Citations

Abstract There is growing evidence showing that sex disparity in lung cancer risk cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotype from a lung cancer cohort including ~ 47,000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR=0.71, p=4.29x10-8); rs79942605 (OR=2.17, p=2.81x10-8); and rs208908 (OR=0.70, p=4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affect lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Abstract Background: The current pandemic of COVID-19 impacted the psychological wellbeing of populations globally. Objectives: We aimed to examine the extent and identify associated factors of psychological distress, fear of COVID-19, and coping.Methods: We conducted a cross-sectional study across 17 countries during Jun-2020 to Jan-2021. Levels of psychological distress (Kessler Psychological Distress Scale), fear of COVID-19 (Fear of COVID-19 Scale), and coping (Brief Resilient Coping Scale) were assessed. Results: A total of 8,559 people participated; mean age (±SD) was 33(±13) years, 64% were females and 40% self-identified as frontline workers. More than two-thirds (69%) experienced moderate-to-very high levels of psychological distress, which was 46% in Thailand and 91% in Egypt. A quarter (24%) had high levels of fear of COVID-19, which was as low as 9% in Libya and as high as 38% in Bangladesh. More than half (57%) exhibited medium to high resilient coping; the lowest prevalence (3%) was reported in Australia and the highest (72%) in Syria. Being female (AOR 1.31 [95% CIs 1.09-1.57]), perceived distress due to change of employment status (1.56 [1.29-1.90]), comorbidity with mental health conditions (3.02 [1.20-7.60]) were associated with higher levels of psychological distress and fear. Doctors had higher psychological distress (1.43 [1.04-1.97]), but low levels of fear of COVID-19 (0.55 [0.41-0.76]); nurses had medium to high resilient coping (1.30 [1.03-1.65]). Conclusions: The extent of psychological distress, fear of COVID and coping varied by country; however, some groups were more vulnerable than others. There is an urgent need to prioritise health and well-being of these people through well-designed intervention that may need to be tailored to meet country specific requirements.

Abstract High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma. Significance: These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease.

Introduction: Cross-sectional studies in patient with hypertensive heart disease (HHD) and heart failure with normal ejection fraction (HFnlEF) suggested impairment of longitudinal myocardial mechanics as assessed by tissue Doppler imaging. It has been suggested that enhanced circumferential, and/or radial LV mechanics or LV remodeling compensates for depression in longitudinal function and thus, preserves EF in HHD or HFnlEF. Hypothesis : We hypothesized that if longitudinal performance is depressed, whether due to increased afterload or to intrinsic myocardial dysfunction, circumferential and radial LV mechanics would also be effected. To test this hypothesis, we used an aged canine model of hypertension. Methods: Elderly dogs (n=22) underwent bilateral renal wrapping to induce hypertension. 2D echocardiography (mid-short axis views) was performed before and 8 weeks after renal wrapping; peak radial (PR) and peak circumferential (PC) regional strains were measured by speckle tracking averaging data from 6 segments. Ejection fraction (EF), LV mass index (LVMI), systolic blood pressure (SBP), and circumferential wall stress (CWS) were assessed as well. Results : See table . PR correlated with PC (r=0.65), EF (r=0.67), LWMI (r=0.71) and CWS (r=0.58) (p<0.005 for all). PC correlated also with EF (r=0.60), LWMI (r=0.49) and CWS (r=0.48) (p<0.01 for all). The relationship between EF and CWS (r 2 =0.64, p<0.001) was modified by the addition of either PC (r 2 =0.74, p for PC =0.005) or PR strain(r 2 =0.69, p for PR =0.04). Conclusions : These data show that development of hypertension with LV hypertrophy does not enhance but impairs circumferential and radial LV mechanics as assessed with strain imaging, and that like EF, circumferential and radial strain are related to afterload (wall stress). However, both confer additional information regarding contractility. Conclusions regarding myocardial function based on strain imaging must account for its load dependence.

