Citations

Introduction: Physical activity (PA) is known to be effective in treating and preventing many lifestyle diseases including CVD, stroke, depression, type II diabetes, Alzheimer’s disease, as well as breast and colon cancer. To date the direct medical cost-savings of PA as a medical intervention are poorly understood. Hypothesis: We hypothesized that a 10% increase in the proportion of US citizens who meet the minimum weekly exercise requirements of 150 minutes per week would lead to savings in direct medical costs (DMC) and cases prevented, as related to the above diseases. Methods: Population Attributable Risk (PAR) was calculated as PAR= (1+Prf x (RR-1))/(Prf x(RR-1)), where Prf is the percentage of the U.S. population not meeting minimum exercise requirements and RR is the relative risk of disease for sedentary versus physically active individuals. Prf and RR data were retrieved from the most recent and comprehensive meta-analyses and systematic reviews. PAR was calculated for each disease under two conditions; first, Prf was equal to the current percent (9.6%) of the population estimated to achieve the minimum weekly PA requirements. Second, Prf was equal to the initial Prf plus 10 percent (19.6%). For each condition the following were calculated: Attributable DMC=(PAR x DMC), preventable cases=(PAR x Prevalence) and Savings=(Condition 2- Condition 1). Results: The Prevalence, RR, PAR and DMC are provided in Table 1. This table also describes the potential savings in DMC and new cases by improving the Prf by 10%. A 10% increase in US citizens who meet the minimum weekly exercise requirements could lead to a total savings of 10.78 billion USD in DMC and 2.1 million cases prevented related to the studied diseases. Conclusion: A healthcare system directed PA intervention that effectively leads to a 10% increase in US citizens that meet minimum weekly exercise requirements and costs less than 10.78 billion dollars has the potential to be cost-effective, and prevent and treat, millions of cases in the United States.

Abstract Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms' tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically. Significance: TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase–positive malignant hematopoietic cells to PARP inhibitors.

Abstract Platinum-based DNA cross-linking agents are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). Remarkably, despite >30 years of literature on platinum responses in human cancer, none of these findings is used clinically as a predictive biomarker to stratify patients for platinum resistance, nor exploited therapeutically to treat platinum-resistant disease. Thus, understanding mechanisms of platinum resistance is an urgent goal, both to identify predictive biomarkers of platinum response (to spare patients with platinum-resistant tumors futile platinum therapy) and to develop efficacious therapies for platinum-resistant disease. To better understand mechanisms underlying platinum resistance in HGSOC, we performed comprehensive, dynamic (+/-carboplatin), multiomic profiling of DNA, RNA, protein and post-translational modifications (phosphorylation, ubiquitination, acetylation) to identify the cellular networks that respond to platinum treatment and associate with platinum resistance in three HGSOC intra-patient cell line pairs (PEA1S/PEA2R, PEO1S/PEO4R, PEO14S/PEO23R). The cell line pairs were derived from ascites or pleural effusions (Langdon et al., 1988) from three patients both before (PEA1S, PEO1S, PEO14S) and after (PEA2R, PEO4R, PEO23R, respectively) their tumors became clinically platinum resistant (i.e., in vivo development of resistance). The molecular profiles revealed extensive responses to carboplatin and differential responses between platinum-sensitive and platinum-resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that pharmacologic inhibition or CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO, and CPT1A in particular, represent a candidate therapeutic target to overcome platinum resistance in HGSOC. Citation Format: Hong Wang, Dongqing Hugang, Shrabanti Chowdhury, Sara Savage, Richard Ivey, Jacob Kennedy, Jeffrey Whiteaker, Chenwei Lin, Xiaonan Hou, Catherine Huntoon, Uliana Voytovich, Zahra Shire, Qing Yu, Steven Gygi, Andrew Hoofnagle, Zachary Herbert, Anna Calinawan, Larry Karnitz, S. John Weroha, Scott Kaufmann, Bing Zhang, Pei Wang, Michael Birrer, Amanda Paulovich. Multiomic analysis identifies CPT1A and fatty acid oxidation as a potential therapeutic target in platinum-refractory high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1426.

