Critical role for ribonucleoside-diphosphate reductase subunit M2 in ALV-J-induced activation of Wnt/ß-catenin signaling via interaction with P27.

Avian leukemia virus subgroup J (ALV-J) causes various diseases associated with tumor formation and decreased fertility and induced immunosuppressive disease, resulting in significant economic losses in the poultry industry globally. Virus usually exploits the host cellular machinery for their replication. Although there are increasing evidences for the cellular proteins involving viral replication, the interaction between ALV-J and host proteins leading to the pivotal steps of viral life cycle are still unclear. Here, we reported that ribonucleoside-diphosphate reductase subunit M2 (RRM2) plays a critical role during ALV-J infection by interacting with capsid protein P27 and activating Wnt/ß-catenin signaling. We found that the expression of RRM2 is effectively increased during ALV-J infection, and that RRM2 facilitates ALV-J replication by interacting with viral capsid protein P27. Furthermore, ALV-J P27 activated Wnt/ß-catenin signaling by promoting ß-catenin entry into the nucleus, and RRM2 activated Wnt/ß-catenin signaling by enhancing its phosphorylation at Ser18 during ALV-J infection. These data suggest that the upregulation of RRM2 expression by ALV-J infection favors viral replication in host cells via activating Wnt/ß-catenin signaling. IMPORTANCE Our results revealed a novel mechanism by which RRM2 facilitates ALV-J growth. That is, the upregulation of RRM2 expression by ALV-J infection favors viral replication by interacting with capsid protein P27 and activating Wnt/ß-catenin pathway in host cells. Furthermore, the phosphorylation of serine at position 18 of RRM2 was verified to be the important factor regulating the activation of Wnt/ß-catenin signaling. This study provides insights for further studies of the molecular mechanism of ALV-J infection.

The attenuated live vaccine strain W2512 provides protection against novel variant infectious bursal disease virus.

Infectious bursal disease virus (IBDV) causes an acute and highly contagious infectious disease characterized by severe immunosuppression, causing great economic losses to the poultry industry globally. Over the past 30 years, this disease has been well controlled through vaccination and strict biosafety measures. However, novel variant IBDV strains have emerged in recent years, posing a new threat to the poultry industry. Our previous epidemiological survey showed that few novel variant IBDV strains had been isolated from chickens immunized with the attenuated live vaccine W2512-, suggesting that this vaccine is efficacious against novel variant strains. Here, we report the protective effect of the W2512 vaccine against novel variant strains in SPF chickens and commercial yellow-feathered broilers. We found that W2512 causes severe atrophy of the bursa of Fabricius in SPF chickens and commercial yellow-feathered broilers, induces high levels of antibodies against IBDV, and protects chickens from infection with the novel variant strains via a placeholder effect. This study highlights the protective effect of commercial attenuated live vaccines against the novel IBDV variant and provides guidance for the prevention and control of this disease.

The Coordination Toolkit and Coaching Project: Cluster-Randomized Quality Improvement Initiative to Improve Patient Experience of Care Coordination.

BACKGROUND: Given persistent gaps in coordination of care for medically complex primary care patients, efficient strategies are needed to promote better care coordination. OBJECTIVE: The Coordination Toolkit and Coaching project compared two toolkit-based strategies of differing intensity to improve care coordination at VA primary care clinics. DESIGN: Multi-site, cluster-randomized QI initiative. PARTICIPANTS: Twelve VA primary care clinics matched in 6 pairs. INTERVENTIONS: We used a computer-generated allocation sequence to randomize clinics within each pair to two implementation strategies. Active control clinics received an online toolkit with evidence-based tools and QI coaching manual. Intervention clinics received the online toolkit plus weekly assistance from a distance coach for 12 months. MAIN MEASURES: We quantified patient experience of general care coordination using the Health Care System Hassles Scale (primary outcome) mailed at baseline and 12-month follow-up to serial cross-sectional patient samples. We measured the difference-in-difference (DiD) in clinic-level-predicted mean counts of hassles between coached and non-coached clinics, adjusting for clustering and patient characteristics using zero-inflated negative binomial regression and bootstrapping to obtain 95% confidence intervals. Other measures included care coordination QI projects attempted, tools adopted, and patient-reported exposure to projects. KEY RESULTS: N = 2,484 (49%) patients completed baseline surveys and 2,481 (48%) completed follow-ups. Six coached clinics versus five non-coached clinics attempted QI projects. All coached clinics versus two non-coached clinics attempted more than one project or projects that were multifaceted (i.e., involving multiple components addressing a common goal). Five coached versus three non-coached clinics used 1-2 toolkit tools. Both the coached and non-coached clinics experienced pre-post reductions in hassle counts over the study period (- 0.42 (- 0.76, - 0.08) non-coached; - 0.40 (- 0.75, - 0.06) coached). However, the DiD (0.02 (- 0.47, 0.50)) was not statistically significant; coaching did not improve patient experience of care coordination relative to the toolkit alone. CONCLUSION: Although coached clinics attempted more or more complex QI projects and used more tools than non-coached clinics, coaching provided no additional benefit versus the online toolkit alone in patient-reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03063294.

