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Metabolic products can lead to crucial biological function alterations. Itaconate is probably the best example of how a metabolic process can be diverted to generate an immunomodulator effect in macrophages. Through inflammatory stimuli, such as lipopolysaccharide, the immune response gene 1 is activated and promotes the production of itaconate from the tricarboxylic acid cycle by decarboxylating cis-aconitate. Itaconate has been reported to have multiple immunoregulatory and antioxidative effects. In addition, reports have described its antibacterial and protumor effects. The involved mechanism in these effects includes the activation of nuclear factor E2-related factor 2 by alkylation of Kelch-like ECH-associated protein 1, inhibition of aerobic glycolysis by targeting glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase A, inhibition of succinate dehydrogenase, and blockade of IκBζ translation. All of these discoveries elucidated the transformation of the pro- into anti-inflammatory status in macrophages, which is crucial in innate immunity and set the ground for the emerging therapeutic implications of itaconate. In this review, we point out that itaconate is a novel and pivotal metabolic determinant of the immunoregulatory response in macrophages and highlight studies that have improved our understanding of the connection between the immune response and metabolism. In addition, we shed light on the therapeutic potential of itaconate and its derivatives to treat inflammatory diseases.

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell–mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4(+)/CD8(+) T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

Introduction: mTNBC progresses rapidly on first-line chemotherapy. For instance, in the TNT trial, median progression-free survival (PFS) was 3 months on first-line carboplatin. Selective inhibition of Wee1, a negative regulator of the G2 cell cycle checkpoint, may enhance the efficacy of DNA-damaging agents by reducing DNA damage repair. We report the results of the first phase II study assessing the efficacy of the Wee1 inhibitor adavosertib (AZD-1775) with cisplatin in mTNBC. Methods: mTNBC patients (pts) with 0-1 prior lines of chemotherapy in the metastatic setting were eligible. Pts received cisplatin 75 mg/m2 IV followed by combination therapy 21 d later with cisplatin plus adavosertib 200 mg oral twice daily x 5 doses over 2.5 d every 21 d. Tumor biopsies were mandatory for patients with safely accessible tumors, and occurred 5-48 h after monotherapy and 5-8 h after the last adavosertib dose in the first combination therapy cycle. The study used a Simon optimal two-stage design that had 90% power to detect the difference between null (20%) and alternative (40%) response rates with a one-sided type I error of 0.1. The primary endpoint was objective response rate (ORR): an ORR > 30% would identify the regimen as worthy of further study. Key secondary endpoints were PFS and overall survival (OS). Exploratory analyses evaluated the association of response, defined as clinical benefit rate (CBR) > 6 months (CR + PR + SD > 6 mos), with transcriptional and immunostaining profiles of on-treatment tumors (n = 16), as well as with targeted panel genomic alterations in archival tissue. Tumor immune cell composition was assessed by CIBERSORT. Results: 34 pts initiated protocol therapy; median age was 56 yrs, 2 (6%) pts had known BRCA2 mutations, and 14 (41%) had 1 prior line of chemotherapy. Median follow-up was 13 mos. ORR was 29% (3 CR + 7 PR), median PFS 4.9 months (95% CI, 2.3-5.8 mos), CBR 35%, and preliminary OS 14.0 mos (95% CI, 11.8-21.8 mos). All-cause AEs occurred in 100% of pts (G3-4, 56%; most commonly diarrhea, 21%), including one death due to sepsis possibly related to study therapy. The primary tumor of the longest responding patient had a possible biallelic loss-of-function alteration (missense mutation and loss of heterozygosity) in the homologous recombination-related gene FANCM. In Hallmark gene set enrichment analyses of 26 on-treatment biopsies across 16 pts, responding tumors (n = 4) demonstrated enriched expression of immune response gene sets (allograft rejection FDR q < 0.001, IL2-STAT5 signaling FDR q = 0.001, inflammatory response FDR q = 0.003), while non-responding tumors (n = 12) showed enrichment of cell cycle gene sets (E2F targets FDR q < 0.001, G2M checkpoint FDR q < 0.001). In the same on-treatment biopsies, responding tumors (n = 4) had higher tumor infiltrating lymphocytes (46% v. 29%, Mann-Whitney p = 0.04) and lower M0 macrophages (3% v. 17%, Mann-Whitney p = 0.04) than non-responding tumors (n =12). Updated data, including OS and tissue immunostaining results, will be presented. Conclusions: Among mTNBC pts, the combination of adavosertib and cisplatin was associated with a 29% ORR, failing to meet the pre-determined ORR of > 30% required to support further investigation. Responses were associated with immune-related gene expression and TILs detected by RNA sequencing. Citation Format: Tanya E. Keenan, Zhenying Tan-Wasielewski, Lorenzo Trippa, Bose Kochupurakkal, Jennifer L. Guerriero, Rie K. Tahara, Grace Winship, Wafa Osmani, Chelsea Andrews, Jake R. Conway, Meng X He, Ricardo Pastorello, Adam Tracy, Robert E. Godin, Beth A. Overmoyer, Eric P. Winer, Elizabeth A. Mittendorf, Geoffrey I Shapiro, Eliezer M Van Allen, Sara M Tolaney. A phase II study of cisplatin and the Wee1 inhibitor adavosertib in metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-08.

While cannabis is among the most used recreational drugs during pregnancy, the impact of maternal cannabis use (mCB) on fetal and child development remains unclear. Here, we assessed the effects of mCB on psychosocial and physiological measures in young children along with the potential relevance of the in utero environment reflected in the placental transcriptome. Children (∼3 to 6 y) were assessed for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children (BASC-2) survey, and heart rate variability (HRV) at rest and during auditory startle. For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing. Hair hormone analysis revealed increased cortisol levels in mCB children. In addition, mCB was associated with greater anxiety, aggression, and hyperactivity. Children with mCB also showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone. In the placenta, there was reduced expression of many genes involved in immune system function including type I interferon, neutrophil, and cytokine-signaling pathways. Finally, several of these mCB-linked immune genes organized into coexpression networks that correlated with child anxiety and hyperactivity. Overall, our findings reveal a relationship between mCB and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood.