Background Ensuring representative data accrual in clinical trials is important to safeguard the generalizability of results and to minimize disparities in care. This study's goal was to evaluate differences in gender representation in trials leading to US Food and Drug Administration (FDA) cancer drug approvals. Methods An observational study was conducted from January 2014 to April 2019 using PubMed and the National Institutes of Health trials registry for primary trial reports. The National Cancer Institute's Surveillance, Epidemiology, and End Results program and US Census were consulted for national cancer incidence. The outcome was an enrollment incidence disparity (EID), which was calculated as the difference between male and female trial enrollment and national incidence, with positive values representing male overrepresentation. Results There were 149 clinical trials with 59,988 participants—60.3% and 39.7% were male and female, respectively—leading to 127 oncology drug approvals. The US incidence rates were 55.4% for men versus 44.6% for women. Gender representation varied by specific tumor type. Most notably, women were underrepresented in thyroid cancer (EID, +27.4%), whereas men were underrepresented in soft tissue cancer (EID, –26.1%). Overall, women were underrepresented when compared with expected incidence (EID, +4.9%; 42% of trials). Conclusions For many specific tumor types, women are underrepresented in clinical trials leading to FDA oncology drug approvals. It is critical to better align clinical trial cohort demographics and the populations to which these data will be extrapolated. Lay Summary This study assesses whether gender disparities exist in clinical trials leading to US Food and Drug Administration (FDA) cancer drug approvals. From January 2014 to April 2019, 149 clinical trials leading to FDA oncology drug approvals showed 60.3% and 39.7% of the enrollees were male and female, respectively. Gender representation varied by specific tumor when compared with the expected incidence rate of cancer in the United States, although women were more often underrepresented. Increased efforts are needed with regard to ensuring equitable representation in oncology clinical trials.

Introduction: Statin dose guidelines for PAD patients are based on coronary artery disease and stroke data. The aim of our study was to determine the effect of statin dose (based on 2013 ACC/AHA guidelines) on PAD outcomes of amputation and mortality. Methods: Patients with PAD in the Veterans Affairs database were identified from 2003-2014. The exposure was highest statin dose usage (none, low-moderate and high intensity) around diagnosis of PAD (within 1 year). The outcomes were risk of incident amputation (below knee or above knee) and mortality at 1, 3 and 5 years. The effect of statin dose on the two outcomes was also analyzed using Cox proportional hazards modeling to adjust for covariates. Results: In 208,275 patients with PAD [Males: 98.1%; Mean age: 67.4 yrs (SD 9.9)], 17,643 amputations and 99,951 deaths occurred in a median follow up of 5.2 years. Almost a quarter (27.7%) of patients were not on a statin while 30.4% were on simvastatin 80 mg (no longer recommended due to drug toxicity). The risk of incident amputation declined significantly at the high intensity statin dose as seen in Table 1. In Cox models adjusting for age, gender, race, comorbidities, cholesterol levels and creatinine, the high intensity statins were associated with lower amputation risk and mortality as compared to no statin [HR 0.67; 95% CI (0.63, 0.72) and HR 0.71; 95% CI (0.68, 0.73), respectively]. Low-moderate-dose statins also had significant but smaller reductions in risk of amputation and mortality [HR amputation 0.78 (0.75, 0.82), HR death 0.78 (0.77, 0.80)]. Conclusion: This is one of the largest population based studies to examine the effect of statins on long-term PAD outcomes and the first to explore the dose-dependent effect of statins on amputation and mortality. High intensity statins are associated with a significant reduction in limb loss and mortality in PAD patients followed by a smaller risk reduction by low-moderate intensity statins as compared to no statin therapy.

