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The incidence of women entering into pregnancy with BMI indicating overweight or obesity is rising with concurrent increases in adverse complications such as gestational diabetes. Although several studies have examined the compositional changes to the microbiome across BMI classifications, there has been no investigation regarding changes in microbial function during pregnancy.A total of 105 gastrointestinal microbiome biospecimens were used in this analysis. Biospecimens were sequenced by using the Illumina NovaSeq 6000 shotgun metagenomics platform.Findings indicate an enrichment in microbiota from the phylum Firmicutes across all pregravid BMI groups with a decrease in α diversity in groups with BMI indicating obesity or overweight compared with a group with BMI indicating normal weight (p = 0.02). More specifically, women with BMI indicating obesity or overweight had enrichment in Bifidobacterium bifidum and B. adolescentis. Women with BMI25 kg/mOur analysis suggests that there are differences in microbial composition and function between BMI groups. Future research should consider how these changes contribute to specific clinical outcomes during pregnancy.

Introduction/Aim: A spectrum of psychological problems is commonly found in CP/CPPS patients, though it is not yet clear whether, a priori, psychological dysfunctions are the cause of these pain syndromes, or whether these pain conditions are themselves causing psychological disturbances. In this article we present the current perspective on the impact of psychological problems in chronic prostatitis syndromes and we discuss the implications thereof from a clinical perspective. Materials and Methods: A database and a manual search were conducted in the MEDLINE database of the National Library of Medicine, EMBASE, and other libraries using the key words “prostatitis syndromes”, “chronic bacterial prostatitis”, “chronic pelvic pain”, in various combinations with the terms “psychological issues”, “depression” “anxiety”, “stress”, “unhappiness”, “cognitive status” and “personality”. Two independent reviewers performed data extraction. We included clinical studies with available information on chronic prostatitis and related psychological conditions. We considered full-text written papers. We excluded reviews and case reports. In order to reduce the risk of bias we analyzed only studies including patients with confirmed CBP or CP/CPPS. Bibliographic information in the selected publications was checked for relevant records not included in the initial search. Results: Database search allowed us to retrieve 638 studies to which we added to 16 additional studies retrieved by hand-searching. After screening, 34 relevant papers were identified for thorough review. Most studies included patients with chronic pelvic pain and prostatitis-like symptoms, whereas a smaller number of studies included patients with methodologically con- firmed CP/CPPS including studies with a microbiologically confirmed diagnosis of CBP. The psychosocial factors examined in the selected studies include pain, catastrophizing, stress, personality factors and social aspects. Comorbid psychiatric disorders evidenced in the studies included depression, anxiety and trauma-related disorders, somatization disorders, and substance abuse. Some studies investigated the association of pain with each individual psychological disturbance, while others examined the impact of pain in association with the overall quality of life. Sample size, study design and diagnostic measures varied among studies. Conclusions: Despite limitations and variations in sample size, study design and diagnostic measures in all included studies, a relation between chronic prostatitis and psychological problems is a consistent finding. The existing evidence does not permit to definitely conclude whether psychological problems are a risk factor for CP/CPPS or whether they represent an array of symptoms that are associated with the exacerbation of this disease.

We use a complete set of deep narrow-band imaging data for 384 galaxies gathered during the VESTIGE survey to derive the first Halpha luminosity function (LF) of the Virgo cluster within R200. The data allow us to cover the whole dynamic range of the Halpha LF (10^3610^14 Mo. The comparison with the IllustrisTNG cosmological hydrodynamical simulations shows a more pronounced decrease at the faint end of the distribution. If Virgo is representative of typical nearby clusters of similar mass, this difference suggests that the stripping process in simulated galaxies in these environments is more efficient than observed., Comment: Accepted for publication on A&A

In this work we study the intracluster medium of a galaxy cluster at the cosmic noon: JKCS041 at z=1.803. A 28h long Sunyaev-Zel'dovich (SZ) observation using MUSTANG-2 allows us to detect JKCS041, even if intrinsically extremely faint compared to other SZ-detected clusters. We found that the SZ peak is offset from the X-ray center by about 220 kpc in the direction of the brightest cluster galaxy, which we interpret as due to the cluster being observed just after first passage of a major merger. JKCS041 has a low central pressure and a low Compton Y compared to local clusters selected by their intracluster medium (ICM), likely because the cluster is still in the process of assembly but also in part because of a hard-to-quantify bias in current local ICM-selected samples. JKCS041 has a 0.5 dex fainter Y signal than another less massive z~1.8 cluster, exemplifying how much different weak-lensing mass and SZ mass can be at high redshift. The observations we present provide us with the measurement of the most distant resolved pressure profile of a galaxy cluster. Comparison with a library of plausibly descendants shows that JKCS041 pressure profile will likely increase by about 0.7 dex in the next 10 Gyr at all radii., MNRAS, in press