CD14 (also known as the monocyte differentiation antigen) is an important immune response gene known to be primarily responsible for innate immunity against bacterial pathogens, and as a pattern recognition receptor (PRR), binds with LPS (endotoxin), lipoproteins, and lipotechoic acid of bacteria. So far very limited work has been conducted in parasitic immunology. In the current study, we reported the role of CD14 in parasitic immunology in livestock species (sheep) for the first time. Ovine CD14 is characterized as a horse-shoe shaped bent solenoid with a hydrophobic amino-terminal pocket for CD14 along with domains. High mutation frequency was observed, out of total 41 mutations identified, 23 mutations were observed to be thermodynamically unstable and 11 mutations were deleterious in nature, causing major functional alteration of important domains of CD14, an indication of variations in individual susceptibility for sheep againstHaemonchus contortusinfestations.In silicostudies with molecular docking reveal a role of immune response againstHaemonchus contortusin sheep, which is later confirmed with experimental evidence through differential mRNA expression analysis for sheep, which revealed better expression of CD14 inHaemonchus contortusinfected sheep compared to that of non-infected sheep. We confirmed the above findings with supportive evidence through haematological and biochemical analyses. Phylogenetic analysis was conducted to assess the evolutionary relationship with respect to humans and it was observed that sheep may well be used as model organisms due to better genetic closeness compared to that of mice.

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss but whether recipient risk allele expression impacts kidney transplant outcomes is unclear. To test whether recipient APOL1 allelic variants independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of genetic ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. Analysis of the CTOT cohort validated these associations. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4+/CD8+ T cells and natural killer cells. We detected enriched immune response gene pathways in G1/G2 allele carriers vs. non-carriers among patients on the kidney waitlist and healthy controls. Together our findings highlight a previously unrecognized contribution of recipient APOL1 risk alleles to renal allograft outcomes. This immunomodulatory role has broader implications for immune mediated injury to native kidneys.

Metabolites have recently been found to be involved in significant biological regulation and changes. Itaconate, an important intermediate metabolite isolated from the tricarboxylic acid cycle, is derived from cis-aconitate decarboxylation mediated by immune response gene 1 in mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component involved in the development and progression of inflammation and immunity. It could directly modify cysteine sites on functional substrate proteins which related to inflammasome, signal transduction, transcription, and cell death. Itaconate can be a connector among immunity, metabolism, and inflammation, which is of great significance for further understanding the mechanism of cellular immune metabolism. And it could be the potential choice for the treatment of inflammation and immune-related diseases. This study is a systematic review of the potential mechanisms of metabolite associated with different pathology conditions. We briefly summarize the structural characteristics and classical pathways of itaconate and its derivatives, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.

CD14 (also known as monocyte differentiation antigen) is an important immune response gene known to be primarily responsible for innate immunity against bacterial pathogen and as pattern recognition receptor (PRR) binds with LPS (endotoxin), lipoproteins, lipotechoic acid of bacteria.So far very limited work has been conducted in parasitic immunology. In the current study, we reported the role of CD14 in parasitic immunology in livestock species (sheep) for the first time. Ovine CD14 is characterized as a horse-shoe shaped as a bent solenoid with a hydrophobic amino-terminal pocket for CD14 along with domains. High mutation frequency was observed, out of total 41 mutations identified, 23 mutations were observed to be thermodynamically unstable and 11 mutations were deleterious in nature, causing major functional alteration of important domains of CD14, an indicative for variations in individual susceptibility for sheeps against Haemonchus contortus infestations. In silico studies with molecular docking reveals a role of immune response against Haemonchus contortus in sheep, which is later confirmed with experimental evidence through differential mRNA expression analysis for sheep, which revealed better expression of CD14 in Haemonchus contortus infected sheep compared to that of healthy sheep. We confirmed the above findings with supportive evidences with haematological and biochemical analyses. Phylogenetic analysis was conducted to assess the evolutionary relationship with respect to human and observed that sheep may well be used as model organism due better genetic closeness compared to that of mouse.

Background and PurposeTo directly reveal the change in genome mutation, RNA transcript of tumor cells, and tumor microenvironment (TME) after stereotactic body radiotherapy (SBRT) in paired human lung tumor specimens.Materials and MethodsPaired tumor samples were collected from 10 patients with non-small cell lung cancer (NSCLC) or lung metastatic carcinoma within a week before and after SBRT. DNA and RNA of tumor tissues was extracted from the paired samples. Whole-exome and RNA sequencing assays were performed by next-generation sequencing. Gene mutation, genomic expression, T-cell receptor (TCR) repertoire, and profiling of tumor-infiltrating immune cells were analyzed through bioinformatics analysis in paired tumor samples. CD8+ T-cell infiltration and PD-L1 expressions were detected by immunostaining in tumor tissues.ResultsThe diversity of TCR repertoire and PD-L1 expression increased significantly in the TME, and the most enriched term of the gene ontology analysis was the immune response gene after receiving SBRT. SBRT induced neo-mutation of genes in tumor cells but did not increase tumor mutation burden in tumor tissues. TME displayed complex immune cell changes and infiltration and expression of immune-regulating factors such as C-X-C motif chemokine (CXCL) 10, CXCL16, interferons (IFNs), and IFN receptors. CD8+ T-cells in tumor tissues did not improve significantly after SBRT while the infiltrating TH1 and TH2 cells decreased remarkably.ConclusionSBRT improved the TCR repertoire diversity and PD-L1 expression in the TME and induced neo-mutation of genes in tumor cells but did not increase CD8+ T-cell infiltration and IFN expression in the tumor tissue within a week.

