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Extracellular vesicles (EVs) mediate intercellular communication in many physiologic processes and can modulate immune responses in individuals with cancer. Most studies of EVs in cancer have focused on their tumour promoting properties. Whether and how EVs might mediate tumour regression besides carrying antigens has not been well characterized. Using a mouse model of highly immunogenic regressor versus poorly immunogenic progressor tumour cells, we have characterized the role of EVs in activating macrophages and promoting tumour rejection. We found that the signalling molecule MAP2K1 (MEK1) is enriched in EVs secreted by regressor relative to progressor cells. Progressor EVs engineered to have levels of MEK1 similar to regressor EVs could inhibit tumour growth by indirectly promoting adaptive immunity in both syngeneic and 3rd party tumours. This effect required MEK1 activity and could occur by activating macrophages to promote adaptive immune responses against the tumour via the cytokine interferon-gamma. Our results suggest that MEK inhibition may be deleterious to cancer treatment, since MEK1 plays an important cell-extrinsic, tumour-suppressive role within EVs. Moreover, the delivery of MEK1 to tumour-associated macrophages, either by EVs, nanoparticles, or some other means, could be a useful strategy to treat cancer via the activation of anti-tumour immunity.

Experiential learning in the field is central to the training of many helping professionals, and field education is the signature pedagogy for social work. Service-learning offers another opportunity for graduate students in the helping professions to get hands on training. Volunteering would also offer a hands-on learning experience but appears to be less common. This study interviewed 14 master of social work (MSW) students who volunteered at a healing camp for bereaved children and adolescents to explore their lived experiences. The study revealed both professional and personal themes, and these were compared to themes divulged by similar students participating in service-learning courses. Based on this study, the researchers concluded that volunteerism can be a valuable means for graduate students in the helping fields to experience personal and professional growth.

Background Overcoming immune suppression is a major barrier to eliciting potent CD8+ T cell responses against cancer. Treatment with anti-CD4 monoclonal antibody is an effective means for eliminating CD4+Foxp3+ regulatory (Treg) cells in preclinical models and has also demonstrated efficacy in early clinical trials. However, the underlying basis for treatment efficacy, more specifically the implications of codepleting other CD4-expressing cell compartments in tumor-bearing hosts, is not well understood.Methods Tumor-bearing mice were treated with anti-CD4 versus other therapies that preserve helper T cell function, and the priming, tissue distribution, and maintenance of tumor antigen-specific CD8 T cells were assessed. Antibody blockade and transgenic mouse models were used to determine the mechanisms of CD8 T cell priming. Single-cell RNA-sequencing (scRNAseq) was used to further characterize CD8 T cells that are primed by anti-CD4 therapy and to identify immunosuppressive CD4 T cell subsets in human melanoma following immune checkpoint blockade (ICB).Results Comparing anti-CD4 to dual ICB therapy, we show that anti-CD4 facilitates more robust priming of TCF-1+, IL-2-producing, tumor-specific CD8+ T cells that disseminate to tissues and form memory. By decoupling priming from homeostatic proliferation and associated cytokines, we find that anti-CD4 functions independently of creating homeostatic space for CD8+ T cells. We also show that depletion of CD4-expressing antigen-presenting cell subsets is not required for anti-CD4 efficacy. Instead, robust tumor-specific CD8+ T cell priming and memory generation required the removal of total antigen-specific CD4+ T cells, including both Tregs and CD4+ Foxp3-negative conventional (Tconv) cells. In particular, the elimination of CD4+ Tconv cells was necessary for the accumulation and maturation of conventional type-1 dendritic cells in tumor-draining LNs, which were required for CD8+ T cell priming. Accordingly, anti-CD4 treatment restored CD8+ T cell responses in mice cotreated with dual ICB. scRNAseq of melanoma tumors from patients who received ICB revealed the presence of Tr1 and Treg subsets, as well as CD4+ Tconv subsets that lacked clear transcriptional evidence of helper differentiation.Conclusions These findings underscore the underappreciated benefit of depleting CD4+ Tconv cells to promote systemic primary and memory CD8+ T cell responses against cancer.

