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The MYBL1 gene is a strong transcriptional activator involved in events associated with cancer progression. Previous data show MYBL1 overexpressed in triple-negative breast cancer (TNBC). There are two parts to this study related to further characterizing the MYBL1 gene. We start by characterizing MYBL1 reference sequence variants and isoforms. The results of this study will help in future experiments in the event there is a need to characterize functional variants and isoforms of the gene. In part two, we identify and validate expression and gene-related alterations of MYBL1, VCIP1, MYC and BOP1 genes in TNBC cell lines and patient samples selected from the Breast Invasive Carcinoma TCGA 2015 dataset available at cBioPortal.org. The four genes are located at chromosomal regions 8q13.1 to 8q.24.3 loci, regions previously identified as demonstrating a high percentage of alterations in breast cancer. We identify alterations, including changes in expression, deletions, amplifications and fusions in MYBL1, VCPIP1, BOP1 and MYC genes in many of the same patients, suggesting the panel of genes is involved in coordinated activity in patients. We propose that MYBL1, VCPIP1, MYC and BOP1 collectively be considered as genes associated with the chromosome 8q loci that potentially play a role in TNBC pathogenesis.

To the Editor.-- The AAP circumcision policy in the March issue of Pediatrics still leaves me with the following questions concerning foreskin and penile hygiene. 1. What active interventions are [...]

Introduction Intimate partner violence (IPV) is a barrier to consistent HIV treatment in South Africa. Previous trials have established that the Common Elements Treatment Approach (CETA), a cognitive-behavioural-based intervention, is effective in reducing mental and behavioural health problems but has not been trialled for effectiveness in improving HIV outcomes. This paper describes the protocol for a randomised trial that is testing the effectiveness of CETA in improving HIV treatment outcomes among women experiencing IPV in South Africa.Methods and analysis We are conducting a randomised trial among HIV-infected women on antiretroviral therapy, who have experienced sexual and/or physical IPV, to test the effect of CETA on increasing retention and viral suppression and reducing IPV. Women living with HIV who have an unsuppressed viral load or are at high risk for poor adherence and report experiencing recent IPV, defined as at least once within in the last 12 months, will be recruited from HIV clinics and randomised 1:1 to receive CETA or an active attention control (text message reminders). All participants will be followed for 24 months. Follow-up HIV data will be collected passively using routinely collected medical records. HIV outcomes will be assessed at 12 and 24 months post-baseline. Questionnaires on violence, substance use and mental health will be administered at baseline, post-CETA completion and at 12 months post-baseline. Our primary outcome is retention and viral suppression (

Fatal influenza (flu) virus infection often activates excessive inflammatory signals, leading to multi-organ failure and death, also referred to as cytokine storm. PPARγ (Peroxisome proliferator-activated receptor gamma) agonists are well-known candidates for cytokine storm modulation. The present study identified that influenza infection reduced PPARγ expression and decreased PPARγ transcription activity in human alveolar macrophages (AMs) from different donors. Treatment with PPARγ agonist Troglitazone ameliorated virus-induced proinflammatory cytokine secretion but did not interfere with the IFN-induced antiviral pathway in human AMs. In contrast, PPARγ antagonist and knockdown of PPARγ in human AMs further enhanced virus-stimulated proinflammatory response. In a mouse model of influenza infection, flu virus dose-dependently reduced PPARγ transcriptional activity and decreased expression of PPARγ. Moreover, PPARγ agonist troglitazone significantly reduced high doses of influenza infection-induced lung pathology. In addition, flu infection reduced PPARγ expression in all mouse macrophages, including AMs, interstitial macrophages, and bone-marrow-derived macrophages but not in alveolar epithelial cells. Our results indicate that the influenza virus specifically targets the PPARγ pathway in macrophages to cause acute injury to the lung.

