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Tissue formation and healing both require cell proliferation and migration, but also extracellular matrix production and tensioning. In addition to restricting proliferation of damaged cells, increasing evidence suggests that cellular senescence also has distinct modulatory effects during wound healing and fibrosis. Yet, a direct role of senescent cells during tissue formation beyond paracrine signaling remains unknown. We here report how individual modules of the senescence program differentially influence cell mechanics and ECM expression with relevance for tissue formation. We compared DNA damage‐mediated and DNA damage‐independent senescence which was achieved through over‐expression of either p16Ink4a or p21Cip1 cyclin‐dependent kinase inhibitors in primary human skin fibroblasts. Cellular senescence modulated focal adhesion size and composition. All senescent cells exhibited increased single cell forces which led to an increase in tissue stiffness and contraction in an in vitro 3D tissue formation model selectively for p16 and p21‐overexpressing cells. The mechanical component was complemented by an altered expression profile of ECM‐related genes including collagens, lysyl oxidases, and MMPs. We found that particularly the lack of collagen and lysyl oxidase expression in the case of DNA damage‐mediated senescence foiled their intrinsic mechanical potential. These observations highlight the active mechanical role of cellular senescence during tissue formation as well as the need to synthesize a functional ECM network capable of transferring and storing cellular forces. Cellular senescence modulates single cell mechanics and ECM formation with consequences for macroscopic tissue tensioning. Components of the SASP and a reduced collagen expression as a result of DNA damage‐mediated senescence competes with the increased mechanical potential of these cells.

Comprehensive enhancer discovery is challenging because most enhancers, especially those contributing to complex diseases, have weak effects on gene expression. Our gene regulatory network modeling identified that nonlinear enhancer gene regulation during cell state transitions can be leveraged to improve the sensitivity of enhancer discovery. Using human embryonic stem cell definitive endoderm differentiation as a dynamic transition system, we conducted a mid-transition CRISPRi-based enhancer screen. We discovered a comprehensive set of enhancers for each of the core endoderm-specifying transcription factors. Many enhancers had strong effects mid-transition but weak effects post-transition, consistent with the nonlinear temporal responses to enhancer perturbation predicted by the modeling. Integrating three-dimensional genomic information, we were able to develop a CTCF-loop-constrained Interaction Activity model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer–promoter contact frequency. Our study provides generalizable strategies for sensitive and systematic enhancer discovery in both normal and pathological cell state transitions. CRISPRi-based screen identifies enhancers that nonlinearly regulate lineage-specifying transcription factors during definitive endoderm differentiation. A new CTCF-loop-constrained Interaction Activity (CIA) model is better at predicting functional enhancers than previous Hi-C-based enhancer–promoter contact frequency models.

Objective We examined how working mothers, who often juggle paid work and family meal preparation, manage work–family boundaries to optimize their family meal practice. Background Despite the well‐established benefits of family meals, reconciliation of work demands with family meal preparation represents a challenge for many working mothers. A better understanding of malleable antecedents of family meals can be instrumental in enabling more families to have meals together. Method Full‐time working mothers of young children (aged below 12) in Singapore were individually interviewed (N = 34). In addition to the information about their typical family meal arrangements, we explored work and family factors that shape family meals and the strategies working mothers use to manage work–family boundaries. Data were analyzed using thematic analysis. Results Working mothers adopt various work–family boundary management strategies (temporal, behavioral, and communication) to achieve desired family meal frequency and quality of mealtime interactions. Mothers' broad views on work–family management and thoughts about family meals undergird their choice of specific strategies. Conclusion This research revealed working mothers' active management of work–family boundaries as a novel answer to the critical question of how working mothers of young children make family meals happen. Implications Our research has practical implications for working mothers' ability to facilitate family meals.

Cancers dependent on hedgehog pathway signaling are susceptible to the BET bromodomain inhibitor JQ1. Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.

Maintaining engagement and support for patients with chronic diseases is challenging. SMS text messaging programs have complemented patient care in a variety of situations. However, such programs have not been widely translated into routine care. We aimed to examine the implementation and utility of a customized SMS text message-based support program for patients with type 2 diabetes (T2D), coronary heart disease, or both within a chronic disease integrated care program. We conducted a 6-month pragmatic parallel-group, single-blind randomized controlled trial that recruited people with T2D or coronary heart disease. Intervention participants received 4 semipersonalized SMS text messages per week providing self-management support to supplement standard care. Preprogrammed algorithms customized content based on participant characteristics, and the messages were sent at random times of the day and in random order by a fully automated SMS text messaging engine. Control participants received standard care and only administrative SMS text messages. The primary outcome was systolic blood pressure. Evaluations were conducted face to face whenever possible by researchers blinded to randomization. Participants with T2D were evaluated for glycated hemoglobin level. Participant-reported experience measures were evaluated using questionnaires and focus groups and summarized using proportions and thematic analysis. A total of 902 participants were randomized (n=448, 49.7% to the intervention group and n=454, 50.3% to the control group). Primary outcome data were available for 89.5% (807/902) of the participants. At 6 months, there was no difference in systolic blood pressure between the intervention and control arms (adjusted mean difference=0.9 mm Hg, 95% CI -1.1 to 2.1; P=.38). Of 642 participants with T2D, there was no difference in glycated hemoglobin (adjusted mean difference=0.1%, 95% CI -0.1% to 0.3%; P=.35). Self-reported medication adherence was better in the intervention group (relative risk=0.82, 95% CI 0.68-1.00; P=.045). Participants reported that the SMS text messages were useful (298/344, 86.6%) and easily understood (336/344, 97.7%) and motivated change (217/344, 63.1%). The lack of bidirectional messaging was identified as a barrier. The intervention did not improve blood pressure in this cohort, possibly because of high clinician commitment to improved routine patient care as part of the chronic disease management program as well as favorable baseline metrics. There was high program engagement, acceptability, and perceived value. Feasibility as part of an integrated care program was demonstrated. SMS text messaging programs may supplement chronic disease management and support self-care. Australian New Zealand Clinical Trials Registry ACTRN12616001689460; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371769&isReview=true. RR2-10.1136/bmjopen-2018-025923.

