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Underserved pregnant women have a greater risk of excessive or inadequate gestational weight gain (GWG) and adverse perinatal outcomes. In the United States, the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) provides supplemental nutrition and is uniquely positioned to deliver equitable interventions that support recommended GWG. Yet to date, no randomized controlled trials have evaluated behavioral strategies for managing GWG in this setting. The primary objective was to examine the effects of a statewide randomized multicomponent mobile eHealth lifestyle intervention trial on change in physical activity and sedentary time across pregnancy. The secondary objective was to explore associations between changes in physical activity, sedentary time, and GWG. A total of 351 pregnant women were recruited from the Louisiana WIC clinics and were randomly assigned to a multicomponent mobile eHealth intervention for GWG management (N=179) or usual care (N=172; standard in-person WIC care) prior to 16 weeks of gestation. The multicomponent mobile intervention included daily weighing, step tracking, counseling, exercise videos, health coach interactions, and social support. For the first objective, physical activity, including movement duration and movement context, and sedentary time were assessed at baseline (early pregnancy) and at the end of the intervention (late pregnancy) using accelerometry and the Pregnancy Physical Activity Questionnaire. For the second objective, GWG was determined based on weight collected at study visits in early and late pregnancy. Linear mixed models assessed intervention effects on physical activity and GWG. Both the Intervention Group and the Usual Care Group significantly increased sedentary time from early to late pregnancy (adjusted effect estimate [95% CI] 62 minutes per day (42-83), P<.001 and 52 minutes per day (31-72), P<.001, respectively). Both the Intervention Group and the Usual Care Group significantly decreased moderate activity (-13 minutes per day (-20 to -6), P<.001 and -10 minutes per day (-17 to -3), P=.01, respectively) and total moderate to vigorous physical activity (-14 minutes per day (-21 to -7), P<.001 and -10 minutes per day (-18 to -3), P=.01, respectively) from early to late pregnancy. For the Pregnancy Physical Activity Questionnaire, the Intervention Group reported an increase in sports participation across pregnancy compared with the Usual Care Group (+4 metabolic equivalent task (MET)-hours per week (2-7); P=.002). There were no associations between physical activity (-7 g (-32 to 18), P=.57) or sedentary time measures (4 g (-4 to 12), P=.31) and GWG. The first of its kind mobile eHealth multicomponent behavioral lifestyle intervention that included guidance to increase physical activity toward national guidelines did not meaningfully impact physical activity outcomes in pregnant women who were enrolled in Louisiana WIC. ClinicalTrials.gov NCT04028843; https://www.clinicaltrials.gov/study/NCT04028843. RR2-10.2196/18211.

Second- and third-line treatments of patients with antibiotic-resistant infections can have serious side effects, such as organ failure with prolonged care and recovery. As clinical practices such as cancer therapies, chronic disease treatment, and organ transplantation rely on the ability of available antibiotics to fight infection, the increased resistance of microbial pathogens presents a multifaceted, serious public health concern worldwide. The pipeline of traditional antibiotics is exhausted and unable to overcome the continuously developing multi-drug resistance. To that end, the widely observed limitation of clinically utilized antibiotics has prompted researchers to find a clinically relevant alternate antimicrobial strategy. In recent decades, the discovery of antimicrobial peptides (AMPs) as an excellent candidate to overcome antibiotic resistance has received further attention, particularly from scientists, health professionals, and the pharmaceutical industry. Effective AMPs are characterized by a broad spectrum of antimicrobial activities, high pathogen specificity, and low toxicity. In addition to their antimicrobial activity, AMPs have been found to be involved in a variety of biological functions, including immune regulation, angiogenesis, wound healing, and antitumor activity. This review provides a current overview of the structure, molecular action, and therapeutic potential of AMPs.

