LncRNA ANRIL Promotes Glucose Metabolism and Proliferation of Colon Cancer in a High-Glucose Environment and is Associated with Worse Outcome in Diabetic Colon Cancer Patients.

BACKGROUND: The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. Epigenetic changes, such as deregulation of long non-coding RNA (lncRNA) and microRNA (miR), have been linked to the advancement of CC; however, the effects of high glucose levels on their deregulation and, in turn, colon cancer remain unexplored. METHODS: Fifty patients had a dual diagnosis of CC and T2DM, and 60 patients with CC without diabetes mellitus were included in the study. qRT-PCR was used to examine the expression of lncRNA ANRIL and miR-186-5p in tissue samples. ANRIL, miR-186-5p, and their downstream target genes HIF-1α, PFK, HK, Bcl-2, and Bax were also determined in CC cell lines under various glucose conditions. Glucose uptake, lactate production and cells proliferation were estimated in CC cell lines. RESULTS: A significant upregulation of ANRIL expression levels (p<0.001) and a significant downregulation of miR-186-5p expression (p<0.001) in diabetic colon cancer specimens compared to those in non-diabetic colon cancer group were observed. MiR-186-5p expression levels were inversely correlated with ANRIL expression levels, blood glucose levels and HbA1c%. Concerning in vitro model, a significant upregulation of ANRIL, downregulation of miR-186-5p, upregulation of HIF-1α, glycolytic enzymes and activation of antiapoptotic pathway was detected in higher glucose concentrations than lower one. There was a significant increase of glucose uptake, lactate accumulation and proliferation of the Caco2 and SW620 cell lines in a dose dependent manner of glucose concentrations. Moreover, a significant positive correlation between glucose uptake and ANRIL expression was shown. CONCLUSIONS: A high-glucose environment can increase the tumor-promoting effect of ANRIL. ANRIL can promote glucose metabolism and colon cancer proliferation by downregulating miR-186-5p with subsequent upregulation of glycolysis enzymes expression and inhibition of apoptosis.

Epidemiology of Geriatric-Dermatology virtual clinic: Teledermatology-Based care for elderly patients with skin diseases in Qatar.

Background: The 'GeriDerm' (geriatric dermatology) clinic, is a new dermatology-based service at Hamad Medical Corporation (HMC), accommodating the needs of our elderly population living in the State of Qatar. Due to the global demographic transition towards an elderly population (≥65 years of age), incidences of chronic diseases, including dermatologic conditions, rise in parallel. Patients of older age are at higher risk of using multiple medications, seeing multiple care providers, often receiving multiple diverging pieces of information, and feeling lost within the system. Taking into consideration the elderly unique characteristics, the Geriatric Dermatology telemedicine clinic is a novel approach to meeting the many challenges our elderly patients face via providing quick, accurate assessments of cognition, functional status, frailty screening, and assessment for polypharmacy. Methods: Data of 1080 elderly patients with various skin disorders from June 2020 to July 2021 was received from the Dermatology Geriatric clinic, and then reviewed. Results: There were 521(48.2%) new cases and 559(51.8%) follow-up cases who attended the clinic either virtually or face to face consultation. A total of 587(54.4%) female and 493(45.6%) male elderly patients attended the clinic. The mean age was 74.6, with a minimum age of 60 and a maximum age of 106 years. 57.9%(625) of GeriDerm patients were Qatari, followed by Palestinian 75(6.9%), Syrian 51(4.7%), Egyptian 46(4.3%), and Indian 44(4.1%); while other nationalities constituted 239(22.1%). The majority of the cases were Contact Dermatitis 146(13%), Bullous Pemphigoid 107 (10%), and Pruritis 101(9.4%). Conclusion: The 'GeriDerm' service at HMC aimed to achieve the best healthcare standards for the elderly population of Qatar during COVID-19 pandemic, and is now established as a continuous advanced technology-based framework facilitating caring for older patients with skin disease via providing a clear pathway for adequate triaging, identification of severe conditions (red flag) requiring in-person clinic visits, while managing non-life threatening dermatoses via a teledermatology based approach.

