Notes

Psychometric qualities in the diabetes mellitus capabilities checklist with regard to young people with your body along with their mother and father.
BACKGROUND Glioblastoma (GBM) are devastating neoplasms with high invasive capacity, which has been difficult to study in vitro in a human-derived model system. Therapeutic progress is also limited by cellular heterogeneity within and between tumors, among other factors such as therapy resistance. To address these challenges, we present an experimental model using human cerebral organoids as a scaffold for patient-derived glioblastoma cell invasion. METHODS This study combined tissue clearing and confocal microscopy with single-cell RNA sequencing of GBM cells before and after co-culture with organoid cells. RESULTS We show that tumor cells within organoids extend a network of long microtubes, recapitulating the in vivo behavior of GBM. Transcriptional changes implicated in the invasion process are coherent across patient samples, indicating that GBM cells reactively upregulate genes required for their dispersion. Potential interactions between GBM and organoid cells identified by an in silico receptor-ligand pairing screen suggest functional therapeutic targets. CONCLUSIONS Taken together, our model has proven useful for studying GBM invasion and transcriptional heterogeneity in vitro, with applications for both pharmacological screens and patient-specific treatment selection at a time scale amenable to clinical practice. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.Replication factor C (RFC), a heteropentamer of RFC1-5, loads PCNA onto DNA during replication and repair. Once DNA synthesis has ceased, PCNA must be unloaded. Recent findings assign the uloader role primarily to an RFC-like (RLC) complex, in which the largest RFC subunit, RFC1, has been replaced with ATAD5 (ELG1 in Saccharomyces cerevisiae). ATAD5-RLC appears to be indispensable, given that Atad5 knock-out leads to embryonic lethality. In order to learn how the retention of PCNA on DNA might interfere with normal DNA metabolism, we studied the response of ATAD5-depleted cells to several genotoxic agents. We show that ATAD5 deficiency leads to hypersensitivity to methyl methanesulphonate (MMS), camptothecin (CPT) and mitomycin C (MMC), agents that hinder the progression of replication forks. We further show that ATAD5-depleted cells are sensitive to poly(ADP)ribose polymerase (PARP) inhibitors and that the processing of spontaneous oxidative DNA damage contributes towards this sensitivity. We posit that PCNA molecules trapped on DNA interfere with the correct metabolism of arrested replication forks, phenotype reminiscent of defective homologous recombination (HR). As Atad5 heterozygous mice are cancer-prone and as ATAD5 mutations have been identified in breast and endometrial cancers, our finding may open a path towards the therapy of these tumours. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.The miRNA pathway has three segments-biogenesis, targeting and downstream regulatory effectors. We aimed to better understand their cellular control by exploring the miRNA-mRNA-targeting relationships. We first used human evolutionarily conserved sites. Strikingly, AGOs 1-3 are all among the top 14 mRNAs with the highest miRNA site counts, along with ANKRD52, the phosphatase regulatory subunit of the recently identified AGO phosphorylation cycle; and the AGO phosphorylation cycle mRNAs share much more than expected miRNA sites. The mRNAs for TNRC6, which acts with AGOs to channel miRNA-mediated regulatory actions onto specific mRNAs, are also heavily miRNA-targeted. In contrast, upstream miRNA biogenesis mRNAs are not, and neither are downstream regulatory effectors. In short, binding site enrichment in miRNA targeting machinery mRNAs, but neither upstream biogenesis nor downstream effector mRNAs, was observed, endowing a cellular capacity for intensive and specific feedback control of the targeting activity. The pattern was confirmed with experimentally determined miRNA-mRNA target relationships. Moreover, genetic experiments demonstrated cellular utilization of this capacity. Thus, we uncovered a capacity for intensive, and specific, feedback-regulation of miRNA targeting activity directly by miRNAs themselves, i.e. segment-specific feedback auto-regulation of miRNA pathway, complementing miRNAs pairing with transcription factors to form hybrid feedback-loop. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.BACKGROUND Anterior column realignment (ACR) is a less invasive alternative to 3-column osteotomy for the correction of sagittal imbalance. We hypothesized that ACR would correct sagittal imbalance with an acceptable neurological risk. OBJECTIVE To assess long-term neurological and radiographic outcomes after ACR. METHODS Patients ≥18 yr who underwent ACR from 2005 to 2013 were eligible. Standing scoliosis radiographs were studied at preoperation, postoperation (≤6 wk), and at minimum 2 yr of follow-up. Clinical/radiographic data were collected through a retrospective chart review, with thoracic 1 spino-pelvic inclination (T1SPi) used as the angular surrogate for sagittal vertical axis. RESULTS A total of 26 patients had complete data, with a mean follow-up of 2.8 yr (1.8-7.4). Preoperative, sagittal parameters were lumbar lordosis (LL) of -16.1°, pelvic incidence (PI)-LL of 41.7°, T1SPi of 3.6°, and pelvis tilt (PT) of 32.4°. LL improved by 30.6° (P less then .001) postoperation. Mean changes in PT (-8.3), sacral slope (8.9), T1SPi (-4.9), and PI-LL (-33.5) were all significant. The motion segment angle improved by 26.6°, from 5.2° to -21.4° (P less then .001). Neurological complications occurred in 32% patients postoperation (n = 8; 1 patient with both sensory and motor). New thigh numbness/paresthesia developed