The MYTHS of De novo Crohn's Disease After Restorative Proctocolectomy with Ileal Pouch-anal Anastomosis for Ulcerative Colitis.

Background: 1.1.Inflammatory Bowel Disease (IBD) are the manifestation of overzealous dys-regulated immune response in the intestinal tract, directed primarily against the indigenous microbes combined with defective functioning of anti-inflammatory pathways. Finding a trustable lead to predicting de novo Crohn's Disease (CD) prior to performing "pouch surgery", Restorative Proctocolectomy (RPC) with Ileal Pouch-Anal Anastomosis (IPAA) for UC and/or Indeterminate Colitis (IC) is clinically important and remains debatable. De novo CD is a subsequent long-term postoperative complication in IBD patients with Ulcerative Colitis (UC) undergoing IPAA. Herewith we discuss this understanding in laboratory-based basic science research, with its molecular application as a possible corner stone tool for clinical progress and success in the IBD Clinic. Crypt Paneth cell (PCs) secreted enteroendocrine alpha-defensin 5 (DEFA5)" if developed properly is likely to solve diagnostic and prognostic difficulty in IBD Clinics. DEFA5 has shown the ability to differentiate the predominant subtypes of colonic IBD (CC vs. UC) at first endoscopy biopsy, avoiding diagnosis delay prior to colectomy. In addition, DEFA5 accurately circumvents indeterminate colitis (IC) patients into accurate IBD subtype (UC or CC). Further, DEFA5 can be used in selecting CC patients that may have positive outcomes after IPAA surgery [1]. Furthermore, likewise, DEFA5 can predict UC patients likely to have positive or poor outcome, e.g. those patients that are likely to transform/ convert and adhere to de novo Crohn's after IPAA can be picked up in endoscopy biopsy before surgery. Aim: 1.2.To assessed comprehensive state-of-the-art understanding domains on the de novo Crohn's disease subsequent to IPAA surgery for ulcerative colitis. Methods: 1.3.A literature search based on preferred reporting items for over-review and meta-analysis protocols (PRISMA-P) was performed. A comprehensive current search of PubMed, MEDLINE, CINAHL, Embase, Google® search engine and Cochrane Database of collected reviews was performed from January 1990 through December 2018. The search consists of retrospective studies and case reports of reporting postoperative de novo CD incidence and adverse events. Secondary and hand/manual searches of reference lists, other studies cross-indexed by authors, reviews, commentaries, books and meeting abstracts were also performed. Studies were included only if the diagnosis of de novo CD was established clinically and histologically based on inflammation of afferent limb(s) or perianal disease. The search excluded non-English language and non-human studies as well as editorials. Results: 1.4.Published data on de novo CD developing after RPC with IPAA are still limited. A total of three hundred and sixty-five (#365) patients in 13 publications reported de novo CD after a median follow-up of 66 (range: 3-236) months. All patients were diagnosed with clinically active pouch CD during follow-up surveillance after IPAA for UC or IC. A de novo CD diagnosis depended on either inflammation in the mucosa involving the small intestine proximal to the ileal pouch any time after IPAA surgery and/or when perianal complications developed after closure of a temporary diverting loop ileostomy. Successful management is facilitated by co-operation within a multidisciplinary team of gastroenterologists and colorectal surgeons and closely involving the patient in therapeutic decisions. Awareness of symptoms leads to timely consultation, diagnosis, treatment and restoration of intestinal continuity. Conclusion: 1.5.The nature history and risk of de novo CD after IPAA for UC remains debatable. Chronic pouchitis and/or pouch failure often precedes a diagnosis of de novo CD. A successful management is facilitated by a triad cooperation between gastroenterologists, colorectal surgeons and the patient.

Inflammatory Bowel Disease On-Line Web-Based Guide to Health Professionals and Patients in Developing and African Nations.

Introduction: 1.1.Inflammatory Bowel Disease (IBD) is recklessly evolving worldwide as incautious disaster, especially in developing nations as a regional duplicitous emergence disease. It has come to light that adaptive Western culture, rapid urbanization lifestyle in the developing nations has been seen to be associated with this increasing trend incidence. Apparent unclassified strategic challenge assessment of how key trends and uncertainties might lead the world over the next decades to help developing nations and plan for the long term. Healthcare professionals are faced with limited resource and unequipped laboratories for IBD diagnostics, prognostics and monitoring management. Limited knowledge on IBD among developing nation's physician's/healthcare providers is painstaking and indisputable challenge. With the emergence of advanced communications technology, the internet offers diverse, substantial, easily accessible, and educational resources that are more time- and cost-efficient than conventional modes of knowledge acquisition. An On-Line Web-Based Resources about IBD, as a guide would greatly assist health professionals and patients. Methods: 1.2.We performed a literature search according to PRISMA-P (preferred reporting items for review and meta-analysis and searches in PubMed (MEDLINE database) to identify and select peer-reviewed articles allied to web-based educational accoutrements for IBD. Results: 1.3.In developing nations, locally trained physicians have limited knowledge on IBD. Mostly, IBD is not included in their training Core Curriculum and research in this field/area is limited in these countries. The healthcare approaches, both at the primary care and referral levels, many times lack the essential regular clinical guidance and laboratory evaluation assessments needs for monitoring patients. Moreover, increasing treatment costs impose additional burden on the healthcare systems. Expensive pharmacological biosimilar and biologic agents/drugs, new treatment targets, and new quality indicators in patient health quality of life and care are significant challenge in addition to early manifestations of IBD are likely to be missed at most health institutions. Conclusion: 1.4.We herewith summarize an on-line web-based e-learning guide for IBD-related educational resources to assist physicians, healthcare personnel and patients worldwide, especially in the developing nations where the epidemiological monitoring studies are limited, due to a lack of medical surveillance systems and reliable and unified registries and databases.

SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer.

EZH2 is crucial for the progression of prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) through upregulation and activation of progenitor genes, as well as androgen receptor (AR)-target genes. However, the mechanisms by which EZH2 is regulated in PCa and CRPC remain elusive. Here we report that EZH2 is post-transcriptionally regulated by SKP2 in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of Skp2, Ezh2 and histone H3 lysine 27 trimethylation (H3K27me3) in both Pten null mouse embryonic fibroblasts (MEFs) and Pten null mouse prostate tissues. Loss of Skp2 resulted in a striking decrease of Ezh2 levels in Pten/Trp53 double-null MEFs and in prostate tumors of Pten/Trp53 double-null mutant mice. SKP2 knockdown decreased EZH2 levels in human PCa cells through upregulation of TRAF6-mediated and lysine(K) 63-linked ubiquitination of EZH2 for degradation. Ectopic expression of TRAF6 promoted the K63-linked ubiquitination of EZH2 to decrease EZH2 and H3K27me3 levels in PCa cells. In contrast, TRAF6 knockdown resulted in a reduced EZH2 ubiquitination with an increase of EZH2 and H3K27me3 levels in PCa cells. Furthermore, the catalytically dead mutant TRAF6 C70A abolished the TRAF6-mediated polyubiquitination of recombinant human EZH2 in vitro. Most importantly, a concurrent elevation of Skp2 and Ezh2 was found in CRPC tumors of Pten/Trp53 mutant mice, and expression levels of SKP2 and EZH2 were positively correlated in human PCa specimens. Taken together, our findings revealed a novel mechanism on EZH2 ubiquitination and an important signaling network of SKP2-TRAF6-EZH2/H3K27me3, and targeting SKP2-EZH2 pathway may be a promising therapeutic strategy for CRPC treatment.

Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(-/-) FORKO mice.

A homozygous missense mutation, C566T, in the follicle stimulation hormone receptor (FSHR) gene has been linked to premature ovarian failure. The disease leads to infertility in a normal karyotype female with an elevated follicle stimulating hormone (FSH) and decreased serum estrogen level. Female mice carrying mutated FSHR gene, called follitropin receptor knockout (FORKO), display similar phenotype and are sterile because of a folliculogenesis block at a primary stage. We investigated the effects of bilateral intra-ovarian injection of an adenovirus expressing a normal copy of human FSHR on the reproductive system of 6-10 weeks female FORKO mice. Ad-LacZ was injected directly into each ovary of the control group. Animals were sacrificed at 2, 4, 8 and 12 weeks post-injection and tissues collected for evaluation. Treated mice showed estrogenic changes in daily vaginal smear whereas control animals remained fixated in the diestrus stage. Histological evaluation showed on average 26 +/- 4 follicles/ovary in treated group with 8 +/- 2 follicles at the antral stage compared with only 5 +/- 2 with zero follicles at antral stage in Ad-LacZ control mice. There was no significant change in serum level of progesterone, however, estrogen level increased 2-3-fold (P < 0.02) and FSH decreased by up to 50% (P < 0.04) in treated animals. FSHR mRNA was detected in the ovaries of the treated group. In conclusion, intra-ovarian injection of an adenovirus expressing human FSHR gene is able to restore FSH responsiveness and reinitiate ovarian folliculogenesis as well as resume estrogen production in female FORKO mice. Ad-LacZ injections indicate the absence of systemic viral dissemination or germ line transmission of adenovirus DNA to offspring.

Squamous-cell carcinoma of the floor of the mouth.

This study was based on the analysis of 100 cases of squamous-cell carcinoma of the floor of the mouth. The male/female ratio was 4.25:1. The peak incidence in women was in the 50 to 59 year age group; in men there was equal frequency in each age group above 50. The five-year survival rate decreased from 86 per cent to 0 as the stage of disease progressed from I to IV. The five-year survival for all stages of disease was 52.7 per cent. Thirty-three per cent developed new primary malignancies; 22 per cent were of the upper alimentary and respiratory tracts. Distant metastases were present in 21 per cent. Fifty per cent were heavy smokers, 33 per cent were heavy drinkers, 28 per cent were both heavy smokers and heavy drinkers, and 21 per cent were nonsmokers and nondrinkers.