Abstract Extracellular vesicles (EVs) mediate intercellular communication in many physiologic processes and can modulate immune responses in individuals with cancer. Most studies of EVs in cancer have focused on their tumour promoting properties. Whether and how EVs might mediate tumour regression besides carrying antigens has not been well characterized. Using a mouse model of highly immunogenic regressor versus poorly immunogenic progressor tumour cells, we have characterized the role of EVs in activating macrophages and promoting tumour rejection. We found that the signalling molecule MAP2K1 (MEK1) is enriched in EVs secreted by regressor relative to progressor cells. Progressor EVs engineered to have levels of MEK1 similar to regressor EVs could inhibit tumour growth by indirectly promoting adaptive immunity in both syngeneic and 3rd party tumours. This effect required MEK1 activity and could occur by activating macrophages to promote adaptive immune responses against the tumour via the cytokine interferon‐gamma. Our results suggest that MEK inhibition may be deleterious to cancer treatment, since MEK1 plays an important cell‐extrinsic, tumour‐suppressive role within EVs. Moreover, the delivery of MEK1 to tumour‐associated macrophages, either by EVs, nanoparticles, or some other means, could be a useful strategy to treat cancer via the activation of anti‐tumour immunity.

Calculation of ionic conductivity including ion-ion correlation effects using equilibrium molecular dynamics (EMD) is computationally demanding, but the correlation is significant in many promising electrolytes such as solid electrolytes. Herein, we have developed a “constant-current” nonequilibrium MD (NEMD) simulation method, in contrast to the conventional constant-field approach, for ion-ion correlated conductivities from a constrained ionic current with fluctuating external field. The improved efficiency of the constant-current NEMD approach is demonstrated by applying it to a representative solid electrolyte, cubic Li_{7}La_{3}Zr_{2}O_{12}. The convergence of the correlated conductivity is faster than that of EMD by 2 orders of magnitude. The low-temperature NEMD simulations also reveal that the ionic conductivity of Li_{7}La_{3}Zr_{2}O_{12} exhibits non-Arrhenius behavior of the activation energy that changes at around 600 K. This work presents not only the high sampling efficiency of constant-current NEMD to calculate the correlated ionic conductivity, but also the importance of direct computations of ionic conductivity at low temperature without Arrhenius extrapolation.

The second harmonic (SH) of an axicon generated Bessel-Gauss beam is created through the nonlinear interaction of photons with a crystal, resulting in the energy doubling of the output photons. In this work, we show experimentally that in addition to frequency doubling, the SH of Bessel-Gauss beams under asymmetric aberrations from an elliptic axicon exhibit intriguing beam formation. Particularly, the central region of the SH beam profile is composed of two central spots of various geometries surrounded by nested ellipses; one of which is the configuration of two central gamma dots with similar radius knotted by nested ellipses for a zeroth-order Bessel-Gauss pump. These SH beams consistently maintain their spatial profile throughout propagation, reminiscing the behavior of screw dislocations in wave patterns. Our numerical simulations produce beam dynamics consistent with that of experiments and further implicate the remarkable interweaving of bright spots with dark vortices. This is especially noticeable when the beams dynamically oscillate along the optical axis, resulting in the genesis of spatially polarized beams with a knotted framework. The insights gained from our study establish a novel paradigm for exploring interactions of Bessel-like beams with vortex dynamics. This, in turn, has the potential to spark innovations in optical applications, fostering new methodologies to harness and manipulate complex light structures. Our experimental findings could spur new methods of generating logical states of light and new opportunities for material processing control.

Environmental conditions during olive fruit development and genotype have shown to be important sources of variability in final fruit weight and oil concentration. There are fewer studies concerning how the environment and genotype modulate growth dynamics. Thus, the present study aimed to evaluate the timing of fruit growth, pit hardening, and oil accumulation in several olive cultivars under different air temperatures along a latitudinal gradient (29°–33° S) with a range of altitudes (450–1250 masl) in Western Argentina; determine parameters derived from the dynamics of fruit growth and oil accumulation along the same gradient; and explore possible relationships between derived parameters and air temperatures. The cultivars evaluated were Arbequina, Arbosana, Coratina, Changlot, and Picual. Pit hardening occurred 20 days earlier in warmer locations, leading to an earlier onset of oil synthesis. The final fruit dry weight was mainly influenced by the cultivar, which was explained by differences in fruit growth rates. Cooler locations had 39% higher average final fruit dry weight and 22% higher oil concentration than warmer ones. Differences in final oil concentration between genotypes × environments were primarily associated with the oil accumulation rate rather than the duration of the oil accumulation period. However, changes in this rate seem to be cultivar-dependent. Interestingly, the rate and oil accumulation duration showed a negative relationship. These results highlight the need to explore genetic variability in temperature response to limit the detrimental impacts of global warming on olive fruit growth and oil concentration.