BackgroundAdherence to dietary interventions is a significant barrier in the treatment of childhood obesity. Time-limited eating (TLE) is a simple dietary approach that limits food intake to a given number of consecutive hours per day, but parental and youth acceptability of TLE in youth with obesity is unknown. This study explored the feasibility of utilizing TLE among parents and youth attending pediatric weight management (PWM).MethodsMembers of COMPASS (Childhood Obesity Multi-Program Analysis and Study System) developed a survey to assess the acceptability of TLE in families attending PWM, which included patient characteristics, current diet and sleep schedules, and interests in trying TLE. The survey was administered electronically via REDCap or manually to parents of patients between the ages of 8-17 years old and to patients 11-17 years old attending one of five PWM practices in the COMPASS network.ResultsPatients (n=213) were 13.0 ± 2.5 years old, 58% female, 52% White, 22% Black, 17% Hispanic/Latino, and 47% reported a diagnosed psychological disorder. On average, parents reported their child’s daily eating spanned 12.5 ± 1.9 hours (7:35am - 8:05pm) and included 5.6 ± 1.6 eating bouts (meals + snacks). Most parents reported being likely to try TLE ≤12 hours/d (TLE12: 66%), which was similar to the likelihood of following a nutrient-balanced diet (59%). Likelihood was lower for TLE ≤10 hours/d (TLE10: 39%) or ≤8 hours/d (TLE8: 26%) (p

Endometriosis (EM) is characterized by the growth of endometrium-like tissue outside the uterus, leading to chronic inflammation and pelvic pain. Lesion proliferation, vascularization, and associated inflammation are the hallmark features of EM lesions. The legalization of recreational cannabinoids has garnered interest in the patient community and is contributing to a greater incidence of self medication; however, it remains unknown if cannabinoids possess marked disease-modifying properties. In this study, we assess the effects of synthetic cannabinoid, WIN 55212-2 (WIN 55), in EM-representative in vitro and in vivo syngeneic mouse models. WIN 55 reduced proliferation and angiogenesis in vitro, via MAPK/Akt-mediated apoptosis. These findings were corroborated in a mouse model of EM, where we found reduced TRPV1 expression in the dorsal root ganglia of the EM mouse model exposed to WIN 55, suggesting reduced signaling of pain stimuli. Ultimately, these pieces of evidence support the use of cannabinoid receptor agonists as a potential therapeutic intervention for EM associated pain and inflammation.

In social insects colony fitness is determined in part by individual worker phenotypes. Across ant species, colony size varies greatly and is thought to affect worker trait variation in both proximate and ultimate ways. Little is known about the relationship between colony size and worker trait evolution, but hypotheses addressing the role of social structure in brain evolution suggest workers of small-colony species may have larger brains or larger brain regions necessary for complex behaviors. In previous work on odorous ants (Formicidae: Dolichoderinae) we found no correlation between colony size and these brain properties, but found that relative antennal lobe size scaled negatively with colony size. Therefore, we now test whether sensory systems scale with colony size, with particular attention to olfactory components thought to be involved in nestmate recognition. Across three species of odorous ants, Forelius mccooki, Dorymyrmex insanus, and D. bicolor, which overlap in habitat and foraging ecology but vary in colony size, we compare olfactory sensory structures, comparing those thought to be involved in nestmate recognition. We use the visual system, a sensory modality not as important in social communication in ants, as a control comparison. We find that body size scaling largely explains differences in eye size, antennal length, antennal sensilla density, and total number of olfactory glomeruli across these species. However, sensilla basiconica and olfactory glomeruli in the T6 cluster of the antennal lobe, structures known to be involved in nestmate recognition, do not follow body size scaling observed for other structures. Instead, we find evidence from the closely related Dorymyrmex species that the larger colony species, D. bicolor, invests more in structures implicated in nestmate recognition. To test for functional consequences, we compare nestmate and non-nestmate interactions between these two species and find D. bicolor pairs of either type engage in more interactions than D. insaus pairs. Thus, we do not find evidence supporting a universal pattern of sensory system scaling associated with changes in colony size, but hypothesize that observed differences in the olfactory components in two closely related Dorymyrmex species are evidence of a link between colony size and sensory trait evolution.