Objective Inadequate sleep is associated with an increased risk of hypertension. Exaggerated blood pressure (BP) reactivity to psychological stress is predictive of the development of hypertension. Following 24‐hours of total sleep deprivation, individuals exhibit an exaggerated BP response to mental stress (MS). The mechanisms contributing to this response and the generalizability to more prolonged exposure to restricted sleep are not clear. Thus we sought to examine the early hemodynamic response to MS in individuals before and during prolonged sleep restriction. We hypothesized the early rise in BP during MS would occur more slowly and would achieve a higher peak following 9 nights of restricted sleep when compared to control. We further hypothesized the contribution of total peripheral resistance (TPR) to the rise in BP would be greater following restricted sleep when compared to control. Methods Individuals completed two visits randomized to control sleep or experimental sleep restriction. Ten young (23±1 yrs) healthy, non‐obese (24±1 kg/m 2 ) men and women (5M/5F) completed the restriction visit and seven of the same individuals (23±1 yrs; 5M/2F; 24±1 kg/m 2 ) completed the control visit. Each visit consisted of 4 days of acclimation (9 hours of sleep per night) followed by 9 days of control (9 hours/night) or restricted (4 hours/night) sleep. For the purpose of this investigation, individuals were studied on days 2 and 13. Beat‐by‐beat heart rate (HR, electrocardiography) and BP (finger plethysmography) were measured continuously during 2 min of quiet rest followed by 5 min of mental arithmetic. Stroke volume (SV) was estimated from the pressure waveform and cardiac output (CO) and TPR were calculated. Peak change, time to peak, and rate of rise in BP were assessed during the initiation of mental stress (first 30‐s). Results BP increased during MS ( P <0.05) and the early peak BP did not differ between conditions ( P =0.35–0.84). However, following prolonged experimental sleep restriction, individuals achieved peak systolic BP earlier (Time to peak: 19±4 vs 9±3 s, P =0.04) and the rate of rise in diastolic BP at the onset of MS was significantly greater (0.7± 0.3 vs 2.3±0.7 mmHg/s, P =0.01) when compared to the acclimation period. No differences in time to peak BP or rate of rise at the onset of MS were observed on the control visit ( P =0.16–0.97). The peak change in SV (0.5±1.4 vs 6.3±2.1, P =0.03) and CO (1.1±0.2 vs 1.7±0.2 L/min, p=0.01) at the onset of MS were greater following prolonged sleep restriction when compared to the acclimation period. No differences in the change in SV or CO were observed on the control visit ( P =0.39–0.41) and no differences in the change in TPR were observed on either visit ( P =0.36–0.86). Conclusions Prolonged (9‐day) experimental sleep restriction (4 hours/night) results in a faster increase in BP in response to mental arithmetic. This rapid increase in BP at the onset of MS is achieved primarily via a greater increase in SV and CO when compared to the acclimation period. These data highlight an important role for CO in the BP response to stress in sleep restricted individuals and provide important insight into potential mechanisms which may contribute to the development of hypertension following inadequate sleep. Support or Funding Information NIH HL130339, NIH HL114676, NIH HL114024, NIH HL083947, APS UGSRF This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

We tested the hypothesis that ventilation (VE) and the hypoxic ventilatory response (HVR) during hyperthermia would be attenuated when carotid body chemosensitivity is blunted by an IV infusion of dopamine (2 µg/kg/min) vs. IV saline. We studied 9 subjects (1 woman, 32 ± 2 years, 25.7 ± 0.7 kg/m2) over two randomized dopamine and saline study visits. We measured VE and HVR (3 minutes at: room air, 16% O2, and 10% O2) at baseline and during normothermia (NORMInf) and hyperthermia (HYPInf) (core temperature 1.2‐1.5°C above baseline) infusion conditions. VE increased during HYPInf vs. NORMInf during dopamine (8.2 ± 0.3 vs. 10.2 ± 1.1 L/min; P = 0.04) and saline (8.9 ± 0.3 vs. 9.7 ± 0.5 L/min; P = 0.04) with no difference between conditions (P = 0.95). HVR during saline increased from baseline (0.30 ± 0.1 L/min/%SaO2; P < 0.01) and NORMInf (0.42 ± 0.1 L/min/%SaO2; P = 0.02) to HYPInf (0.77 ± 0.2 L/min/%SaO2). HVR did not change throughout the dopmaine visit (baseline = 0.38 ± 0.1; NORMInf = 0.27 ± 0.1; HYPInf 0.42 ± 0.1 L/min/%SaO2; P > 0.46). Dopamine HVR was lower than saline during HYPInf (P < 0.01). These data indicate that carotid body chemosensitivity to hypoxia is augmented during hyperthermia and that low dose dopamine was unable to lower normoxic VE during hyperthermia. Grant Funding Source : Supported by NIH R01DK090541 and RO1HL61388