PurposeNeighborhood environment is increasingly recognized as an important determinant of cardiovascular health (CVH) among Black adults. Most research to date has focused on negative aspects of the neighborhood environment, with little attention being paid to the specific positive features, in particular the social environment, that promote cardiovascular resilience among Black adults.We examined whether better neighborhood physical and social characteristics are associated with ideal CVH among Black adults, as measured by Life's Simple 7 (LS7) scores.MethodsWe recruited 392 Black adults (age 53 ± 10 years, 39% men) without known CV disease living in Atlanta, GA. Seven neighborhood domains were assessed via questionnaire: asthetic quality, walking environment, safety, food access, social cohesion, activity with neighbors, and violence. CVH was determined by LS7 scores calculated from measured blood pressure; glucose; cholesterol; body mass index (BMI); and self-reported exercise, diet, and smoking, and categorized into poor (0-8), intermediate (9-10), and ideal (11-14). Multinomial logistic regression was used to examine the association between neighborhood characteristics and the odds of intermediate/ideal CVH categories compared with poor CVH after adjustment for age, gender, household income, education, marital status, and employment status.ResultsBetter scores in the neighborhood domains of social cohesion and activity with neighbors were significantly associated with higher adjusted odds of ideal LS7 scores (OR 2.02, 95% CI [1.36-3.01] and 1.71 [1.20-2.45] per 1 standard deviation [SD] increase in respective scores). These associations were stronger for both social cohesion (OR 2.61, 95% CI [1.48-4.61] vs. 1.40 [0.82-2.40]) and activity with neighbors (OR 1.82, 95% CI [1.15-2.86] vs. 1.53 [0.84-2.78]) in Black women than men. Specifically, better scores in social cohesion were associated with higher odds of ideal CVH in exercise (OR 1.73 [1.16-2.59]), diet (OR 1.90 [1.11-3.26]), and BMI (OR 1.52 [1.09-2.09]); better scores in activity with neighbors were also similarly associated with higher odds of ideal CVH in exercise (OR 1.48 [1.00-2.19]), diet (OR 2.15 [1.23-3.77]), and BMI (OR 1.45 [1.07-1.98]; per 1 SD in respective scores).ConclusionsMore desirable neighborhood characteristics, particularly social cohesion and activity with neighbors, were associated with better CVH among Black adults.

Abstract Research Impact Assessment (RIA) represents one of a suite of policies intended to improve the impact generated from investment in health and medical research (HMR). Positivist indicator-based approaches to RIA are widely implemented but increasingly criticised as theoretically problematic, unfair, and burdensome. This commentary proposes there are useful outcomes that emerge from the process of applying an indicator-based RIA framework, separate from those encapsulated in the metrics themselves. The aim for this commentary is to demonstrate how the act of conducting an indicator-based approach to RIA can serve to optimise the productive gains from the investment in HMR. Prior research found that the issues regarding RIA are less about the choice of indicators/metrics, and more about the discussions prompted and activities incentivised by the process. This insight provides an opportunity to utilise indicator-based methods to purposely optimise the research impact. An indicator-based RIA framework specifically designed to optimise research impacts should: focus on researchers and the research process, rather than institution-level measures; utilise a project level unit of analysis that provides control to researchers and supports collaboration and accountability; provide for prospective implementation of RIA and the prospective orientation of research; establish a line of sight to the ultimate anticipated beneficiaries and impacts; Include process metrics/indicators to acknowledge interim steps on the pathway to final impacts; integrate ‘next’ users and prioritise the utilisation of research outputs as a critical measure; Integrate and align the incentives for researchers/research projects arising from RIA, with those existing within the prevailing research system; integrate with existing peer-review processes; and, adopt a system-wide approach where incremental improvements in the probability of translation from individual research projects, yields higher impact across the whole funding portfolio. Optimisation of the impacts from HMR investment represents the primary purpose of Research Impact policy. The process of conducting an indicator-based approach to RIA, which engages the researcher during the inception and planning phase, can directly contribute to this goal through improvements in the probability that an individual project will generate interim impacts. The research project funding process represents a promising forum to integrate this approach within the existing research system.

