Baseline factors associated with self-reported disease flares following COVID-19 vaccination among adults with systemic rheumatic disease: results from the COVID-19 global rheumatology alliance vaccine survey.

OBJECTIVE: To examine the frequency of, and risk factors for, disease flare following COVID-19 vaccination in patients with systemic rheumatic disease (SRD). METHODS: An international study was conducted from 2 April to 16 August 2021, using an online survey of 5619 adults with SRD for adverse events following COVID-19 vaccination, including flares of disease requiring a change in treatment. We examined risk factors identified a priori based on published associations with SRD activity and SARS-CoV-2 severity, including demographics, SRD type, comorbidities, vaccine type, cessation of immunosuppressive medications around vaccination and history of reactions to non-COVID-19 vaccines, using multivariable logistic regression. RESULTS: Flares requiring a change in treatment following COVID-19 vaccination were reported by 4.9% of patients. Compared with rheumatoid arthritis, certain SRD, including systemic lupus erythematosus (OR 1.51, 95% CI 1.03, 2.20), psoriatic arthritis (OR 1.95, 95% CI 1.20, 3.18) and polymyalgia rheumatica (OR 1.94, 95% CI 1.08, 2.48) were associated with higher odds of flare, while idiopathic inflammatory myopathies were associated with lower odds for flare (OR 0.54, 95% CI 0.31-0.96). The Oxford-AstraZeneca vaccine was associated with higher odds of flare relative to the Pfizer-BioNTech vaccine (OR 1.44, 95% CI 1.07, 1.95), as were a prior reaction to a non-COVID-19 vaccine (OR 2.50, 95% CI 1.76, 3.54) and female sex (OR 2.71, 95% CI 1.55, 4.72). CONCLUSION: SRD flares requiring changes in treatment following COVID-19 vaccination were uncommon in this large international study. Several potential risk factors, as well as differences by disease type, warrant further examination in prospective cohorts.

Developing effective combination therapy for pancreatic cancer: An overview.

Pancreatic cancer is a fatal disease. The five-year survival for patients with all stages of this tumor type is less than 10%, with a majority of patients dying from drug resistant, metastatic disease. Gemcitabine has been a standard of care for the treatment of pancreatic cancer for over 20 years, but as a single agent gemcitabine is not curative. Since the only therapeutic option for the over 80 percent of pancreatic cancer patients ineligible for surgical resection is chemotherapy with or without radiation, the last few decades have seen a significant effort to develop effective therapy for this disease. This review addresses preclinical and clinical efforts to identify agents that target molecular characteristics common to pancreatic tumors and to develop mechanism-based combination approaches to therapy. Some of the most promising combinations include agents that inhibit transcription dependent on BET proteins (BET bromodomain inhibitors) or that inhibit DNA repair mediated by PARP (PARP inhibitors).

Improving Hurricane Harvey Disaster Research Response Through Academic-Practice Partnerships.

After Hurricane Harvey, researchers, media, and public health agencies collected data in Houston, Texas, to assess potential health effects and inform the public. To limit redundancy and ensure sampling coverage of impacted areas, research and practice partners used disaster research response (DR2) resources and relied on partnerships formed during a 2015 DR2 workshop in Houston. Improved coordination after the disaster can improve the effectiveness and efficiency of DR2 and enable the use of data to improve recovery and preparedness for future disasters.

Deepwater Horizon oil spill exposures and neurobehavioral function in GuLF study participants.