Background and Aim: Thermal stress (hot or cold) is one of many environmental stressors that severely affects the health of broiler chickens. One negative effect of thermal stress is the disruption of the intestinal barrier function in broiler chickens. This study aimed to evaluate the effect of thermal manipulation (TM) on the small intestine in terms of histomorphometry as well as junctional, heat-shock, and immune response gene expression during post-hatch exposure to thermal stress. Materials and Methods: The experiment was conducted by dividing 928 fertile Ross eggs into three incubation groups: The control (C) group (incubated at 37.8°C and 56% relative humidity [RH] for the whole incubation period), the TM using low temperature TML group (incubated at 36°C and 56% RH for 18 h/day from embryonic days 7 to 16), and the TM using high temperature (TMH) group (incubated at 39°C and 65% RH for 18 h/day from embryonic days 7 to 16). On post-hatch day 21, 90 chicks were randomly selected from each incubation group and were equally subdivided into three subgroups for the post-hatch thermal stress experiment: The TN subgroup (room temperature maintained at 24°C), the heat stress (HS) subgroup (room temperature maintained at 35°C), and the cold stress (CS) subgroup (room temperature maintained at 16°C). After 1 day of thermal stress exposure (age 22 days), five birds from each subgroup were euthanized and ileum samples were collected to evaluate the transcription of the Claudin (CLDN1), CLDN-5, Occludin, Cadherin-1, heat shock factors (HSF1), HSF3, 70 kilodalton heat shock protein, 90 kilodalton heat shock protein, Interleukin 6 (IL6), IL8, toll-like receptors-2 (TLR2), and TLR4 genes by Real-Time Quantitative Reverse Transcription polymerase chain reaction analysis. Finally, after 4 and 7 days of thermal stress (age 25 and 28 days, respectively), nine chicks were euthanized, and their jejunum and ileum were collected for histomorphometric analysis. Results: After exposure to 1 day of thermal stress, the C subgroups exposed to thermal stress (HS and CS) possessed significantly increased expression of junctional, heat-shock, and immune response genes compared to the C-TN subgroup, and similar results were observed for the TMH. In contrast, thermally stressed TMH subgroups had significantly lower expression of the studied genes compared to C subgroups exposed to thermal stress. Furthermore, no significant changes were detected between the TML subgroups exposed to thermal stress and TML-TN. Moreover, significant alterations in villus height (VH), villus surface area, crypt depth (CD), and VH to CD ratio were observed between the TML, TMH, and C subgroups exposed to CS. Conclusion: It might be suggested that TM may have a protective impact on the small intestine histomorphometry and epithelial integrity of broilers during post-hatch exposure to thermal stress.

Simple Summary The aim of this analysis was to reveal the effects of Citrus aurantium essential oil on growth performance, histopathological effect on digestive system organs, expression levels of some growth-related genes in the muscle tissue and some immune-related genes in the head kidney of common carp Cyprinus carpio. To determine the effect of essential oil on carp, experimental diets containing different concentrations of essential oil were prepared, and the fish were fed these diets for 60 days. At the end of the feeding experiment, it was observed that low-dose essential oil supplementation increased immune related gene expression levels and growth-related gene expression levels in head kidney and muscle tissue, respectively. Pathological findings were observed in the liver and intestines of fish fed with high doses of essential oil supplemented diets. Abstract The aim of this study was to detect effects of bitter orange (Citrus aurantium) essential oil, commonly called neroli oil (NO) (0, 0.25, 0.50, 1, and 1.5% referred to as NO0 NO0.25, NO0. 05, NO1 and NO1.5, respectively) on growth performance output and expression levels of some growth-related genes in the muscle tissue and some immune-related genes in the head kidney and pathological differences in digestive system organs of common carp Cyprinus carpio. The NO0.25 group had a large improvement in growth efficiency at the end of the 60-day feeding cycle. Real-time PCR (Bio RAD, USA) system was used to detect variations in gene expression levels. Furthermore, NO supplementation of up to 0.25% in muscle tissue controlled the release of growth hormone (GH) and insulin-like growth factor I (IGF-I). Furthermore, in the NO0.25 treatment category, immune response gene levels TNF-α, IL-8 and IL-1ß increased in head kidney tissue. In the histological examination of the liver and intestine, there were significant differences between fish fed with N1 and N1.5 diets. This study confirms that dietary supplementation of NO up to 0.25% can improve common carp growth efficiency and increase the expression of genes (GH and IGF-I) related to muscle growth, TNF-α, IL-8 and IL-1ß genes related to immune status, and liver and intestine histological status of common carp.

Avian influenza is an alarming disease, which has every possibility to evolve as human to human pandemic situation due to frequent mutation and genetic reassortment or recombination of Avian influenza(AI) virus. The greatest concern is that till date no satisfactory medicine or vaccines are available, leading to massive culling of poultry birds causing huge economic loss, and ban on export of chicken products, which emphasise the need develop alternative strategy for control of AI. In the current study we attempt to explore the molecular mechanism of innate immune potential of ducks against common viral diseases including Avian influenza. In the present study, we have characterized immune response molecules as duck TLR3, TLR7, and RIGI and predicted to have potent antiviral activities against different identified strains of Avian influenza through in silico studies (molecular docking). Future exploitation involve immunomodulation with the recombinant protein, transgenic or gene-edited chicken resistant to bird flu.

Background Functional disruptions by large germline genomic structural variants in susceptible genes are known risks for cancer. We used deletion structural variants (DSVs) generated from germline whole-genome sequencing (WGS) and DSV immune-related association tumor microenvironment (TME) to predict cancer risk and prognosis. Methods We investigated the contribution of germline DSVs to cancer susceptibility and prognosis by silicon and causal inference models. DSVs in germline WGS data were generated from the blood samples of 192 cancer and 499 non-cancer subjects. Clinical information, including family cancer history (FCH), was obtained from the National Cheng Kung University Hospital and Taiwan Biobank. Ninety-nine colorectal cancer (CRC) patients had immune response gene expression data. We used joint calling tools and an attention-weighted model to build the cancer risk predictive model and identify DSVs in familial cancer. The survival support vector machine (survival-SVM) was used to select prognostic DSVs. Results We identified 671 DSVs that could predict cancer risk. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) of the attention-weighted model was 0.71. The 3 most frequent DSV genes observed in cancer patients were identified as ADCY9, AURKAPS1, and RAB3GAP2 (p < 0.05). The DSVs in SGSM2 and LHFPL3 were relevant to colorectal cancer. We found a higher incidence of FCH in cancer patients than in non-cancer subjects (p < 0.05). SMYD3 and NKD2DSV genes were associated with cancer patients with FCH (p < 0.05). We identified 65 immune-associated DSV markers for assessing cancer prognosis (p < 0.05). The functional protein of MUC4 DSV gene interacted with MAGE1 expression, according to the STRING database. The causal inference model showed that deleting the CEP72 DSV gene affect the recurrence-free survival (RFS) of IFIT1 expression. Conclusions We established an explainable attention-weighted model for cancer risk prediction and used the survival-SVM for prognostic stratification by using germline DSVs and immune gene expression datasets. Comprehensive assessments of germline DSVs can predict the cancer risk and clinical outcome of colon cancer patients.

