PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.

Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.

Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates.

Current antiretroviral therapy (ART) regimens efficiently limit HIV replication, thereby improving life expectancy of people living with HIV, but also cause metabolic side effects. The ongoing obesity epidemic has resulted in more people with metabolic comorbidities at the time of HIV infection, yet the impact of pre-existing metabolic dysregulation on infection sequelae and response to ART is unclear. Here, to investigate the impact of preexisting obesity and insulin resistance on acute infection and subsequent long-term ART, we infected a cohort of lean and obese adult male macaques with SIV and administered ART. The responses of lean and obese macaques to SIV and ART were similar with respect to plasma and cell-associated viral loads, ART drug levels in plasma and tissues, SIV-specific immune responses, adipose tissue and islet morphology, and colon inflammation, with baseline differences between lean and obese groups largely maintained. Both groups exhibited a striking depletion of CD4+ T cells from adipose tissue that did not recover with ART. However, differential responses to SIV and ART were observed for body weight, omental adipocyte size, and the adiponectin/leptin ratio, a marker of cardiometabolic risk. Thus, obesity and insulin resistance had limited effects on multiple responses to acute SIV infection and ART, while several factors that underlie long-term metabolic comorbidities were influenced by prior obesity and insulin resistance. These studies provide the foundation for future investigations into the efficacy of adjunct therapies such as metformin and glucagon-like peptide-1 receptor agonists in the prevention of metabolic comorbidities in people living with HIV.

Chromatin remodellers as therapeutic targets.

Large-scale cancer genome sequencing studies have revealed that chromatin regulators are frequently mutated in cancer. In particular, more than 20% of cancers harbour mutations in genes that encode subunits of SWI/SNF (BAF) chromatin remodelling complexes. Additional links of SWI/SNF complexes to disease have emerged with the findings that some oncogenes drive transformation by co-opting SWI/SNF function and that germline mutations in select SWI/SNF subunits are the basis of several neurodevelopmental disorders. Other chromatin remodellers, including members of the ISWI, CHD and INO80/SWR complexes, have also been linked to cancer and developmental disorders. Consequently, therapeutic manipulation of SWI/SNF and other remodelling complexes has become of great interest, and drugs that target SWI/SNF subunits have entered clinical trials. Genome-wide perturbation screens in cancer cell lines with SWI/SNF mutations have identified additional synthetic lethal targets and led to further compounds in clinical trials, including one that has progressed to FDA approval. Here, we review the progress in understanding the structure and function of SWI/SNF and other chromatin remodelling complexes, mechanisms by which SWI/SNF mutations cause cancer and neurological diseases, vulnerabilities that arise because of these mutations and efforts to target SWI/SNF complexes and synthetic lethal targets for therapeutic benefit.

Developmental origins shape the paediatric cancer genome.

In the past two decades, technological advances have brought unprecedented insights into the paediatric cancer genome revealing characteristics distinct from those of adult cancer. Originating from developing tissues, paediatric cancers generally have low mutation burden and are driven by variants that disrupt the transcriptional activity, chromatin state, non-coding cis-regulatory regions and other biological functions. Within each tumour, there are multiple populations of cells with varying states, and the lineages of some can be tracked to their fetal origins. Genome-wide genetic screening has identified vulnerabilities associated with both the cell of origin and transcription deregulation in paediatric cancer, which have become a valuable resource for designing new therapeutic approaches including those for small molecules, immunotherapy and targeted protein degradation. In this Review, we present recent findings on these facets of paediatric cancer from a pan-cancer perspective and provide an outlook on future investigations.

History and Current State of Neurosurgery in the Gambia.

BACKGROUND: Despite global efforts to improve surgical care access, many low- and middle-income countries, especially in neurosurgery, face significant shortages. The Gambia exemplifies this, with only 1 fully qualified neurosurgeon serving its population of 2.5 million people. This scarcity results in higher morbidity and mortality. OBJECTIVE: We aim to document the history and current state of neurosurgery in the Gambia to raise awareness and promote neurosurgery development. METHODS: The study reviews the Gambia's health care system, infrastructure, neurosurgical history, workforce, disease burden, and progress, with information derived from reference sources as well as author experience and interviews with key partners in Gambian health care. RESULTS: Neurosurgery in the Gambia began in the 1970s, facing constraints due to competing health care demands. Significant progress occurred much later in the early 2010s, marked by the initiation of Banjul Neuro Missions and the establishment of a dedicated neurosurgery unit. We report significant progress with neurosurgical interventions in the past few years showcasing the unit's dedication to advancing neurosurgical care in the Gambia. However, challenges persist, including a lack of trained neurosurgeons, equipment shortages such as ventilators and diagnostic imaging. Financial barriers for patients, particularly related to the costs of computer tomography scans, pose significant hurdles, impacting the timely diagnosis and intervention for neurological conditions. CONCLUSIONS: Neurosurgery in the Gambia is progressing, but challenges like equipment scarcity hinder further progress. We emphasize the need for addressing cost barriers, improving infrastructure, and fostering research. Engaging the government and international collaborations are vital for sustained development in Gambian neurosurgery.

