BACKGROUND & AIMS: Chronic colonic inflammation leads to dysplasia and cancer in patients with inflammatory bowel disease. We have described the critical role of innate immune signaling via Toll-like receptor 4 (TLR4) in the pathogenesis of dysplasia and cancer. In the current study, we interrogate the intersection of TLR4 signaling, epithelial redox activity, and the microbiota in colitisassociated neoplasia. METHODS: Inflammatory bowel disease and colorectal cancer data sets were analyzed for expression of TLR4, dual oxidase 2 (DUOX2), and NADPH oxidase 1 (NOX1). Epithelial production of hydrogen peroxide (H 2 O 2 ) was analyzed in murine colonic epithelial cells and colonoid cultures. Colorectal cancer models were carried out in villin-TLR4 mice, carrying a constitutively active form of TLR4, their littermates, and villin-TLR4 mice backcrossed to DUOXA-knockout mice. The role of the TLR4-shaped microbiota in tumor development was tested in wild-type germ-free mice. RESULTS: Activation of epithelial TLR4 was associated with up-regulation of DUOX2 and NOX1 in inflammatory bowel disease and colorectal cancer. DUOX2 was exquisitely dependent on TLR4 signaling and mediated the production of epithelial H 2 O 2 . Epithelial H 2 O 2 was significantly increased in villin-TLR4 mice; TLR4-dependent tumorigenesis required the presence of DUOX2 and a microbiota. Mucosa-associated microbiota transferred from villin-TLR4 mice to wild-type germ-free mice caused increased H 2 O 2 production and tumorigenesis. CONCLUSIONS: Increased TLR4 signaling in colitis drives expression of DUOX2 and epithelial production of H 2 O 2 . The local milieu imprints the mucosal microbiota and imbues it with pathogenic properties demonstrated by enhanced epithelial reactive oxygen species and increased development of colitis-associated tumors. The interrelationship between epithelial reactive oxygen species and tumor-promoting microbiota requires a 2-pronged strategy to reduce the risk of dysplasia in colitis patients.

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Prostate cancer is one of the major threats to the man's health. There are several mechanisms of the prostate cancer development characterized by the involvement of various androgen-related and androgen-unrelated factors in prostate cancer pathogenesis and in the metastatic carcinogenesis of prostate. In all these processes, proteins play various important roles, and the KEGG database has information on 88 human proteins experimentally shown to be involved in prostate cancer. It is known that many proteins associated with different human maladies are intrinsically disordered (i.e., they do not have stable secondary and/or tertiary structure in their unbound states). The goal of this review is to consider several highly disordered proteins known to be associated with the prostate cancer pathogenesis in order to better understand the roles of disordered proteins in this disease. We also hope that consideration of the pathology-related proteins from the perspective of intrinsic disorder can potentially lead to future experimental studies of these proteins to find novel pathways associated with prostate cancer.

Background: SYNJ1 encodes Synaptojanin-1, a dual-function polyphosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy.Methods: Proband-only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant. Results:We present an Afro-Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242-2A > G variant

8066 Background: Outcome data for pPCL is limited due to the rare & aggressive nature of the disease. In this retrospective analysis, we utilized NCDB to identify factors contributing to 1 & 5-year OS of pPCL patients treated at CoC-accredited facilities across USA. Methods: Using the NCDB, we identified N= 325 pPCL patients diagnosed between 2004-2009 after excluding entries missing relevant values. Univariate analysis was used to summarize & assess the potential survival factors individually & multivariate Cox regression analysis with backward elimination (using significance level of p<0.05) was utilized to identify the independent survival factors. Kaplan-Meier (KM) survival curves of patient cohort were also produced. SAS version 9.4 was used to analyze the data. Results: Multivariate Cox regression analysis with backward elimination method revealed that there were 4 significant independent survival factors including sex, Charlson-Deyo Comorbidity Index (CCI), facility type, and insurance, while age & year-of-diagnosis were not independent survival factors (Table). Male patients were more likely to die compared to female patients (HR=1.40, p=0.005); patients with CCI ≥1 had higher chance to suffer death compared to patients with CCI= 0 (HR=1.52, p=0.002); patients not treated at an academic center (AC) had lower survival compared to those treated at ACs (HR=1.35, p=0.001); and patients without private insurance (PI) were more likely to suffer death compared to those with PI (HR=1.54, p=0.001). The 1 & 5-year survival rates for whole cohort were 51.3% (95%CI: 45.8%-56.8%), and 18.9% (95%CI: 14.6%-23.2%) using KM estimate, respectively. Only 6/325 =1.8% patients underwent autologous hematopoietic stem cell transplant (HSCT). Detailed analysis will be presented. Conclusions: In this large analysis of pPCL patients, we identified that being female, having less comorbidities, getting treatment at ACs, and having PI had significantly greater OS. Overall, pPCL is associated with low survival rates both at 1 & 5-years and HSCT may be enormously under-utilized for pPCL patients in the real world setting. [Table: see text]