The premalignant process preceding squamous cell lung cancer is not inevitable; it can stop at any of the bronchial lesions: basal cell hyperplasia (BCH), squamous metaplasia (SM), and dysplasia and then progress or regress. At present, the mechanisms underlying the progression of the bronchial lesions remain undefined. Previously, we hypothesized that bronchial lesions that presented individually or combined with each other in the bronchi of lung cancer patients mirror the different "scenarios" of the premalignant process: individual BCH-the stoppage at the stage of hyperplasia, BCH plus SM-the progression of hyperplasia to metaplasia, and SM plus dysplasia-the progression of metaplasia to dysplasia. In this study, we analyzed gene expression profiles of BCH, SM, and dysplasia depending on their cooccurrence in the bronchi of lung cancer patients. The immune response gene expression was found to be a key difference between the individual BCH and BCH combined with SM lesions and a potential mechanism that determines the progression of hyperplasia to metaplasia. Upregulation of the cell cycle and downregulation of the cilium assembly genes mainly distinguished SM that copresented with dysplasia from SM that copresented with BCH and is a probable mechanism of the progression of metaplasia to dysplasia. Dysplasia showed mainly overexpression of the cell division genes and underexpression of the inflammation genes. Thus, this study demonstrates the significant gene expression differences between the premalignant lesions depending on their cooccurrence in the bronchi and sheds light on the mechanisms of the precancerous process preceding squamous cell lung cancer.

RNA binding proteins regulate gene expression through several post-transcriptional mechanisms. The broadly expressed HuR/ELAVL1 is important for proper function of multiple immune cell types, and has been proposed to regulate cytokine and other mRNA 3′ UTRs upon activation. However, this mechanism has not been previously dissected in stable cellular settings. In this study, HuR demonstrated strong anti-apoptotic and activation roles in Jurkat T cells. Detailed transcriptomic analysis of HuR knockout cells revealed a substantial negative impact on the activation program, coordinately preventing the expression of immune response gene categories, including all cytokines. Knockout cells showed a significant defect in IL-2 production, which was rescued upon reintroduction of HuR. Interestingly, the mechanism of HuR regulation did not involve control of the cytokine 3′ UTRs: HuR knockout did not affect the activity of 3′ UTR reporters in 293 cells, and had no effect on IL-2 and TNF 3′ UTRs in resting or activated Jurkats. Instead, impaired cytokine production corresponded with defective induction of the IL-2 promoter upon activation. Accordingly, upregulation of NFATC1 was also impaired, without 3′ UTR effects. Together, these results indicate that HuR controls cytokine production through coordinated upstream pathways, and that additional mechanisms must be considered in investigating its function.

Background Obesity is a well-known risk factor for endometrial cancer, but the mechanisms of obesity-related carcinogenesis are not well defined, particularly for premenopausal women. With the continuing obesity epidemic, increases in the incidence of endometrial cancer and a younger age of diagnosis are often attributed to a hyperestrogenic state created by hormone production in adipose tissue, but significant knowledge gaps remain. The balance of estrogen-responsive signals has not been defined in the endometrium of premenopausal women with obesity, where obesity may not create hyperestrogenism in the context of ovaries being the primary source of estrogen production. Obesity is associated with a state of low-grade, chronic inflammation that can promote tumorigenesis, and it is also known that hormonal changes alter the immune microenvironment of the endometrium. However, limited research has been conducted on endometrial immune-response changes in women who have an increased risk for cancer due to obesity. Objective Endometrial estrogen-regulated biomarkers, previously shown to be dysregulated in endometrial cancer, were evaluated in a cohort of premenopausal women to determine if obesity is associated with differences in the biomarker expression levels, which might reflect an altered risk of developing cancer. The expression of a multiplexed panel of immune-related genes was also evaluated for expression differences related to obesity. Study Design Premenopausal women with a body mass index of ≥30 kg/m2 (n=97) or a body mass index of ≤25 kg/m2 (n=33) were prospectively enrolled in this cross-sectional study, which included the assessment of serum metabolic markers and a timed endometrial biopsy for pathologic evaluation, hormone-regulated biomarker analysis, and immune response gene expression analysis. Medical and gynecologic histories were obtained. Endometrial gene expression markers were also compared across the body mass index groups in a previous cohort of premenopausal women with an inherited cancer risk (Lynch syndrome). Results In addition to known systemic metabolic differences, histologically normal endometria from women with obesity showed a decrease in gene expression of progesterone receptor (P=.0027) and the estrogen-induced genes retinaldehyde dehydrogenase 2 (P=.008), insulin-like growth factor 1 (P=.016), and survivin (P=.042) when compared with women without obesity. The endometrial biomarkers insulin-like growth factor 1, survivin, and progesterone receptor remained statistically significant in multivariate linear regression models. In contrast, women with obesity and Lynch syndrome had an increased expression of insulin-like growth factor 1 (P=.017). There were no differences in endometrial proliferation, and limited endometrial immune differences were observed. Conclusion When comparing premenopausal women with and without obesity in the absence of endometrial pathology or an inherited cancer risk, the expression of the endometrial biomarkers does not reflect a local hyperestrogenic environment, but it instead reflects a decreased cancer risk profile that may be indicative of a compensated state. In describing premenopausal endometrial cancer risk, it may be insufficient to attribute a high-risk state to obesity alone; further studies are warranted to evaluate individualized biomarker profiles for differences in the hormone-responsive signals or immune response. In patients with Lynch syndrome, the endometrial biomarker profile suggests that obesity further increases the risk of developing cancer.

The human lymphocyte antigen (HLA) system was originally defined as the human histocompatibility complex (MHC) because its products are strong histocompatibility antigens. HLA class I and II products are essential for T-cell activation and for the regulation of the immune response. Moreover, they are immune response gene products because their polymorphism leads to interindividual differences in immune responsiveness. HLA class I molecules are produced by and present on the membrane of basically all nucleated cells. HLA class II molecules are mainly present on cells of the immune system: macrophages and other antigen-presenting cells, B-cells, and activated T-cells. The etiological fraction indicates how much this HLA-associated factor contributes to susceptibility for a given disease at the population level. The problem with this approach is that it involves two unknowns: HLA and autoimmunopathogenesis. Most autoimmune diseases are associated with class II HLA antigens. Another observation of more recent date is the expression of class II molecules on cells which normally do not express these molecules.