High Prevalence of Sexually Transmitted Infections in Pregnant Women Living in Southern Brazil.

BACKGROUND: Porto Alegre, Brazil, has the highest rates of congenital syphilis and HIV in the country. Other treatable sexually transmitted infections (STIs) are associated with poor pregnancy and neonatal outcomes, but are only diagnosed by syndromic algorithms. METHODS: Between September 2018 and November 2019, we offered all pregnant women clinic-based STI testing for HIV antibody and treponemal antibody (via lateral flow assay rapid tests provided by the Brazilian Government) and for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis (via polymerase chain reaction-based testing provided by Gene Xpert, Sunnyvale, CA) in 10 public prenatal health clinics in Porto Alegre. Participating women answered a brief survey via audio computer-assisted survey instrument regarding demographics, partnerships, and sexual behaviors. All infected individuals received appropriate treatment and referrals. RESULTS: Of 400 pregnant women recruited, 94 (24%) were diagnosed with an STI, including 2% with HIV, 11% with syphilis, 9% with chlamydia, 1% with gonorrhea, 5% with trichomoniasis, and 3% with more than 1 STI. In our multivariate analysis, younger age (adjusted odds ratio [AOR], 1.1; 95% confidence interval [CI], 1-1.2), being non-White (AOR, 1.8; 95% CI, 1.1-3.1), having less education (AOR, 2; 95% CI, 1.2-3.4), and having a relationship <1 year (AOR, 2; 95% CI, 1.1-3.6) were all independent predictors of women having an STI. Endorsing symptoms of an STI (e.g., vaginal ulcers/lesions and vaginal discharge) was not predictive of having a laboratory-diagnosed STI (OR, 1.1; 95% CI, 0.7-1.7). CONCLUSIONS: Etiologic-based screening for STIs was uniformly accepted by women attending both hospital-based and primary health clinics in the south of Brazil and can result in appropriate treatment of pregnant women.

Baseline pro-inflammatory gene expression in whole blood is related to adverse long-term outcomes after transcatheter aortic valve replacement: a case control study.

BACKGROUND: Age-associated inflammation and immune system dysfunction have been implicated as mechanisms that increase risk for adverse long-term procedural outcomes in older adults. The purpose of this study was to investigate relationships between baseline inflammatory and innate antiviral gene expression and outcomes after transcatheter aortic valve replacement (TAVR) in older adults with severe aortic stenosis. METHODS: We performed a retrospective case-control study comparing pre-procedural pro-inflammatory and Type 1 interferon (IFN) gene expression in 48 controls with favorable outcomes (alive 1 year after TAVR with improved quality of life [QoL]) versus 48 individuals with unfavorable outcomes (dead by 1 year or alive at 1 year but with reduced QoL). Gene expression was evaluated in whole blood via (1) pre-defined composite scores of 19 inflammation-associated genes and 34 Type I IFN response genes, and (2) pro-inflammatory and antiviral transcription factor activity inferred from promotor based bioinformatics analyses of genes showing > 25% difference in average expression levels across groups. All analyses were adjusted for age, gender, body mass index, diabetes, immunosuppression, cardiovascular disease (CVD), and frailty. RESULTS: Relative to controls, those with unfavorable outcomes demonstrated higher expression of the pro-inflammatory gene composite prior to TAVR (p < 0.01) and bioinformatic indicators of elevated Nuclear Factor kB (p < 0.001) and Activator Protein 1 (p < 0.001) transcription factor activity, but no significant differences in Type I IFN-related gene expression. CONCLUSIONS: These results demonstrate that a pro-inflammatory state prior to TAVR, independent of CVD severity and frailty status, is associated with worse long-term procedural outcomes.

