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Background Genetic correlations, causalities and pathways between large-scale complex exposures and ovarian and breast cancers need systematic exploration. Methods Mendelian randomisation (MR) and genetic correlation (GC) were used to identify causal biomarkers from 95 cancer-related exposures for risk of breast cancer [BC: oestrogen receptor-positive (ER + BC) and oestrogen receptor-negative (ER - BC) subtypes] and ovarian cancer [OC: high-grade serous (HGSOC), low-grade serous, invasive mucinous (IMOC), endometrioid (EOC) and clear cell (CCOC) subtypes]. Results Of 31 identified robust risk factors, 16 were new causal biomarkers for BC and OC. Body mass index (BMI), body fat mass (BFM), comparative body size at age 10 (CBS-10), waist circumference (WC) and education attainment were shared risk factors for overall BC and OC. Childhood obesity, BMI, CBS-10, WC, schizophrenia and age at menopause were significantly associated with ER + BC and ER - BC. Omega-6:omega-3 fatty acids, body fat-free mass and basal metabolic rate were positively associated with CCOC and EOC; BFM, linoleic acid, omega-6 fatty acids, CBS-10 and birth weight were significantly associated with IMOC; and body fat percentage, BFM and adiponectin were significantly associated with HGSOC. Both GC and MR identified 13 shared factors. Factors were stratified into five priority levels, and visual causal networks were constructed for future interventions. Conclusions With analysis of large-scale exposures for breast and ovarian cancers, causalities, genetic correlations, shared or specific factors, risk factor priority and causal pathways and networks were identified.

CD8+ cytotoxic T-lymphocytes are essential components of the anti-tumor immunity. To better understand the expansion of CD8+ T-cells we used multiplex fluorescence immunohistochemistry to study Ki67+CD8+ cells in normal lymphoid tissues, selected inflammatory diseases and cancers in 41 large sections/ microenvironment tissue microarrays (TMAs) as well as 765 samples in a conventional TMA format. The evaluation of more than 20 different compartments of normal lymphoid tissues revealed that the percentage of proliferating (ki67+) CD8+ cells did commonly not exceed 3%. In inflammations, the percentage of Ki67+CD8+ cells was more variable and higher compared to normal tissues. In cancers, the percentage of Ki67+CD8+ cells was higher in the tumor center than at the invasive margin. In the tumor center of 765 colorectal cancers, the density of Ki67+CD8+ cells and the percentage of proliferating CD8+ cytotoxic T-cells was significantly associated with microsatellite instability (p

Purpose Expansion of CD8+ cytotoxic Tlymphocytes is a prerequisite for anti-cancer immune activity and has gained interest in the era of immune checkpoint therapy. Methods To understand the CD8+ T cell dynamics in the tumor microenvironment, we used multiplex fluorescence immunohistochemistry to quantitate CD8+ proliferation (Ki67 co-expression) in tissue microarrays from 1107 colorectal, 642 renal cell, 1066 breast, 375 ovarian, 451 pancreatic and 347 gastric cancer samples. Results The density and the percentage of proliferating (Ki67+) CD8+ T cells were both highly variable between tumor types as well as between patients with the same tumor type. Elevated density and percentage of proliferating CD8+ cytotoxic T cells were significantly associated with favorable tumor parameters such as low tumor stage, negative nodal stage (p ≤ 0.0041 each), prolonged overall survival (p ≤ 0.0028 each) and an inflamed immune phenotype (p = 0.0025) in colorectal cancer and, in contrast, linked to high tumor stage, advanced ISUP/Fuhrman/Thoenes grading (each p ≤ 0.003), shorter overall survival (p ≤ 0.0330 each) and an immune inflamed phenotype (p = 0.0094) in renal cell cancer. In breast, ovarian, pancreatic and gastric cancer the role of (Ki67+)CD8+ Tcells was not linked to clinicopathological data. Conclusion Our data demonstrate a tumor type dependent prognostic impact of proliferating (Ki67+)CD8+ Tcells and an inverse impact in colorectal and renal cell cancer.

We used a transparent systematic review framework based on best practices for evaluating study quality and integrating evidence to conduct a review of the available epidemiology studies evaluating associations between long-term exposure to ambient concentrations of PM2.5 and mortality (all-cause and non-accidental) conducted in North America. We found that while there is some consistency across studies for reporting positive associations, these associations are weak and several important methodological issues have led to uncertainties with regard to the evidence from these studies, including potential confounding by measured and unmeasured factors, exposue measurement error, and model misspecification. These uncertainties provide a plausible, alternative explanation to causality for the weakly positive findings across studies. Using a causality framework that incorporates best practices for making causal determinations, we concluded that the evidence for a causal relationship between long-term exposure to ambient PM2.5 concentrations and mortality from these studies is inadequate.