Down-regulated MiRNA 29-b as a diagnostic marker in colorectal cancer and its correlation with ETV4 and Cyclin D1 immunohistochemical expression.

BACKGROUND: Colorectal cancer (CRC) is the most common malignant tumor of the gastrointestinal tract with unfavorable prognosis. Therefore, novel biomarkers that may be used for new diagnostic strategies and drug-targeting therapy should be developed. OBJECTIVES: To investigate the expression of miR-29b in CRC and its association with ETV4 and cyclin D1 expression. Moreover, the current work aims to investigate the association between them and the clinicopathological features of CRC. METHODS: The expression of miR-29b and ETV4 (by qRT-PCR) and ETV4 and cyclin D1 (immunohistochemistry) was investigated in 65 cases of colon cancer and surrounding healthy tissues. RESULTS: MiR-29b down-regulated and ETV4 and Cyclin D1 up-regulated significantly in colon cancer tissues compared to normal nearby colonic tissues. In addition, significant associations between ETV4 and cyclin D1 expressions and progressive stage and lymph node (LN) metastasis (P< 0.001 for each) were found. Furthermore, there was a negative correlation between miR-29b gene expression and ETV4 gene expression (r=-0.298, P<0.016). CONCLUSION: Down-regulation of miR-29b and over-expression of ETV4 and cyclin D1 may be utilized as early diagnostic marker for development of colon cancer. ETV4 and cyclin D1 correlate with poor prognostic indicators and considered as a possible target for therapy in colon cancer.

MIR-379-5p Expression in Endometrial Cancer and Its Correlation with ROR1 Expression.

OBJECTIVE: To asses miR-379-5p expression in endometrial cancer (EC) and its correlation with ROR1 expression and to investigate the relation between miR-379-5p and ROR1 expressions and the clinicopathological picture of EC. METHODS: Fifty female of EC were joined to this study. The gene expression of miR-379-5p (by quantitative real time-PCR) and ROR1 (by quantitative real time-PCR and immunohistochemistry) were studied in EC and normal nearby endometrial tissue. RESULTS: The gene expression of miR-379-5p was significantly downregulated while that of ROR1 was significantly upregulated in EC tissues compared to adjacent normal endometrial tissues. Furthermore, miR-379 and ROR1 expressions significantly associated with tumor stage (P< 0.045), grade (P< 0.001), myometrial invasion (P <0.001) and LN metastasis (P< 0.034). In addition, miR-3795p and ROR1 gene expression were negatively correlated (r = -0.746, P < 0.001). CONCLUSIONS: In EC, miR-379-5p can be used as a diagnostic marker, and ROR1 could be a potential target of miR-379-5p.

SATB-1 and Her2 as predictive molecular and immunohistochemical markers for urothelial cell carcinoma of the bladder.

Studying bladder cancer molecular biology revealed the presence of genetic alterations. So, detection of molecular biomarkers that help in monitoring the disease, evaluating the prognosis of the patients, and their response to therapy is needed. In this study, we investigated the expression and the prognostic significance of SATB-1 and ERBB2 mRNA and protein by quantitative RT-PCR and immunohistochemical analysis in urothelial bladder cancer cases and the surrounding normal bladder tissue. The correlations between the expression of both markers and the clinicopathological parameters were performed with further analysis of the correlation between the expression of SATB-1 and ERBB2. Compared to control, the expression of SATB-1 and ERBB2 mRNA and protein in cancer tissues were significantly up-regulated (p< 0.05). Also, a positive correlation between both markers was found (r= 0.53, p< 0.001). Moreover, elevated levels of both markers were significantly associated with the stage, lymph node involvement at both mRNA and protein levels (p< 0.001). In conclusion, there is a clinical significance of SATB-1 and ERBB2 as potential biomarkers for predicting bladder cancer patients of aggressive behavior and poor prognosis.