Toolkit and distance coaching strategies: a mixed methods evaluation of a trial to implement care coordination quality improvement projects in primary care.

BACKGROUND: Care coordination tools and toolkits can be challenging to implement. Practice facilitation, an active but expensive strategy, may facilitate toolkit implementation. We evaluated the comparative effectiveness of distance coaching, a form of practice facilitation, for improving the implementation of care coordination quality improvement (QI) projects. METHODS: We conducted a mixed methods evaluation of the Coordination Toolkit and Coaching (CTAC) initiative. Twelve matched US Veterans Health Administration primary care clinics were randomized to receive coaching and an online care coordination toolkit ("coached"; n = 6) or access to the toolkit only ("non-coached"; n = 6). We did interviews at six, 12, and 18 months. For coached sites, we'ly collected site visit fieldnotes, prospective coach logs, retrospective coach team debriefs, and project reports. We employed matrix analysis using constructs from the Consolidated Framework for Implementation Research and a taxonomy of outcomes. We assessed each site's project(s) using an adapted Complexity Assessment Tool for Systematic Reviews. RESULTS: Eleven sites implemented a local CTAC project. Eight sites (5 coached, 3 non-coached) used at least one tool from the toolkit. Coached sites implemented significantly more complex projects than non-coached sites (11.5 vs 7.5, 95% confidence interval 1.75-6.25, p < 0.001); engaged in more formal implementation processes (planning, engaging, reflecting and evaluating); and generally had larger, more multidisciplinary QI teams. Regardless of coaching status, sites focused on internal organizational improvement and low-intensity educational projects rather than the full suite of care coordination tools. At 12 months, half the coached and non-coached sites had clinic-wide project implementation; the remaining coached sites had implemented most of their project(s), while the remaining non-coached sites had either not implemented anything or conducted limited pilots. At 18 months, coached sites reported ongoing effort to monitor, adapt, and spread their CTAC projects, while non-coached sites did not report much continuing work. Coached sites accrued benefits like improved clinic relationships and team QI skill building that non-coached sites did not describe. CONCLUSIONS: Coaching had a positive influence on QI skills of (and relationships among) coached sites' team members, and the scope and rigor of projects. However, a 12-month project period was potentially too short to ensure full project implementation or to address cross-setting or patient-partnered initiatives. TRIAL REGISTRATION: NCT03063294 .

DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer.

A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive ([Formula: see text]) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative ([Formula: see text]) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.

Outcomes related to intravenous fluid administration in sickle cell patients during vaso-occlusive crisis.

While fluid replacement therapy is a primary treatment modality used in vaso-occlusive crises for sickle cell disease, data is limited on its safety, efficacy, and variability. We performed a retrospective analysis on 157 unique patient encounters from 49 sickle cell patients hospitalized with a vaso-occlusive episode at our institution from 2013 to 2017. The median length of hospital stay was 4 days (IQR 2-7). The mean total amount of intravenous fluid administered during the hospitalization was 7.4 L (Std 9.6). The mean total amount of fluid intake including intravenous fluids, blood transfusions, and oral fluids was 14.2 L (Std 18.2). Multivariate analyses revealed significant associations between the development of any adverse event (including a new oxygen requirement, acute chest syndrome, aspiration event, other hospital-acquired infection, acute kidney injury, and intensive care unit transfer) and the following variables: intravenous fluid administered in the first 24 h (p = 0.001, OR 1.899, 95% CI 1.319-2.733), total amount of intravenous fluid administered (p = 0.005, OR 1.081, 95% CI 1.023-1.141), and total amount of fluid intake including oral fluids, blood transfusions, and intravenous fluids (p = 0.009, OR 1.046, 95% CI 1.011-1.081). Other factors found to be significantly associated with any adverse event were dialysis dependence prior to admission (p < 0.001, OR 12.984, 95% CI 3.660-46.056) and admission to an inpatient service versus an emergency room or observation unit (p = 0.008, OR 3.201, 95% CI 1.346-7.612). While fluid administration may theoretically slow the sickling process, this data suggests that fluid administration during a vaso-occlusive episode, and especially total volume given in the first 24 h, may also lead to adverse events.

gpGrouper: A Peptide Grouping Algorithm for Gene-Centric Inference and Quantitation of Bottom-Up Proteomics Data.