Male rhesus monkeys (n = 24) had a biopsy of prefrontal cortical area 46 prior to chronic ethanol self-administration (n = 17) or caloric control (n = 7). Fourteen months of daily self-administration (water vs. 4% alcohol, 22 h access/day termed “open-access”) was followed by two cycles of prolonged abstinence (5 weeks) each followed by 3 months of open-access alcohol and a final abstinence followed by necropsy. At necropsy, a biopsy of Area 46, contralateral to the original biopsy, was obtained. Gene expression data (RNA-Seq) were collected comparing biopsy/necropsy samples. Monkeys were categorized by drinking status during the final post-abstinent drinking phase as light (LD), binge (BD), heavy (HD) and very heavy (VHD drinkers). Comparing pre-ethanol to post-abstinent biopsies, four animals that converted from HD to VHD status had significant ontology enrichments in downregulated genes (necropsy minus biopsy n = 286) that included immune response (FDR < 9 × 10−7) and plasma membrane changes (FDR < 1 × 10−7). Genes in the immune response category included IL16 and 18, CCR1, B2M, TLR3, 6 and 7, SP2 and CX3CR1. Upregulated genes (N = 388) were particularly enriched in genes associated with the negative regulation of MAP kinase activity (FDR < 3 × 10−5), including DUSP 1, 4, 5, 6 and 18, SPRY 2, 3, and 4, SPRED2, BMP4 and RGS2. Overall, these data illustrate the power of the NHP model and the within-subject design of genomic changes due to alcohol and suggest new targets for treating severe escalated drinking following repeated alcohol abstinence attempts.

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here, we tested the hypothesis that the unfolded protein response (UPR) mechanistically links aneuploidy and local immune dysregulation. Using a single somatic copy number alteration (SCNA) score inclusive of whole-chromosome, chromosome arm, and focal alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups. Pathway activity scores showed increased activity of multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and arginase 1 transcription in receiver bone marrow-derived macrophages and markedly diminished the production of IFN-γ and granzyme B in activated human T cells. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment.

BackgroundEarly trauma (general, emotional, physical, and sexual abuse before age 18 years) has been associated with both cardiovascular disease risk and lifestyle-related risk factors for cardiovascular disease, including smoking, obesity, and physical inactivity. Despite higher prevalence, the association between early trauma and cardiovascular health (CVH) has been understudied in Black Americans, especially those from low-income backgrounds, who may be doubly vulnerable. Therefore, we investigated the association between early trauma and CVH, particularly among low-income Black Americans.MethodsWe recruited 457 Black adults (age 53±10, 38% male) without known cardiovascular disease from the Atlanta, GA, metropolitan area using personalized, community-based recruitment methods. The Early Trauma Inventory was administered to assess overall early traumatic life experiences which include physical, sexual, emotional abuse, and general trauma. Our primary outcome was the American Heart Association Life's Simple 7, which is a set of 7 CVH metrics, including 4 lifestyle-related factors (smoking, body mass index, physical activity, and diet) and three physiologically measured health factors (blood pressure, total blood cholesterol, and blood glucose). We used linear regression models adjusting for age, sex, socioeconomic status, and depression to test the association between early trauma and CVH and tested the early trauma by household income (

ObjectiveTo characterize the association between residential environmental manganese (Mn) exposure and depression and anxiety, given prior associations among occupationally-exposed workers.MethodsWe administered the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) to 697 study participants in their preferred languages. These participants represented a population-based sample of residents aged ≥40 from two predominantly Black African communities in Gauteng province, South Africa: 605 in Meyerton, adjacent to a large Mn smelter, and 92 in Ethembalethu, a comparable non-exposed community. We investigated the associations between community (Meyerton vs. Ethembalethu) and severity of depression and anxiety, using linear regression, adjusting for age and sex. To document community-level differences in Mn exposure, we measured airborne PM2.5-Mn.ResultsMeyerton residents had BDI scores 5.63 points (95 % CI 3.07, 8.20) higher than Ethembalethu residents, with all questions contributing to this significant difference. STAI-state scores were marginally higher in Meyerton than Ethembalethu residents [2.12 (95 % CI -0.17, 4.41)], whereas STAI-trait scores were more similar between the communities [1.26 (95 % CI -0.82, 3.35)]. Mean PM2.5-Mn concentration was 203 ng/m3 at a long-term fixed site in Meyerton and 10 ng/m3 in Ethembalethu.ConclusionResidence near Mn emission sources may be associated with greater depression symptomatology, and possibly current, but not lifetime, anxiety.