Aspergillus flavus (A. flavus) infection and aflatoxin contamination is a major bottleneck for peanut cultivation and value chain industry. In this study, a transcriptomic network study was conducted by retrieving publically available RNA-seq datasets of resistant and susceptible peanut varieties infected by A. flavus separately to understand the peanut defense mechanism against A. flavus. The gene expression analysis revealed differentially expressed genes (DEGs) in response to the different levels of infection and coexpression network of DEGs deciphered hub genes involved in the immune process in resistant and susceptible varieties. The interplay of resistance conferring genes and cell wall related genes was observed through functional enrichment analysis in response to pathogen infection and identified few key genes such as Protein P21, R genes, Pattern Recognition Receptor genes, Pectinesterases, Laccase and Thaumatin-like protein 1b as candidate genes in imparting immune response against A. flavus.

Pegbovigrastim is a commercial long-acting analog of bovine granulocyte colony-stimulating factor (rbG-CSF) that promotes the increased count and functionality of polymorphonuclear cells in dairy cows around the time of parturition. We hypothesized that pegbovigrastim administered to periparturient cows at approximately seven days before parturition and within 24 hours after calving could affect the profiles of gene networks involved in leukocyte function. Blood was collected on Day 3 after calving from treated groups (pegbovigrastim (PEG), 13 Simmental (seven multiparous and six primiparous) and 13 Holstein (seven multiparous and six primiparous) cows) that received pegbovigrastim (Imrestor, Elanco Animal Health) and controls (CTR, 13 Simmental (seven multiparous and six primiparous) and 13 Holstein (six multiparous and seven primiparous) cows) that received saline solution. Blood from all cows was sampled from the jugular vein in a PAXgene Blood RNA System tube (Preanalytix, Hombrechtikon, Switzerland) for RNA extraction. The RT-qPCR analysis was performed to investigate a panel of 34 genes of interest, representing recognition, immune mediation, migration, cell adhesion, antimicrobial strategies, inflammatory cascade, oxidative pattern, and leukotrienes in whole blood leukocytes. Normalized data were subjected to the MIXED model of SAS (ver. 9.4) with treatment, breed, parity, and their interaction as fixed effects. Compared with CTR, whole blood leukocytes of PEG cows had higher expression of genes involved in recognition and immune modulation (CD14, CD16, MYD88, TLR2, and TLR4), cell adhesion (ITGB2, ITGAL, TLN1, SELL, SELPLG, and CD44), antimicrobial activity (MMP9, LTF, and LCN2), and inflammatory cascade (CASP1, TNFRSF1A, IL1B, IL1R, IL18, IRAK1, NLRP3, and S100A8). This suggested an improvement of migration, adhesion, and antimicrobial ability and an enhanced inflammatory response, which in turn could trigger immune cell activation and enhance function. Expression of SOD2 and ALOX5 was also greater in the PEG group. In contrast, compared with CTR cows, PEG led to lower expression of RPL13A, ALOX15, IL8, and TNF. Overall, leukocytes from Simmental compared with Holstein cows had greater expression of IDO1, RPL13A, ALOX5, CD44, CX3CR1, ITGB2, and TNFA, whereas expression of CD16 and TLR2 was lower. Overall, compared with multiparous cows, primiparous cows had higher expression of IL1B, IL18, MYD88, SELL, and TLR2 and lower expression of MMP9. Simmental cows seemed more sensitive to induction of the immune system after calving, as revealed by the greater abundance of genes involved in immune system adaptation, regardless of pegbovigrastim treatment. Primiparous cows undergoing a new stress condition with respect to older cows were characterized by leukocytes with a higher inflammatory response. In conclusion, pegbovigrastim led to higher expression levels of most genes involved in the processes investigated, suggesting a thorough activation of the immune machinery during the critical post-partum period.

Helicobacter pylori infection occurs predominantly in childhood. Host immune response gene polymorphism is reported to affect the susceptibility to H pylori infection and the outcome of H pylori-related gastric cancer. Not all H pylori-infected patients, however, exhibit iron deficiency (ID). The relationship between host genetic polymorphisms and ID mediated by H pylori infection is not well understood.Subjects (n = 644) from the general population of age 10 to 18 years were divided into 2 groups based on serology testing for anti-H pylori IgG: seropositive study group; and seronegative control group. Five single nucleotide polymorphisms (SNPs) in IL1B (rs1143627 and rs16944), IL8 (rs4073), IL10 (rs1800896), and ABO (rs505922), were genotyped and the iron status of the 2 groups was compared.The seroprevalence rate for H pylori was 10.7% in this study. Infected subjects were significantly older and had lower serum iron levels than uninfected subjects (P = 0.0195 and 0.0059, respectively). Multivariate analysis revealed a significantly higher frequency of the T allele of rs505922 (odds ratio [OR] = 6.128; P 0.001) and lower frequency of the T allele of rs1143627 (OR = 0.846; P = 0.014) in seropositive subjects. Among 59 seropositive subjects, the T allele frequency of rs1143627 was significantly higher in those with ID (OR = 3.156; P = 0.043), compared with those without ID.ABO (rs505922) and IL1B (rs1143627) may affect H pylori infection susceptibility, and IL1B (rs1143627) may also influence ID risk in infected children.