SummaryBackground Endothelin B receptor (ETBR) is involved in melanoma pathogenesis and is overexpressed in metastatic melanoma. The antibody-drug conjugate DEDN6526A targets ETBR and is comprised of the humanized anti-ETBR monoclonal antibody conjugated to the anti-mitotic agent monomethyl auristatin E (MMAE). Methods This Phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of DEDN6526A (0.3–2.8 mg/kg) given every 3 weeks (q3w) in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma. Results Fifty-three patients received a median of 6 doses of DEDN6526A (range 1–49). The most common drug-related adverse events (>25% across dose levels) were fatigue, peripheral neuropathy, nausea, diarrhea, alopecia, and chills. Three patients in dose-escalation experienced a dose-limiting toxicity (infusion-related reaction, increased ALT/AST, and drug-induced liver injury). Based on cumulative safety data across all dose levels, the recommended Phase II dose (RP2D) for DEDN6526A was 2.4 mg/kg intravenous (IV) q3w. The pharmacokinetics of antibody-conjugated MMAE and total antibody were dose-proportional at doses ranging from 1.8–2.8 mg/kg. A trend toward faster clearance was observed at doses of 0.3–1.2 mg/kg. There were 6 partial responses (11%) in patients with metastatic cutaneous or mucosal melanoma, and 17 patients (32%) had prolonged stable disease ≥6 months. Responses were independent of BRAF mutation status but did correlate with ETBR expression. Conclusion DEDN6526A administered at the RP2D of 2.4 mg/kg q3w had an acceptable safety profile and showed evidence of anti-tumor activity in patients with cutaneous, mucosal, and uveal melanoma. ClinicalTrials.gov identifier: NCT01522664.

IntroductionIn pregnancy, people with obesity or excess adiposity are prone to excess gestational weight gain (GWG) and have the highest risks for multiple maternal morbidities. Epidemiological studies suggest that the lowest incidence of adverse maternal and infant outcomes occurs with GWG lower than current recommendations (<5 kg) and with gestational weight maintenance, resulting in fat mass loss, in those with obesity. Data from randomised clinical trials are needed to evaluate the efficacy of a fat mass loss intervention on pregnancy outcomes. The objective of this proof-of-principle randomised controlled trial is to test the effect of a gestational fat mass loss intervention in pregnant individuals with obesity on changes in weight, fat mass and cardiometabolic disease risk factors.Methods and analysisIn this two-site randomised parallel group, 100 women (30% black; 30% Hispanic) with pre-existing obesity (31.0≤body mass index≤55.0 kg/m2) are randomised to usual care (Provider Directed Group) or usual care plus a fat mass loss intervention with food provision (Weight Maintenance Group). The primary outcomes of the trial (Healthy Mamas/Mamis Saludables) are weight, fat mass (via three-compartment model) and cardiometabolic disease risk factors (ie, blood pressure, lipids, glucose, insulin) from baseline (~13 weeks gestation) to ~35 weeks gestation and at 2 weeks postpartum. Secondary aims evaluate the safety of the fat mass loss intervention during pregnancy and test the hypotheses that compared with usual care, the intervention will have no significant adverse effect on fetal growth, neonatal size, infant body composition and other adverse events. Mediators (eg, eating, activity) and moderators (eg, parity, obesity grade, race/ethnicity) of intervention effects are also examined. Finally, the study will explore the effect of prenatal fat mass loss on reducing the incidence of adverse obstetrical outcomes, including non-elective caesarean delivery, gestational diabetes, hypertension and pre-eclampsia.Ethics and disseminationThe trial has been approved by the Pennington Biomedical Research Center Institutional Review Board, is monitored by an independent data and safety monitoring board and will be conducted in agreement with the Declaration of Helsinki. All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals.Trial registration number NCT04731688.

Mucosal melanoma (MM) is a rare, aggressive cancer whose incidence has increased continuously over the years. This subtype of melanoma arises from melanocytes on hairless surfaces, typically in the respiratory tract, gastrointestinal (GI) tract, and urogenital tract. The most common sites of occurrence include the head and neck, the anorectal region, and the vulvovaginal region, while the rare sites of MM are the urinary tract and the upper and lower GI tract, including the esophagus, duodenum and the gallbladder. MM arises in melanocytes of the ectodermal mucosa that originate from neural crest cells and migrate through embryonic mesenchyme to their destination. Although melanocytes are located mainly in the epidermis and dermis, their presence in various extracutaneous sites, such as the eyes, mucosal tissue, and leptomeninges, is known. Although both cutaneous melanoma (CM) and MM differ in their epidemiology, genetic profile, and clinical presentation, their treatment options are similar. In contrast to the higher treatment response of CM, MM is characterized by a lower response rate to available treatment options, resulting in a poorer survival rate. In this review, we provide an overview of the biology of MM and the mechanisms regulating its development, progression and treatment resistance.