Comparison between the effect of human Wharton's jelly-derived mesenchymal stem cells and levetiracetam on brain infarcts in rats.

BACKGROUND: Stroke represents one of the major causes of death worldwide. Neuroprotection remains an important goal of stroke therapy. Stem cell therapeutic effect is attributed to the neuroprotective effect and the regulation of the oxidant stress. Levetiracetam (LEV), a second-generation antiepileptic drug, was reported to confer neuronal protection after cerebral ischemia reperfusion. AIM: To investigate the effect of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) and LEV on the size of brain infarcts, the histological structure, the neurotrophic, and the antioxidant gene expression in middle cerebral artery occlusion in rats. METHOD: The rats were divided into five equal groups of 12 rats each as follows. Sham control group: received phosphate-buffered saline (PBS); ischemia/reperfusion (I/R) group: received PBS before ligation; stem cell-treated group: the animal received MSCs before ligation; LEV-treated group: the animal received LEV before occlusion; combined group: the animals received both MSCs and LEV before occlusion. Hematoxylin and eosin staining was performed to study the histological structure of the brain. Real-time polymerase chain reaction (RT-PCR) was performed to assess gene expression. RESULTS: Both MSCs and LEV improved memory and learning in the treated groups compared with I/R group. Significant reduction of the infarct size in WJ-MSC- or LEV-treated groups when compared with untreated ones was found. By RT-PCR, a significant decrease of the expression values of glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), phosphatidylethanolamine binding protein 1 (PEBP1), and copper-zinc SOD (Cu/ZnSOD) genes and a significant increase of pro-oxidant iNOS gene in the I/R rats compared with the sham group was detected. There was a significant increase in the expression values of GDNF, BDNF, PEBP1, and Cu/ZnSOD genes in both treated groups when compared with the I/R group. Rats treated with WJ-MSCs showed better results than rats treated with LEV. Finally, the combined use of LEV and WJ-MSCs was the most effective regimen as regard infarction volume and functional learning and memory tests. CONCLUSION: In the brain ischemia model, combined WJ-MSCs and LEV have demonstrated striking protective effects in brain infarction by the modulation of the oxidant status and neuroprotective effect.

Prognostic significance of the genetic and the immunohistochemical expression of epithelial-mesenchymal-related markers in colon cancer.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is one of the main events in colorectal cancer (CRC) spread. Snail-1 is a zinc transcription factor that mediates EMT in tumor cells probably by down-regulation of E-cadherin and claudin-1. OBJECTIVES: To detect the expression of epithelial markers (claudin-1 and E-cadherin) and mesenchymal markers (snail-1 and vimentin) in primary cancer colon. Also, to select stage II cancer patients of a high risk that can benefit from postoperative adjuvant chemotherapy. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical analysis were performed to investigate snail-1, claudin-1, E-cadherin and vimentin expressions at mRNA and protein levels in fresh tissues of cancer colon and normal colonic mucosa. The correlations between the expression of these markers and clinicopathological parameters were performed. RESULTS: Normal colonic mucosa revealed complete membranous expression of claudin-1, preserved E-cadherin and negative snail-1 and vimentin expressions. Compared to control, the expression of snail-1 and vimentin mRNA in cancer colon was significantly up-regulated while the expression of claudin-1 and E-cadherin mRNA was significantly down-regulated. These changes were significantly associated with stage and lymph node involvement at both mRNA and protein levels (p< 0.05). There were significant negative correlations between vimentin and each of E-cadherin and claudin-1 gene expression and between snail-1 and each of E-cadherin and claudin-1 gene expression. Moreover, these changes were independent predictors of recurrence of stage II cancer colon cases. CONCLUSION: There is a clinical significance of snail-1, claudin-1, E-cadherin and vimentin as possible markers for recognizing patients with lymph node involvement, advanced stage and high incidence of tumor recurrence in cancer colon.