Cancer immunotherapy has significantly improved patient survival. Yet, half of patients do not respond to immunotherapy. Gut microbiomes have been linked to clinical responsiveness of melanoma patients on immunotherapies; however, different taxa have been associated with response status with implicated taxa inconsistent between studies. We used a tumor-agnostic approach to find common gut microbiome features of response among immunotherapy patients with different advanced stage cancers. A combined meta-analysis of 16S rRNA gene sequencing data from our mixed tumor cohort and three published immunotherapy gut microbiome datasets from different melanoma patient cohorts found certain gut bacterial taxa correlated with immunotherapy response status regardless of tumor type. Using multivariate

Background: Alpha-adrenoreceptor antagonists or alpha-blockers are used in the treatment of hypertension, in the therapy of benign prostatic hyperplasia and in medical expulsive treatment of ureteral stones. These agents may affect the sexual function, with differences between drugs within the same class, depending on their selectivity for receptor subtypes. The aim of this review was to analyze the effects of alpha-blockers on sexual function. Materials and methods: We conducted a systematic review and meta-analysis by searching PubMed, EMBASE and other databases for randomized controlled trials (RCTs) reporting sexual adverse effects in patients treated with alpha-blockers. Odds ratios for sexual dysfunction were calculated using random effects Mantel-Haenszel statistics. Results: Out of 608 records retrieved, 75 eligible RCTs were included in the meta-analysis. Compared with placebo, alphablockers were associated with increased odds of ejaculatory disorders both in patients with lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia (BPH) (OR: 7.53, 95% CI: 3.77-15.02, Z = 5.73, p < 0.00001, I2 = 55%) and in patients with ureteral stones (OR: 2.88, 95% CI: 1.50-5.44, Z = 3.19, p < 0.001, I2 = 31%). Uroselective alpha-blockers showed higher odds of ejaculatory disorders. Conversely, nonselective alpha-blockers were not associated with higher odds of ejaculatory dysfunction. Silodosin was associated with increased odds of ejaculatory dysfunction compared with tamsulosin (OR: 3.52, 95% CI: 2.18-5.68, 15 series, 1512 participants, Z = 5.15, p < 0.00001, I2 = 0%). Naftopidil and alfuzosin showed lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers.No statistically significant differences in the odds of erectile dysfunction were observed when alpha-blockers were compared to placebo.

Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig­naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. Significance: HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825

We aim at studying scaling relations of a small but well defined sample of galaxy clusters that includes the recently discovered class of objects that are X-ray faint for their mass. These clusters have an average low X-ray surface brightness, a low gas fraction and are under-represented (by a factor of 10) in X-ray surveys or entirely absent in SZ surveys. With the inclusion of these objects, we find that the temperature-mass relation has an unprecedented large scatter, 0.20+-0.03 dex at fixed mass, as wide as allowed by the temperature range, and the location of a cluster in this plane depends on its surface brightness. Clusters obey a relatively tight luminosity-temperature relation independently of the their brightness. We interpret the wide difference in scatter around the two relations as due to the fact that X-ray luminosity and temperature are dominated by photons coming from small radii (in particular for T we used a 300 kpc aperture radius) and strongly affected by gas thermodynamics (e.g. shocks, cool-cores), whereas mass is dominated by dark matter at large radii. We measure a slope of 2.0+-0.2 for the L500-T relation. Given the characteristics of our sample, this value is free from the collinearity (degeneracy) between evolution and slope and from hypothesis on the undetected population, that both affect the analysis of X-ray selected samples, and can therefore be profitably used both as reference and to break the above degeneracy of X-ray selected-samples., Comment: MNRAS, 511, 4991: https://doi.org/10.1093/mnras/stac307 ; arxiv version is prior to english polishing, hyperlink, hyperref

Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig­naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC.Significance:HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease.This article is highlighted in the In This Issue feature, p. 1825

Supplementary Data from IL27 Signaling Serves as an Immunologic Checkpoint for Innate Cytotoxic Cells to Promote Hepatocellular Carcinoma

Supplemental table 1: RNA profiling of differentially expressed genes in CD3+ sorted cell population isolated from MyD88fl/fl and MyD88CD4-Cre chronically TPA-treated skins. (A) List of genes from RNA profiling that are significantly affected (by at least 1.3-fold change and FDR

Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders; however, its effect on antitumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects antitumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma which promote tumor development in mice, caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). A decrease in gut barrier function observed in mice with PSC and colitis allowed gut-derived bacteria and lipopolysaccharide to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSCs. In contrast, neomycin treatment blocked CXCL1 expression and PMN-MDSC accumulation and inhibited tumor growth even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSCs to promote liver cancer.Significance:MDSCs have been shown to be induced by tumors and suppress antitumor immunity. Here we show that the gut microbiome can control accumulation of MDSCs in the liver in the context of a benign liver disease or colitis.See related commentary by Chagani and Kwong, p. 1014.This article is highlighted in the In This Issue feature, p. 995

Predicted risk group (BRBarray)_LMedits

TLR4 signature genes

Supplementary figures and figure legends

Supplementary Figure 7 - PDF file 111K, Characterization of myeloid cells in lung, tumor, spleen, and lymph nodes

Supplementary Figure 1 - PDF file 183K, Overproduction of immature myeloid cells in both tumor bearing mice and cancer patients, flow cytometry analysis and sorting