INTRODUCTION: The 2010 Deepwater Horizon (DWH) disaster exposed tens of thousands of oil spill response and cleanup (OSRC) workers to hydrocarbons and other hazardous chemicals. Some hydrocarbons, such as toluene and hexane, have been found to have acute adverse effects on the central nervous system in occupational settings. However, no studies have examined the association between oil spill exposures and neurobehavioral function. METHODS: We used data from the Gulf Long-term Follow-up Study, a cohort of adults who worked on the DWH response and cleanup. Total hydrocarbon (THC) exposure attributed to oil spill cleanup work was estimated from a job-exposure matrix linking air measurement data to detailed cleanup work histories. Participants were also categorized into 6 job categories, or OSRC classes, based on their activity with the highest exposure. Neurobehavioral performance was assessed at a clinical exam 4-6 years after the spill. We used multivariable linear regression to evaluate relationships of ordinal THC levels and OSRC classes with 16 neurobehavioral outcomes. RESULTS: We found limited evidence of associations between THC levels or OSRC classes and decreased neurobehavioral function, including attention, memory, and executive function. Workers exposed to ≥3 ppm THC scored significantly worse (difference1.0-2.9ppm = -0.39, 95% confidence interval (CI) = -0.74, -0.04) than workers exposed to <0.30 ppm THC for the digit span forward count test. There was also a possible threshold effect above 1 ppm THC for symbol digit test total errors (difference1.0-2.9ppm = -0.56 (95% CI = -1.13, -0.003), difference≥3.0ppm = -0.55 (95% CI = -1.20, 0.10)). Associations appeared to be stronger in men than in women. A summary latency measure suggested an association between more highly exposed jobs (especially support of operations workers) and decreased neurobehavioral function. CONCLUSION: OSRC-related exposures were associated with modest decreases in neurobehavioral function, especially attention, memory, and executive function.

Lung Function in Oil Spill Response Workers 1-3 Years After the Deepwater Horizon Disaster.

BACKGROUND: Little is known about the effects of inhalation exposures on lung function among workers involved in the mitigation of oil spills. Our objective was to determine the relationship between oil spill response work and lung function 1-3 years after the Deepwater Horizon (DWH) disaster. METHODS: We evaluated spirometry for 7,775 adults living in the Gulf states who either participated in DWH response efforts (workers) or received safety training but were not hired (nonworkers). At an enrollment interview, we collected detailed work histories including information on potential exposure to dispersants and burning oil/gas. We assessed forced expiratory volume in 1 second (FEV1; mL), forced vital capacity (FVC; mL), and the ratio (FEV1/FVC%) for differences by broad job classes and exposure to dispersants or burning oil/gas using multivariable linear and modified Poisson regression. RESULTS: We found no differences between workers and nonworkers. Among workers, we observed a small decrement in FEV1 (Beta, -71 mL; 95% confidence interval [CI], -127 to -14) in decontamination workers compared with support workers. Workers with high potential exposure to burning oil/gas had reduced lung function compared with unexposed workers: FEV1 (Beta, -183 mL; 95% CI, -316 to -49) and FEV1/FVC (Beta, -1.93%; 95% CI, -3.50 to -0.36), and an elevated risk of having a FEV1/FVC in the lowest tertile (prevalence ratio, 1.38; 95% CI, 0.99 to 1.92). CONCLUSIONS: While no differences in lung function were found between workers and nonworkers, lung function was reduced among decontamination workers and workers with high exposure to burning oil/gas compared with unexposed workers.

Deepwater Horizon oil spill exposures and nonfatal myocardial infarction in the GuLF STUDY.

BACKGROUND: Workers involved in the response and clean-up of the 2010 Deepwater Horizon oil spill faced possible exposures to crude oil, burning oil, dispersants and other pollutants in addition to physical and emotional stress. These exposures may have increased risk of myocardial infarction (MI) among oil spill workers. METHODS: Gulf Long-term Follow-up (GuLF) STUDY participants comprise individuals who either participated in the Deepwater Horizon response efforts or registered for safety training but were not hired. Oil spill-related exposures were assessed during enrollment interviews conducted in 2011-2013. We estimated risk ratios (RR) and 95% confidence intervals for the associations of clean-up work characteristics with self-reported nonfatal MI up to three years post-spill. RESULTS: Among 31,109 participants without history of MI prior to the spill, 77% worked on the oil spill. There were 192 self-reported MI during the study period; 151 among workers. Among the full cohort, working on the oil spill clean-up (vs not working on the clean-up) and living in proximity to the oil spill (vs further away) were suggestively associated with a possible increased risk of nonfatal MI [RR: 1.22 (0.86, 1.73) and 1.15 (0.82, 1.60), respectively]. Among oil spill workers, working for > 180 days was associated with MI [RR for > 180 days (vs 1-30 days): 2.05 (1.05, 4.01)], as was stopping working due to heat [RR: 1.99 (1.43, 2.78)]. There were suggestive associations of maximum total hydrocarbon exposure ≥3.00 ppm (vs < 0.30 ppm) [RR: 1.69 (0.90, 3.19)] and working on decontaminating oiled equipment (vs administrative support) [1.72 (0.96, 3.09)] with nonfatal MI. CONCLUSION: This is the first study to assess the associations between oil spill exposures and MI. Results suggest that working on the spill for > 180 days and stopping work due to heat increased risk of nonfatal MI. Future research should evaluate whether the observed associations are related to specific chemical exposures or other stressors associated with the spill.