Type 2 diabetes (T2D) is affected by a combination of genetic and environmental factors. However, the comprehensive genomic risk scores (GRSs) for T2D prediction have not been evaluated. Using a meta-scoring approach, we developed a metaGRS for T2D; T2D-related traits consist of 1,692 genetic variants in the UK Biobank training set (n = 40,423 + 7,558 events) and evaluate this score in the validation set (n = 303,053). The hazard ratio (HR) for T2D was 1.32 (95% confidence interval [CI]: 1.29–1.35) per standard deviation of metaGRS and was larger than previously published T2D-GRS. Individuals, in the top 25% of metaGRS, have an HR of 2.08 (95%CI: 1.93–2.23) compared with those in the bottom 25%. The addition of metaGRS to all conventional risk factors significantly increased the AUC (P

Background: Lupus nephritis (LN) is the most severe organ manifestations of systemic lupus erythematosus (SLE). Although increased knowledge of the disease pathogenesis has improved treatment options, outcomes have plateaued as current immunosuppressive therapies have failed to prevent disease relapse in more than half of treated patients. Thus, there is still an urgent need for novel therapy. Mesenchymal stem cells (MSCs) possess a potently immunosuppressive regulation on immune responses, and intravenous transplantation of MSCs ameliorates disease symptoms and has emerged as a potential beneficial therapy for LN. The objective of this review is to discuss the defective functions of MSCs in LN patients and the application of MSCs in the treatment of both LN animal models and patients. Summary: Bone marrow MSCs from SLE patients exhibit impaired capabilities of migration, differentiation, and immune regulation and display senescent phenotype. Allogeneic MSCs suppress autoimmunity and restore renal function in mouse models and patients with LN by inducing regulatory immune cells and suppressing Th1, Th17, T follicular helper cell, and B-cell responses. In addition, MSCs can home to the kidney and integrate into tubular cells and differentiate into mesangial cells. Key Messages: The efficacy of MSCs in the LN treatment remains to be confirmed, and future advances from stem cell science can be expected to pinpoint significant MSC subpopulations, as well as specific mechanisms of action, leading the way to the use of more potent stimulated or primed pretreated MSCs to treat LN.

Purpose Immune checkpoint inhibitors have recently been approved by the US FDA as first and/or second line therapy in a subset of cancer types. Recent evidence suggests that the quantity of tumor infiltrating lymphocytes (TILs) influences the likelihood of response to immune checkpoint inhibitors. Here, we set out to assess the density of CD8+ lymphocytes in a wide range of different cancer types and subtypes. Methods The density of CD8+ lymphocytes was compared across different cancer types using tissue microarrays (TMAs) composed of up to 50 tumor samples each from 84 different cancer types and subtypes. In total 2652 cancers and 608 normal tissues were successfully analyzed by CD8 immunohistochemistry followed by automated image analysis of digitized slides. Results We found that the median CD8+ lymphocyte counts ranged from 6 cells/mm2 in pleomorphic adenoma up to 1573 cells/mm2 in Hodgkin’s lymphoma. The CD8 counts were generally lower in normal tissues compared to cancer tissues. Blood vessels of the spleen were the only non-lymphatic tissue staining positive for CD8. Tumor types approved for checkpoint inhibitor therapy, including malignant melanoma (81), muscle invasive urothelial carcinoma (119), small cell lung cancer (120), clear cell renal cell cancer (153), squamous cell carcinoma (189) and adenocarcinoma of the lung (328) as well as Hodgkin’s lymphoma (1573) were all ranking among the upper half of our list. Comparably high CD8 densities (median cells/mm2) were also found in several rare and aggressive cancer types including Merkel cell carcinoma (70), angiosarcoma (95), anaplastic thyroid cancer (156) and embryonal carcinoma of the testis (186). In 73 of the 84 analyzed cancer types, the highly variable CD8 counts occasionally exceeded the average CD8 count of tumors for which checkpoint inhibitors have been approved. Conclusion These data support the concept that among most tumor types at least some individual cancers may benefit from treatment with immune checkpoint inhibitors.

Background: Zinc finger protein of cerebellum 2 (ZIC2) is a transcriptional activator or repressor that is important for the organogenesis of the central nervous system. Previous studies have reported that ZIC2 is widely upregulated in a variety of tumors. Methods: Oncomine database was used to evaluate the expression levels of ZIC2 in hepatocellular carcinoma (HCC) and normal liver tissues. Quantitative real-time polymerase chain reaction and immunohistochemistry were conducted to validate the results from the database. Cox regression analysis and survival curves were performed to assess the survival effect of ZIC2 in HCC. Results: Increased expression of ZIC2 was detected in HCC tissues compared with normal liver tissues. In addition, patients with high ZIC2 levels had a poor prognosis. Multivariate analysis showed that clinical stage (T or M classification) and ZIC2 levels were independent prognostic factors for overall survival. Moreover, a subgroup analysis revealed that patients with moderate or poor grade tumors, T1–2 tumors, N0 tumors, early American Joint Committee on Cancer (AJCC) stage, and old age were more likely to present with overexpression of ZIC2. To conclude, ZIC2 is upregulated in HCC and associated with the histology and survival of HCC patients. Conclusions: The expression status of ZIC2 may serve as an independent prognostic marker of HCC. Keywords: Zinc finger protein of cerebellum 2 (ZIC2), Prognosis, Hepatocellular carcinoma (HCC), Liver, Biomarker

Background Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking. Methods To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. Results In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 + tumor infiltrating lymphocytes in tumors with (mean = 685, median = 626) than without (mean = 227; median = 124) MMR deficiency (p Conclusions Our data suggest that MSI occurs early in a small subset of ductal adenocarcinomas of the pancreas and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate MMR status of the entire cancer mass.