in 3 (13%) patients postoperation; only 1 (4%) persisted at latest follow-up. A total of 6 (24%) patients developed a new lower extremity motor deficit postoperation, with 4 (8%) having persistent new weakness at last follow-up. Out of 8 patients with preoperative motor deficit, half saw improvement postoperation and 75% improved by last follow-up. CONCLUSION There was net motor improvement, with 24% of patients improving and 16% having persistent new weakness at latest follow-up; 60% were unchanged. Radiographic results demonstrate that ACR is a useful tool to treat severe sagittal plane deformity. Copyright © 2020 by the Congress of Neurological Surgeons.A correlation between histone acetylation and transcription has been noted for a long time, but little is known about what step(s) in the transcription cycle is influenced by acetylation. We have examined the immediate transcriptional response to histone deacetylase (HDAC) inhibition, and find that release of promoter-proximal paused RNA polymerase II (Pol II) into elongation is stimulated, whereas initiation is not. Although histone acetylation is elevated globally by HDAC inhibition, less than 100 genes respond within 10 min. These genes are highly paused, are strongly associated with the chromatin regulators NURF and Trithorax, display a greater increase in acetylation of the first nucleosomes than other genes, and become transcriptionally activated by HDAC inhibition. Among these rapidly up-regulated genes are HDAC1 (Rpd3) and subunits of HDAC-containing co-repressor complexes, demonstrating feedback regulation upon HDAC inhibition. Our results suggest that histone acetylation stimulates transcription of paused genes by release of Pol II into elongation, and that increased acetylation is not a consequence of their enhanced expression. HS148 We propose that HDACs are major regulators of Pol II pausing and that this partly explains the presence of HDACs at active genes. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.Importance Broad-spectrum antibiotics are recommended for all patients with suspected sepsis to minimize the risk of undertreatment. However, little is known regarding the net prevalence of antibiotic-resistant pathogens across all patients with community-onset sepsis or the outcomes associated with unnecessarily broad empiric treatment. Objective To elucidate the epidemiology of antibiotic-resistant pathogens and the outcomes associated with both undertreatment and overtreatment in patients with culture-positive community-onset sepsis. Design, Setting, and Participants This cohort study included 17 430 adults admitted to 104 US hospitals between January 2009 and December 2015 with sepsis and positive clinical cultures within 2 days of admission. Data analysis took place from January 2018 to December 2019. Exposures Inadequate empiric antibiotic therapy (ie, ≥1 pathogen nonsusceptible to all antibiotics administered on the first or second day of treatment) and unnecessarily broad empiric therapy (ie, active ahogens, yet broad-spectrum antibiotics were frequently administered. Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality. These findings underscore the need for better tests to rapidly identify patients with resistant pathogens and for more judicious use of broad-spectrum antibiotics for empiric sepsis treatment.Importance Immunotherapy using immune checkpoint inhibitors has been remarkably effective for treating multiple cancer types, and the gut microbiome is a possible factor affecting immune checkpoint inhibitor efficacy. However, the association between the gut microbiome and immune status of the tumor microenvironment remains unclear. Short-chain fatty acids (SCFAs) are major end product metabolites produced by the gut microbiota and have wide-ranging impacts on host physiology. Objective To evaluate fecal and plasma SCFAs in patients with solid cancer tumors treated with programmed cell death-1 inhibitors (PD-1i). Design, Setting, and Participants This was a prospective cohort biomarker study of patients with cancer who planned therapy with PD-1i at Kyoto University Hospital between July 2016 and February 2019. Data were analyzed from October 2019 to February 2020. Exposures Patients who were treated with nivolumab or pembrolizumab were classified into 2 groups based on their treatment response using Response sma isovaleric acid (HR, 0.38; 95% CI, 0.14-0.99). Conclusions and Relevance Results of this study suggest that fecal SCFA concentrations may associated with PD-1i efficacy; thus, SCFAs may be the link between the gut microbiota and PD-1i efficacy. Because fecal examinations are completely noninvasive, they may be applicable for routine monitoring of patients.Importance Among the United Nations' Sustainable Development Goals is to reduce the neonatal mortality rate to 12 per 1000 live births by 2030. Identifying high-risk pregnancies can help achieve this target in low-resource countries, such as India, which accounts for one-fourth of global neonatal deaths. Objective To analyze the association of maternal history of neonatal death with subsequent neonatal mortality. Design, Setting, and Participants This cross-sectional study included a nationally representative sample of singleton live births from multiparous women. Data were obtained from the 2016 National Family Health Survey in India. Data were analyzed from November 2018 to January 2020. Exposures Maternal history of neonatal death and a comprehensive set of covariates, including socioeconomic environment, maternal anthropometry, and pregnancy care. Main Outcomes and Measures Subsequent neonatal mortality. Population-attributable risk associated with history of neonatal death was calculated, and sensitivity analyses were performed.
My Website: https://www.selleckchem.com/products/hs148.html