The Gulf Long-Term Follow-Up Study (GuLF STUDY): Biospecimen collection at enrollment.

The 2010 Deepwater Horizon (DWH) explosion in the Gulf of Mexico led to the largest ever marine oil spill by volume. The GuLF STUDY is investigating possible adverse human health effects associated with oil spill activities. One objective of the study was to utilize biological specimens from study participants to examine spill-related adverse health effects. This study describes the methods for collecting, processing, shipping, and storing specimens during the enrollment phase of the study. GuLF STUDY participants living in Gulf States (Alabama, Florida, Louisiana, Mississippi, and eastern Texas) were eligible to complete a home visit at enrollment, one to three years after the DWH explosion. During this visit, blood, urine, toenail and hair clippings, and house dust samples were collected. Specimens were shipped overnight to a central processing laboratory in containers with cold and ambient temperature compartments. Most blood and urine specimens were then aliquoted and stored in liquid nitrogen vapor or at -80°C, with some samples stored at -20°C. A total of 11,193 participants completed a home visit, and over 99% provided at least one biospecimen. Most participants provided blood (93%), urine (99%), and toenail clippings (89%), and 40% provided hair. Nearly all participants (95%) provided house-dust samples. Most samples were received by the laboratory one (58%) or two (25%) days after collection. These biospecimens enable investigation of a range of biomarkers of spill-related adverse health effects, and possibly some biomarkers of spill-related exposures. The biospecimen collection, handling, and storage protocols were designed to maximize current and future scientific value within logistical and budgetary constraints and might serve as a template for future studies conducted in similar time-critical and geographically dispersed settings.

Does Zoning Winter Recreationists Reduce Recreation Conflict?

Parks and protected area managers use zoning to decrease interpersonal conflict between recreationists. Zoning, or segregation, of recreation-often by non-motorized and motorized activity-is designed to limit physical interaction while providing recreation opportunities to both groups. This article investigated the effectiveness of zoning to reduce recreation conflict in the Vail Pass Winter Recreation Area in Colorado, USA. Despite a zoning management system, established groomed travel routes were used by both non-motorized recreationists (backcountry skiers, snowboarders, snowshoers) and motorized recreationists (snowmobilers). We hypothesized that persistent recreation conflict reported by non-motorized recreationists was the result of recreation occurring in areas of mixed non-motorized and motorized use, mostly along groomed routes. We performed a geospatial analysis of recreation [from Global Positioning System (GPS) points, n = 1,233,449] in the Vail Pass Winter Recreation Area to identify areas of mixed non-motorized and motorized use. We then surveyed non-motorized recreationists (n = 199) to test whether reported conflict is higher for respondents who traveled in areas of mixed-use, compared with respondents traveling outside areas of mixed-use. Results from the geospatial analysis showed that only 0.7 % of the Vail Pass Winter Recreation Area contained recreation from both groups, however that area contained 14.8 % of all non-motorized recreation and 49.1 % of all motorized recreation. Survey analysis results showed higher interpersonal conflict for all five standard conflict variables among non-motorized respondents who traveled in areas of mixed-use, compared with those traveling outside mixed-use areas. Management implications and recommendations for increasing the effectiveness of zoning are provided.

Erionite exposure in North Dakota and Turkish villages with mesothelioma.

Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted.

BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine.

Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an enzyme involved in cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models. Mechanistic data demonstrate the novel findings that HMGCS2 contributes to gemR and confers metastatic properties in PDAC models, and that HMGCS2 is BRD4 dependent. Further, BET inhibitor JQ1 decreases levels of HMGCS2, sensitizes PDAC cells to gemcitabine, and a combination of gemcitabine and JQ1 induced regressions of gemR tumors in vivo. Our data suggest that decreasing HMGCS2 may reverse gemR, and that HMGCS2 represents a useful therapeutic target for treating gemcitabine resistant PDAC.

Gene-environment interactions within a precision environmental health framework.

Understanding the complex interplay of genetic and environmental factors in disease etiology and the role of gene-environment interactions (GEIs) across human development stages is important. We review the state of GEI research, including challenges in measuring environmental factors and advantages of GEI analysis in understanding disease mechanisms. We discuss the evolution of GEI studies from candidate gene-environment studies to genome-wide interaction studies (GWISs) and the role of multi-omics in mediating GEI effects. We review advancements in GEI analysis methods and the importance of large-scale datasets. We also address the translation of GEI findings into precision environmental health (PEH), showcasing real-world applications in healthcare and disease prevention. Additionally, we highlight societal considerations in GEI research, including environmental justice, the return of results to participants, and data privacy. Overall, we underscore the significance of GEI for disease prediction and prevention and advocate for integrating the exposome into PEH omics studies.

Analyses of canine cancer mutations and treatment outcomes using real-world clinico-genomics data of 2119 dogs.

Spontaneous tumors in canines share significant genetic and histological similarities with human tumors, positioning them as valuable models to guide drug development. However, current translational studies have limited real world evidence as cancer outcomes are dispersed across veterinary clinics and genomic tests are rarely performed on dogs. In this study, we aim to expand the value of canine models by systematically characterizing genetic mutations in tumors and their response to targeted treatments. In total, we collect and analyze survival outcomes for 2119 tumor-bearing dogs and the prognostic effect of genomic alterations in a subset of 1108 dogs. Our analysis identifies prognostic concordance between canines and humans in several key oncogenes, including TP53 and PIK3CA. We also find that several targeted treatments designed for humans are associated with a positive prognosis when used to treat canine tumors with specific genomic alterations, underscoring the value of canine models in advancing drug discovery for personalized oncology.

Shared hotspot mutations in oncogenes position dogs as an unparalleled comparative model for precision therapeutics.

Naturally occurring canine cancers have remarkable similarities to their human counterparts. To better understand these similarities, we investigated 671 client-owned dogs from 96 breeds with 23 common tumor types, including those whose mutation profile are unknown (anal sac carcinoma and neuroendocrine carcinoma) or understudied (thyroid carcinoma, soft tissue sarcoma and hepatocellular carcinoma). We discovered mutations in 50 well-established oncogenes and tumor suppressors, and compared them to those reported in human cancers. As in human cancer, TP53 is the most commonly mutated gene, detected in 22.5% of canine tumors overall. Canine tumors share mutational hotspots with human tumors in oncogenes including PIK3CA, KRAS, NRAS, BRAF, KIT and EGFR. Hotspot mutations with significant association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E (equivalent of V600E in humans) in urothelial carcinoma. Our findings better position canines as a translational model of human cancer to investigate a wide spectrum of targeted therapies.

Identification of genomic alterations with clinical impact in canine splenic hemangiosarcoma.