Background and purpose Previous studies have found ischemic stroke is associated with atrial fibrillation. However, the causal association between ischemic stroke and atrial fibrillation is not clear. Furthermore, the network relationship among ischemic stroke, atrial fibrillation and its risk factors need further attention. This study aims to examine the potential causal association between ischemic stroke and atrial fibrillation and further to explore potential mediators in the causal pathway from ischemic stroke to atrial fibrillation. Methods Summary statistics from the ISGC (case = 10,307 and control = 19,326) were used as ischemic stroke genetic instruments, AFGen Consortium data (case = 65,446 and control = 522,744) were used for atrial fibrillation, and other consortia data were used for potential mediators (fasting insulin, white blood cell count, procalcitonin, systolic and diastolic blood pressure, body mass index, waist circumference, and height). Under the framework of network Mendelian randomization, two-sample Mendelian randomization study was performed using summary statistics from several genome-wide association studies. Inverse-variance weighted method was performed to estimate causal effect. Results Blood pressure mediates the causal pathways from ischemic stroke to atrial fibrillation. The total odds ratio of ischemic stroke on atrial fibrillation was 1.05 (95% confidence interval [CI], 1.02 to 1.07; P = 1.3 × 10−5). One-unit increase of genetically determined ischemic stroke was associated with 0.02 (DBP: 95% CI, 0.001 to 0.034, P = 0.029; SBP: 95% CI, 0.006 to 0.034, P = 0.003) upper systolic and diastolic blood pressure levels. Higher genetically determined systolic and diastolic blood pressure levels were associated with higher atrial fibrillation risk (DBP: RR, 1.18; 95% CI, 1.03 to 1.35; P = 0.012. SBP: RR, 1.18; 95% CI, 1.01 to 1.38; P = 0.04). Specially, we also found the bidirectional causality between blood pressure and ischemic stroke. Conclusions Our study provided a strong evidence that raised blood pressure in stroke patients increases the risk of atrial fibrillation and active acute blood pressure lowering can improve the outcome in ischemic stroke patients.

SS-31 is a kind of mitochondrion-targeted peptide. Recent studies indicated significant neuroprotective effects of SS-31. In this study, we investigated that SS-31 protected the murine cultured microglial cells (BV-2) against lipopolysaccharide (LPS)-induced inflammation and oxidative stress through stabilizing mitochondrial morphology. The morphological study showed that SS-31 preserved LPS-induced mitochondrial ultrastructure by reducing the fission protein 1 (Fis1) expression. Flow cytometry and Western blot verified that SS-31 defended the BV-2 cells against LPS-stimulated inflammation and oxidative stress via suppressing Fis1. To sum up, our study represents that SS-31 preserves BV-2 cells from LPS-stimulated inflammation and oxidative stress by down-regulating the Fis1 expression.

BackgroundAccumulated studies reported abnormal gene expression profiles of hepatocellular carcinoma (HCC) by cDNA microarray. We tried to merge cDNA microarray data from different studies to search for stably changed genes, and to find out better diagnostic and prognostic markers for HCC.MethodsA systematic review was performed by searching publications indexed in Pubmed from March 1, 2001 to July 1, 2016. Studies that reporting cDNA microarray profiles in HCC, containing both tumor and nontumor data and published in English-language were retrieved. The differentially expressed genes from eligible studies were summarized and ranked according to the frequency. High frequency genes were subjected to survival analyses. The expression and prognostic value of alanine-glyoxylate and serine-pyruvate aminotransferase (AGXT) was further evaluated in HCC datasets in Oncomine and an independent HCC tissue array cohort. The role of AGXT in HCC progression was evaluated by proliferation and migration assays in a human HCC cell line.ResultsA total of 43 eligible studies that containing 1917 HCC patients were included, a list of 2022 non redundant abnormally expressed genes in HCC were extracted. The frequencies of reported genes were ranked. We finally obtained a list of only five genes (AGXT; ALDOB; CYP2E1; IGFBP3; TOP2A) that were differentially expressed in tumor and nontumor tissues across studies and were significantly correlated to HCC prognosis. Only AGXT had not been reported in HCC. Reduced expression of AGXT reflected poor differentiation of HCC and predicts poor survival. Knocking down of AGXT enhanced cell proliferation and migration of HCC cell line.ConclusionsThe present study supported the feasibility and necessity of systematic review on discovering new and reliable biomarkers for HCC. We also identified a list of high frequency prognostic genes and emphasized a critical role of AGXT deletion during HCC progression.