Water management within vulnerable ecosystems managed by multiple jurisdictions can be very complex. This study compares regulatory environments and deconstructs the approaches used for watershed governance and environmental management inside two UNESCO’s Biosphere Reserves to identify possible transferability between the two management entities. Three methodological approaches were applied: participatory observation, in-depth interviews of key informants, and document research. We concluded that while there are differences between the regulatory frameworks and localized practices, at a foundational level the goals and desired outcomes relating to environmental protection are not dependent on location, but mainly on the integration and the establishment of common objectives among the diverse social actors involved in the management and from the interaction between different organisms of social control. Additionally, there are elements in the application of regulations and practices in both locales that could be transferred to other jurisdictions interested in addressing watershed protection in vulnerable ecosystems governed by multiple jurisdictions.

BACKGROUND: To investigate if treatment with an aldosterone antagonist affects the outcomes of treatment by fixed dose combination of isosorbide dinitrate/hydralazine (FDC I/H) or placebo in black heart failure (HF) patients treated with contemporary HF medications. In the African-American Heart Failure Trial (A-HeFT), FDC I/H was effective in reducing mortality and improving event-free survival. The beneficial effects of aldosterone antagonist (spironolactone [SP]), however have not been adequately assessed in black patients with or without the use of FDC I/H. METHODS AND RESULTS: A retrospective analysis was performed in A-HeFT data base (n = 1050) to determine the effect of using SP (39% of patients) on outcomes. Baseline comparisons were done by 2-sample t-test or Fisher's exact test. Kaplan-Meier survival analyses were used for comparing between and within groups for outcomes. SP had no effect on mortality, event-free survival, or first HF hospitalization in the overall A-HeFT population. However, SP decreased mortality risk in the FDC I/H group by 59% (P = .03), and a favorable trend was noted on event-free survival and first HF hospitalization. In contrast, the use of SP was not associated with a decrease in mortality or HF hospitalizations in the placebo group. CONCLUSIONS: This study suggests that in black patients with systolic heart failure on standard therapy of beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists, the beneficial effects of aldosterone antagonists require a background therapy of FDC I/H. [ABSTRACT FROM AUTHOR]

People with psychiatric disabilities experience disproportionately high rates of unemployment. As research evidence is mounting regarding effective vocational programs, interest is growing in identifying subgroup variations. Data from a multisite research and demonstration program were analyzed to identify demographic characteristics associated with employment outcomes, after adjusting for the effects of program, services, and study site. Longitudinal analyses found that people with more recent work history, younger age, and higher education were more likely to achieve competitive employment and to work more hours per month, while race and gender effects varied by employment outcome. Results provide strong evidence of demographic subgroup variation and need. [ABSTRACT FROM AUTHOR]

Background: We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional benefit in blacks with advanced heart failure, a subgroup previously noted to have a favorable response to this therapy.Methods: A total of 1050 black patients who had New York Heart Association class III or IV heart failure with dilated ventricles were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life.Results: The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02). The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group (-0.1+/-1.9 vs. -0.5+/-2.0, P=0.01; range of possible values, -6 to +2), as were its individual components (43 percent reduction in the rate of death from any cause [hazard ratio, 0.57; P=0.01] 33 percent relative reduction in the rate of first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001], and an improvement in the quality of life [change in score, -5.6+/-20.6 vs. -2.7+/-21.2, with lower scores indicating better quality of life; P=0.02; range of possible values, 0 to 105]).Conclusions: The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure. [ABSTRACT FROM AUTHOR]

Despite increased demand for sustainable development in Canada and around the world, the efforts to change unsustainable growth frameworks have been piecemeal and wholly ineffective. Neoliberal capitalism and economy-first philosophies supersede efforts at addressing the root causes of climate change and minimal sustainable development strategies. Beginning with Scott Campbell’s “Planner’s Triangle”, effective policies and tactics can be implemented to challenge contemporary development and establish a broader framework that informs planners concerned with sustainable development.

