HIV-1-infected infants develop broadly neutralizing antibodies (bnAbs) more rapidly than adults, suggesting differences in the neonatal versus adult responses to the HIV-1 envelope (Env). Here, trimeric forms of HIV-1 Env immunogens elicit increased gp120- and gp41-specific antibodies more rapidly in neonatal macaques than adult macaques. Transcriptome analyses of neonatal versus adult immune cells after Env vaccination reveal that neonatal macaques have higher levels of the apoptosis regulator BCL2 in T cells and lower levels of the immunosuppressive interleukin-10 (IL-10) receptor alpha (IL10RA) mRNA transcripts in T cells, B cells, natural killer (NK) cells, and monocytes. In addition, immunized neonatal macaques exhibit increased frequencies of activated blood T follicular helper-like (Tfh) cells compared to adults. Thus, neonatal macaques have transcriptome signatures of decreased immunosuppression and apoptosis compared with adult macaques, providing an immune landscape conducive to early-life immunization prior to sexual debut.

Cognitive deterioration and symptom progression occur in schizophrenia over the course of the disorder. A dysfunction of the immune system/neuroinflammatory pathways has been linked to schizophrenia (SZ). These altered processes in the dorsolateral prefrontal cortex (DLPFC) could contribute to the worsening of the deficits. However, limited studies are available in this brain region in elderly population with long-term treatments. In this study, we explore the possible deregulation of 21 key genes involved in immune homeostasis, including pro- and anti-inflammatory cytokines, cytokine modulators (toll-like receptors, colony-stimulating factors, and members of the complement system) and microglial and astroglial markers in the DLPFC in elderly chronic schizophrenia. We used quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) on extracts from postmortem DLPFC of elderly subjects with chronic SZ (n = 14) compared to healthy control individuals (n = 14). We report that CSF1R, TLR4, IL6, TNFα, TNFRSF1A, IL10, IL10RA, IL10RB, and CD68 were down-regulated in elderly SZ subjects. Moreover, we found that the expression levels of all the altered inflammatory genes in SZ correlated with the microglial marker CD68. However, no associations were found with the astroglial marker GFAP. This study reveals a decrease in the gene expression of cytokines and immune response/inflammation mediators in the DLPFC of elderly subjects with chronic schizophrenia, supporting the idea of a dysfunction of these processes in aged patients and its possible relationship with active microglia abundance. These findings include elements that might contribute to the cognitive decline and symptom progression linked to DLPFC functioning at advanced stages of the disease.

BACKGROUND

Although deleterious mutations in interleukin-10 and its receptor molecules cause severe infantile-onset inflammatory bowel disease, there are no reports of mutations affecting this signaling pathway in Japanese patients. Here we report a novel exonic mutation in the IL10RA gene that caused unique splicing aberrations in a Japanese patient with infantile-onset of inflammatory bowel disease in association with immune thrombocytopenic purpura and a transient clinical syndrome mimicking juvenile myelomonocytic leukemia.

METHODS

A Japanese boy, who was the first child of non-consanguineous healthy parents, developed bloody diarrhea, perianal fistula, and folliculitis in early infancy and was diagnosed with inflammatory bowel disease. He also developed immune thrombocytopenic purpura and transient features mimicking juvenile myelomonocytic leukemia. The patient failed to respond to various treatments, including elemental diet, salazosulfapyridine, metronidazole, corticosteroid, infliximab, and adalimumab. We identified a novel mutation (c.537G>> A, p.T179T) in exon 4 of the IL10RA gene causing unique splicing aberrations and resulting in lack of signaling through the interleukin-10 receptor. At 21 months of age, the patient underwent allogeneic hematopoietic stem cell transplantation and achieved clinical remission.

CONCLUSIONS

We describe a novel exonic mutation in the IL10RA gene resulting in infantile-onset inflammatory bowel disease. This mutation might also be involved in his early-onset hematologic disorders. Physicians should be familiar with the clinical phenotype of IL-10 signaling defects in order to enable prompt diagnosis at an early age and referral for allogeneic hematopoietic stem cell transplantation.