Rationale: Although mesenchymal stem cell (MSC) transplantation has been proved to be an effective therapeutic approach to treat experimental Sjogren's syndrome (SS), the detailed underlying mechanisms remains unknown. IL-27 has diverse influences on the regulation of T cell differentiation and was involved in SS through modulating immune response. Here we aimed to explore whether IL-27-mediated regulation of immune cells was responsible for the beneficial effects of MSC transplantation on SS. Methods: The SS-like symptoms were evaluated in IL-27 deficient and recombinant IL-27-treated NOD mice. The MSCs were infused into NOD mice via the tail vein. The histological features of submandibular glands, saliva flow rate and serum IL-27 were examined. The effects of MSCs on the IL-27 production and Th17/Treg cell in SS patients and mice in vitro and in vivo were determined for the mechanistic study. Results: This study showed that SS patients had decreased IL-27 level and increased ratio of Th17/Treg cells. Consistently, exacerbated SS-like symptoms were observed in IL-27 deficient NOD mice, along with increased ratio of Th17/Treg cells. Importantly, MSC transplantation alleviated SS-like symptoms by elevating the level of IL-27 to restore Th17/Treg balance in NOD mice. Mechanistically, MSC-secreted interferon-β (IFN-β) promote dendritic cells to produce IL-27. Conclusions: Thus, we have revealed a previously unrecognized function of MSC-mediated IL-27 production by DCs in suppressing SS-like syndrome, which provided evidences for clinical application of MSC in patients with SS.

Uric acid is the final product of purine metabolism, and excessive serum uric acid can cause gouty arthritis and uric acid nephropathy. Therefore, lowering the uric acid level and alleviating inflammation in the body are the key points to treating these diseases. A stable nanosuspension of peptide BmK9 was prepared by the precipitation-ultrasonication method. By combining uricase on the surface of a positively charged carrier, a complex consisting of neutral rod-shaped BmK9 and uricase nanoparticles (Nplex) was formed to achieve the delivery of BmK9 and uricase, respectively. The formulation of Nplex has a diameter of 180 nm and drug loading up to 200%, which releases BmK9 and uricase slowly and steadily in drug release tests in vitro. There was significantly improved pharmacokinetic behavior of the two drugs because Nplex prolonged the half-life and increased tissue accumulation. Histological assessments showed that the dual drug Nplex can reduce the inflammation response in acute gouty arthritis and chronic uric acid nephropathy in vivo. In the macrophage system, there was lower toxicity and increased beneficial effect on inflammation with Nplex than free BmK9 or uricase. Collectively, this novel formulation provides a dual drug delivery system that can treat gouty arthritis and uric acid nephropathy.

Introduction Chronic eosinophilic pneumonia (CEP) is a rare disease with unknown etiology. Due to lack of specificity of CEP symptoms, clinicians are not experienced in establishing its diagnosis. Objectives To summarize the clinical data of CEP patients to improve the understanding of CEP and reduce misdiagnosis. Methods Data of patients pathologically diagnosed with CEP in the PLA General Hospital between May 2013 and May 2019 were collected, and clinical manifestations, imaging characteristics, pathological features, and treatment were retrospectively analyzed. Results Twenty patients, including 6 males and 14 females, were diagnosed with CEP. The average age was 47.0 ± 10.2 years. The main clinical manifestations were cough and dyspnea. The average duration of CEP was 15.5 ± 11.5 months. The average proportion of eosinophils in the peripheral blood was 18.9 ± 17.8%, and the average proportion of eosinophils in the bronchoalveolar lavage fluid was 41.5 ± 19.4%. The main imaging features were patchy shadows and consolidation shadows. The most common manifestations on bronchoscopic examination were congestion and edema of the bronchial mucosa. Two patients had granular protrusions of the endotracheal membrane. Histological examination indicated infiltration of numerous eosinophils. All patients improved after prednisone therapy. Conclusion CEP onset is insidious, and clinical manifestations lack specificity. Typical imaging features are peripheral and subpleural distribution of lung infiltrates. Some patients have a normal proportion of eosinophils in the peripheral blood, but most have an increased number of eosinophils in the BALF, which contributes to CEP diagnosis. A biopsy is necessary when differential diagnosis is difficult. A systemic glucocorticoid is effective.