Contribution: A roadmap is provided for building a quantum engineering education program to satisfy U.S. national and international workforce needs. Background: The rapidly growing quantum information science and engineering (QISE) industry will require both quantum-aware and quantum-proficient engineers at the bachelor's level. Research Question: What is the best way to provide a flexible framework that can be tailored for the full academic ecosystem? Methodology: A workshop of 480 QISE researchers from across academia, government, industry, and national laboratories was convened to draw on best practices; representative authors developed this roadmap. Findings: 1) For quantum-aware engineers, design of a first quantum engineering course, accessible to all STEM students, is described; 2) for the education and training of quantum-proficient engineers, both a quantum engineering minor accessible to all STEM majors, and a quantum track directly integrated into individual engineering majors are detailed, requiring only three to four newly developed courses complementing existing STEM classes; 3) a conceptual QISE course for implementation at any postsecondary institution, including community colleges and military schools, is delineated; 4) QISE presents extraordinary opportunities to work toward rectifying issues of inclusivity and equity that continue to be pervasive within engineering. A plan to do so is presented, as well as how quantum engineering education offers an excellent set of education research opportunities; and 5) a hands-on training plan on quantum hardware is outlined, a key component of any quantum engineering program, with a variety of technologies, including optics, atoms and ions, cryogenic and solid-state technologies, nanofabrication, and control and readout electronics.

A large district has some unique challenges when planning support for a reflective growth process around implementing the "National School Library Standards for Learners, School Librarians, and School Libraries." This type of setting typically has a wide variety of school demographics, budgetary constraints, school library staffing configurations, administrators' visions, faculty dynamics, and school librarians' learning curves to take into consideration when planning a large-scale rollout of the American Association of School Librarians (AASL) Standards. However, this type of setting also brings some unique opportunities. It has the advantages of an existing tight support network for school librarians, economy of scale for providing resources and professional development (PD), and central office staff with dedicated time and attention specifically for supporting school librarians in implementing the standards as part of a vision for world-class school libraries. This article will describe how the author's district, the Knox County Schools in Tennessee, has worked to leverage its strengths and support the AASL Standards in ways that may be adapted for school libraries in all kinds of districts across the country.

Plant density is increasing in modern olive orchards to improve yields and facilitate mechanical harvesting. However, greater density can reduce light quantity and modify its quality. The objective was to evaluate plant morphology, biomass, and photosynthetic pigments under different red/far-red ratios and photosynthetically active radiation (PAR) combinations in an olive cultivar common to super-high-density orchards. In a greenhouse, young olive trees (cv. Arbequina) were exposed to low (L) or high (H) PAR with or without lateral FR supplementation (L+FR, L-FR, H+FR, H-FR) using neutral-density shade cloth and FR light-emitting diode (LED) modules. Total plant and individual organ biomass were much lower in plants under low PAR than under high PAR, with no response to +FR supplementation. In contrast, several plant morphological traits, such as main stem elongation, individual leaf area, and leaf angle, did respond to both low PAR and +FR. Total chlorophyll content decreased with +FR when PAR was low, but not when PAR was high (i.e., a significant FR*PAR interaction). When evaluating numerous plant traits together, a greater response to +FR under low PAR than under high PAR appeared to occur. These findings suggest that consideration of light quality in addition to quantity facilitates a fuller understanding of olive tree responses to a light environment. The +FR responses found here could lead to changes in hedgerow architecture and light distribution within the hedgerow.