Background: Exercise normally enhances LV relaxation with minimal change in filling pressure (P). We hypothesize that exercise in hypertensive (HTN) patients increases LV diastolic P through a direct effect on relaxation and ventricular-vascular coupling. Methods: Patients (n=21) with HTN, normal EF, and no coronary disease underwent simultaneous micromanometer LV P and echo-Doppler measurements at rest and with low level supine exercise (12 bicycle; 9 arm weight). Continuous volume (V) was obtained from mitral Doppler inflow and end-diastolic (ED) and end-systolic (ES) V from 2-D echo. Relaxation-corrected LV diastolic P was used for PV relationship P = α.e β*V ; to account for covariance in α and β, LV capacitance (EDV 20 = Ln[20mmHg/α]/β) was reported. Single beat method was used for LV ES elastance (Ees). Group 1 did not increase mean LV diastolic P (mDP) with exercise, Group 2 increased mDP >6mmHg. Results: LV diastolic P and arterial and LV ES elastance increased with exercise; EDV was stable; EDV 20 decreased. Compared to Group 1, Group 2 had a greater exercise-induced increase in afterload, associated with increase in LV minimal P and impaired augmentation of relaxation rate (Table & Figure ). Conclusions: In patients with HTN, impairment of ventricular relaxation plays a major role in causing LV filling P increase with exercise, which is related to ventricular-vascular coupling.

Limited information exists regarding the echocardiographic and clinical predictors of exercise capacity and their effects on exercise with advancing age or by sex. We hypothesized that LV diastolic function (DF) impacts exercise capacity to a greater degree with advancing age. This was a prospective cohort study of consecutive patients undergoing routine exercise echocardiography with the Bruce protocol (n=2955). DF assessments at rest and exercise were performed. Those with echocardiographic exercise-induced ischemia and significant valvular disease were excluded. Univariate and multivariate analyses were conducted to determine the strongest echocardiographic and clinical predictors of exercise capacity (METs). Results were reported as unstandardized β coefficient (Standard Error) as outlined beside each variable. Age and sex interactions of these predictors with exercise capacity were determined. The strongest independent multivariate predictors of exercise capacity were female vs. male sex [−1.98 (0.07), p<0.0001], body mass index >30 kg/m 2 [−1.24 (0.08), p<0.0001], age per 10 year increment [−0.85 (0.01), p<0.0001], mild resting diastolic dysfunction vs. normal [−0.70 (0.10), p<0.0001], and moderate/severe resting diastolic dysfunction vs. normal [−1.3 (0.13), p<0.0001]. LV filling pressures measured by a resting E/e’ ≥ 15 [−0.42 (0.14), p=0.004] or exercise E/e’≥ 15 [−0.31 (0.14), p<0.0001] similarly predicted a reduction in exercise capacity, each in separate multivariate analyses. The impact of impaired relaxation and left ventricular filling pressures on exercise capacity increased with advancing age (p<0.001 and p=0.02 respectively), and was most marked after age 50. These predictors had a similar negative effect on exercise capacity among men and women (p=NS). In conclusion, in this large population referred for exercise echocardiography and not limited by ischemia, resting DF and resting/exercise LV filling pressures independently predicted exercise capacity. The increasingly potent effect of impaired relaxation and exercise LV filling pressures with advancing age suggest that DF plays an important role in the development of exercise intolerance in the elderly.

Background: Chronic renal insufficiency (CRI) is a strong predictor of increased mortality in the presence of heart failure (HF) and its prevalence has been increasing in the US. In addition, CRI is a major contributing factor to the progression of HF as it is associated with chronic volume overload, accelerated atherosclerosis and hypertension (HTN). The first aim of the current study was to evaluate the prevalence of CRI in an adult general population. The second aim was to address whether calculated glomerular filtration rate (cGFR) adds value to the cardiac biomarkers BNP and NT-proBNP in detecting early cardiac structural and functional impairments in the general population. Methods: From 1997 to 1999 medical history, physical examination, echocardiography, BNP (Biosite) and NT-proBNP (Roche) and serum creatinine (SCr) were obtained in 1,982 randomly selected residents of Olmsted County, MN >= 45 years (range 45 – 96 years). GFR was calculated using the Cockroft Gault equation. CRI was defined as a GFR < 60 ml/min. Cardiac structure and function were evaluated by in-depth echocardiographic examination. Results: The prevalence of cardiovascular co-morbidities was coronary atherosclerosis 12%, HTN 29.5% and diabetes mellitus 7.5%. The prevalence of CRI was 22.8% when cGFR was used for its detection. Importantly, by Chi-Square model, cGFR significantly increased the ability of BNP in detecting left ventricular hypertrophy (LVH) (p=0.004), increased relative wall thickness (p=0.0036), diastolic dysfunction (DDF) (p=0.0001) and HTN (p=0.0002). Similarly, when combined with NT-proBNP, cGFR increased the predictive power of detecting DDF (p=0.0001) and HTN (p=0.0366). Conclusion: This study reports a higher than predicted prevalence of CRI in this general US population equal to 23% and closely associated with the prevalence of HTN (29.5%). Importantly, this study also demonstrates that cGFR has additive predictive power when used in combination with two cardiac biomarkers of cardiac dysfunction and remodeling, BNP and NT-proBNP. These studies underscore the increasing burden of CRI in the general population and the utility of assessing cardiorenal function by combining renal and cardiac biomarkers in assessment of cardiac structure and function.