Infection is a common cause of hospitalization and mortality in patients with systemic lupus erythematosus (SLE). How the underlying immune dysfunctions affect the antimicrobial immunity remains largely unknown. In the present study, employing the pulmonary infection model, we determined the antimicrobial defence of lupus-prone mice. After infecting with opportunistic bacterium Haemophilus influenzae (Hi), lupus-prone mice (B6/lpr) exhibited inefficient bacterial elimination and recovered slowly. They generated severer inflammation at the early stage of infection, as excessive accumulation of neutrophils and enhanced production of proinflammatory cytokines were observed in the lung. In addition, a large number of apoptotic cells were detected in the lungs of B6/lpr mice. For adaptive immune responses, B6/lpr mice were capable to generate enough protective Hi-specific Th17 cells. They evoked stronger Hi-specific γδ T17 response in both lungs and spleens. Unexpectedly, both CD4 and γδ T cells from lupus-prone mice showed deficiency in IFN-γ production. For humoral immune responses, compared with those of WT mice, the concentrations of Hi-specific IgA, IgM, and IgG, especially IgG, were significantly higher in the B6/lpr mice. Our findings suggest that lupus mice are capable to generate antibacterial immune responses; however, the overwhelming inflammation and overactivated immune responses increase the severity of infection.

Background Defective clearance of apoptotic cells (ACs) has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on SLE, but whether MSCs phagocytose ACs and contributes to the underlying mechanism in the treatment of SLE remain unknown. Methods Human umbilical cord (UC) MSCs were co-cultured with ACs, and the engulfment of ACs by MSCs was either detected by flow cytometry or observed under confocal laser scanning microscope. Peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) were cultured in MSC conditioned medium (MCM) or MSC exposed to ACs (AC-MSC) conditioned medium (ACMCM), and then CD4+ T cell proliferation was detected. Soluble factors including prostaglandin (PG)E2 in the supernatants of MSCs and AC-MSCs, as well as in the mouse peritoneal lavage fluids (PLF) were determined by enzyme-linked immunosorbent assay (ELISA). Cyclooxygenase (COX)2 inhibitors and siRNA transfection were utilized to determine the function of COX2/PGE2 in AC-MSC-mediated immunosuppression. PGE2 metabolites (PGEM) in the plasma of SLE patients were measured before and 24 h after MSC transplantation respectively. Findings Human UC MSCs possessed the ability to engulf ACs. AC-MSCs increased MSC-mediated suppression of CD4+ T cell proliferation compared to MSCs alone. Mechanistically, ACs stimulated MSCs to express COX2 and consequently produced PGE2 that inhibited T cell responses. NF-κB signalling pathway mediated the activation of COX2/PGE2 in AC-MSCs. Importantly, in patients with SLE, the plasma PGEM levels increased significantly in those with reduced apoptotic mononuclear cells in peripheral blood after MSC transplantation. Interpretation Clearance of ACs by MSCs contributes to immunosuppressive function via increasing PGE2 production. These findings reveal a previously unrecognized role of MSC-mediated phagocytosis of ACs in MSC-based immunotherapy. Fund This study was supported by grants from the Chinese Major International (Regional) Joint Research Project (No. 81720108020), the Jiangsu Province Major Research and Development Program (No. BE2015602) and the Jiangsu Province 333 Talent Grant (BRA2016001). WJ. Chen was supported by the Intramural Research Program of NIH, NIDCR.

This study presents an experimental and numerical investigation on the static behavior of headed stud shear connectors in ultra-high performance concrete (UHPC) of composite bridges. Four push-out specimens were tested. It was found that no cracking, crushing or splitting was observed on the concrete slab, indicating that UHPC slab exhibited good performance and could resist the high force transferred from the headed studs. The numerical and experimental results indicated that the shear capacity is supposed to be composed of two parts stud shank shear contribution and concrete wedge block shear contribution. The stiffness increment of a stud in UHPC was at least 60% higher than that in normal strength concrete. Even if the stud height was reduced from 6d to 2d, there was no reduction in the shear strength of a stud. Short stud shear connectors with an aspect ratio as small as 2 could develop full strength in UHPC slabs. An empirical load-slip equation taking into account stud diameter was proposed to predict the load-slip response of a stud. The reliability and accuracy of the proposed load-slip equation was verified by the experimental and numerical load-slip curves.

Background: Gene Regulatory Network (GRN) inference algorithms aim to explore casual interactions between genes and transcriptional factors. High-throughput transcriptomics data including DNA microarray and single cell expression data contain complementary information in network inference. Objective: To enhance GRN inference, data integration across various types of expression data becomes an economic and efficient solution. Method: In this paper, a novel E-alpha integration rule-based ensemble inference algorithm is proposed to merge complementary information from microarray and single cell expression data. This paper implements a Gradient Boosting Tree (GBT) inference algorithm to compute importance scores for candidate gene-gene pairs. The proposed E-alpha rule quantitatively evaluates the credibility levels of each information source and determines the final ranked list. Results: Two groups of in silico gene networks are applied to illustrate the effectiveness of the proposed E-alpha integration. Experimental outcomes with size50 and size100 in silico gene networks suggest that the proposed E-alpha rule significantly improves performance metrics compared with single information source. Conclusion: In GRN inference, the integration of hybrid expression data using E-alpha rule provides a feasible and efficient way to enhance performance metrics than solely increasing sample sizes.

