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.

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.

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.

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.

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.

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.

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.

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.

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.

Development of gemcitabine-resistant patient-derived xenograft models of pancreatic ductal adenocarcinoma.

AIM: Gemcitabine is a frontline agent for locally-advanced and metastatic pancreatic ductal adenocarcinoma (PDAC), but neither gemcitabine alone nor in combination produces durable remissions of this tumor type. We developed three PDAC patient-derived xenograft (PDX) models with gemcitabine resistance (gemR) acquired in vivo, with which to identify mechanisms of resistance relevant to drug exposure in vivo and to evaluate novel therapies. METHODS: Mice bearing independently-derived PDXs received 100 mg/kg gemcitabine once or twice weekly. Tumors initially responded, but regrew on treatment and were designated gemR. We used immunohistochemistry to compare expression of proteins previously associated with gemcitabine resistance [ribonucleotide reductase subunit M1 (RRM1), RRM2, human concentrative nucleoside transporter 1 (hCNT1), human equilibrative nucleoside transporter 1 (hENT1), cytidine deaminase (CDA), and deoxycytidine kinase (dCK)] in gemR and respective gemcitabine-naive parental tumors. RESULTS: Parental and gemR tumors did not differ in tumor cell morphology, amount of tumor-associated stroma, or expression of stem cell markers. No consistent pattern of expression of the six gemR marker proteins was observed among the models. Increases in RRM1 and CDA were consistent with in vitro-derived gemR models. However, rather than the expected decreases of hCNT1, hENT1, and dCK, gemR tumors expressed no change in or higher levels of these gemR marker proteins than parental tumors. CONCLUSION: These models are the first PDAC PDX models with gemcitabine resistance acquired in vivo. The data indicate that mechanisms identified in models with resistance acquired in vitro are unlikely to be the predominant mechanisms when resistance is acquired in vivo. Ongoing work focuses on characterizing unidentified mechanisms of gemR and on identifying agents with anti-tumor efficacy in these gemR models.

Developing an Environmental Health Sciences COVID-19 Research Agenda: Results from the NIEHS Disaster Research Response (DR2) Work Group's Modified Delphi Method.

Leveraging the community of practice recently established through the U.S. National Institute of Environmental Health Sciences (NIEHS) Disaster Research Response (DR2) working group, we used a modified Delphi method to identify and prioritize environmental health sciences Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and associated Coronavirus Disease 2019 (COVID-19) research questions. Twenty-six individuals with broad expertise across a variety of environmental health sciences subdisciplines were selected to participate among 45 self-nominees. In Round 1, panelists submitted research questions and brief justifications. In Round 2, panelists rated the priority of each question on a nine-point Likert scale. Responses were trichotomized into priority categories (low priority; medium priority; and high priority). A research question was determined to meet consensus if at least 69.2% of panelists rated it within the same priority category. Research needs that did not meet consensus in round 2 were redistributed for re-rating. Fourteen questions met consensus as high priority in round 2, and an additional 14 questions met consensus as high priority in round 3. We discuss the impact and limitations of using this approach to identify and prioritize research questions in the context of a disaster response.

The pharmacist's role in disaster research response.

PURPOSE: The need for high-quality research during disaster responses has been well described in the literature, and such research is supported by efforts at the federal level through the National Institutes of Health Disaster Research Response (DR2) Program. This article describes the fourth DR2 workshop with a specific focus on opportunities for pharmacists to get involved with disaster research efforts. SUMMARY: Pharmacists have historically played a significant role in disaster planning and response, and there are a number of opportunities for pharmacists to bring their unique perspective, positioning, and skills to disaster research response (ie, onsite and other research on the medical and public health aspects of disasters and public health emergencies). In February 2019, the fourth DR2 workshop was held in Tucson, AZ, in conjunction with the University of Arizona College of Medicine-Tucson, the university's Mel and Enid Zuckerman College of Public Health, University of Arizona College of Pharmacy, and the university's Bio5 Institute to explore clinical and population-based research in a simulated disaster setting. This article describes the workshop and discusses several opportunities for pharmacists to design, lead, and support research efforts during disaster scenarios through involvement in research areas including clinical, operational, educational, and logistic aspects of pharmacy practice. CONCLUSION: Due to their positioning throughout health systems, unique perspective, training, and skills, pharmacists are uniquely situated to play an important role in disaster research response.

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.

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).

The combination of BET and PARP inhibitors is synergistic in models of cholangiocarcinoma.

Our previous finding that the BET inhibitor (BETi) JQ1 increases levels of the DNA damage marker γH2AX suggested that JQ1 might enhance the sensitivity of tumor cells to PARP inhibitors (PARPi), which are selectively toxic to cells that harbor relatively high levels of DNA damage. To address this hypothesis, we evaluated the effect of a BETi (JQ1 or I-BET762) combined with a PARPi (olaparib or veliparib) in KKU-055 and KKU-100 cholangiocarcinoma (CCA) cell lines and of JQ1 with olaparib in a xenograft model of CCA. Each combination was more effective than any of the four drugs as single agents. Combination indices ranged from 0.1 to 0.8 at the ED50 for all combinations, indicating synergy and demonstrating that synergy was not limited to a specific combination. Mechanistically, downregulation of BETi molecular targets BRD2 or BRD4 by shRNA sensitized CCA cells to BETi as single agents as well as to the combination of a BETi + a PARPi. Our data indicate that combinations of a BETi with a PARPi merit further evaluation as a promising strategy for CCA.

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.

Developing Large-Scale Research in Response to an Oil Spill Disaster: a Case Study.

Research conducted in the wake of a disaster can provide information to help mitigate health consequences, support future recovery efforts, and improve resilience. However, a number of barriers have prevented time-sensitive research responses following previous disasters. Furthermore, large-scale disasters present their own special challenges due to the number of people exposed to disaster conditions, the number of groups engaged in disaster response, and the logistical challenges of rapidly planning and implementing a large study. In this case study, we illustrate the challenges in planning and conducting a large-scale post-disaster research study by drawing on our experience in establishing the Gulf Long-term Follow-up (GuLF) Study following the 2010 Deepwater Horizon disaster. We describe considerations in identifying at-risk populations and appropriate comparison groups, garnering support for the study from different stakeholders, obtaining timely scientific and ethics review, measuring and characterizing complex exposures, and addressing evolving community health concerns and unmet medical needs. We also describe the NIH Disaster Research Response (DR2) Program, which provides a suite of resources, including data collection tools, research protocols, institutional review board guidance, and training materials to enable the development and implementation of time-critical studies following disasters and public health emergencies. In describing our experiences related to the GuLF Study and the ongoing efforts through the NIH DR2 Program, we aim to help improve the timeliness, quality, and value of future disaster-related data collection and research studies.

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.