Background Patients with heart failure and preserved ejection fraction (HFpEF) have diastolic dysfunction, but are traditionally considered to have normal left ventricular (LV) systolic function. However, ventricular remodeling can result in preservation of EF despite abnormal myocardial contractility. Methods We performed echo-Doppler characterization of LV chamber and myocardial systolic properties in a population-based study, comparing patients with HFpEF (N=244) to healthy controls (CON, N=617), and hypertensives without HF (HTN, N=719), then examined long term outcome. Results All subjects had a normal EF (>50%). However, systolic chamber function, measured by wall stress-corrected endocardial fractional shortening (sc-eFS), was impaired in HFpEF (96±12%) compared to both CON (100±8%, p<0.0001) and HTN (108±11%, p<0.0001). Myocardial contractility, assessed by wall stress-corrected midwall shortening (sc-mFS), was also reduced in HFpEF (91±13%) compared to CON (100±10%, p<0.0001) and HTN (105±12%, p<0.0001). HTN had increased sc-eFS and sc-mFS compared with both HFpEF and CON (p<0.0001). In HFpEF, impaired sc-mFS was associated with increased mortality, independent of age (Figure ), while EF and sc- eFS were not. Conclusions Despite preservation of EF, unselected HFpEF patients from the community have significantly impaired systolic chamber function and depressed myocardial contractility. Abnormal myocardial contractility in HFpEF is associated with increased mortality. These data suggest that myocardial systolic dysfunction contributes to the pathophysiology of HFpEF and may represent a potential therapeutic target.

Abstract Background: Metastatic undifferentiated pleomorphic sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, in the 2nd line setting and beyond, efficacy remains limited. Pazopanib, the only approved treatment in the refractory setting has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: MSI-H cancer and biliary tract cancer. The activity of envafolimab is similar to other PD-1 antibodies administered intra-venously. Envafolimab demonstrated a 32% ORR in MSI-H colorectal cancer that failed three approved chemotherapeutics, similar to the ORR of 28% and 33%, with nivolumab and pembrolizumab, respectively. The rationale for the ENVASARC trial is based on the previously reported efficacy of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ~25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n=80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks intra-venously for four doses (cohort B; n=80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Citation Format: Sandra D'Angelo, Steven Robinson, Joelle Lam, Bonne Adams, James Freddo, Charles P. Theuer, Robert Maki. ENVASARC: A Pivotal Trial of Envafolimab, and Envafolimab in Combination with Ipilimumab, in Patients with Advanced or Metastatic Undifferentiated Pleomorphic Sarcoma or Myxofibrosarcoma who have Progressed on Prior Chemotherapy [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 CT239.

Background: Closed-loop control (CLC) has been shown to improve glucose time in range and other glucose metrics; however, randomized trials >3 months comparing CLC with sensor-augmented pump (SAP) therapy are limited. We recently reported glucose control outcomes from the 6-month international Diabetes Closed-Loop (iDCL) trial; we now report patient-reported outcomes (PROs) in this iDCL trial. Methods: Participants were randomized 2:1 to CLC ( N = 112) versus SAP ( N = 56) and completed questionnaires, including Hypoglycemia Fear Survey, Diabetes Distress Scale (DDS), Hypoglycemia Awareness, Hypoglycemia Confidence, Hyperglycemia Avoidance, and Positive Expectancies of CLC (INSPIRE) at baseline, 3, and 6 months. CLC participants also completed Diabetes Technology Expectations and Acceptance and System Usability Scale (SUS). Results: The Hypoglycemia Fear Survey Behavior subscale improved significantly after 6 months of CLC compared with SAP. DDS did not differ except for powerless subscale scores, which worsened at 3 months in SAP. Whereas Hypoglycemia Awareness and Hyperglycemia Avoidance did not differ between groups, CLC participants showed a tendency toward improved confidence in managing hypoglycemia. The INSPIRE questionnaire showed favorable scores in the CLC group for teens and parents, with a similar trend for adults. At baseline and 6 months, CLC participants had high positive expectations for the device with Diabetes Technology Acceptance and SUS showing high benefit and low burden scores. Conclusion: CLC improved some PROs compared with SAP. Participants reported high benefit and low burden with CLC. Clinical Trial Identifier: NCT03563313.