Genetic Research Using Archival Tissue: Ethical, Social, and Legal Considerations in the United Arab Emirates

© 2018, National University of Singapore and Springer Nature Singapore Pte Ltd. Pathological archival tissue has been used as a source of research material for many years. The advancement in molecular techniques led to an escalated interest in genetic research on archival tissue. Research on archival tissue has been used without obtaining consents from patients, although the ethical justification for such a practice is unlikely to apply for genetic research that involves whole genome sequencing, for instance. Issues of confidentiality and patients’ autonomy are being raised as institutions consider when approval for this type of research should be granted. In addition, patients’ advocate is mandating some of these changes. In the context of the United Arab Emirates, this paper makes clear the current uncertainties arising from the use of archival tissue in genetic research, as it could be highly invasive of privacy interests and also fails to respect autonomous choice. It further explains what needs to change in order to support such research that is directed at promoting public good, but in a way that is not detrimental to the welfare of patients as research participants

Hodgkin Lymphoma in a Thymic Cyst: Report of a Case with Multiple Secondary Neoplasms

The presentation of Hodgkin Lymphoma in a thymic cyst is rare. We describe a case in a 9 year-old boy, with a long follow-up course, complicated by two secondary neoplasms and a post bone marrow transplant lymphoproliferative disorder. We also review the literature on such presentations and second malignant neoplasms in childhood

Utility of Tissue Transglutaminase Immunohistochemistry in Pediatric Duodenal Biopsies: Patterns of Expression and Role in Celiac Disease—A Clinicopathologic Review

Tissue transglutaminase (tTG) is a ubiquitous multifunctional protein. It has roles in various cellular processes. tTG is a major target of autoantibodies in celiac disease, and its expression by immunohistochemistry in pediatric celiac disease has not been fully examined. We studied tTG expression in 78 pediatric duodenal biopsies by utilizing an antibody to transglutaminase 2. Serum tTG was positive in all celiac cases evaluated. Serum antiserum endomysial antibody (EMA) and tTG were negative in all control subjects and in inflammatory bowel disease and eosinophilic gastroenteritis. There was a statistically significant difference between cases of celiac disease and normal controls in terms of tTG immunohistochemical staining in duodenal biopsies surface epithelium ( value = 0.0012). There was no significant statistical difference in terms of staining of the villous surface or crypt between the cases of celiac disease and cases with IBD ( value = 0.5970 and 0.5227, resp.). There was no detected correlation between serum tTG values and immunohistochemical positivity on duodenal biopsy in cases of celiac disease ( value = 1). There was no relationship between Marsh classification and positivity of villous surface for tTG ( value = 0.4955). We conclude that tTG has limited utility in diagnosis of celiac disease in pediatric duodenal biopsies

Frequency of rare and multi viral high-risk HPV types infection in cervical high grade squamous intraepithelial lesions in a non-native dominant middle eastern country: a polymerase chain reaction-based pilot study

Abstract Background The incidence of abnormal cervical smears in the United Arab Emirates (UAE) is 3.6%. Data regarding specific high-risk HPV (hrHPV) genotypes are insufficient. Identification of hrHPV subtypes is essential to allow formulating effective vaccination strategies. Methods A total of 75 archival cervical cone biopsies with HSIL or higher lesions (2012–2016) were retrieved from a tertiary hospital, including HSIL (n = 70), adenocarcinoma in-situ (n = 1) and squamous cell carcinoma (n = 4). Five tissue sections (10-μ-thick each) were cut and DNA extracted using the QIAamp DNA FFPE Tissue Kit. GenomeMeTM’s GeneNavTM HPV One qPCR Kit was used for specific detection of HPV 16 and 18; and non-16/18 samples were typed by GenomeMeTM’s GeneNavTM HPV Genotyping qPCR Kit. Results Median age was 34 years (range 19–58) with 70% UAE Nationals. hrHPV detected were 16, 18, 31, 33, 35, 39, 45, 51, 52, 58, 59, 66 & 68. hrHPV testing was negative in 12% of cases. Most common types were HPV 16 (49%), HPV 31 (20%) and HPV 18 (6.6%). hrHPV 16 and/or 18 represented 56% and rare subtypes 32%. Co-infection was present in 16%. Eight cases had two-viral subtype infections and 4 cases had 3 subtype infections. Multi-viral HPV infection was limited to hrHPV 16, 18, 31 & 33 subtypes. Conclusions Infection by non HPV 16/18 is fairly common. A higher than expected incidence of rare subtype (20% hrHPV31) and multi-viral hrHPV (16%) were detected. This finding stresses the importance of this pilot study as currently only quadravalent vaccine is offered to control the HPV infection in the UAE population