The heterogeneity in head and neck squamous cell carcinoma (HNSCC) has made reliable stratification extremely challenging. Behavioral risk factors such as smoking and alcohol consumption contribute to this heterogeneity. To help elucidate potential mechanisms of progression in HNSCC, we focused on elucidating patterns of gene interactions associated with tumor progression. We performed de-novo gene co-expression network inference utilizing 229 patient samples from The Cancer Genome Atlas (TCGA) previously annotated by Bornstein et al. (2016). Differential network analysis allowed us to contrast progressor and non-progressor cohorts. Beyond standard differential expression (DE) analysis, this approach evaluates changes in gene expression variance (differential variability DV) and changes in covariance, which we denote as differential wiring (DW). The set of affected genes was overlaid onto the co-expression network, identifying 12 modules significantly enriched in DE, DV, and/or DW genes. Additionally, we identified modules correlated with behavioral measures such as alcohol consumption and smoking status. In the module enriched for differentially wired genes, we identified network hubs including IL10RA, DOK2, APBB1IP, UBASH3A, SASH3, CELF2, TRAF3IP3, GIMAP6, MYO1F, NCKAP1L, WAS, FERMT3, SLA, SELPLG, TNFRSF1B, WIPF1, AMICA1, PTPN22; the network centrality and progression specificity of these genes suggest a potential role in tumor evolution mechanisms related to inflammation and microenvironment. The identification of this network-based gene signature could be further developed to guide progression stratification, highlighting how network approaches may help improve clinical research end points and ultimately aid in clinical utility.

In order to screen the genome for linkage disequilibrium (LD) in multiple sclerosis (MS), we typed 2537 microsatellite markers in separately pooled DNA from 200 cases and 200 controls from N. Ireland. Twenty two markers showing significant evidence of association were identified including three from the HLA region on chromosome 6p21. Putative candidate genes mapping close to the 19 novel markers include the IL10RA and CD3E genes on 11q23 (which both lie close to the marker D11S1998). Individual typing of the marker D11S1998 confirmed its association.

Gastric (GC) and esophageal (EC) cancers are highly lethal. Better understanding of molecular abnormalities is needed for new therapeutic targets and biomarkers to be found. Expression of 18 cancer-related genes in 31 paired normal-tumor samples was quantified by reversely-transcribed quantitative polymerase chain reaction (RTqPCR) and systemic concentration of 27 cytokines/chemokines/growth factors in 195 individuals was determined using Luminex xMAP technology. Only Ki67, CLDN2, and BCLxL were altered in GC while Ki67, CDKN1A, ODC1, SLC2A1, HIF1A, VEGFA, NOS2, CCL2, PTGS2, IL10, IL10Ra, and ACTA2 were changed in EC. The relatively unaltered molecular GC landscape resulted from high expression of BCLxL, CDKN1A, BCL2, Ki67, HIF1A, VEGFA, ACTA2, TJP1, CLDN2, IL7Ra, ODC1, PTGS2, and CCL2 in non-cancerous tissue. The NOS2 expression and IL-4, IL-9, FGF2, and RANTES secretion were higher in cardiac than non-cardiac GC. Four-cytokine panels (interleukin (IL)-1β/IL-1ra/IL-6/RANTES or IL-1β/IL-6/IL-4/IL-13) differentiated GC from benign conditions with 87-89% accuracy. Our results showed increased proliferative, survival, inflammatory and angiogenic capacity in gastric tumor-surrounding tissue, what might contribute to GC aggressiveness and facilitate cancer recurrence. Further studies are needed to determine the CLDN2 and NOS2 suitability as candidate molecular targets in GC and cardiac GC, respectively, and discern the role of CLDN2 or to verify IL-1β/IL-1ra/IL-6/RANTES or IL-1β/IL-6/IL-4/IL-13 usefulness as differential biomarkers.