Embryonic implantation involves a complex and well-coordinated interaction between the developing conceptus and maternal uterus, and the preimplantation period has a major impact on litter size in pigs. The present study aimed to investigate the vital messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) that regulate preimplantation in Meishan pigs. The enriched Gene Ontology terms were all related to "binding." Furthermore, "ECM-receptor interaction" was predicted as an important pathway that regulated the success of implantation. We speculated that the differentially expressed mRNAs S100A9, ANXA8, MUC16, and FGL2 and the differentially expressed lncRNAs TCONS_11206566, TCONS_09904861, and TCONS_1252933 may play vital roles in the process of implantation. Furthermore, this study verified that FGL2 was highly expressed on Day 12 of pregnancy, and we also investigated the function of FGL2 during preimplantation in vivo. In conclusion, this study provides useful information for further analyses of the molecular mechanisms of implantation in Chinese domestic pigs.

TIGIT is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. Here, we analysed two different types of tissue microarrays of healthy lymphatic and various inflamed tissues, colorectal and lung cancers, as well as >1700 tumour samples from 86 different tumour entities for TIGIT and/or PD-1 by bright field and/or multiplex fluorescence immunohistochemistry. TIGIT was detected in CD8+ cytotoxic T cells, CD4+ T helper cells, FOXP3+ regulatory T cells, and NK cells, but not in CD11c+ dendritic cells, CD68+ macrophages, and CD20+ B lymphocytes. TIGIT expression paralleled that of PD-1. More than 70% of TIGIT+ cells were PD-1+, and more than 90% of the PD-1+ cells were TIGIT+. Expression varied between different tissue compartments. TIGIT expression in tonsil gradually increased from the interfollicular area over the marginal/mantle zone to the germinal centre in all T cell subtypes. In inflammatory diseases, the strongest expression of TIGIT/PD-1 was found in Hashimoto thyroiditis. TIGIT+ lymphocytes were seen in all 86 different tumour entities with considerable high variability of TIGIT positivity within and between different cancer entities. Particularly, high densities of TIGIT+ lymphocytes were, for example, seen in squamous cell cancers of various origins. In summary, the variable expression levels of TIGIT and PD-1 in cell types and tissue compartments illustrate the high complexity of immune microenvironments. The high frequency of TIGIT (and PD-1) expressing lymphocytes in cancers highlights considerable opportunities for cotargeting with checkpoint inhibitors.

Osteoarthritis (OA) has been recognized as the most common chronic age-related disease. Cartilage degeneration influences OA therapy. Here we report that hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP) is essential for OA development. Elevated HPIP levels are found in OA patients. Col2a1-CreERT2/HPIPf/f mice exhibit obvious skeletal abnormalities compared with their HPIPf/f littermates. HPIP deficiency in mice protects against developing OA. Moreover, intra-articular injection of adeno-associated virus carrying HPIP-specific short hairpin RNA in vivo attenuates OA histological signs. Notably, in vitro RNA-sequencing and chromatin immunoprecipitation sequencing profiles identify that HPIP modulates OA cartilage degeneration through transcriptional activation of Wnt target genes. Mechanistically, HPIP promotes the transcription of Wnt targets by interacting with lymphoid enhancer binding factor 1 (LEF1). Furthermore, HPIP potentiates the transcriptional activity of LEF1 and acetylates histone H3 lysine 56 in the promoters of Wnt targets, suggesting that HPIP is an attractive target in OA regulatory network., Osteoarthritis (OA) is associated with cartilage degeneration, and no effective therapy exists. Here, the authors show that the HPIP protein modulates OA progression by regulating Wnt signaling, and that its knockdown in joints via AAV-mediated gene silencing attentuates pathology.

Aim Cardiovascular complications related to atherosclerosis are major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). However, the underlying mechanisms are not fully understood. Endothelial dysfunction has been identified as having involvement in pathogenesis of cardiovascular diseases and SLE. This study aims to evaluate endothelial cell injury in mice with the combination of lupus and atherosclerosis. Methods The mouse model of accelerated atherosclerosis in lupus (gld.apoE- / - mouse) was generated from apolipoprotein E-deficient (apoE- / - ) and Faslgld C57BL/6 mice. The lupus-like autoimmunity and atherosclerotic lesions were evaluated. The endothelial cell injury was determined. Results The results showed that the double-mutant gld.apoE- / - mice were generated. Spleens from 5-month-old gld.apoE- / - mice were significantly enlarged compared with wild-type mice (WT mice). The gld.apoE- / - mice produced high levels of total immunoglobulin G (IgG) and IgM and showed marked increase of IgG and C3 deposits in the glomeruli. The gld.apoE- / - mice displayed a pattern of glomerulonephritis typically found in SLE. The gld.apoE- / - mice have high levels of serum creatinine. The total cholesterol, low-density lipoprotein cholesterol and triglycerides were significantly increased, while high-density lipoprotein cholesterol decreased in the double-mutant mice. The circulating endothelial progenitor cells were significantly decreased. The serum levels of thrombomodulin and vascular cell adhesion molecule-1 were significantly elevated in gld.apoE- / - mice. The gld.apoE- / - mice simultaneously exhibited SLE and atherosclerosis characteristics. Conclusion Our findings indicated that endothelial cell injury might be a biomarker for evaluating risks of cardiovascular disease in SLE and targeting endothelial cell dysfunction might prevent and treat atherosclerosis in SLE.