In quantitative mass spectrometry, the method by which peptides are grouped into proteins can have dramatic effects on downstream analyses. Here we describe gpGrouper, an inference and quantitation algorithm that offers an alternative method for assignment of protein groups by gene locus and improves pseudo-absolute iBAQ quantitation by weighted distribution of shared peptide areas. We experimentally show that distributing shared peptide quantities based on unique peptide peak ratios improves quantitation accuracy compared with conventional winner-take-all scenarios. Furthermore, gpGrouper seamlessly handles two-species samples such as patient-derived xenografts (PDXs) without ignoring the host species or species-shared peptides. This is a critical capability for proper evaluation of proteomics data from PDX samples, where stromal infiltration varies across individual tumors. Finally, gpGrouper calculates peptide peak area (MS1) based expression estimates from multiplexed isobaric data, producing iBAQ results that are directly comparable across label-free, isotopic, and isobaric proteomics approaches.

A Cross-Linking-Aided Immunoprecipitation/Mass Spectrometry Workflow Reveals Extensive Intracellular Trafficking in Time-Resolved, Signal-Dependent Epidermal Growth Factor Receptor Proteome.

Ligand binding to the cell surface receptors initiates signaling cascades that are commonly transduced through a protein-protein interaction (PPI) network to activate a plethora of response pathways. However, tools to capture the membrane PPI network are lacking. Here, we describe a cross-linking-aided mass spectrometry workflow for isolation and identification of signal-dependent epidermal growth factor receptor (EGFR) proteome. We performed protein cross-linking in cell culture at various time points following EGF treatment, followed by immunoprecipitation of endogenous EGFR and analysis of the associated proteins by quantitative mass spectrometry. We identified 140 proteins with high confidence during a 2 h time course by data-dependent acquisition and further validated the results by parallel reaction monitoring. A large proportion of proteins in the EGFR proteome function in endocytosis and intracellular protein transport. The EGFR proteome was highly dynamic with distinct temporal behavior; 10 proteins that appeared in all time points constitute the core proteome. Functional characterization showed that loss of the FYVE domain-containing proteins altered the EGFR intracellular distribution but had a minor effect on EGFR proteome or signaling. Thus, our results suggest that the EGFR proteome include functional regulators that influence EGFR signaling and bystanders that are captured as the components of endocytic vesicles. The high-resolution spatiotemporal information of these molecules facilitates the delineation of many pathways that could determine the strength and duration of the signaling, as well as the location and destination of the receptor.

Understanding the Racial/Ethnic Gap in Bank Account Ownership among Older Adults.

The observed racial/ethnic gap in bank account ownership among older adults is substantial. We investigate socioeconomic, cognitive, and cultural barriers underling it. As additional potential barriers are accounted for, the residual gaps in financial inclusion with respect to Whites are reduced by 19% for blacks and 46% for Hispanics. We find that citizenship and "taste for privacy" play a limited role for both minority groups, while real asset ownership, health, cognitive ability, and cultural hurdles contribute substantially to the gap. For Hispanics, language barriers explain most of the gap, while neighborhood-level socioeconomic characteristics are more salient for blacks. We also examine how the racial/ethnic composition of couples influences financial decisions. We estimate a significantly smaller residual gap between "mixed" and white couples than between minority and white couples. We provide empirical evidence suggesting that, other things equal, mixed couples are less concerned with the cultural/psychological barriers facing minority couples.

Predictors of Out-of-ACO Care in the Medicare Shared Savings Program.