Household chaos is an emerging risk factor for childhood obesity development, especially in families with lower socioeconomic status (SES). It is unclear if changes in household chaos, especially in pregnancy, may mediate the effectiveness of weight-related behavioral interventions. This study aimed to describe how household chaos changed across gestation and determine whether household chaos mediated the effect of an eHealth behavioral gestational weight gain (GWG) intervention in pregnant people with low SES. Pregnant people who were enrolled in the US Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) were recruited for a randomized controlled trial testing the effectiveness of an eHealth-based pragmatic intervention for GWG management. The usual care group received the standard WIC program guidance and monthly health coach support with general pregnancy recommendations. The intervention group received the standard WIC program plus health information via email and weekly health coach discussions to promote healthy eating and adequate physical activity. Weight and household chaos were measured at baseline (early pregnancy, 10 to 16 weeks gestation) and at the end of the intervention (late pregnancy, 35 to 37 weeks gestation). Household chaos changes across time were examined using a paired t test for the continuous score and using the McNemar test for household chaos category (improved or no change vs declined). Serial linear regression models and mediation analyses assessed the relationship between the intervention group (predictor), household chaos change (mediator), and GWG (outcome) with adjustment for covariates. Among 258 participants, 53.9% (n=139) were Black, 43.4% (n=112) were nulliparous, 36.0% (n=93) were obese, and almost half (n=124, 48.1%) were classified as low household chaos at baseline. Overall, there were minimal changes in household chaos scores from early to late pregnancy (P=.34), although scores and categories tended to be higher in late pregnancy. Household chaos changes were divided; some improved or had no change (n=140, 54.3%), and some declined (n=118, 45.7%) across gestation. Household chaos did not mediate the effect of the intervention on GWG. In this sample, household chaos did not change across gestation and did not explain the effect of an eHealth behavioral GWG intervention in pregnant people with lower SES. Routine-focused and multilevel interventions may improve upon these findings to support an organized home for future parent and child health. ClinicalTrials.gov NCT04028843; https://www.clinicaltrials.gov/study/NCT04028843.

Smoking is a major risk factor for the development of cardiovascular and pulmonary diseases. The importance of the renin-angiotensin system in the development of cardiovascular and pulmonary disease is well established. Angiotensin-II, by means of its type 1 receptor (angiotensin type 1 receptor, AT R), promotes increased sympathetic activity, salt and water reabsorption, vasoconstriction, inflammation, and aldosterone and vasopressin release, contributing to tissue fibrosis, endothelium dysfunction, and hypertension. Angiotensin-converting enzyme 2 cleaves angiotensin-II into the vasodilator peptide, angiotensin-(1-7), hence playing a pivotal role in the angiotensin-converting enzyme 2/angiotensin-(1-7) compensatory axis of the renin-angiotensin system. Angiotensin type 2 receptor (AT R), another receptor for angiotensin-II, opposes the deleterious effects of AT R activation, and angiotensin-converting enzyme 2-formed angiotensin-(1-7) has been shown to activate AT R. The goal of the present study was to examine how nicotine, the addictive component of cigarette smoke, alters the homeostasis of the renin-angiotensin system. Quantitative real-time polymerase chain reaction was performed to examine the expression of the components of the renin-angiotensin system after cigarette smoke exposure or direct nicotine inhalation. Radio telemetry was used for continuous blood pressure recording in conscious, unrestrained mice. Our study showed that cigarette smoke or direct nicotine inhalation inhibits the expression of angiotensin-converting enzyme 2/AT R in multiple organs and cell types. In the lung, cigarette smoke (6 cigarettes/d, 12 wk) inhibited the expression of both angiotensin-converting enzyme 2 and AT R. In cardiac fibroblasts, nicotine exposure resulted in near complete suppression of angiotensin-converting enzyme 2 and AT R. In the brain, nicotine vapor inhalation inhibited angiotensin-converting enzyme 2 expression in the hypothalamus, a region involved in central regulation of cardiopulmonary function. In addition, cultured Neuro2A cells exposed to nicotine showed a dose-dependent reduction of enzymatic activity of angiotensin-converting enzyme 2. Functionally, mice exposed to nicotine vapor (12 h/d, 4 wk) exhibited significantly increased mean arterial blood pressure, which was more pronounced during the night active cycle (mean ± SE, 124 ± 0.6 mm Hg in nicotine vapor-exposed mice vs. 107 ± 0.4 mm Hg in air control mice; P < 0.0001). Our findings suggest that, by downregulating the compensatory angiotensin-converting enzyme 2/AT R elements, nicotine disrupts the homeostasis of the renin-angiotensin system in multiple organs, which is likely an important mechanism leading to the development of cardiovascular and pulmonary disease.