Midday stem water potential (SWP) is rapidly becoming adopted as a standard tool for plant-based irrigation management in many woody perennial crops. A reference or "baseline" SWP has been used in some crops (almond, prune, grape, and walnut) to account for the climatic influence of air vapor pressure deficit (VPD) on SWP under non-limiting soil moisture conditions. The baseline can be determined empirically for field trees maintained under such non-limiting conditions, but such conditions are difficult to achieve for an entire season. We present the results of an alternative survey-based approach, using a large set of SWP and VPD data collected over multiple years, from irrigation experiments in olive orchards located in multiple countries [Spain, United States (California), Italy, and Argentina]. The relation of SWP to midday VPD across the entire data set was consistent with an upper limit SWP which declined with VPD, with the upper limit being similar to that found in Prunus. A best fit linear regression estimate for this upper limit (baseline) was found by selecting the maximum R 2 and minimum probability for various upper fractions of the SWP/VPD relation. In addition to being surprisingly similar to the Prunus baseline, the olive baseline was also similar (within 0.1 MPa) to a recently published mechanistic olive soil-plant-atmosphere-continuum (SPAC) model for "super high density" orchard systems. Despite similarities in the baseline, the overall physiological range of SWP exhibited by olive extends to about -8 MPa, compared to about -4 MPa for economically producing almond. This may indicate that, despite species differences in physiological responses to low water availability (drought), there may be convergent adaptations/acclimations across species to high levels of water availability. Similar to its use in other crops, the olive baseline will enable more accurate and reproducible plant-based irrigation management for both full and deficit irrigation practices, and we present tentative SWP guidelines for this purpose.

"Big data" approaches in the form of large-scale human genomic studies have led to striking advances in autism spectrum disorder (ASD) genetics. Similar to many other psychiatric syndromes, advances in genotyping technology, allowing for inexpensive genome-wide assays, has confirmed the contribution of polygenic inheritance involving common alleles of small effect, a handful of which have now been definitively identified. However, the past decade of gene discovery in ASD has been most notable for the application, in large family-based cohorts, of high-density microarray studies of submicroscopic chromosomal structure as well as high-throughput DNA sequencing-leading to the identification of an increasingly long list of risk regions and genes disrupted by rare, de novo germline mutations of large effect. This genomic architecture offers particular advantages for the illumination of biological mechanisms but also presents distinctive challenges. While the tremendous locus heterogeneity and functional pleiotropy associated with the more than 100 identified ASD-risk genes and regions is daunting, a growing armamentarium of comprehensive, large, foundational -omics databases, across species and capturing developmental trajectories, are increasingly contributing to a deeper understanding of ASD pathology.

BackgroundDespite well-documented cardiovascular disparities between racial groups, within-race determinants of cardiovascular health among Black adults remain understudied. Factors promoting cardiovascular resilience among Black adults in particular warrant further investigation. Our objective was to examine whether individual psychosocial resilience and neighborhood-level cardiovascular resilience were associated with better cardiovascular health in Black adults, measured utilizing Life's Simple 7 (LS7) scores.MethodsWe assessed LS7 scores in 389 Black adults (mean age, 53±10 years; 39% men) living in Atlanta, Georgia. A composite score of individual psychosocial resilience was created by assessing environmental mastery, purpose in life, optimism, resilient coping, and depressive symptoms. Neighborhood-level cardiovascular resilience was separately determined by the census tract-level rates of cardiovascular mortality/morbidity events. Generalized linear mixed regression models were used to examine the association between individual psychosocial resilience, neighborhood cardiovascular resilience, and LS7 scores.ResultsHigher individual psychosocial resilience was significantly associated with higher LS7 (β=0.38 [0.16-0.59] per 1 SD) after adjustment for sociodemographic factors. Similarly, higher neighborhood-level cardiovascular resilience was significantly associated with higher LS7 (β=0.23 [0.02-0.45] per 1 SD). When jointly examined, high individual psychosocial resilience (>median) was independently associated with higher LS7 (β=0.73 [0.31-1.17]), whereas living in high-resilience neighborhoods (>median) was not. The largest difference in LS7 score was between those with high and low psychosocial resilience living in low-resilience neighborhoods (8.38 [7.90-8.86] versus 7.42 [7.04-7.79]).ConclusionsIndividual psychosocial resilience in Black adults is associated with better cardiovascular health.