IMPORTANCE: Patients treated outside of their Medicare Shared Savings Program (MSSP) accountable care organization (ACO) likely benefit less from the ACO's integration of care. Consequently, the MSSP's open-network design may preclude ACOs from improving value in care. OBJECTIVES: Quantify out-of-ACO care in a single urban ACO and examine associations between patient-level predictors and out-of-ACO expenditures. RESEARCH DESIGN: Secondary data analysis using Centers for Medicare and Medicaid ACO Program Claim and Claim Line Feed dataset (dates of service January 1, 2013-December 31, 2013). Two-part modeling was used to examine associations between patient-level predictors and likelihood and level of out-of-ACO expenditures. SUBJECTS: Patients were included if they were prospectively assigned to the MSSP in 2013. Patients were excluded if they declined to share data with the ACO, were not retrospectively confirmed to be in the ACO, or had missing data on covariates. Analytic sample included 11,922 patients. MEASURES: Total out-of-ACO expenditures and out-of-ACO expenditures by place of service. RESULTS: Of total expenditures, 32.9% were paid to out-of-ACO providers, and 89.8% of beneficiaries had out-of-ACO expenditures. The presence of almost all medical comorbidities increased out-of-ACO expenditures ($800-$3000 per comorbidity) across the study population. Racial/ethnic minority groups spent between $1076 and $1422 less outside of the ACO than white patients, which was driven by less out-of-ACO outpatient office expenditures ($417-$517 less for each racial/ethnic minority group). CONCLUSIONS: Out-of-ACO expenditures represented a significant portion of expenditures for the study population. Medically complex patients spent more outside of the ACO and represent an important population to study further.

PICH and BLM limit histone association with anaphase centromeric DNA threads and promote their resolution.

Centromeres nucleate the formation of kinetochores and are vital for chromosome segregation during mitosis. The SNF2 family helicase PICH (Plk1-interacting checkpoint helicase) and the BLM (the Bloom's syndrome protein) helicase decorate ultrafine histone-negative DNA threads that link the segregating sister centromeres during anaphase. The functions of PICH and BLM at these threads are not understood, however. Here, we show that PICH binds to BLM and enables BLM localization to anaphase centromeric threads. PICH- or BLM-RNAi cells fail to resolve these threads in anaphase. The fragmented threads form centromeric-chromatin-containing micronuclei in daughter cells. Anaphase threads in PICH- and BLM-RNAi cells contain histones and centromere markers. Recombinant purified PICH has nucleosome remodelling activities in vitro. We propose that PICH and BLM unravel centromeric chromatin and keep anaphase DNA threads mostly free of nucleosomes, thus allowing these threads to span long distances between rapidly segregating centromeres without breakage and providing a spatiotemporal window for their resolution.

Effectiveness of a smartphone application for weight loss compared with usual care in overweight primary care patients: a randomized, controlled trial.

BACKGROUND: Many smartphone applications (apps) for weight loss are available, but little is known about their effectiveness. OBJECTIVE: To evaluate the effect of introducing primary care patients to a free smartphone app for weight loss. DESIGN: Randomized, controlled trial. (ClinicalTrials.gov: NCT01650337). SETTING: 2 academic primary care clinics. PATIENTS: 212 primary care patients with body mass index of 25 kg/m2 or greater. INTERVENTION: 6 months of usual care without (n = 107) or with (n = 105) assistance in downloading the MyFitnessPal app (MyFitnessPal). MEASUREMENTS: Weight loss at 6 months (primary outcome) and changes in systolic blood pressure and behaviors, frequency of app use, and satisfaction (secondary outcomes). RESULTS: After 6 months, weight change was minimal, with no difference between groups (mean between-group difference, -0.30 kg [95% CI, -1.50 to 0.95 kg]; P = 0.63). Change in systolic blood pressure also did not differ between groups (mean between-group difference, -1.7 mm Hg [CI, -7.1 to 3.8 mm Hg]; P = 0.55). Compared with patients in the control group, those in the intervention group increased use of a personal calorie goal (mean between-group difference, 2.0 d/wk [CI, 1.1 to 2.9 d/wk]; P < 0.001), although other self-reported behaviors did not differ between groups. Most users reported high satisfaction with MyFitnessPal, but logins decreased sharply after the first month. LIMITATIONS: Despite being blinded to the name of the app, 14 control group participants (13%) used MyFitnessPal. In addition, 32% of intervention group participants and 19% of control group participants were lost to follow-up at 6 months. The app was given to patients by research assistants, not by physicians. CONCLUSION: Smartphone apps for weight loss may be useful for persons who are ready to self-monitor calories, but introducing a smartphone app is unlikely to produce substantial weight change for most patients. PRIMARY FUNDING SOURCE: Robert Wood Johnson Foundation Clinical Scholars Program, National Institutes of Health/National Center for Advancing Translational Sciences for the UCLA Clinical and Translational Science Institute, and the Resource Centers for Minority Aging Research Center for Health Improvement of Minority Elderly under the National Institutes of Health/National Institute on Aging.