In the era of newborn screening (NBS) for severe combined immunodeficiency (SCID) and the possibility of gene therapy (GT), it is important to link SCID phenotype to the underlying genetic disease. In western countries, X-linked interleukin 2 receptor gamma chain (IL2RG) and adenosine deaminase (ADA) deficiency SCID are two of the most common types of SCID and can be treated by GT. As a challenge, both IL2RG and ADA genes are highly polymorphic and a gene–based diagnosis may be difficult if the variant is of unknown significance or if it is located in non-coding areas of the genes that are not routinely evaluated with exon-based genetic testing (e.g., introns, promoters, and the 5′and 3′ untranslated regions). Therefore, it is important to extend evaluation to non-coding areas of a SCID gene if the exon-based sequencing is inconclusive and there is strong suspicion that a variant in that gene is the cause for disease. Functional studies are often required in these cases to confirm a pathogenic variant. We present here two unique examples of X-linked SCID with variable immune phenotypes, where IL2R gamma chain expression was detected and no pathogenic variant was identified on initial genetic testing. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy.

A prior history of excessive drinking induces a negative affective state in both humans and laboratory rodents, the manifestation of which varies with the age of drinking-onset. In adolescent male mice, negative affect incubates over the course of a 30-day alcohol withdrawal period. In contrast, the negative affect exhibited by adult male mice is robust at 1 day withdrawal, but dissipates with the passage of time. As females tend to consume more alcohol than males, we aimed to explore the affective disturbances exhibited by adolescent and adult C57BL/6J mice of both sexes during more protracted alcohol withdrawal and to relate any behavioral changes observed to plasma corticosterone levels as a biochemical index of stress. Male and female, adolescent and adult, mice were subjected to 14 consecutive days of binge alcohol-drinking using a multi-bottle-choice Drinking-in-the-Dark (DID) procedure (5, 10, 20 and 40% v/v). Age- and sex-matched control mice consumed water only. On either withdrawal day 1 or 70, subgroups of animals were subjected a to 1-day behavioral test battery that included the light–dark box shuttle test, marble-burying test, and Porsolt forced swim test. As expected, adolescent mice consumed more alcohol than adults and females consumed more alcohol than males. However, despite binge-like levels of alcohol consumption, we detected relatively few signs of alcohol withdrawal-induced negative affect and there was no correlation between affective behavior and circulating corticosterone levels. We discuss these findings within the context of our published work, highlighting procedural differences that might account for the relatively weak effect of binge-drinking history upon anxiety and depressive-like behavior observed herein.

AbstractThe objective of our study was to evaluate the exercise and educational intervention in the city of Lubbock via the GET FiT Lubbock (GFL) program. The GFL program was designed to increase exercise and educational opportunities, which positively impact health risk factors in Lubbock residents. The GFL program design included the recruitment of subjects to participate on a team that consisted of four individuals, each subject tracked their exercise minutes, and their educational session attendance. The tracking of exercise and educational sessions was done on the GFL website. Biometric testing was conducted pre- and post- intervention. The program was located within the Lubbock community in places that were close to their place of residence. The intervention included walking and educational sessions, including goal setting lectures, nutrition information, and exercise demonstrations. Study participants, included male and female adults who tracked their exercise time and educational sessions. Exercise minutes and educational session attendance were self-reported. Our data analysis revealed that significant difference was found between pre- and post- intervention measures, including weight, body mass index (BMI), high-density lipoprotein (HDL). Significant difference was found for weight, BMI, and HDL in females. Based on these findings, we conclude that the intervention showed positive effects on exercise and lifestyle.