Molecular factors regulating E-cadherin expression in urothelial bladder cancer and their correlations with the clinicopathological features.

This study aimed to assess the expression of S100A4, Twist and E-cadherin (mRNA and protein) in urothelial bladder cancer, investigate the correlation between them and evaluate their association with the clinicopathological features of the disease. The study included 54 patients diagnosed as urothelial bladder cancer of different stages and grades. The expression levels of S100A4, Twist and E-cadherin (mRNA and protein) in tissue samples were determined by quantitative RT-PCR and immunohistochemistry. The expression of S100A4 and Twist was significantly upregulated while E- cadherin was significantly downregulated in urothelial bladder cancer tissues compared to the adjacent surrounding normal bladder tissues at both mRNA and protein levels (p < 0.001). Expression levels of S100A4 and Twist were significantly higher in recurrent tumor than in non-recurrent tumors (p < 0.001) while the expression level of E-cadherin was significantly lower in recurrent tumors than in non-recurrent tumors at both mRNA and protein levels (p < 0.001). There was a significant positive correlation between S100A4 and Twist expressions (r = 0.875, p < 0.001) while significant negative correlations were found between E- cadherin and S100A4 expressions(r=- 0.803, p < 0.001) and between E-cadherin and Twist (r = -0.809, p < 0.001). Up-regulation of S100A4 and Twist and down-regulation of E-cadherin in urothelial bladder cancer tissues compared to adjacent normal tissues were observed. There was a significant negative correlation between S100A4 and E- cadherin and between E- cadherin and Twist expression. However, there was a significant positive correlation between S100A4 and Twist expressions. Furthermore, the alterations in the gene expression were associated with disease stage and grade.

Up-regulated miR-221 expression as a molecular diagnostic marker in laryngeal squamous cell carcinoma and its correlation with Apaf-1 expression.

BACKGROUND: Despite the improvement in the diagnosis and the management of laryngeal squamous cell carcinoma (LSCC), many patients with advanced-stage have poor prognosis in the form of recurrence, metastasis or death. So, recognition of new molecular markers would facilitate the development of targeted therapies. OBJECTIVES: To investigate miR-221 expression in LSCC and its possible correlation to apoptotic protease activating factor-1 (Apaf-1). Also, we aimed to investigate the association between miR-221 and Apaf-1 expressions and the clinicopathological features of LSCC. METHODS: We investigated the expression of miR-221 (by qRT-PCR) and Apaf-1 (by qRT-PCR and immunohistochemistry) in primary LSCC and adjacent normal tissues. RESULTS: We found significant up-regulation of miR-221 and significant down-regulation of Apaf-1 expression in LSCC tissues compared to normal nearby laryngeal tissues. In addition, significant associations between up-regulated miR-221 and down-regulated Apaf-1 expressions and clinical stage and lymph node (LN) metastasis (P< 0.001 for each) were found. Furthermore, there was a negative correlation between miR-221 gene expression and Apaf-1 gene expression (r=-0.73, P< 0.001). CONCLUSION: miR-221 can be considered as a diagnostic marker in LSCC and Apaf-1 may be considered as a possible target of miR-221.

Prognostic significance of CD133 and ezrin expression in colorectal carcinoma.

Despite the improvement in the diagnostic and the therapeutic modalities, colorectal cancer (CRC) morbidity and mortality remain high in both the developed and the developing countries. So, we are in a need to recognize new efficient diagnostic and prognostic biomarkers of CRC. That may help in providing individualized targeted therapy for this lethal malignancy. In this study, we investigated the expression and the prognostic significance of CD133 and ezrin mRNA and protein by quantitative RT-PCR and immunohistochemical analysis in primary CRC cases and the surrounding normal colonic mucosa. The correlations between the expression of both markers and clinicopathological parameters were performed. Compared to control, the expression of CD133 and ezrin mRNA and protein in CRC were significantly up-regulated (P < 0.05). In addition, a strong positive correlation between both markers was found (r = 0.867, P < 0.001). Moreover, elevated levels of both markers were significantly associated with the stage, lymph node involvement, distant metastasis, and recurrence at both mRNA and protein levels (P < 0.05). In conclusion, there is a clinical significance of CD133 and ezrin as potential biomarkers for predicting CRC patients of aggressive behavior and poor prognosis. © 2017 IUBMB Life, 69(5):328-340, 2017.