Nuclear BAG6-UBL4A-GET4 complex mediates DNA damage signaling and cell death.

BCL2-associated athanogene 6 (BAG6) is a member of the BAG protein family, which is implicated in diverse cellular processes including apoptosis, co-chaperone, and DNA damage response (DDR). Recently, it has been shown that BAG6 forms a stable complex with UBL4A and GET4 and functions in membrane protein targeting and protein quality control. The BAG6 sequence contains a canonical nuclear localization signal and is localized predominantly in the nucleus. However, GET4 and UBL4A are found mainly in cytoplasm. Whether GET4 and UBL4A are also involved in DDR in the context of the BAG6 complex remains unknown. Here, we provide evidence that nuclear BAG6-UBL4A-GET4 complex mediates DDR signaling and damage-induced cell death. BAG6 appears to be the central component for the process, as depletion of BAG6 leads to the loss of both UBL4A and GET4 proteins and resistance to cell killing by DNA-damaging agents. In addition, nuclear localization of BAG6 and phosphorylation of BAG6 by ATM/ATR are also required for cell killing. UBL4A and GET4 translocate to the nucleus upon DNA damage and appear to play redundant roles in cell killing, as depletion of either one has no effect but co-depletion leads to resistance. All three components of the BAG6 complex are required for optimal DDR signaling, as BAG6, and to a lesser extent, GET4 and UBL4A, regulate the recruitment of BRCA1 to sites of DNA damage. Together our results suggest that the nuclear BAG6 complex is an effector in DNA damage response pathway and its phosphorylation and nuclear localization are important determinants for its function.

Local supersaturation dictated branching and faceting of submicrometer PbS particles with cubic growth habit.

Hierarchical cubelike submicrometer PbS particles consisting of truncated octahedrons, cuboctahedrons, and cubes were prepared in ethylene glycol solution under favorable high mole ratio of thiourea (Tu) to Pb(AC)2 (R(S/Pb)) via a pumping process. A qualitative analysis based on the classical nucleation theory coupled with the crystal growth theory is employed to interpret the observed experimental phenomena. By varying the concentration of reactants, R(S/Pb), and reaction temperature, it is possible to tune the local supersaturation degree (LSD), which is determined by the number of nuclei and overall growth unit (or concentration), surrounding each growing particle that dictates the branching and faceting of PbS particle. Relatively high LSD that is required for branching growth could be achieved at lower concentration of Tu and reaction temperature. Increasing the concentration of Tu and reaction temperature resulted in less LSD and yielded cubic PbS particles.

Risk factors for cardiovascular disease among Mexican-American adults in the United States and Mexico: a comparative study.

OBJECTIVE: To compare cardiovascular disease (CVD) risk factors in a cohort of Mexican health workers with representative samples of US-born and Mexico-born Mexican-Americans living in the US. MATERIALS AND METHODS: Data were obtained from the Mexican Health Worker Cohort Study (MHWCS) in Mexico and the National Health and Nutrition Examination Survey (NHANES) IV 1999-2006 in the US. Regression analyses were used to investigate CVD risk factors. RESULTS: In adjusted analyses, NHANES participants were more likely than MHWCS participants to have hypertension, high total cholesterol, diabetes, obesity, and abdominal obesity, and were less likely to have low HDL cholesterol and smoke. Less-educated men and women were more likely to have low HDL cholesterol, obesity, and abdominal obesity. CONCLUSIONS: In this binational study, men and women enrolled in the MHWCS appear to have fewer CVD risk factors than US-born and Mexico-born Mexican-American men and women living in the US.