// Julien Broseus 1,2,* , Samia Mourah 3,4,5,* , Gerard Ramstein 6 , Sophie Bernard 7 , Nicolas Mounier 8 , Wendy Cuccuini 9 , Philippe Gaulard 10,11 , Christian Gisselbrecht 7,12 , Josette Briere 13 , Remi Houlgatte 1,14,** and Catherine Thieblemont 3,7 1 Inserm U954, Faculty of Medicine, University of Lorraine, Nancy, France 2 University Hospital of Nancy, Hematology Laboratory, Nancy, France 3 Paris Diderot University, Sorbonne Paris Cite, Paris, France 4 APHP, Saint Louis University Hospital, Pharmacology-Biologic Laboratory, Paris, France 5 Inserm UMRS 976, France 6 LS2N - DUKe, University of Nantes, Nantes, France 7 APHP, Saint-Louis University Hospital, Hemato-Oncology, Paris, France 8 University Hospital of L’archet, Nice, France 9 APHP, Saint-Louis University Hospital, Hematology Laboratory, Paris, France 10 Department of Pathology, APHP, Henri Mondor University Hospital, Creteil, France 11 Inserm U955, University Paris-Est, Creteil, France 12 Lymphoma Study Association, Pierre-Benite, France 13 Department of Pathology, APHP, Saint-Louis University Hospital, Paris, France 14 University Hospital of Nancy, DRCI, Nancy, France * Julien Broseus and Samia Mourah have contributed equally to this work ** Catherine Thieblemont and Remi Houlgatte have contributed equally to this work Correspondence to: Catherine Thieblemont, email: // Remi Houlgatte, email: // Keywords : ABC, like DLBCL, angiogenesis, immune response, cancer Received : June 12, 2017 Accepted : July 03, 2017 Published : July 19, 2017 Abstract Tumor microenvironment including endothelial and immune cells plays a crucial role in tumor progression and has been shown to dramatically influence cancer survival. In this study, we investigated the clinical relevance of the gene expression of key mediators of angiogenesis, VEGF isoforms 121, 165, and 189, and their receptors (VEGFR-1 and R-2) in a cohort of patients ( n = 37) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL). In patients with ABC-like DLBCL, but not in patients with GCB-like DLBCL, low VEGF 121 expression was associated with a significantly better survival than in those with high VEGF 121 level: 4-year overall survival at 100% vs 36% ( p = .011), respectively. A specific gene signature including 57 genes was correlated to VEGF 121 expression level and was analyzed using a discovery process in 1,842 GSE datasets of public microarray studies. This gene signature was significantly expressed in other cancer datasets and was associated with immune response. In conclusion, low VEGF 121 expression level was significantly associated with a good prognosis in relapsed/refractory ABC-like DLBCL, and with a well-conserved gene-expression profiling signature related to immune response. These findings pave the way for rationalization of drugs targeting immune response in refractory/relapsed ABC-like DLBCL.

BACKGROUND: CC-486, a DNA hypomethylating agent and epigenetic modifier, is an oral formulation of azacitidine (AZA) that is administered at lower exposures for extended durations (300 mg/day [d] for 14 or 21d/28d cycle) compared with the injectable formulation of AZA, which is given in a high exposure, limited duration regimen of 75mg/m2 for 7d/28d cycle. AZA induces DNA damage and cytotoxicity, and promotes changes in gene expression leading to cellular differentiation. As DNA incorporation of AZA is S-phase-dependent, it has been hypothesized that extended dosing with CC-486 prolongs drug exposure and DNA incorporation to enhance epigenetic activity. The mechanism of action imparted by extended dosing schedules of CC-486 is not fully understood. In patients with myeloid malignancies, DNA hypomethylation in blood is sustained throughout the 28d Tx cycle with extended CC-486 dosing regimens (Laille, 2015; Garcia-Manero, 2016). To better understand the mechanism of CC-486, we assessed the kinetics of expression of myeloid markers of cellular differentiation and cytotoxicity with various AZA dosing schedules in in vitro and in vivo models of AML. METHODS: AML cell lines (AML-193, KG1a, and MV4-11) were treated in vitro with AZA (0.05 - 5 µM daily for 5d or 15d), and at cumulative concentrations of 1 or 3 µM administered once or fractionated over 2-5d to experimentally model CC-486 extended exposures: 1 µM cumulative dose (1 µM × 1d, 0.5 µM × 2d, 0.33 µM × 3d, 0.25 µM × 4d, or 0.2 µM × 5d); 3 µM cumulative dose (3 µM × 1d, 1.5 µM × 2d, 1 µM × 3d, 0.75 µM × 4d, or 0.6 µM × 5d). AZA- or vehicle-treated cells were analyzed by flow cytometry, DNA methylation (Illumina Infinium EPIC assay), and RNA-Seq. Temporal expression of CD11b was assessed as a surface marker of myeloid differentiation, and Annexin-V staining was used to determine the extent of apoptosis and cell death. In efficacy studies, mouse models of AML (syngeneic, cell line-derived xenografts) were treated intraperitoneally with AZA regimens at 1 mg/kg/d × 15d (extended) or 3 mg/kg/d x 5d. RESULTS: Tx of AML-193 cells with 0.05 - 5 µM daily AZA led to upregulation of markers of myeloid differentiation (including CD11b) at lower doses, and a dose-dependent increase in apoptosis up to 7d after Tx initiation. Following Tx with 1 µM AZA for 1d, maximal cellular differentiation (ie, CD11b expression) occurred at d3 in 30% of AML-193 cells; conversely, cells treated with 0.2 µM/d AZA for 5d showed greater differentiation (40%) peaking on d7 (Fig A). CD11b expression was increased upon each subsequent cell division; after 5 cell divisions, CD11b upregulation was 4-fold higher in cells treated with multiple, lower AZA doses than with 1 µM AZA administered for 1d (Fig B). CD11b upregulation was not observed in the absence of cell division under serum starvation conditions for 3d (to induce cell cycle arrest), further suggesting that cell division is a requirement for AZA-induced CD11b changes (Fig C). Similarly, AML-193 cells treated with a 3 µM cumulative AZA dose over 1, 2, 3, 4, or 5d showed greater changes in myeloid differentiation marker expression, with peak apoptosis at d7 with extended dosing regimens (Fig D). In KG1a and MV4-11 cells, Tx with 1 µM AZA QD for 5d led to induction of myeloid differentiation by d7, and cell death (followed by recovery of undifferentiated cells) by d28. In contrast, daily Tx with 0.3 µM AZA for 15d led to slower, more robust upregulation of differentiation markers, peaking at d21 and accompanied by a gradual loss of cell viability. Extended AZA exposure to cells led to pronounced changes in gene expression (Fig E) and DNA methylation (Fig F) at both d7 (immune response gene signature) and d28 (cell adhesion gene signature) compared with limited duration exposure AZA. In mice, low exposure, extended regimens of AZA exhibited higher DNA and RNA incorporation into peripheral blood mononuclear cells (PBMCs) and bone marrow cells when compared with higher exposure, limited duration regimens. Extended AZA dosing led to significant efficacy in murine AML models. CONCLUSIONS: In AML cell lines, low exposure, extended duration AZA schedules modeling CC-486 induced robust changes in differentiation. These results suggest that CC-486-mediated effects using extended exposure regimens preferentially promote a differentiation effect and cell death of AML tumor cells. These mechanistic insights may help inform rational CC-486 combination Tx strategies. Disclosures Dunshee: Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Dai:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jang:Bristol Myers Squibb: Ended employment in the past 24 months. Risueño:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Named in BMS (before Celgene) patent filings related to predictive patient response biomarkers in hematological malignancies. Jeyaraju:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hagner:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. See:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. MacBeth:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