Fatal Acute Myocardial Infarction With Normal Epicardial Coronary Arteries Shortly Following COVID-19 Vaccination.

Myocarditis and acute myocardial infarction (AMI) have been reported after COVID-19 messenger ribonucleic acid vaccination. Nearly all reported patients with myocarditis or AMI after COVID-19 vaccination have survived and become asymptomatic. Described herein is a previously healthy man who developed severe heart decompensation shortly after receiving a COVID-19 vaccination and died approximately 40 hours later. An autopsy disclosed massive AMI.

Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

Adipose Tissue Analysis Toolkit (ATAT) for automated analysis of adipocyte size and extracellular matrix in white adipose tissue.

OBJECTIVE: The pathological expansion of white adipose tissue (WAT) in obesity involves adipocyte hypertrophy accompanied by expansion of the collagen-rich pericellular extracellular matrix (ECM) and development of crown-like structures (CLS). Traditionally, WAT morphology is assessed through immunohistochemical analysis of WAT sections. However, manual analysis of large histological sections is time-consuming, and the available digital tools for analyzing adipocyte size and pericellular ECM are limited. To address this gap, the authors developed the Adipose Tissue Analysis Toolkit (ATAT), an ImageJ plugin facilitating analysis of adipocyte size, WAT ECM, and CLS. METHODS AND RESULTS: ATAT utilizes local and image-level differentials in pixel intensity to independently threshold image background, distinguishing adipocyte-free tissue without user input. It accurately captures adipocytes in histological sections stained with common dyes and automates the analysis of adipocyte cross-sectional area, total-field, and localized region-of-interest ECM. ATAT allows fully automated batch analysis of histological images using default or user-defined adipocyte detection parameters. CONCLUSIONS: ATAT provides several advantages over existing WAT image analysis tools, enabling high-throughput analyses of adipocyte-specific parameters and facilitating the assessment of ECM changes associated with WAT remodeling due to weight changes and other pathophysiological alterations that affect WAT function.

Classification of the Urgency of the Procedure and Outcome of Acute Type A Aortic Dissection.

Surgery for type A aortic dissection (TAAD) is associated with a high risk of early mortality. The prognostic impact of a new classification of the urgency of the procedure was evaluated in this multicenter cohort study. Data on consecutive patients who underwent surgery for acute TAAD were retrospectively collected in the multicenter, retrospective European Registry of TAAD (ERTAAD). The rates of in-hospital mortality of 3,902 consecutive patients increased along with the ERTAAD procedure urgency grades: urgent procedure 10.0%, emergency procedure grade 1 13.3%, emergency procedure grade 2 22.1%, salvage procedure grade 1 45.6%, and salvage procedure grade 2 57.1% (p <0.0001). Preoperative arterial lactate correlated with the urgency grades. Inclusion of the ERTAAD procedure urgency classification significantly improved the area under the receiver operating characteristics curves of the regression model and the integrated discrimination indexes and the net reclassification indexes. The risk of postoperative stroke/global brain ischemia, mesenteric ischemia, lower limb ischemia, dialysis, and acute heart failure increased along with the urgency grades. In conclusion, the urgency of surgical repair of acute TAAD, which seems to have a significant impact on the risk of in-hospital mortality, may be useful to improve the stratification of the operative risk of these critically ill patients. This study showed that salvage surgery for TAAD is justified because half of the patients may survive to discharge.

Atomic Layer Deposition of Cu Electrocatalysts on Gas Diffusion Electrodes for CO2 Reduction.

Electrochemical reduction of CO2 using Cu catalysts enables the synthesis of C2+ products including C2H4 and C2H5OH. In this study, Cu catalysts were fabricated using plasma-enhanced atomic layer deposition (PEALD), achieving conformal deposition of catalysts throughout 3-D gas diffusion electrode (GDE) substrates while maintaining tunable control of Cu nanoparticle size and areal loading. The electrochemical CO2 reduction at the Cu surface yielded a total Faradaic efficiency (FE) > 75% for C2+ products. Parasitic hydrogen evolution was minimized to a FE of ∼10%, and a selectivity of 42.2% FE for C2H4 was demonstrated. Compared to a line-of-sight physical vapor deposition method, PEALD Cu catalysts show significant suppression of C1 products compared to C2+, which is associated with improved control of catalyst morphology and conformality within the porous GDE substrate. Finally, PEALD Cu catalysts demonstrated a stable performance for 15 h with minimal reduction in the C2H4 production rate.

Lessons from the life of William Harvey.