The association between hypercholesterolemia and elevated serum apolipoprotein B (APOB) has generated interest in APOB as a therapeutic target for patients at risk of developing cardiovascular disease. In the clinic, mipomersen, an antisense oligonucleotide (ASO) APOB inhibitor, was associated with a trend toward increased hepatic triglycerides, and liver steatosis remains a concern. We found that siRNA-mediated knockdown of ApoB led to elevated hepatic triglycerides and liver steatosis in mice engineered to exhibit a human-like lipid profile. Many genes required for fatty acid synthesis were reduced, suggesting that the observed elevation in hepatic triglycerides is maintained by the cell through fatty acid uptake as opposed to fatty acid synthesis. Fatty acid transport protein 5 ( Fatp5 / Slc27a5 ) is required for long chain fatty acid (LCFA) uptake and bile acid reconjugation by the liver. Fatp5 knockout mice exhibited lower levels of hepatic triglycerides due to decreased fatty acid uptake, and shRNA-mediated knockdown of Fatp5 protected mice from diet-induced liver steatosis. Here, we evaluated if siRNA-mediated knockdown of Fatp5 was sufficient to alleviate ApoB knockdown-induced steatosis. We determined that, although Fatp5 siRNA treatment was sufficient to increase the proportion of unconjugated bile acids 100-fold, consistent with FATP5's role in bile acid reconjugation, Fatp5 knockdown failed to influence the degree, zonal distribution, or composition of the hepatic triglycerides that accumulated following ApoB siRNA treatment.

Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.

Background In the United States (US), the incidence and severity of COVID-19 infections, hospitalizations, and deaths are higher in Black compared to White residents. Systemic inequities and differences in health behaviors may contribute to disparities in COVID-19 health outcomes. The aim of this study was to examine the impact of COVID-19 stay-at-home orders on changes in health behaviors and anxiety in Black and White adults residing in the US. Methods Beginning April 2020, the Pennington Biomedical Research Center COVID-19 Health Behaviors Study collected information on changes to employment, income, diet, physical activity, anxiety, and sleep patterns through a global online survey. Results Of 4542 survey respondents in the US, 7% identified as Black and 93% as White. Prior to the COVID-19 stay-at-home orders, a greater proportion of Blacks compared to Whites reported earning < US$50,000 per year ( p  < 0.0001). A greater proportion of Blacks reported being laid off, working fewer hours, and working from home following COVID-19 stay-at-home orders ( p  < 0.0001 for all). In the overall sample, eating behaviors improved, physical activity decreased, sleep time prolonged, and anxiety heightened following COVID-19 stay-at-home orders ( p  < 0.01 for all), which were universal between Black and White respondents ( p  ≥ 0.315 for all). Conclusions This study highlights the disproportionate changes to employment and income in Blacks, with no differential impact on health behaviors and anxiety compared to Whites due to COVID-19 stay-at-home orders. As the COVID-19 pandemic continues, disproportionate changes to employment and income status may widen among Blacks and Whites, which may influence health behaviors and anxiety.