Keywords: angiogenesis; cardia cancer; claudin-2; differential biomarkers; epithelial-mesenchymal transition; esophageal cancer; inflammation; metabolic reprogramming; tight junction proteins.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a member of a sub-family of phosphoinositol 3-kinases, has been reported overexpressed in various human cancers, but its significance is unclear. In the present study, we generated the stable cell line HeLa(siRNAH1) of silenced DNA-PKcs by transfecting HeLa cells with the siRNA construct targeting the catalytic motif of DNA-PKcs. The expression of DNA-PKcs was markedly suppressed in HeLa(siRNAH1) cells, and eventuating in increased cellular sensitivity to ionizing radiation as well as cisplatin. Microarray assay was used to explore the transcriptional profiling of signal transduction-associated genes. The results demonstrated that 15 genes were up-regulated and eight were down-regulated in HeLa(siRNAH1) as compared with the HeLa(control) cells that transfected with non-specific siRNA construct. Seven of the up-regulated genes are associated with the interferon-signaling events, the others function in the BMP signal pathway, or as regulators of cell cycle and differentiation. The down-regulated genes include IL8, IL10RA, DAPK3, and those involved in nuclear factor of activated T cells (NFAT) signal pathway and endocrine responsiveness. Using the NFAT-driving secreted alkaline phosphatase reporter expression system, we further confirmed that NFAT transcriptional activity was markedly minimized after silencing DNA-PKcs. These results demonstrated that inactivation of DNA-PKcs altered the transcriptional level of certain signal transduction-associated genes related to proliferation and differentiation.

Cytomegalovirus (CMV) is the most common viral agent of congenital infections and a leading nongenetic cause of sensorineural hearing loss (SNHL). The host immunologic factors that render a developing foetus prone to intrauterine CMV infection and development of hearing loss are unknown. The aim of this study was to assess the potential associations between the polymorphisms within cytokine and cytokine receptors genes, and the risk of congenital CMV infection, and the hearing outcome. A panel of 11 candidate single nucleotide polymorphisms (SNPs): TNF rs1799964, TNF rs1800629, TNFRSF1A rs4149570, IL1B rs16944, IL1B rs1143634, IL10 rs1800896, IL10RA rs4252279, IL12B rs3212227, CCL2 rs1024611, CCL2 rs13900, CCR5 rs333 was genotyped in 470 infants (72 with confirmed intrauterine CMV infection and 398 uninfected controls), and related to congenital CMV infection, and the outcome. In multivariate analysis, the IL1B rs16944 TT and TNF rs1799964 TC genotypes were significantly associated with intrauterine CMV infection (aOR = 2.32; 95% CI, 1.11-4.89; p = 0.032, and aOR = 2.17, 95% CI, 1.25-3.77; p = 0.007, respectively). Twenty-two out of 72 congenitally infected newborns had confirmed SNHL. Carriers of CT or TT genotype of CCL2 rs13900 had increased risk of hearing loss at birth and at 6 months of age (aOR = 3.59; p = 0.028 and aOR = 4.10; p = 0.039, respectively). This is the first study to report an association between SNPs in IL1B, TNF, and CCL2, and susceptibility to congenital CMV infection (IL1B and TNF) and SNHL (CCL2).

Infantile-onset inflammatory bowel disease (IBD) comprises rare and clinically severe disorders. We examined the phenotypes and genetic causes of patients with infantile-onset IBD from a tertiary medical center.

We enrolled 38 patients with infantile-onset IBD and applied standardized treatment with medical, surgical, and supportive care. Targeted sequencing and whole-exome sequencing were performed. Clinical data were retrieved from medical records.

Median age of onset of disease was 12.5 (interquartile range: 7.0-30.0) days. All patients had diarrhea, whereas 18 (47.4%) patients reported hematochezia. Thirteen (34.2%) patients had oral ulcers, 15 (39.5%) patients had perianal abscess, and 9 (52.9%) female patients had rectovaginal fistula. Six (18.8%) patients had intestinal strictures and 4 (12.1%) patients had perforation. Twelve (31.6%) patients underwent surgical procedures. Median age of surgery was 272.5 days, and cumulative probability for surgery during first year was 32.1%. One-year mortality of patients was 25.9%. Sequencing showed 24 (63.2%) patients had causative IL10RA mutations, 1 patient had EPCAM mutation, 1 patient had TNFAIP3 mutation, and 1 patient had LRBA mutation, whereas causative mutations cannot be identified in the other 11 (28.9%) patients. Umbilical cord blood stem cell transplantation has been applied to 8 cases with IL10RA mutations, of whom 5 (71.4%) patients have achieved clinical remission.