The resistance of silkworm to infection by Bombyx mori nuclear polyhedrosis virus (BmNPV) is a main focus of sericultural research. Previously, a BmNPV-resistant strain, NB, was identified among a collection of Chinese silkworm strains in our lab. To better understand the molecular mechanism of NB strain resistance, the patterns of host immune response gene transcription in resistant (NB) and susceptible (306) strains were examined. Quantative real-time PCR (qRT-PCR) revealed that multiple insect innate immune signaling pathways (Toll, Imd and JAK/STAT) were strongly activated upon infection with BmNPV. Notably, Suppressor of cytokine signaling 2 (BmSOCS2) mRNA expression was significantly up-regulated in midgut tissues of the resistant NB strain, suggesting that the BmSOCS2 gene product may be involved in host immune defense against BmNPV infection. A significant inhibition of BmNPV replication was also observed in BmN cells transfected with a vector encoding BmSOCS2. The results suggest that BmSOCS2 is a key gene involved in the resistance of the NB silkworm strain to BmNPV infection.

Background Chronic obstructive pulmonary disease (COPD) is commonly associated with both a pro-inflammatory and a T-helper 1 (Th1) immune response. It was hypothesized that cannabis oil extract can alleviate COPD symptoms by eliciting an anti-inflammatory Th2 immune response. Accordingly, the effects of cannabis oil extract on the expression of 84 Th2 and related immune response genes in human small airways epithelial cells (HSAEpC) were investigated. Methods HSAEpC from a single donor were treated with three dilutions of a standardized cannabis oil extract (1:400, 1:800 and 1:1600) along with a solvent control (0.25% [2.5 ul/ml] ethanol) for 24 h. There were four replicates per treatment dilution, and six for the control. RNA isolated from cells were employed in pathway-focused quantitative polymerase chain reaction (qPCR) microarray assays. Results The extract induced significant (P Conclusions This exploratory investigation indicates that cannabis oil extract may affect expression of specific airway epithelial cell genes that could modulate pro-inflammatory or Th1 processes in COPD. These results provide a basis for further investigations and have prompted in vivo studies of the effects of cannabis oil extract on pulmonary function. Trial registration NONE (all in vitro experiments).

Highlights • The hippocampus, the sagittal stratum, the cingulum, the parahippocampal gyrus, the superior temporal white matter and the fusiform white matter are among the top ranked regions with memory impairment and microstructural changes in AD. • The hippocampus, the sagittal stratum left, the parahippocampal gyrus right and the cingulum (hippocampus) are significantly associated with clinical/cognitive traits as well as amyloid beta accumulation in AD. • Hippocampus right and sagittal stratum left are the two top regions shared in our ranking highly correlated with memory scores as well as AD-pathology endophenotypes. • Though fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1) and radial diffusivity (RD) features were highly correlated with clinical/cognitive/pathology endophenotypes, planarity of the tensor (PLA) and mode of the tensor (MOD) features are not informative to predict white matter changes in AD. • An immune response, interferon signaling and cytokine signaling enriched gene subnetwork derived from the matched blood gene expression data is most correlated with DTI features across all the brain regions. • CELF1, a GWAS AD risk gene, is significantly associated with white matter microstructural changes in the hippocampus., Introduction Microstructural abnormalities in white matter (WM) are often reported in Alzheimer's disease (AD). However, it is unclear which brain regions have the strongest WM changes in presymptomatic AD and what biological processes underlie WM abnormality during disease progression. Methods We developed a systems biology framework to integrate matched diffusion tensor imaging (DTI), genetic and transcriptomic data to investigate regional vulnerability to AD and identify genetic risk factors and gene subnetworks underlying WM abnormality in AD. Results We quantified regional WM abnormality and identified most vulnerable brain regions. A SNP rs2203712 in CELF1 was most significantly associated with several DTI-derived features in the hippocampus, the top ranked brain region. An immune response gene subnetwork in the blood was most correlated with DTI features across all the brain regions. Discussion Incorporation of image analysis with gene network analysis enhances our understanding of disease progression and facilitates identification of novel therapeutic strategies for AD.

The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.

Colorectal cancer (CRC) is the third most common diagnosed cancer of which risk factors include unhealthy diet, smoking, and chronic inflammation. Weakening the inflammatory response emerges as an effective therapeutic strategy to prevent the progression of CRC. Inflammatory macrophages produce substantial amounts of immunoregulatory metabolite itaconate, which is synthesized by the immune response gene 1 (Irg1). In this study, we use a membrane-permeable itaconate derivative, dimethyl itaconate (DI), for the protection against CRC in mouse model. DI decreased the high inflammatory state of ulcerative colitis and reduced the colitis-associated cancer (CAC) risk. Mechanistically, DI inhibited the secretion of the cytokines IL-1β and CCL2 from intestinal epithelial cells, and therefore reduced the recruitment of macrophages into tumor microenvironment. Meanwhile, the decrease of macrophage infiltration was accompanied by a decrease of myeloid-derived suppressor cell (MDSC) infiltration and the differentiation of T cell subsets into cytotoxic T cells. We showed that itaconate derivative limits inflammatory response, indicating a negative feedback loop that involves an inflammatory agent and itaconate. Our findings demonstrate the potential application of DI for the prevention of colitis-associated CRC. KEY MESSAGES: Dimethyl itaconate (DI) suppresses ulcerative colitis and colitis-associated colorectal cancer DI decreases infiltration of macrophages and myeloid-derived suppressor cells into tumor DI weakens the inflammatory response via inhibiting the secretion of IL-1β and CCL2.

