillbirths by placental abruption.
Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine ...(SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer. We found that DLL3 is expressed in most of the castration-resistant neuroendocrine prostate cancer (CRPC-NE) (36 of 47, 76.6%) and in a subset of castration-resistant prostate adenocarcinomas (7 of 56, 12.5%). It shows minimal to no expression in localized prostate cancer (1 of 194) and benign prostate (0 of 103). DLL3 expression correlates with neuroendocrine marker expression,
loss, and aggressive clinical features. DLL3 in circulating tumor cells was concordant with matched metastatic biopsy (87%). Treatment of DLL3-expressing prostate cancer xenografts with a single dose of SC16LD6.5 resulted in complete and durable responses, whereas DLL3-negative models were insensitive. We highlight a patient with neuroendocrine prostate cancer with a meaningful clinical and radiologic response to SC16LD6.5 when treated on a phase 1 trial. Overall, our findings indicate that DLL3 is preferentially expressed in CRPC-NE and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer.
Epigenetic alterations, including changes in DNA methylation, histone modifications and nucleosome remodeling, result in abnormal gene expression patterns that contribute to prostate tumor initiation ...and continue to evolve during the course of disease progression. Epigenetic modifications are responsible for silencing tumor-suppressor genes, activating oncogenic drivers, and driving therapy resistance and thus have emerged as promising targets for antineoplastic therapy in prostate cancer. In this review, we discuss the role of epigenetics in prostate cancer with a particular emphasis on clinical implications. We review how epigenetic regulators crosstalk with critical biological pathways, including androgen receptor signaling, and how these interactions dynamically control prostate cancer transcriptional profiles. Because of their potentially reversible nature, restoration of a "normal" epigenome could provide a basis for innovative therapeutic strategies in prostate cancer. We highlight how particular epigenetic alterations are emerging as potential diagnostic and prognostic biomarkers and/or targets for the treatment of advanced prostate cancer.
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