To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into "responder" and "non-responder". By RNASeq analysis we found that the non-responder phenotype is significantly linked with the expression of UPR genes, and in particular ERN1 (IRE1) and ATF4. We also identified two additional genes selectively overexpressed among non-responders, IGFBP3 and IGFBP5. CRISPR-mediated deletion of the ERN1, IGFBP3, IGFBP5 signature genes in the U251 human GBM cell line increased responsiveness to 12ADT. Remarkably, >65% of GBM cases in The Cancer Genome Atlas express the non-responder (ERN1, IGFBP3, IGFBP5) gene signature. Thus, elevated levels of IRE1α and IGFBPs predict a poor response to drugs inducing unresolvable UPR and possibly other forms of chemotherapy helping in a better stratification GBM patients.

Background Cardiovascular disease incidence, prevalence, morbidity, and mortality have declined in the past several decades; however, disparities persist among subsets of the population. Notably, blacks have not experienced the same improvements on the whole as whites. Furthermore, frequent reports of relatively poorer health statistics among the black population have led to a broad assumption that black race reliably predicts relatively poorer health outcomes. However, substantial intraethnic and intraracial heterogeneity exists; moreover, individuals with similar risk factors and environmental exposures are often known to experience vastly different cardiovascular health outcomes. Thus, some individuals have good outcomes even in the presence of cardiovascular risk factors, a concept known as resilience. Methods and Results The MECA (Morehouse-Emory Center for Health Equity) Study was designed to investigate the multilevel exposures that contribute to "resilience" in the face of risk for poor cardiovascular health among blacks in the greater Atlanta, GA, metropolitan area. We used census tract data to determine "at-risk" and "resilient" neighborhoods with high or low prevalence of cardiovascular morbidity and mortality, based on cardiovascular death, hospitalization, and emergency department visits for blacks. More than 1400 individuals from these census tracts assented to demographic, health, and psychosocial questionnaires administered through telephone surveys. Afterwards, ≈500 individuals were recruited to enroll in a clinical study, where risk biomarkers, such as oxidative stress, and inflammatory markers, endothelial progenitor cells, metabolomic and microRNA profiles, and subclinical vascular dysfunction were measured. In addition, comprehensive behavioral questionnaires were collected and ideal cardiovascular health metrics were assessed using the American Heart Association's Life Simple 7 measure. Last, 150 individuals with low Life Simple 7 were recruited and randomized to a behavioral mobile health (eHealth) plus health coach or eHealth only intervention and followed up for improvement. Conclusions The MECA Study is investigating socioenvironmental and individual behavioral measures that promote resilience to cardiovascular disease in blacks by assessing biological, functional, and molecular mechanisms. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT03308812.

IntroductionMedulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark.MethodsGenotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2.ResultsFifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p

This pilot study sought to evaluate the circulating levels of immune cells, particularly regulatory T-cell (Treg) subsets, before and after lung resection for non-small cell lung cancer. Twenty-five patients consented and had specimens collected. Initially, peripheral blood of 21 patients was collected for circulating immune cell studies. Two of these patients were excluded due to technical issues, leaving 19 patients for the analyses of circulating immune cells. Standard gating and high-dimensional unsupervised clustering flow cytometry analyses were performed. The blood, tumors and lymph nodes were analyzed via single-cell RNA and TCR sequencing for Treg analyses in a total of five patients (including four additional patients from the initial 21 patients). Standard gating flow cytometry revealed a transient increase in neutrophils immediately following surgery, with a variable neutrophil–lymphocyte ratio and a stable CD4–CD8 ratio. Unexpectedly, the total Treg and Treg subsets did not change with surgery with standard gating in short- or long-term follow-up. Similarly, unsupervised clustering of Tregs revealed a dominant cluster that was stable perioperatively and long-term. Two small FoxP3hi clusters slightly increased following surgery. In the longer-term follow-up, these small FoxP3hi Treg clusters were not identified, indicating that they were likely a response to surgery. Single-cell sequencing demonstrated six CD4+FoxP3+ clusters among the blood, tumors and lymph nodes. These clusters had a variable expression of FoxP3, and several were mainly, or only, present in tumor and lymph node tissue. As such, serial monitoring of circulating Tregs may be informative, but not completely reflective of the Tregs present in the tumor microenvironment.