Novel variant infectious bursal disease virus diminishes FAdV-4 vaccination and enhances pathogenicity of FAdV-4.

Infectious bursal disease virus (IBDV) caused an acute and highly contagious infectious disease characterized by severe immunosuppression, causing considerable economic losses to the poultry industry globally. Although this disease was well-controlled under the widely use of commercial vaccines in the past decades, the novel variant IBDV strains emerged recently because of the highly immunized-selection pressure in the field, posting new threats to poultry industry. Here, we reported novel variant IBDV is responsible for a disease outbreak, and assessed the epidemic and pathogenicity of IBDV in this study. Moreover, we constructed a challenge model using Fowl adenovirus serotype 4 (FAdV-4) to study on the immunosuppressive effect. Our findings underscore the importance of IBDV surveillance, and provide evidence for understanding the pathogenicity of IBDV.

Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity.

Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. A better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate cancer (CRPC). Molecular, genetic, or pharmacologic inhibition of ATGL impaired human and murine prostate cancer growth in vivo and in cell culture or organoids under conditions mimicking the tumor microenvironment. Mass spectrometry imaging demonstrated that ATGL profoundly regulates lipid metabolism in vivo, remodeling membrane composition. ATGL inhibition induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by cotargeting both metabolic pathways. Patient-derived phosphoproteomics identified ATGL serine 404 as a target of CAMKK2-AMPK signaling in CRPC cells. Mutation of serine 404 did not alter the lipolytic activity of ATGL but did decrease CRPC growth, migration, and invasion, indicating that noncanonical ATGL activity also contributes to disease progression. Unbiased immunoprecipitation/mass spectrometry suggested that mutation of serine 404 not only disrupts existing ATGL protein interactions but also leads to new protein-protein interactions. Together, these data nominate ATGL as a therapeutic target for CRPC and provide insights for future drug development and combination therapies. SIGNIFICANCE: ATGL promotes prostate cancer metabolic plasticity and progression through both lipase-dependent and lipase-independent activity, informing strategies to target ATGL and lipid metabolism for cancer treatment.

The risk of developing invasive breast cancer in Hispanic women : a look across Hispanic subgroups.

BACKGROUND: Current evidence on breast cancer among US Hispanic women indicates a significant public health threat, although few studies have assessed the heterogeneity in breast cancer risk among Hispanics of different origin. METHODS: The 2000 and 2005 National Health Interview Survey Cancer Control Modules were used to examine the Breast Cancer Risk Assessment Tool (BCRAT) 5-year risk and lifetime risk of invasive breast cancer among Mexican/Mexican American, Puerto Rican, Cuban/Cuban American, Dominican (Republic), Central/South American, Other Hispanic, and non-Hispanic white (NHW) women ages 35 to 84 years. Multiple linear regression models were used to compare the BCRAT 5-year and lifetime breast cancer risk between 1) Hispanics and NHWs and 2) Hispanic subgroups. RESULTS: Hispanic women had significantly lower mean BCRAT 5-year and lifetime breast cancer risk compared with NHW women (P < .001). Among Hispanic subgroups, Cuban/Cuban Americans had a higher BCRAT 5-year risk (P < .05), whereas Dominicans had a higher lifetime risk (P < .001) compared with Mexican/Mexican Americans. Approximately 2.6% of Hispanic women were at high risk for breast cancer (BCRAT 5-year risk ≥1.67%), ranging from 1% of Central/South Americans to 3.7% of Puerto Ricans; few Hispanics (0.2%) had a lifetime risk ≥20%. CONCLUSIONS: The current findings indicate that Hispanic women have a significantly lower risk of breast cancer compared with NHW women, although the risk according to BCRAT differed significantly between specific Hispanic subgroups. We provide estimates of the number of US Hispanic women from six subgroups who may be eligible for prophylactic breast cancer chemoprevention. The authors concluded that future studies should further investigate the heterogeneity in breast cancer risk and risk factors between Hispanic women of different origins.