Background Although observational studies have shown an association between sex hormone-binding globulin (SHBG), testosterone (T) and cardiovascular diseases (CVD), controversy remains. In this study, we aim to explore the causal effects of SHBG and T on Coronary heart disease (CHD). Methods We used univariable, network and multivariable mendelian randomization (MR) analysis to investigate the causal effect of SHBG and T on CHD. We performed inverse variance weighted (IVW) MR as the primary analysis, with the robustness of this approach further tested by other methods in sensitivity analysis. The SHBG and T were collected from the UK Biobank data, about 180,000 men aged 40 to 69 years. CHD was collected from CARDIoGRAMplusC4D 1000 Genomes-based GWAS, which was a meta-analysis including 48 studies and involving 60,801 CHD cases and 123,504 controls. Results Using univariable MR-IVW, the results suggested that a one standard deviation (SD) increase in SHBG, the risk of CHD decreased by approximately 14% (OR (95% CI): 0.86(0.76,0.97)), and that a SD increase in total testosterone (TT), the risk also decreased, approximately 8% (OR (95% CI): 0.92(0.85,0.99)). Multivariable MR showed that both SHBG and TT had no direct causal effect with CHD (a SD increase in SHBG: OR (95% CI):0.75(0.57,1.00), P = 0.053; a SD increase in TT: OR (95% CI): 1.05(0.90,1.22), P = 0.53). In the network MR analysis, the results suggested that TT might act as mediator in the causal pathway from SHBG to CHD and account for 93% of the total effect of SHBG on CHD, and that SHBG might be a mediator in the causal pathway from TT to CHD and account for 67% of the total effect of TT on CHD. Conclusions Genetically predicted SHBG and TT were negatively correlated with CHD in both univariable and network MR, which may provide a causal explanation behind the observed conclusion. In addition, TT and SHBG had a bidirectional causal effect. Further work is required to disentangle the downstream effects of SHBG/TT on CHD and the molecular pathways involved, as the simultaneous regulation of SHBG and TT may make it a viable strategy for the prevention or treatment of CHD.

Background: The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking.Methods: A comprehensive factorial Mendelian randomization (MR) was performed in the UK Biobank cohort involving 273,368 individuals with European ancestry to assess and quantify these effects. The factorial MR, MR-PRESSO, MR-Egger, meta-regression, sensitivity analysis, positive control, and external verification were utilized. Outcomes include major outcomes [overall CVD, ischemic heart diseases (IHD), and cerebrovascular diseases (CED)] and minor outcomes [angina pectoris (AP), acute myocardial infarction (AMI), chronic IHD (CIHD), heart failure (HF), hemorrhagic stroke (HS), and ischemic stroke (IS)].Results: The TyG index significantly increased the risk of overall CVD [OR (95% CI): 1.20 (1.14–1.25)], IHD [OR (95% CI): 1.22 (1.15–1.29)], CED [OR (95% CI): 1.14 (1.05–1.23)], AP [OR (95% CI): 1.29 (1.20–1.39)], AMI [OR (95% CI): 1.27 (1.16–1.39)], CIHD [OR (95% CI): 1.21 (1.13–1.29)], and IS [OR (95% CI): 1.22 (1.06–1.40)]. Joint exposure to genetically higher GLU and TG was significantly associated with a higher risk of overall CVD [OR (95% CI): 1.17 (1.12–1.23)] and IHD [OR (95% CI): 1.22 (1.16–1.29)], but not with CED. The effect of GLU and TG was independent of each other genetically and presented dose–response effects in bivariate meta-regression analysis.Conclusions: Lifelong genetic exposure to higher GLU and TG was jointly associated with higher cardiac metabolic risk while the TyG index additionally associated with several cerebrovascular diseases. The TyG index could serve as a more sensitive pre-diagnostic indicator for CVD while the joint GLU and TG could offer a quantitative risk for cardiac metabolic outcomes.

