A plethora of growth factors regulate keratinocyte proliferation and differentiation that control hair morphogenesis and skin barrier formation. Wavy hair phenotypes in mice result from naturally ...occurring loss-of-function mutations in the genes for TGF-α and EGFR. Conversely, excessive activities of TGF-α/EGFR result in hairless phenotypes and skin cancers. Unexpectedly, we found that mice lacking the
Trpv3 gene also exhibit wavy hair coat and curly whiskers. Here we show that keratinocyte TRPV3, a member of the
transient
receptor
potential (TRP) family of Ca
2+-permeant channels, forms a signaling complex with TGF-α/EGFR. Activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-α release. TRPV3 is also required for the formation of the skin barrier by regulating the activities of transglutaminases, a family of Ca
2+-dependent crosslinking enzymes essential for keratinocyte cornification. Our results show that a TRP channel plays a role in regulating growth factor signaling by direct complex formation.
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► Mice deficient in TRPV3, EGFR, or TGF-α exhibit wavy hair coat and curly whiskers ► Activation of EGFR leads to increased TRPV3 channel activity in keratinocytes ► Activation of TRPV3 channel stimulates TGF-α release in keratinocytes ► TRPV3 regulates transglutaminase activity and skin barrier formation
Problem:
Academic medical centers need to mitigate the negative effects of implicit bias with approaches that are empirically-based, scalable, sustainable, and specific to departmental needs. Guided ...by Kotter's Model of Change to create and sustain cultural change, we developed the Bias Reduction Improvement Coaching Program (BRIC), a two-year, train-the-trainer implicit bias coaching program designed to meet the increasing demand for bias training across a university medical center.
Intervention:
BRIC trained a cohort of faculty and staff as coaches during four quarterly training sessions in Year 1 that covered 1) the science of bias, 2) bias in selection and hiring, 3) bias in mentoring, and 4) bias in promotion, retention, and workplace culture. In Year 2, coaches attended two booster sessions and delivered at least two presentations. BRIC raises awareness of bias mitigation strategies in a scalable way by uniquely building capacity through department-level champions, providing programming that addresses the 'local context,' and setting a foundation for sustained institutional change.
Context:
In a U.S. academic medical center, 27 faculty and staff from 24 departments were trained as inaugural BRIC coaches. We assessed outcomes at multiple levels: BRIC coach outcomes (feedback on the training sessions; coach knowledge, attitudes, and skills), departmental-level outcomes (program attendee feedback, knowledge, and intentions) and institutional outcomes (activities to sustain change).
Impact:
After Year 1, coaches reported high satisfaction with BRIC and a statistically significant increase in self-efficacy in their abilities to recognize, mitigate, and teach about implicit bias. In Year 2, attendees at BRIC coach presentations reported an increase in bias mitigation knowledge, and the majority committed to taking follow-up action (e.g., taking an Implicit Association Test). Coaches also launched activities for sustaining change at the broader university and beyond.
Lessons Learned:
The BRIC Program indicates a high level of interest in receiving bias mitigation training, both among individuals who applied to be BRIC coaches and among presentation attendees. BRIC's initial success supports future expansion. The model appears scalable and sustainable; future efforts will formalize the emerging community of practice around bias mitigation and measure elements of on-going institutional culture change.
The current study reports the results of a randomized controlled trial examining the impact of the Getting Ready parent-engagement intervention on expressive language skills of children (N = 267) ...with developmental concerns upon entry into preschool. Latent growth for expressive language and moderating roles of parental stress and parental involvement in learning at home were analyzed using a structural equation modeling framework. Probing of interaction effects indicates that when families report below-average levels of stress or involvement in learning at home, children in the intervention group demonstrate accelerated growth in expressive language skills compared with peers in the comparison condition. Getting Ready is most salient when families report low to moderate levels of stress and can serve as a buffer for families who report low to moderate levels of involvement in learning at preschool entry. Results have implications for connections between families and educators across the preschool period.