Canine hemangiosarcoma (HSA) is an aggressive cancer of endothelial cells with short survival times. Understanding the genomic landscape of HSA may aid in developing therapeutic strategies for dogs and may also inform therapies for the rare and aggressive human cancer angiosarcoma. The objectives of this study were to build a framework for leveraging real-world genomic and clinical data that could provide the foundation for precision medicine in veterinary oncology, and to determine the relationships between genomic and clinical features in canine splenic HSA. One hundred and nine dogs with primary splenic HSA treated by splenectomy that had tumour sequencing via the FidoCure® Precision Medicine Platform targeted sequencing panel were enrolled. Patient signalment, weight, metastasis at diagnosis and overall survival time were retrospectively evaluated. The incidence of genomic alterations in individual genes and their relationship to patient variables including outcome were assessed. Somatic mutations in TP53 (n = 44), NRAS (n = 20) and PIK3CA (n = 19) were most common. Survival was associated with presence of metastases at diagnosis and germline variants in SETD2 and NOTCH1. Age at diagnosis was associated with somatic NRAS mutations and breed. TP53 and PIK3CA somatic mutations were found in larger dogs, while germline SETD2 variants were found in smaller dogs. We identified both somatic mutations and germline variants associated with clinical variables including age, breed and overall survival. These genetic changes may be useful prognostic factors and provide insight into the genomic landscape of hemangiosarcoma.

The BET Inhibitor JQ1 Potentiates the Anticlonogenic Effect of Radiation in Pancreatic Cancer Cells.

We reported previously that the BET inhibitor (BETi) JQ1 decreases levels of the DNA repair protein RAD51 and that this decrease is concomitant with increased levels of DNA damage. Based on these findings, we hypothesized that a BETi would augment DNA damage produced by radiation and function as a radiosensitizer. We used clonogenic assays to evaluate the effect of JQ1 ± ionizing radiation (IR) on three pancreatic cancer cell lines in vitro. We performed immunofluorescence assays to assess the impact of JQ1 ± IR on DNA damage as reflected by levels of the DNA damage marker γH2AX, and immunoblots to assess levels of the DNA repair protein RAD51. We also compared the effect of these agents on the clonogenic potential of transfectants that expressed contrasting levels of the principle molecular targets of JQ1 (BRD2, BRD4) to determine whether levels of these BET proteins affected sensitivity to JQ1 ± IR. The data show that JQ1 + IR decreased the clonogenic potential of pancreatic cancer cells more than either modality alone. This anticlonogenic effect was associated with increased DNA damage and decreased levels of RAD51. Further, lower levels of BRD2 or BRD4 increased sensitivity to JQ1 and JQ1 + IR, suggesting that pre-treatment levels of BRD2 or BRD4 may predict sensitivity to a BETi or to a BETi + IR. We suggest that a BETi + IR merits evaluation as therapy prior to surgery for pancreatic cancer patients with borderline resectable disease.

Association of Deepwater Horizon Oil Spill Response and Cleanup Work With Risk of Developing Hypertension.

Importance: Exposure to hydrocarbons, fine particulate matter (PM2.5), and other chemicals from the April 20, 2010, Deepwater Horizon disaster may be associated with increased blood pressure and newly detected hypertension among oil spill response and cleanup workers. Objective: To determine whether participation in cleanup activities following the disaster was associated with increased risk of developing hypertension. Design, Setting, and Participants: This cohort study was conducted via telephone interviews and in-person home exams. Participants were 6846 adults who had worked on the oil spill cleanup (workers) and 1505 others who had completed required safety training but did not do cleanup work (nonworkers). Eligible participants did not have diagnosed hypertension at the time of the oil spill. Statistical analyses were performed from June 2018 to December 2021. Exposures: Engagement in cleanup activities following the Deepwater Horizon oil spill disaster, job classes, quintiles of cumulative total hydrocarbons exposure level, potential exposure to burning or flaring oil, and estimated PM2.5 were examined. Main Outcomes and Measures: Systolic and diastolic blood pressure measurements were collected during home exams from 2011 to 2013 using automated oscillometric monitors. Newly detected hypertension was defined as antihypertensive medication use or elevated blood pressure since the spill. Log binomial regression was used to calculate prevalence ratios (PR) and 95% CIs for associations between cleanup exposures and hypertension. Multivariable linear regression was used to estimate exposure effects on continuous blood pressure levels. Results: Of 8351 participants included in this study, 6484 (77.6%) were male, 517 (6.2%) were Hispanic, 2859 (34.2%) were non-Hispanic Black, and 4418 (52.9%) were non-Hispanic White; the mean (SD) age was 41.9 (12.5) years at enrollment. Among workers, the prevalence of newly detected hypertension was elevated in all quintiles (Q) of cumulative total hydrocarbons above the first quintile (PR for Q3, 1.29 [95% CI, 1.13-1.46], PR for Q4, 1.25 [95% CI, 1.10-1.43], and PR for Q5, 1.31 [95% CI, 1.15-1.50]). Both exposure to burning and/or flaring oil and gas (PR, 1.16 [95% CI, 1.02-1.33]) and PM2.5 from burning (PR, 1.26 [95% CI, 0.89-1.71]) for the highest exposure category were associated with increased risk of newly detected hypertension, as were several types of oil spill work including cleanup on water (PR, 1.34 [95% CI, 1.08-1.66]) and response work (PR, 1.51 [95% CI, 1.20-1.90]). Conclusions and Relevance: Oil spill exposures were associated with newly detected hypertension after the Deepwater Horizon disaster. These findings suggest that blood pressure screening should be considered for workers with occupational hydrocarbon exposures.