William Harvey (1578-1658) discovered that blood flows in a circle and described this new finding in a short book in 1628. He had superb educational opportunities but also faced great difficulties, which he met with personal and professional resilience. A study of his life is worthwhile. Presented here are 11 lessons drawn from Harvey's life and legacy.

Causes of Malfunction of Bioprostheses Inserted Percutaneously in the Aortic Valve Position in Patients Whose Native Aortic Valve Was Congenitally Bicuspid and Stenotic.

Transcatheter aortic valve implantation (TAVI) has brought in recent years relief of cardiac-induced symptoms to a large number of patients with aortic stenosis. Whether it is better to use TAVI for the treatment of aortic valve stenosis superimposed on a congenitally bicuspid valve has been debated in contrast to its proved usefulness in aortic valve stenosis involving a tricuspid aortic valve. From January 2020 to March 2023, surgical aortic valve replacement of TAVI valve and native aortic valve was done in 6 patients. The clinical findings of the patients and morphologic findings from the surgical specimens submitted to the cardiac pathology department were subsequently examined. All the 6 native aortic valves had bicuspid configuration. The TAVI valve in each patient was excised from 9 to 88 months (mean 36 months) after it had been implanted because of paravalvular leak in 4, severe stenosis of the prosthetic valve in 1, and bioprosthetic cuspal degeneration in 1. Prosthetic valve endocarditis was clinically suspected in 2 patients, but the specimen culture was negative. Before surgical aortic valve replacement, 3 patients experienced stroke after TAVI. All 6 patients had low hemoglobin levels (mean 9.5 mg/100 ml) and low hematocrit levels (mean 29.5%). Reticulocyte count was available in 4 patients and was increased in all (mean 3.5%). When the stenotic native aortic valve configuration is bicuspid, the raphe tends to be calcified first and located perpendicular to the flow of the blood and may prevent the ring of the caged bioprosthesis from being transferred to the aortic wall, which is a requirement for full opening of the lumen of the bioprosthesis. Thus, thorough consideration needs to be made before performing TAVI in patients whose native aortic valve is stenotic and bicuspid.

RECOVER identifies synergistic drug combinations in vitro through sequential model optimization.

For large libraries of small molecules, exhaustive combinatorial chemical screens become infeasible to perform when considering a range of disease models, assay conditions, and dose ranges. Deep learning models have achieved state-of-the-art results in silico for the prediction of synergy scores. However, databases of drug combinations are biased toward synergistic agents and results do not generalize out of distribution. During 5 rounds of experimentation, we employ sequential model optimization with a deep learning model to select drug combinations increasingly enriched for synergism and active against a cancer cell line-evaluating only ∼5% of the total search space. Moreover, we find that learned drug embeddings (using structural information) begin to reflect biological mechanisms. In silico benchmarking suggests search queries are ∼5-10× enriched for highly synergistic drug combinations by using sequential rounds of evaluation when compared with random selection or ∼3× when using a pretrained model.

Western-style diet in the presence of elevated circulating testosterone induces adipocyte hypertrophy without proinflammatory responses in rhesus macaques.

PROBLEM: Anovulatory infertility is commonly associated with hyperandrogenemia (elevated testosterone, T), insulin resistance, obesity, and white adipose tissue (WAT) dysfunction associated with adipocyte hypertrophy. However, whether hyperandrogenemia and adipocyte hypertrophy per se induce a proinflammatory response is unknown. METHOD OF STUDY: Young adult female rhesus macaques were exposed to an obesogenic Western-style diet (WSD) in the presence of elevated circulating testosterone (T+WSD) or a low-fat control diet with no exogenous T. Immune cells residing in visceral omental white adipose tissue (OM-WAT), corpus luteum and the contralateral ovary, endometrium, lymph nodes, bone marrow, and peripheral blood mononuclear cells were characterized by flow cytometry during the luteal phase of the reproductive cycle. RESULTS: Following one year of treatment, T+WSD animals became more insulin-resistant and exhibited increased body fat and adipocyte hypertrophy compared to controls. T+WSD treatment did not induce macrophage polarization toward a proinflammatory phenotype in the tissues examined. Additionally, T+WSD treatment did not affect TNFα production by bone marrow macrophages in response to toll-like receptor agonists. While the major lymphoid subsets were not significantly affected by T+WSD treatment, we observed a significant reduction in the frequency of effector memory CD8+ T-cells (Tem) in OM-WAT, but not in other tissues. Notably, OM-WAT Tem frequencies were negatively correlated with insulin resistance as assessed by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). CONCLUSION: This study shows that short-term T+WSD treatment induces weight gain, insulin resistance, and adipocyte hypertrophy, but does not have a significant effect on systemic and tissue-resident proinflammatory markers, suggesting that adipocyte hypertrophy and mild hyperandrogenemia alone are not sufficient to induce a proinflammatory response.