Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network ...analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.
The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this ...clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e.g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumor sample. By doing so, we can track tumor evolution and identify the spatial origins of cells resisting therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adult mammals have lost multi-tissue regenerative capacity, except for the distal digit, which is able to regenerate via mechanisms that remain largely unknown. Here, we show that, after adult mouse ...distal digit removal, nerve-associated Schwann cell precursors (SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. When SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased and nail and bone regeneration were impaired. Transplantation of exogenous SCPs rescued these regeneration defects. We found that SCPs secrete factors that promote self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and platelet-derived growth factor AA (PDGF-AA), are made by SCPs in the regenerating digit and rescued the deficits in regeneration caused by loss of SCPs. As all peripheral tissues contain nerves, these results could have broad implications for mammalian tissue repair and regeneration.
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•Schwann cell precursors (SCPs) enter the regenerating digit tip•Ablation of SCPs by inducible deletion or denervation inhibits regeneration•SCPs secrete growth factors to promote mesenchymal cell proliferation•Oncostatin M and PDGF-AA can rescue regeneration in a denervated digit tip
Johnston et al. show that, during regeneration of the mouse digit tip, nerve-associated Schwann cell precursors dedifferentiate and move into the injured tissue, where they secrete paracrine factors, including oncostatin M and PDGF-AA, to promote mesenchymal cell proliferation, expansion of the blastema, and regeneration.
The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point ...mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Today's college students are at increased risk for depression. Therefore, accurate and sustainable assessment of depressive symptoms among college students has become an important issue. One ...promising instrument for depression screening in college settings is the Patient Health Questionnaire-9 (PHQ-9), a 9-item self-report measure developed in primary care and designed to assess the presence of Diagnostic and Statistical Manual of Mental Disorders (4th ed.) symptom criteria for major depressive disorder. Although the PHQ-9 has been well validated in primary care settings, no studies have examined its factor structure for diverse college populations in the United States. This study used confirmatory factor analysis to test competing measurement models and the measurement invariance of the PHQ-9 across gender (men and women) and racial/ethnic groups (African American, Asian American, European American, Latino/a American) in a sample of 857 U.S. college students. Results supported a 1-factor model of the PHQ-9. Based on configural, metric, and scalar invariance test results, the PHQ-9 assesses depressive symptoms equivalently across gender and racial/ethnic groups. In support of validity evidence, PHQ-9 scores were positively associated with alcohol use and negatively associated with mental well-being. Implications for future research and assessment are discussed.
Public Significance Statement
The current study found that the PHQ-9 assesses depressive symptoms equivalently across diverse gender and racial/ethnic college student populations. The results support the promising utility of PHQ-9 as a brief depression assessment in college settings.
In this study, investigators compared genome sequencing with cytogenetic analysis in 263 patients with acute myeloid leukemia or myelodysplastic syndromes. Prospective sequencing detected new genetic ...information that was not revealed by cytogenetic analysis in nearly 25% of the patients, which altered the risk category for most of these patients.
Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an ...immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling
. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8
T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.
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The skin is a source of infection associated with surgery. In this multicenter, randomized trial, the preoperative application of chlorhexidine–alcohol was found to be a more effective skin ...preparation than povidone–iodine for preventing incisional infections.
The preoperative application of chlorhexidine–alcohol was found to be a more effective skin preparation than povidone–iodine for preventing incisional infections.
Despite the implementation of preoperative preventive measures, which include skin cleansing with povidone–iodine, surgical-site infection occurs in 300,000 to 500,000 patients who undergo surgery in the United States each year.
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Since the patient's skin is a major source of pathogens, it is conceivable that improving skin antisepsis would decrease surgical-site infections.
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The Centers for Disease Control and Prevention (CDC) recommends that 2% chlorhexidine-based preparations be used to cleanse the site of insertion of vascular catheters.
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However, the CDC has not issued a recommendation as to which antiseptics should be used preoperatively to prevent postoperative surgical-site infection in the 27 . . .
The Milky Way hosts a hot, diffuse, gaseous halo based on detections of z = 0 Ov II and Ov III absorption lines in quasar spectra and emission lines in blank-sky spectra. Here we improve constraints ...on the structure of the hot gas halo by fitting a radial model to a much larger sample of Ov II and Ov III emission line measurements from XMM-Newton/EPIC-MOS spectra compared to previous studies. We assume a modified beta -model for the halo density distribution and a constant-density Local Bubble from which we calculate emission to compare with the observations. The combination of absorption and emission line analysis implies a sub-solar gas metallicity that decreases with radius, but that also must be 0.3 Z to be consistent with the pulsar dispersion measure toward the Large Magellanic Cloud.
We summarize and reanalyze observations bearing on missing galactic baryons, where we propose a consistent picture for halo gas in L L* galaxies. The hot X-ray-emitting halos are detected to 50-70 ...kpc, where typically Mhot(<50 kpc) ∼ 5 × 109 M , and with density n ∝ r−3/2. When extrapolated to R200, the gas mass is comparable to the stellar mass, but about half of the baryons are still missing from the hot phase. If extrapolated to 1.7R200-3R200, the ratio of baryon to dark matter approaches the cosmic value. Significantly flatter density profiles are unlikely for R < 50 kpc, and they are disfavored but not ruled out for R > 50 kpc. For the Milky Way, the hot halo metallicity lies in the range 0.3-1 solar for R < 50 kpc. Planck measurements of the thermal Sunyaev-Zel'dovich (SZ) effect toward stacked luminous galaxies (primarily early type) indicate that most of their baryons are hot, are near the virial temperature, and extend beyond R200. This stacked SZ signal is nearly an order of magnitude larger than that inferred from the X-ray observations of individual (mostly spiral) galaxies with M* > 1011.3 M . This difference suggests that the hot halo properties are distinct for early- and late-type galaxies, possibly due to different evolutionary histories. For the cooler gas detected in UV absorption line studies, we argue that there are two absorption populations: extended halos, and disks extending to ∼50 kpc, containing most of this gas, and with masses a few times lower than the stellar masses. Such extended disks are also seen in 21 cm H i observations and in simulations.
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