We tested the hypothesis that administering low‐dose dopamine (2 mcg/kg/min) to desensitize the carotid body chemoreceptors would alter metrics of heart rate variability (HRV). Electrocardiogram (ECG) recordings were obtained from 18 healthy adults (age = 31 ± 2 years; BMI = 24.6 ± 0.6 kg/m 2 ) during two randomized study days where they received an IV infusion of saline (S) or dopamine (DA). HRV was analyzed during five minute segments at baseline and during infusions of S and DA. Time‐domain analysis of the root mean square of the successive differences (RMSSD) along with spectral domain analysis of low (LF) and high frequency (HF) were obtained. There were no differences (P > 0.05) in respiration rate or blood pressure at any time point. Heart rate increased from baseline during DA (60 ± 2 vs. 63 ± 2 bpm; P < 0.01) and during infusion it was greater in DA vs. S (63 ± 2 vs. 58 ± 2 bpm; P < 0.01). RMSSD decreased from baseline to infusion during DA (68.2 ± 7.6 vs. 51.6 ± 6.0 ms; P < 0.01) and during infusion it was lower in DA vs. S (78.3 ± 10.3 vs. 51.6 ± 6.0 ms; P < 0.01). HF was reduced during DA vs. baseline (1733± 301 vs. 870 ± 171 ms 2 ; P < 0.01), and during infusion DA was also lower than S (1936 ± 471 vs. 870 ± 171 ms 2 ; P = 0.02). There were no changes (P > 0.05) in LF, LF/HF or normalized HF and LF values. These data indicate that during resting conditions the carotid body chemoreceptors likely modulate parasympathetic components of HRV in healthy adults. Grant Funding Source : Supported by NIH R01DK090541 and RO1HL61388

AbstractBackgroundBamlanivimab and casirivimab-imdevimab are authorized for emergency use treatment of mild to moderate coronavirus disease 2019 (COVID-19) in patients at high risk for developing severe disease or hospitalization. Their safety and efficacy have not been specifically evaluated in solid organ transplant recipients.MethodsWe retrospectively reviewed solid organ transplant recipients who received monoclonal antibody infusion for COVID-19 at Mayo Clinic sites through January 23, 2021. Outcomes included emergency department visit, hospitalization, mortality, and allograft rejection.ResultsSeventy-three patients were treated, most commonly with bamlanivimab (75.3%). The median age was 59 years, 63% were male, and the median Charlson comorbidity index was 5. Transplant type included 41 kidney (56.2%), 13 liver (17.8%), 11 heart (15.1%), 4 kidney-pancreas (5.5%), 2 lung (2.7%), 1 heart-liver, and 1 pancreas. Eleven (15.1%) patients had an emergency department visit within 28 days of infusion, including 9 (12.3%) who were hospitalized for a median of 4 days. One patient required intensive care unit admission for a nonrespiratory complication. No patients required mechanical ventilation, died, or experienced rejection. Ten adverse events occurred, with 1 seeking medical evaluation. Hypertension was associated with hospital admission (P &lt; .05), while other baseline characteristics were similar. The median time from symptom onset to antibody administration was 4 days in nonhospitalized patients compared with 6 days among hospitalized patients (P &lt; .05).ConclusionsMonoclonal antibody treatment has favorable outcomes with minimal adverse effects in solid organ transplant recipients with mild to moderate COVID-19. Earlier administration of monoclonal antibody therapy appears to be more efficacious.