Patients with infantile-onset IBD had severe phenotype and early onset. Medical, surgical interventions with supportive care are essential. High-throughput sequencing ensures appropriate treatment. Hematopoietic stem cell transplantation can be performed in selected patients with IL10RA mutations (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B657).

The introduction of proteasome inhibitors in the treatment of multiple myeloma (MM) patients has been a therapeutic success. Peripheral neuropathy (PNP) remains one of the most frequent side-effects experienced by patients who receive these novel agents. Recent investigations on the mechanisms of PNP in patients treated with bortezomib have suggested genetic susceptibility to neurotoxicity. We used data from a genome-wide association study conducted on 646 bortezomib-treated German MM patients to replicate the previously reported associations between single-nucleotide polymorphisms (SNPs) in candidate genes and PNP in MM patients, including 298 SNPs with a nominal significance (p value <0.05). Twelve associations were confirmed at a significance level p value <0.05. The corresponding SNPs are located in genes involved in drug metabolism (ABCC1, ABCC6), development and function of the nervous system (POGZ, NFAT pathway, EDN1), modulation of immune responses (IL17RD, IL10RA) and the NF-κB signaling pathway (PSMB4, BTCR, F2). We systematically investigated functional consequences of those variants using several bioinformatics tools, such as HaploRegV4.1, RegulomeDB and UCSC Genome Browser. Expression quantitative trait loci (eQTL) data suggested that some of the identified SNPs might influence gene expression through a differential recruitment of transcription factors. In conclusion, we confirmed some of the recently reported associations between germline variation and PNP. Elucidating the mechanisms underlying these associations will contribute to the development of new strategies for the prevention or reduction of PNP.

Theiler's murine encephalomyelitis virus (TMEV) infection represents an experimental mouse model to study hippocampal damage induced by neurotropic viruses. IL-10 is a pleiotropic cytokine with profound anti-inflammatory properties, which critically controls immune homeostasis. In order to analyze IL-10R signaling following virus-induced polioencephalitis, SJL mice were intracerebrally infected with TMEV. RNA-based next generation sequencing revealed an up-regulation of Il10, Il10rα and further genes involved in IL-10 downstream signaling, including Jak1, Socs3 and Stat3 in the brain upon infection. Subsequent antibody-mediated blockade of IL-10R signaling led to enhanced hippocampal damage with neuronal loss and increased recruitment of CD3+ T cells, CD45R+ B cells and an up-regulation of Il1α mRNA. Increased expression of Tgfβ and Foxp3 as well as accumulation of Foxp3+ regulatory T cells and arginase-1+ macrophages/microglia was detected in the hippocampus, representing a potential compensatory mechanism following disturbed IL-10R signaling. Additionally, an increased peripheral Chi3l3 expression was found in spleens of infected mice, which may embody reactive regulatory mechanisms for prevention of excessive immunopathology. The present study highlights the importance of IL-10R signaling for immune regulation and its neuroprotective properties in the context of an acute neurotropic virus infection.

Anaplastic Large Cell Lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive Anaplastic Lymphoma Kinase (ALK) fusion protein. ALK inhibitors such as crizotinib provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by NPM1-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54-90% in clinical trials. However, a subset of patients progress within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide CRISPR activation and knockout screens in ALCL cell lines combined with RNA-seq data derived from ALK inhibitor relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of IL10RA. Elevated IL10RA expression rewires the STAT3 signaling pathway bypassing otherwise critical phosphorylation by NPM1-ALK. IL10RA expression does not correlate with response to standard chemotherapy in pediatric patients suggesting that combination of crizotinib with chemotherapy could prevent ALK-inhibitor resistance-specific relapse. Trials registered as NCT01979536/NCT02034981/UMIN000028075.

Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood arthropathy with features of autoinflammation. Monocytes and macrophages in SJIA have a complex phenotype with both pro- and anti-inflammatory properties that combine features of several well characterized in vitro conditions used to activate macrophages. An important anti-inflammatory phenotype is expression of CD163, a scavenger receptor that sequesters toxic pro-inflammatory complexes that is highly expressed in both active SJIA and macrophage activation syndrome (MAS). CD163 is most strongly up-regulated by IL-10 (M(IL-10)), and not by other conditions that reflect features seen in SJIA monocytes such as M(LPS+IC). MicroRNA plays key roles in integrating cellular signals such as those in macrophage polarization, and as such we hypothesize microRNAs regulate macrophage functional responses in SJIA including CD163 expression. We find that 2 microRNAs previously found to be elevated in active SJIA, miR-125a-5p and miR-181c, significantly reduced macrophage CD163 expression through 2 distinct mechanisms. Neither microRNA was elevated in M(IL-10) with robust CD163 expression, but were instead induced in M(LPS+IC) where they restricted CD163 mRNA expression. Mir-181 species directly targeted CD163 mRNA for degradation. In contrast, miR-125a-5p functions indirectly, as transcriptome analysis of miR-125a-5p overexpression identified "cytokine-cytokine receptor interactions" as the most significantly repressed gene pathway, including decreased IL10RA, required for IL-10-mediated CD163 expression. Finally, overexpression of miR-181c inhibited CD163 anti-inflammatory responses to hemoglobin or high mobility group box 1 (HMGB1) complexes. Together, these data show that microRNA utilizes multiple mechanisms to integrate well-characterized polarization phenotypes and regulate macrophage functional properties seen in SJIA.

Convergent evidence from multiple and independent genetics studies implicate a small number of genes that predispose individuals to multiple autoimmune disorders (AuD). These intersecting loci reinforced the hypothesis that disorders with overlapping etiology group into a cluster of closely related genes within a whole genome molecular interaction network. We tested the hypothesis that "biological network proximity" within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. Using a set of nine previously published genome wide association studies (GWAS) of AuD genes, we generated AuD-specific molecular interaction networks to identify networks of associated genes. We show that all nine "seed genes" can be connected within a 35-member network via interactions with 26 connecting genes. We show that this network is more connected than expected by chance, and 13 of the connecting genes showed association with multiple AuD upon GWAS reanalysis. Furthermore, we report association of SNPs in five new genes (IL10RA, DGKA, GRB2, STAT5A, and NFATC2) which were not previously considered as AuD candidates, and show significant association in novel disease samples of Crohn's disease and systemic lupus erythematosus. Furthermore, we show that the connecting genes show no association in four non-AuD GWAS. Finally, we test the connecting genes in psoriasis GWAS, and show association to previously identified loci and report new loci. These findings support the hypothesis that molecular interaction networks can be used to inform the search for multigene disease etiology, especially for disorders with overlapping etiology.

Natural killer (NK) cells can produce IFNγ or IL-10 to regulate inflammation and immune responses but the factors driving NK cell IL-10 secretion are poorly-defined. Here, we identified NK cell-intrinsic STAT3 activation as vital for IL-10 production during both systemic Listeria monocytogenes (Lm) infection and following IL-15 cytokine/receptor complex (IL15C) treatment for experimental cerebral malaria (ECM). In both contexts, conditional Stat3 deficiency in NK cells abrogated production of IL-10. Initial NK cell STAT3 phosphorylation was driven by IL-15. During Lm infection, this required capture or presentation of IL-15 by NK cell IL-15Rα. Persistent STAT3 activation was required to drive measurable IL-10 secretion and required NK cell expression of IL-10Rα. Survival-promoting effects of IL-15C treatment in ECM were dependent on NK cell Stat3 while NK cell-intrinsic deficiency for Stat3, Il15ra, or Il10ra abrogated NK cell IL-10 production and increased resistance against Lm. NK cell Stat3 deficiency did not impact production of IFNγ, indicating the STAT3 activation initiated by IL-15 and amplified by IL-10 selectively drives the production of anti-inflammatory IL-10 by responding NK cells.