Causal evidence of circulating lipids especially the remnant cholesterol with cardiovascular and cerebrovascular disease (CVD) is lacking. This research aimed to explore the causal roles of extensive lipid traits especially the remnant lipids in CVD.Two-sample Mendelian randomization (TSMR) analysis was performed based on large-scale meta-analysis datasets in European ancestry. The causal effect of 15 circulating lipid profiles including 6 conventional lipids and 9 remnant lipids on coronary heart disease (CHD) and ischemic stroke (IS), as well as the subtypes, was assessed.Apolipoprotein B (Apo B), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were still important risk factors for CHD and myocardial infarction (MI) but not for IS. Apo B is the strongest which increased the CHD and MI risk by 44% and 41%, respectively. The odds ratios (ORs) of total TG on CHD and MI were 1.25 (95% confidence interval [CI], 1.13-1.38) and 1.24 (95% CI, 1.11-1.38), respectively. A one standard deviation difference increased TG in medium very-low-density lipoproteins (M.VLDL.TG), TG in small VLDL (S.VLDL.TG), TG in very small VLDL (XS.VLDL.TG), TG in intermediate-density lipoproteins (IDL.TG), TG in very large HDL (XL.HDL.TG), and TG in small HDL (S.HDL.TG) particles also robustly increased the risk of CHD and MI by 9-28% and 9-27%, respectively. TG in very/extremely large VLDL (XXL.VLDL.TG and XL.VLDL.TG) were insignificant or even negatively associated with CHD (in multivariable TSMR), and negatively associated with IS as well.The remnant lipids presented heterogeneity and two-sided effects for the risk of CHD and IS that may partially rely on the particle size. The findings suggested that the remnant lipids were required to be intervened according to specific components. This research confirms the importance of remnant lipids and provides causal evidence for potential targets for intervention.

China has conducted a long-term low-carbon technology innovation (LCTI), but there was a faster increase of CO2 emission in 2017 and 2018 than in 2016, which has lead scholars to doubt the effect of LCTI on CO2 emission. This paper builds a spatial auto regression (SAR) model with provincial panel data from 2011 to 2017 to calculate the spatial spillover effect of China's LCTI on regional CO2 emission. The results show that regional LCTI can reduce the local CO2 emission, but will increase the CO2 emission of adjacent regions due to spatial spillover effect. This produces the uncertainty of the promotion effect of LCTI on China's low-carbon transformation. Therefore, this paper suggests innovation resources should be appropriately and evenly distributed among regions to avoid their agglomeration in few regions.

The inhalation of dust containing certain nickel compounds has been associated with an increased risk of lung and nasal cancers in occupational studies of workers who process or refine sulfidic nickel ores and are exposed to relatively high levels of mixtures of water-soluble, sulfidic, oxidic, and/or metallic forms of nickel. We conducted a systematic review of the potential carcinogenicity of metallic nickel, focusing on cancers of the respiratory tract. We evaluated the quality and risk of bias (RoB) of the relevant epidemiology, experimental animal, and in vitro mechanistic studies using the National Toxicology Program's Office of Health Assessment and Translation (OHAT) RoB Rating Tool. We then used a systematic review protocol based on the OHAT approach to critically assess whether metallic nickel should be considered a human respiratory carcinogen. Our evaluation of the epidemiology studies indicates that there is no substantive evidence of increased respiratory cancer risk in workers exposed predominantly to metallic nickel. Animal evidence indicates that metallic nickel does not increase the incidence of respiratory tumors in rodents exposed by inhalation. The in vitro studies are limited in value, as they bypass normal clearance mechanisms. Nevertheless, the mechanistic evidence indicates that metallic nickel is not mutagenic but can induce DNA strand breaks under certain conditions. Based on a standard framework for assessing causality, we conclude that the evidence does not support a causal relationship between metallic nickel exposure and respiratory cancer in humans.

Background In epidemiology studies, ambient measurements of PM2.5 are often used as surrogates for personal exposures. However, it is unclear the degree to which ambient PM2.5 reflects personal exposures. Objective In order to examine potential sources of bias in epidemiology studies, we conducted a review and meta-analysis of studies to determine the extent to which short-term measurements of ambient PM2.5 levels are related to short-term measurements of personal PM2.5 levels. Methods We conducted a literature search of studies reporting both personal and ambient measurements of PM2.5 published in the last 10 years (2009–2019) and incorporated studies published prior to 2009 from reviews. Results Seventy-one studies were identified. Based on 17 studies reporting slopes, a meta-analysis revealed an overall slope of 0.56 μg/m3 (95% CI: [0.39, 0.73]) personal PM2.5 per μg/m3 increase in ambient PM2.5. Slopes for summer months were higher (slope = 0.73, 95% CI: [0.64, 0.81]) than for winter (slope = 0.46, 95% CI: [0.36, 0.57]). Based on 44 studies reporting correlations, we calculated an overall personal-ambient PM2.5 correlation of 0.63 (95% CI: [0.55, 0.71]). Correlations were stronger in studies conducted in Canada (r = 0.86, 95% CI: [0.67, 0.94]) compared to the USA (r = 0.60, 95% CI: [0.49, 0.70]) and China (r = 0.60, 95% CI: [0.46, 0.71]). Correlations also were stronger in urban areas (r = 0.53, 95% CI: [0.43, 0.62]) vs. suburban areas (r = 0.36, 95% CI: [0.21, 0.49]). Significance Our results suggest a large degree of variability in the personal-ambient PM2.5 association and the potential for exposure misclassification and measurement error in PM2.5 epidemiology studies.