Effect of human umbilical cord blood mesenchymal stem cells administered by intravenous or intravitreal routes on cryo-induced retinal injury.

Traumatic optic neuropathy is an important cause of severe vision loss. So, many attempts were performed to transplant stem cells systemically or locally to regenerate the injured retina. In this study, we investigated the effect of human umbilical cord blood mesenchymal stem cells (hUBMSCs) on histological structure, apoptotic, antiapoptotic, oxidant and antioxidant markers in an experimental model of cryo-induced retinal damage in mice. Forty-eight mice were included with 4 major groups; group I contained 18 mice as controls. The others included 30 mice exposed to cryo-induced retinal injury and were subdivided into three equal groups: group II received no treatment after injury. Group III was intravenously injected with hUCBMSCs after injury and group IV received an intravitreal injection with hUCBMSCs into both eyes. Retinal tissues were used for histopathological, immunological and gene expression studies. Real time-PCR was performed to assess B-cell lymphoma 2 (bcl2), Bcl2-associated X protein (bax), heme oxygenase-1 (hmox-1) and thioredoxin-2 (tnx-2) expression and to assess the differentiation of the stem cells into the retinal tissue. Immunohistochemical analysis was performed to assess caspase-3, 3-nitrotyrosine (3-NT) and basic fibroblast growth factor (bFGF). Disturbed retinal structure was seen in cryo-injured mice while hUCBMSCs treated groups showed nearly normal structure. By real time-PCR, significantly reduced mRNA expressions of Bax and notably enhanced mRNA expression of Bcl-2, hmox-1 and txn-2 were demonstrated in retinal injured mice with hUCBMSCs treatment compared to those without. In addition, immunohistochemical analysis confirmed downregulation of 3-NT and caspase-3 and upregulation of bFGF after hUCBMSCs injection in injured retina. Furthermore, there was no differentiation of transplanted stem cells into the retinal tissue. In conclusions, hUCBMSCs could improve the morphological retinal structure in cryo-induced retinal damage model by modulation of the oxidant-apoptotic status and by increased the expression of bFGF. © 2017 IUBMB Life, 69(3):188-201, 2017.

Neuroprotective effects of placenta-derived mesenchymal stromal cells in a rat model of experimental autoimmune encephalomyelitis.

BACKGROUND: Current therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stromal cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS. A preparation of MSCs derived from full-term human placenta (PDMSCs) is a new approach in the treatment of patients with MS. OBJECTIVE: This study aimed to rule out the possible therapy by PDMSCs in experimental autoimmune encephalomyelitis (EAE), a rat model of MS. METHODS AND RESULTS: Thirty-five female Wistar rats were classified into the following groups: I, control; II, EAE untreated; III and IV, EAE treated with phosphate-buffered saline (PBS) at 9 and 16 days post-immunization (dpi), respectively; V and VI, EAE treated with PDMSCs at 9 and 16 dpi, respectively. Intravenous administration of PDMSCs at 9 or 16 dpi significantly ameliorated the disease course, decreasing brain inflammation and degenerating neurons. A reduction of axonal damage as well as an increase of oligodendrocyte precursors were recorded. Moreover, there was an engraftment of the PDMSCs into the brain tissue. Human brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin 3 (NTF3) were significantly expressed in brains of rats treated by PDMSCs. CONCLUSIONS: Human PDMSCs have demonstrated striking therapeutic effects when delivered at the onset or at the peak of the disease. PDMSCs have direct neurotrophic support after their engraftment within the lesion through expression of the neurotrophins.