Effect of Sirolimus/Metformin Co-Treatment on Hyperglycemia and Cellular Respiration in BALB/c Mice

Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4–6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings

Sirolimus alters lung pathology and viral load following influenza A virus infection

Abstract Background Inhibitors of mTOR, such as sirolimus, have been shown to induce thymus involution and inflammatory lung disease in mice. The latter effect supports the role of this serine/threonine kinase in ameliorating lung inflammation. Other studies have shown sirolimus reduces/delays lung disease associated with various strains of influenza A virus (IAV). Thus, the effects of mTOR inhibitors on influenza infection deserve further studies. Methods Here, we examined the changes in lung viral copies, pathology and pulmonary function associated with IAV (A/PR/8/34) infection in mice treated with sirolimus. Results Body weight loss peaked between days 6–11 post-infection and was more severe in IAV-infected mice that were administered sirolimus as compared to mice that received IAV alone (p = 0.030). Natural log viral gene copies, mean ± SD per mg lung tissue, in IAV-infected mice that were administered sirolimus were 17.31 ± 1.27 on day 4, 19.31 ± 7.46 on day 10, and 0 on day 25. The corresponding number of copies in mice that received IAV alone were 18.56 ± 0.95 on day 4 (p = 0.132), 1.52 ± 1.39 on day 10 (p = 0.008), and 0 on day 25. Lung pathology was evident on days 4, 10, and 25 post infection, with mean ± SD inflammatory score of 9.0 ± 4.5 in IAV-infected mice that were administered sirolimus, as compared to 11.5 ± 4.5 (p = 0.335) in mice received IAV alone (maximum score, 26.0). Impaired lung function was evident in IAV-infected mice on days 4 and 10, as demonstrated by increased airway resistance and decreased compliance. Conclusions In this model, the effects of sirolimus on influenza infection included severe weight loss and modified viral replication, respiratory function and lung inflammation. The adverse events associated with sirolimus treatment are consistent with its potent immunosuppressive activity and, thus, preclude its use in IAV infection

Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models

Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1β, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation

Cis-Nerolidol Inhibits MAP Kinase and NF-κB Signaling Pathways and Prevents Epithelial Tight Junction Dysfunction in Colon Inflammation: In Vivo and In Vitro Studies

Inflammation of the GI tract leads to compromised epithelial barrier integrity, which increases intestine permeability. A compromised intestinal barrier is a critical event that leads to microbe entry and promotes inflammatory responses. Inflammatory bowel diseases that comprise Crohn’s disease (CD) and ulcerative colitis (UC) show an increase in intestinal permeability. Nerolidol (NED), a naturally occurring sesquiterpene alcohol, has potent anti-inflammatory properties in preclinical models of colon inflammation. In this study, we investigated the effect of NED on MAPKs, NF-κB signaling pathways, and intestine epithelial tight junction physiology using in vivo and in vitro models. The effect of NED on proinflammatory cytokine release and MAPK and NF-κB signaling pathways were evaluated using lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophages. Subsequently, the role of NED on MAPKs, NF-κB signaling, and the intestine tight junction integrity were assessed using DSS-induced colitis and LPS-stimulated Caco-2 cell culture models. Our result indicates that NED pre-treatment significantly inhibited proinflammatory cytokine release, expression of proteins involved in MAP kinase, and NF-κB signaling pathways in LPS-stimulated RAW macrophages and DSS-induced colitis. Furthermore, NED treatment significantly decreased FITC-dextran permeability in DSS-induced colitis. NED treatment enhanced tight junction protein expression (claudin-1, 3, 7, and occludin). Time-dependent increases in transepithelial electrical resistance (TEER) measurements reflect the formation of healthy tight junctions in the Caco-2 monolayer. LPS-stimulated Caco-2 showed a significant decrease in TEER. However, NED pre-treatment significantly prevented the fall in TEER measurements, indicating its protective role. In conclusion, NED significantly decreased MAPK and NF-κB signaling pathways and decreased tight junction permeability by enhancing epithelial tight junction protein expression