Pluripotent stem cells have remarkable self-renewal capacity: the ability to proliferate indefinitely while maintaining the pluripotent identity essential for their ability to differentiate into almost any cell type in the body. To investigate the interplay between these two aspects of self-renewal, we perform four parallel genome-scale CRISPR-Cas9 loss-of-function screens interrogating stem cell fitness in hPSCs and the dissolution of primed pluripotent identity during early differentiation. These screens distinguish genes with distinct roles in pluripotency regulation, including mitochondrial and metabolism regulators crucial for stem cell fitness, and chromatin regulators that control pluripotent identity during early differentiation. We further identify a core set of genes controlling both stem cell fitness and pluripotent identity, including a network of chromatin factors. Here, unbiased screening and comparative analyses disentangle two interconnected aspects of pluripotency, provide a valuable resource for exploring pluripotent stem cell identity versus cell fitness, and offer a framework for categorizing gene function. Pluripotent cells are defined by their ability to self-renew: to proliferate indefinitely while maintaining their identity. Here, authors use genome-scale CRISPR knockout screens to untangle these two aspects of self-renewal.

The aim of this study was to investigate the effects of the use of an occlusal splint on postural balance considering the occlusal splint as a device for treating temporomandibular joint disorder. A randomized, controlled, prospective clinical trial was conducted. The research group consisted of 49 patients (36 as test group and 13 as control group) between 18 and 75 years old, both genders, diagnosed as temporomandibular disorder by Research Diagnostic Criteria/Temporomandibular Disorders questionnaire and magnetic resonance imaging of the temporomandibular joints. Test group was treated with orientations for physiotherapeutic exercises and occlusal splint, whereas control group received orientation for physiotherapeutic exercises only. Postural equilibrium was evaluated by means of a force plate. After 12 weeks, the groups were re‐evaluated. Patients from both groups presented a significant increase in antero‐posterior speed with eyes closed, test group (P < 0.001) and control group (P = 0.046). Only patients of the test group presented a significant increase in antero‐posterior speed with eyes opened (P = 0.023). We concluded that the use of occlusal splint affected the postural balance.

The malaria genome encodes over 5,000 proteins and many of these have also been proposed to be potential vaccine candidates, although few of these have been tested clinically. RH5 is one of the leading blood-stage malaria vaccine antigens and Phase I/II clinical trials of vaccines containing this antigen are currently underway. Its likely mechanism of action is to elicit antibodies that can neutralize merozoites by blocking their invasion of red blood cells (RBC). However, many other antigens could also elicit neutralizing antibodies against the merozoite, and most of these have never been compared directly to RH5. The objective of this study was to compare a range of blood-stage antigens to RH5, to identify any antigens that outperform or synergize with anti-RH5 antibodies. We selected 55 gene products, covering 15 candidate antigens that have been described in the literature and 40 genes selected on the basis of bioinformatics functional prediction. We were able to make 20 protein-in-adjuvant vaccines from the original selection. Of these, S-antigen and CyRPA robustly elicited antibodies with neutralizing properties. Anti-CyRPA IgG generally showed additive GIA with anti-RH5 IgG, although high levels of anti-CyRPA-specific rabbit polyclonal IgG were required to achieve 50% GIA. Our data suggest that further vaccine antigen screening efforts are required to identify a second merozoite target with similar antibody-susceptibility to RH5.

Abstract Introduction: Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide. While there has been rapid evolution in the treatment paradigm of HCC across the past decade, the extent to which these newly approved therapies are utilized in clinical practice in the real world is, however, unknown. The INSIGHT study was an investigator-initiated, multi-site longitudinal cohort study conducted to reflect real-world epidemiology and clinical practice in Asia-Pacific in the immediate 7-year period after the conclusion of the BRIDGE study. Methods: Data were collected both retrospectively (planned 30% of the total cohort size) and prospectively (planned 70%) from January 2013 to December 2019 from eligible patients newly diagnosed with HCC from 33 participating sites across 9 Asia-Pacific countries. Results: A total of 2,533 newly diagnosed HCC patients (1,052 in retrospective cohort and 1,481 in prospective cohort) were enrolled. The most common risk factor was hepatitis B in all countries except Japan, Australia, and New Zealand, where the prevalence of hepatitis C and diabetes were more common. The top three comorbidities reported in the INSIGHT study include cirrhosis, hypertension, and diabetes. We observe high heterogeneity in the first-line treatment recorded across countries and across disease stages, which significantly affects survival outcomes. Stratification by factors such as etiologies, tumor characteristics, the presence of extrahepatic metastases or macrovascular invasion, and the use of subsequent lines of treatment were performed. Conclusion: The INSIGHT study describes a wide spectrum of clinical management practices in HCC, where patient demographics, differential costs, and patient access to therapies may lead to wide geographical variations through the patient’s treatment cycle, from diagnosis to clinical outcome. The high heterogeneity in patient outcomes demonstrates the need for more robust and clinical management strategies to be designed and adopted to bring about better patient outcomes.

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells. Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.