Background: Pancreatic adenocarcinoma (PAAD) is a nonimmunogenic tumor, and very little is known about the relationship between the host immune response and patient survival. We aimed to develop an immune prognostic model (IPM) and analyze its relevance to the tumor immune profiles of patients with PAAD.

Methods: We investigated differentially expressed genes between tumor and normal tissues in the TCGA PAAD cohort. Immune-related genes were screened from highly variably expressed genes with weighted gene correlation network analysis (WGCNA) to construct an IPM. Then, the influence of IPM on the PAAD immune profile was comprehensively analyzed.

Results: A total of 4902 genes highly variably expressed among primary tumors were used to construct a weighted gene coexpression network. One hundred seventy-five hub genes in the immune-related module were used for machine learning. Then, we established an IPM with four core genes (FCGR2B, IL10RA, and HLA-DRA) to evaluate the prognosis. The risk score predicted by IPM was an independent prognostic factor and had a high predictive value for the prognosis of patients with PAAD. Moreover, we found that the patients in the low-risk group had higher cytolytic activity and lower innate anti-PD-1 resistance (IPRES) signatures than patients in the high-risk group.

Conclusions: Unlike the traditional methods that use immune-related genes listed in public databases to screen prognostic genes, we constructed an IPM through WGCNA to predict the prognosis of PAAD patients. In addition, an IPM prediction of low risk indicated enhanced immune activity and a decreased anti-PD-1 therapeutic response.

Keywords: Immune profile; Immune prognostic model; Immunotherapy; Pancreatic cancer; WGCNA.

Immune regulation of the skin plays an important role in susceptibility and development of illnesses. The aim of our study was to localise the interleukin (IL)-10 family of cytokines, in children's skin and to determine possible age-related differences in the expression level. The mRNA expression level of IL10, IL19, IL20, IL22, IL24, IL26, IL28B, IL29 and their receptors IL10RA, IL10RB, IL20RA, IL20RB, IL22RA1, IL22RA2, IL28RA was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time PCR (qRT-PCR). Immunohistochemistry was performed to confirm the qRT-PCR findings. We found age-related differences in the expression of IL10RB, IL20, IL20RA, IL22RA1, IL22RA2, IL26 and IL28RA genes. Cell type-dependent expression of IL10 family cytokines was apparent in the skin. In addition to previously known differences in systemic immunological response of adults and children, the present results reveal differences in immune profile of adult and juvenile skin.

OBJECTIVE

To observe the influence of Sijunzi decoction and Yupingfeng powder on the expression of the relevant DNAs of janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal pathway of the brain in spleen-deficiency model rats.

METHODS

Eighty male Wistar rats of sanitary degree were divided randomly into four groups: normal group, model group, treatment group 1, treatment group 2. Besides the rats in the normal group, all the rats in other 3 groups were prepared as spleen deficiency model. The treatment group 1 were treated with Sijunzi decoction and the treatment group 2 were treated with Yupingfeng powder. After treatment for 6 weeks, perfusion was given and the brain was taken for detection of the expression of the relevant DNAs of JAK-STAT signal pathway of the brain in SD rats bygene chip method.

RESULTS

Spleen deficiency could lead to increase expression of JAK1, STAT1 and Interleukin 4 (IL-4) in the brain, but the decrease expression of Suppressor of cytokine signaling 1 (SOCS1), prolactin receptor (PRLR) and binding protein 3 (GATA 3). Sijunzi decoction could increase expression of STAT3, Prolactin (PRL) and GATA3, but decrease expression of JAK1, STAT, STAT4, Interleukin 10 receptor, alpha (IL10RA), Coagulation factor II (F2), PRLR, MAD homolog 3 (SMAD3) and IL-4. Yupingfeng powder could decrease expression of JAK1, STAT1, STAT4, SOCS4_ predicted, Epidermal growth factor receptor (EGFR), PRLR, High mobility group AT-hook 1 (HMGA10), IL-4.