Developing a Concept of Operations Template to Guide Collaborative Disaster Research Response Between Academic Public Health and Public Health Agencies.

Research conducted in the context of a disaster or public health emergency is essential to improve knowledge about its short- and long-term health consequences, as well as the implementation and effectiveness of response and recovery strategies. Integrated approaches to conducting Disaster Research Response (DR2) can answer scientific questions, while also providing attendant value for operational response and recovery. Here, we propose a Concept of Operations (CONOPS) template to guide the collaborative development and implementation of DR2 among academic public health and public health agencies, informed by previous literature, semi-structured interviews with disaster researchers from academic public health across the United States, and discussion groups with public health practitioners. The proposed CONOPS outlines actionable strategies to address DR2 issues before, during, and after disasters for public health scholars and practitioners who seek to operationalize or enhance their DR2 programs. Additional financial and human resources will be necessary to promote widespread implementation of collaborative DR2 programs.

Institutional Review Board Preparedness for Disaster Research: a Practical Approach.

PURPOSE OF REVIEW: Disasters are becoming more common and challenge national and global resiliency and response efforts. As a result, government agencies have increased interest in disaster research to understand their environmental impact and health-related consequences. With the research field greatly expanding, Institutional Review Boards (IRBs) are being asked to review research protocols aimed at assessing health risks, exposures, and outcomes from disaster survivors. Few IRBs have experience reviewing disaster research protocols. This article describes approaches for IRB preparedness in reviewing disaster research. RECENT FINDINGS: From a human research protections perspective, primary attention has focused on vulnerability of individuals and/or populations affected by a disaster who may serve as research participants [3, 4]. From our review of the current literature, there is a lack of best practices and/or guidance for IRBs in the review of disaster research protocols. The growth of the disaster research field has brought more attention to potential ethical concerns of disaster research studies. Disaster survivors, responders, and those that assist in cleanup and remedial efforts may be left with significant unmet needs and long-term physical and emotional challenges as a result of their experiences. It is important for IRBs and investigators to collaboratively address how best to protect the welfare of individuals and communities affected by a disaster. A new approach is needed to systematically consider the various factors relevant to an assessment of human research protection issues following disasters.

The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer.

Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.

Patient-Derived Xenograft Models of Pancreatic Cancer: Overview and Comparison with Other Types of Models.

Pancreatic cancer (PC) is anticipated to be second only to lung cancer as the leading cause of cancer-related deaths in the United States by 2030. Surgery remains the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. Multiple recent preclinical studies focus on identifying effective treatments for PDAC, but the models available for these studies often fail to reproduce the heterogeneity of this tumor type. Data generated with such models are of unknown clinical relevance. Patient-derived xenograft (PDX) models offer several advantages over human cell line-based in vitro and in vivo models and models of non-human origin. PDX models retain genetic characteristics of the human tumor specimens from which they were derived, have intact stromal components, and are more predictive of patient response than traditional models. This review briefly describes the advantages and disadvantages of 2D cultures, organoids and genetically engineered mouse (GEM) models of PDAC, and focuses on the applications, characteristics, advantages, limitations, and the future potential of PDX models for improving the management of PDAC.