Supplementary Figure 4 - PDF file 129K, Validation of over expression of TGFbeta1, IL-4, IL10, as well as Arginase1 and iNOS in Tgfbr2

Supplementary Figure 3 - PDF file 76K, IFN-gamma production by T cells and its effect on tumor growth in Tgfbr2MyeKOand Tgfbr2flox/flox control mice

Control and cirrhosis patients

Supplementary Figure 8 - PDF file 84K, Immune cell profiling and IFN-gamma production in CD8 T cells in tumor tissues between Tgfbr2flox/flox and Tgfbr2MyeKO mice bearing 4T1 tumors

MDSC signiture genes

PSC patients information

Supplemental table 2: List of genes from RNA profiling, the expression of which is significantly affected (by at least 1.5-fold change and FDR

Cancer development requires a favorable tissue microenvironment. By deleting Myd88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis, we show that IL17 from infiltrating T cells and IκBζ signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS-transformed keratinocytes respond to tumor promoters by activating canonical NF-κB and IκBζ signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88-dependent signaling in T cells. The release of IL17 into the microenvironment elevates IκBζ in normal and RAS-transformed keratinocytes. Activation of IκBζ signaling is required for the expression of specific promoting factors induced by IL17 in normal keratinocytes and constitutively expressed in RAS-initiated keratinocytes. Deletion of Nfkbiz in keratinocytes impairs RAS-mediated benign tumor formation. Transcriptional profiling and gene set enrichment analysis of IκBζ−deficient RAS-initiated keratinocytes indicate that IκBζ signaling is common for RAS transformation of multiple epithelial cancers. Probing The Cancer Genome Atlas datasets using this transcriptional profile indicates that reduction of IκBζ signaling during cancer progression associates with poor prognosis in RAS-driven human cancers.Implications:The paradox that elevation of IκBζ and stimulation of IκBζ signaling through tumor extrinsic factors is required for RAS-mediated benign tumor formation while relative IκBζ expression is reduced in advanced cancers with poor prognosis implies that tumor cells switch from microenvironmental dependency early in carcinogenesis to cell-autonomous pathways during cancer progression.

Supplementary Figure 9 - PDF file 150K, Gating strategy, sorting efficiency, and TbetaRII expression in myeloid cell subsets

16s rRNA sequencing of PSC patients

Supplemental table 3: List of genes from RNA profiling, the expression of which is significantly affected (by at least 1.5-fold change and FDR

Supplementary Figure 10 - PDF file 82K, Time course study for in vivo cell trafficking; the expression of TGFbeta ligands and receptors in myeloid cells and subsets

TGF-β is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-β functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2MyeKO) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2MyeKO bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-γ production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2MyeKO mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-β receptor II expression. Our studies show that myeloid-specific TGF-β signaling is an essential component of the metastasis-promoting puzzle of TGF-β. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.Significance: Our study identifies myeloid-specific TGF-β signaling as a critical mediator in tumor metastasis, distinct from the tumor-suppressive effect of TGF-β signaling in epithelial cells, fibroblasts, and T cells. We further provide mechanistic insight into host antitumor immunity and suggest a cell type–specific cancer-targeting strategy. Cancer Discov; 3(8); 936–51. ©2013 AACR.See related commentary by Souza-Fonseca-Guimaraes and Smyth, p. 846This article is highlighted in the In This Issue feature, p. 826

Supplementary Figure 5 - PDF file 382K, Analysis of percentage or number in B cells, T cells, or myeloid cell subsets in the lungs between Tgfbr2MyeKO and control littermates under normal or tumor conditions

Primers used for mouse colonies genotyping.

Key Resources Table

LD1 CNV_Sequencing

PDF file - 835K, TREM-1 expression on KC of WT mice increased after DEN administration

MDSC from μMT mice express reduced levels of ROS and Arg1.

The loss of B cells affects function of human monocyte-derived MDSC.

PDF file - 680K, Deletion of TREM-1 inhibits cytokine and chemokine production by bone marrow-derived macrophages stimulated with the product of necrotic hepatocytes (PNH)

Supplementary Figure 5 from Tumor-Specific CD8+ T Cells Expressing Interleukin-12 Eradicate Established Cancers in Lymphodepleted Hosts

Supplementary Figure 3 from Redirecting In vivo Elicited Tumor Infiltrating Macrophages and Dendritic Cells towards Tumor Rejection

PDF file - 2.5MB, Deletion of TREM-1 down regulates genes associated with DNA repair and genes involved in hepatocellular carcinoma development

PDF file - 2.9MB, Targeting strategy for the Trem1 genomic locus and generation of Trem1-deficient mice

Supplementary Figure 4 from Tumor-Specific CD8+ T Cells Expressing Interleukin-12 Eradicate Established Cancers in Lymphodepleted Hosts

Supplementary Figure 2 from Redirecting In vivo Elicited Tumor Infiltrating Macrophages and Dendritic Cells towards Tumor Rejection

Supplementary Table 1. Th1 vs. Th2 Cytokine Trend. Supplementary Table 2. Effect of L-NAME on Radiation-induced Cytokine Expression.

tBreg-induced education of MDSC inhibits production of cytokines in CD8+ cells.