CONCLUSIONS

Sijunzi decoction and Yupingfeng powder can improve immune function of the rat through influencing the genetic expression of JAK-STAT signal pathway.

Sulforaphane (SFN), a potent antioxidant and anti-inflammatory agent, has been shown to protect against cancers especially at early stages. However, how SFN affects UVB-mediated epigenome/DNA methylome and transcriptome changes in skin photodamage has not been fully assessed. Herein, we investigated the transcriptomic and DNA methylomic changes during tumor initiation, promotion, and progression and its impact and reversal by SFN using next-generation sequencing (NGS) technology. The results show that SFN reduced tumor incidence and tumor number. SFN's protective effects were more dramatic in the early stages than with later stages. Bioinformatic analysis of RNA-seq data shows differential expressed genes (DEGs) and identifies the top canonical pathways related to SFN treatment of UVB-induced different stages of epidermal carcinogenesis. These pathways include p53 signaling, cell cycle: G2/M DNA damage checkpoint regulation, Th1, and Th2 activation pathway, and PTEN signaling pathways. The top upstream regulators related to UVB and SFN treatment as time progressed include dextran sulfate, TP53, NFE2L2 (Nrf2), IFNB1 and IL10RA. Bioinformatic analysis of Methyl-seq data shows several differential methylation regions (DMRs) induced by UVB were attenuated by SFN. These include Notch1, Smad6, Gnai3, and Apc2. Integrative analysis of RNA-Seq and DNA-seq/CpG methylome yields a subgroup of genes associated with UVB and SFN treatment. The changes in gene expression were inversely correlated with promoter CpG methylation status. These genes include Pik3cd, Matk, and Adm2. In conclusion, our study provides novel insights on the impact of SFN on the transcriptomic and DNA methylomic of UVB-induced different stages of skin cancer in mice.

African ancestry and obesity are associated with higher risk of prostate cancer (PC). In a pilot study, we explored interactions between obesity (as measured by waist to hip ratio (WHR)) and inflammatory SNPs in relation to PC risk among Jamaican men. This study evaluated 87 chemokine and cytokine associated SNPs in obese and normal weight cases (N=109) and controls (N=102) using a stepwise penalized logistic regression approach in multivariable analyses. Upon stratification by WHR (normal weight (WHR<0.90) or obese (WHR≥0.90)), inheritance of CCR6 rs2023305 AG+GG (OR=1.75, p=0.007), CCR9 rs7613548 AG+GG (OR=1.71, p=0.012) and IL10ra rs2229113 AG+GG (OR=1.45, p=0.01) genotypes was associated with increase in overall or low grade (Gleason score<7) PC risk among normal weight men. These odds were elevated among obese men who possessed the CCR5 rs1799987 AG+GG (OR=1.95, p=0.003) and RNASEL rs12135247 CT+TT genotypes (OR=1.59, p=0.05). CCR7 rs3136685 AG+GG (p=0.032) was associated with a 1.52-1.70 fold increase in the risk of high grade cancer (Gleason score≥7) among obese men. CCR7 variant emerged as an important factor associated with high grade PC risk among obese men in our analyses. Overall, genetic loci found significant in normal weight men were not significant in obese men and vice-versa, partially explaining the role of obesity on PC risk among black men. Also, older age was an important risk factor both in normal weight and obese men but only with regard to low grade PC. Associations of inflammatory SNPs with obesity are suggestive and require further validation in larger cohorts to help develop an understanding of PC risk among obese and non-obese men of African descent.

Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn's disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A>> G p.K953E) and two already described missense variants in the IL10RA gene (S159G and G351R). The new NOD2 missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. Although cumulative effect of these variations in the early onset of the disease can be only hypothesized, we demonstrated that family information and in silico studies can be used to predict association with the disease.