Quantifying the microstructural and macrostructural geometrical features of the human brain’s connections is necessary for understanding normal aging and disease. Here, we examine brain white matter ...diffusion magnetic resonance imaging data from one cross-sectional and two longitudinal data sets totaling in 1218 subjects and 2459 sessions of people aged 50–97 years. Data was drawn from well-established cohorts, including the Baltimore Longitudinal Study of Aging data set, Cambridge Centre for Ageing Neuroscience data set, and the Vanderbilt Memory & Aging Project. Quantifying 4 microstructural features and, for the first time, 11 macrostructure-based features of volume, area, and length across 120 white matter pathways, we apply linear mixed effect modeling to investigate changes in pathway-specific features over time, and document large age associations within white matter. Conventional diffusion tensor microstructure indices are the most age-sensitive measures, with positive age associations for diffusivities and negative age associations with anisotropies, with similar patterns observed across all pathways. Similarly, pathway shape measures also change with age, with negative age associations for most length, surface area, and volume-based features. A particularly novel finding of this study is that while trends were homogeneous throughout the brain for microstructure features, macrostructural features demonstrated heterogeneity across pathways, whereby several projection, thalamic, and commissural tracts exhibited more decline with age compared to association and limbic tracts. The findings from this large-scale study provide a comprehensive overview of the age-related decline in white matter and demonstrate that macrostructural features may be more sensitive to heterogeneous white matter decline. Therefore, leveraging macrostructural features may be useful for studying aging and could facilitate comparisons in a variety of diseases or abnormal conditions.
Background
Vasoplegia is associated with adverse outcomes following cardiac surgery; however, its impact following left ventricular assist device implantation is largely unexplored.
Methods and ...Results
In 252 consecutive patients receiving a left ventricular assist device, vasoplegia was defined as the occurrence of normal cardiac function and index but with the need for intravenous vasopressors within 48 hours following surgery for >24 hours to maintain a mean arterial pressure >70 mm Hg. We further categorized vasoplegia as none; mild, requiring 1 vasopressor (vasopressin, norepinephrine, or high‐dose epinephrine >5 μg/min); or moderate to severe, requiring ≥2 vasopressors. Predictors of vasoplegia severity were determined using a cumulative logit (ordinal logistic regression) model, and 1‐year mortality was evaluated using competing‐risks survival analysis. In total, 67 (26.6%) patients developed mild vasoplegia and 57 (22.6%) developed moderate to severe vasoplegia. The multivariable model for vasoplegia severity utilized preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time, which yielded an area under the curve of 0.76. Although no significant differences were noted in stroke or pump thrombosis rates (P=0.87 and P=0.66, respectively), respiratory failure and major bleeding increased with vasoplegia severity (P<0.01). Those with moderate to severe vasoplegia had a significantly higher risk of mortality than those without vasoplegia (adjusted hazard ratio: 2.12; 95% confidence interval, 1.08–4.18; P=0.03).
Conclusions
Vasoplegia is predictive of unfavorable outcomes, including mortality. Risk factors for future research include preoperative INTERMACS profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time.
The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression ...to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell-based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.
Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; ...however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC ≥ |1.5|,
≤ 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (
≥ |0.50|,
≤ 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.
Background
Prenatal alcohol exposure (PAE) causes neurodevelopmental disability. Clinical and animal studies show gestational iron deficiency (ID) exacerbates PAE's behavioral and growth deficits. In ...rat, PAE manifests an inability to establish iron homeostasis, increasing hepcidin (maternal and fetal), and fetal liver iron while decreasing brain iron and promoting anemia. Here, we hypothesize dietary iron fortification during pregnancy may mitigate alcohol's disruption of fetal iron homeostasis.
Methods
Pregnant Long‐Evans rats, fed iron‐sufficient (100 ppm iron) or iron‐fortified (IF; 500 ppm iron) diets, received either 5 g/kg alcohol (PAE) or isocaloric maltodextrin daily on gestational days (GD) 13.5 through 19.5. Maternal and fetal outcomes were evaluated on GD20.5.