Background Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardless of specific phenotype or ethnicity. Objective To examine transethnic gene-IMD associations for single nucleotide polymorphism (SNP) frequencies of prototypic xenobiotic response genes—aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), AHR repressor (AHRR) — and a prototypic immune response gene, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), in subjects from the Environmental Polymorphisms Registry (EPR). Methods Subjects (n = 3731) were genotyped for 14 SNPs associated with functional variants of the AHR, ARNT, AHRR, and PTPN22 genes, and their frequencies were compared among African Americans (n = 1562), Caucasians (n = 1838), and Hispanics (n = 331) with previously reported data. Of those genotyped, 2015 EPR subjects completed a Health and Exposure survey. SNPs were assessed via PLINK for associations with IMD, which included those with autoimmune diseases, allergic disorders, asthma, or idiopathic pulmonary fibrosis. Transethnic meta-analyses were performed using METAL and MANTRA approaches. Results ARNT SNP rs11204735 was significantly associated with autoimmune disease by transethnic meta-analyses using METAL (odds ratio, OR [95% confidence interval] = 1.29 [1.08–1.55]) and MANTRA (ORs ranged from 1.29 to 1.30), whereas ARNT SNP rs1889740 showed a significant association with autoimmune disease by METAL (OR = 1.25 [1.06–1.47]). For Caucasian females, PTPN22 SNP rs2476601 was significantly associated with autoimmune disease by allelic association tests (OR = 1.99, [1.30–3.04]). In Caucasians and Caucasian males, PTPN22 SNP rs3811021 was significantly associated with IMD (OR = 1.39 [1.12–1.72] and 1.50 [1.12–2.02], respectively) and allergic disease (OR = 1.39 [1.12–1.71], and 1.62 [1.19–2.20], respectively). In the transethnic meta-analysis, PTPN22 SNP rs3811021 was significantly implicated in IMD by METAL (OR = 1.31 [1.10–1.56]), and both METAL and MANTRA suggested that rs3811021 was associated with IMD and allergic disease in males across all three ethnic groups (IMD METAL OR = 1.50 [1.15–1.95]; IMD MANTRA ORs ranged from 1.47 to 1.50; allergic disease METAL OR = 1.58 [1.20–2.08]; allergic disease MANTRA ORs ranged from 1.55 to 1.59). Conclusions Some xenobiotic and immune response gene polymorphisms were shown here, for the first time, to have associations across a broad spectrum of IMD and ethnicities. Our findings also suggest a role for ARNT in the development of autoimmune diseases, implicating environmental factors metabolized by this pathway in pathogenesis. Further studies are needed to confirm these data, assess the implications of these findings, define gene-environment interactions, and explore the mechanisms leading to these increasingly prevalent disorders.

Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXRβ to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXRβ, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXRβ gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses cells revealed that LXRβ regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXRβ in glioblastoma might be effective through diverse mechanisms.

Xenobiotic exposure activates or inhibits transcription of hundreds of protein-coding genes in mammalian liver, impacting many physiological processes and inducing diverse toxicological responses. Little is known about the effects of xenobiotic exposure on long noncoding RNAs (lncRNAs), many of which play critical roles in regulating gene expression. Objective: to develop a computational framework to discover liver-expressed, xenobiotic-responsive lncRNAs (xeno-lncs) with strong functional, gene regulatory potential and elucidate the impact of xenobiotic exposure on their gene regulatory networks. We analyzed 115 liver RNA-seq data sets from male rats treated with 27 individual chemicals representing seven mechanisms of action (MOAs) to assemble the long non-coding transcriptome of xenobiotic-exposed rat liver. Ortholog analysis was combined with co-expression data and causal inference methods to infer lncRNA function and deduce gene regulatory networks, including causal effects of lncRNAs on protein-coding gene expression and biological pathways. We discovered >1,400 liver-expressed xeno-lncs, many with human and/or mouse orthologs. Xenobiotics representing different MOAs were often regulated common xeno-lnc targets: 123 xeno-lncs were dysregulated by at least 10 chemicals, and 5 xeno-lncs responded to at least 20 of the 27 chemicals investigated. 81 other xeno-lncs served as MOA-selective markers of xenobiotic exposure. Xeno-lnc–protein-coding gene co-expression regulatory network analysis identified xeno-lncs closely associated with exposure-induced perturbations of hepatic fatty acid metabolism, cell division, and immune response pathways. We also identified hub and bottleneck lncRNAs, which are expected to be key regulators of gene expression incisor intrans. This work elucidates extensive networks of xeno-lnc–protein-coding gene interactions and provides a framework for understanding the extensive transcriptome-altering actions of diverse foreign chemicals in a key responsive mammalian tissue.

Summary Although various long noncoding RNAs (lncRNAs) are specifically expressed in activated macrophages, their in vivo functions and mechanisms of action are largely unexplored. Here, we identify a long intergenic noncoding RNA associated with activated macrophage (linc-AAM) and elucidate its function and mechanisms. linc-AAM is highly expressed in activated macrophages. In vitro function analysis reveals that linc-AAM facilitates macrophage activation and promotes the expression of immune response genes (IRGs). In mechanisms, linc-AAM interacts with heterogeneous nuclear ribonucleoprotein L (hnRNPL) via two CACACA motifs, resulting in its dissociation from histone H3 to activate chromatin and facilitate transcription of IRGs. Of note, linc-AAM knockout (KO) mice manifest impaired antigen-specific cellular and humoral immune responses to ovalbumin (OVA) in vivo. Altogether, the results uncover a mechanism of lncRNA in modulating hnRNPL function and confirm that linc-AAM acts as a transcription enhancer to activate macrophages and promote adaptive immunity.

Androgenetic alopecia is the most common form of hair loss in males. It is a multifactorial condition involving genetic predisposition and hormonal changes. The role of microflora during hair loss remains to be understood. We therefore analyzed the microbiome of hair follicles from hair loss patients and the healthy. Hair follicles were extracted from occipital and vertex region of hair loss patients and healthy volunteers and further dissected into middle and lower compartments. The microbiome was then characterized by 16S rRNA sequencing. Distinct microbial population were found in the middle and lower compartment of hair follicles. Middle hair compartment was predominated by Burkholderia spp. and less diverse; while higher bacterial diversity was observed in the lower hair portion. Occipital and vertex hair follicles did not show significant differences. In hair loss patients, miniaturized vertex hair houses elevated Propionibacterium acnes in the middle and lower compartments while non-miniaturized hair of other regions were comparable to the healthy. Increased abundance of P. acnes in miniaturized hair follicles could be associated to elevated immune response gene expression in the hair follicle.