Results
PAE reduced mean fetal weight (p < 0.001) regardless of maternal iron status, suggesting iron fortification did not improve fetal growth. Both PAE (p < 0.01) and IF (p = 0.035) increased fetal liver iron. In fetal brain, PAE (p = 0.015) affected total (p < 0.001) and nonheme iron (p < 0.001) such that iron fortification normalized (p = 0.99) the alcohol‐mediated reductions in brain iron and nonheme iron. Iron fortification also improved fetal hematologic indices in PAE including hemoglobin, hematocrit, and mean cell volume (ps<0.001). Iron fortification also normalized hepcidin expression in alcohol‐exposed maternal and fetal liver. Neither diet nor PAE affected transferrin (Tf) and ferritin (FTN) content in fetal liver, nor Tf or transferrin receptor in fetal brain. However, IF‐PAE fetal brains trended to less FTN content (p = 0.074), suggesting greater availability of nonstorage iron. In PAE, hepcidin levels were linearly related to increased liver iron stores and decreased red blood cell count and brain iron.
Conclusions
Maternal oral iron fortification mitigated PAE's disruption of fetal iron homeostasis and improved brain iron content, hematologic indices, and hepcidin production in this rat PAE model. Clinical studies show maternal ID substantially enhances fetal vulnerability to PAE, and our work supports increased maternal dietary iron intake may improve fetal iron status in alcohol‐exposed pregnancies.
Maternal nutrition affects fetal outcomes in response to prenatal alcohol exposure (PAE). Low maternal iron stores render fetuses vulnerable to PAE‐mediated disruption of fetal iron homeostasis and brain iron content. This increases the risk of impaired brain function and fetal anemia. We show here that maternal dietary iron fortification reduces fetal vulnerability to PAE and improves fetal iron homeostasis, hematological indices, and brain iron content, thereby partially mitigating some negative outcomes associated with fetal alcohol spectrum disorders.
Summary
Bleeding events have been observed among a subgroup of chronic lymphocytic leukaemia (CLL) patients treated with ibrutinib. We analysed data from two studies of single‐agent ibrutinib to ...better characterize bleeding events and pattern of anticoagulation and antiplatelet use. Among 327 ibrutinib‐treated patients, concomitant anticoagulation (11%) or antiplatelet use (34%) was common, but major bleeding was infrequent (2%). Bleeding events were primarily grade 1, and infrequently (1%) led to discontinuation. Among 175 patients receiving concomitant anticoagulant or antiplatelet agents, 5 had major bleeding events (3%). These events were typically observed in conjunction with other factors, such as coexisting medical conditions and/or concurrent medications.
Adding feedback messages (FB) to self-monitoring (SM) may reinforce behavior change. However, socio-environmental conditions (e.g., limited access to parks or low walkability) may limit one's ability ...to respond to FB focused on physical activity (PA). In this analysis, we hypothesized that high neighborhood walkability will positively modify the treatment effect of FB on PA, and residents of high walkability neighborhoods will achieve higher PA levels at 12 months than those in low walkability neighborhoods. The study is a secondary analysis of a 12-month behavioral weight-loss trial. Adults with overweight/obesity were randomized to SM + FB (n = 251) or SM alone (n = 251). SM + FB group received smartphone pop-up messages thrice/week tailored to their PA SM data. The assessment included neighborhood walkability via Walk Score (low <50 vs. high ≥50), moderate to vigorous PA (MVPA) and step count via Fitbit Charge 2™, and weight via smart scale. We report adjusted linear regression coefficients (b) with standard errors (SE). The analysis included participants who were primarily white, female, and with obesity. In adjusted models, neighborhood walkability did not moderate the effect of treatment assignment on log-transformed (ln) MVPA or steps count over 12 months. The SM + FB group had greater lnMVPA than the SM group, but lnMVPA and steps were similar between walkability groups. There were no significant interactions for group and time or group, time, and walkability. These findings suggest that adding FB to SM had a small but significant positive impact on PA over 12 months, but neighborhood walkability did not moderate the treatment effect of FB on PA.
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