Myelodysplastic syndrome (MDS) & Acute Myeloid Leukemia (AML) arise from a population of aberrant hematopoietic stem cells (HSCs) that have been altered by multiple genetic & epigenetic alterations. A preliminary genomewide transcriptomic and epigenomic analysis of stem and progenitor cells from MDS and AML patients revealed STAT3 upregulation with corresponding loss of promoter methylation in diseased samples (Will et al, Blood, 2012). We now demonstrate that STAT3 is overexpressed in highly purified FACS sorted disease initiating populations in MDS/AML. STAT3 expression was determined to be significantly higher in phenotypic LT-HSC (CD34+/CD38-/CD90+/Lin -ve), ST-HSC (CD34+/CD38-/CD90-/Lin -ve) and GMP (CD34+/CD38+/CD123+/CD45Ra+/Lin -ve) from 10 diseased and 6 control sorted samples. Transcriptomic data from another cohort of CD34+ cells from 183 MDS patients found significantly increased expression of STAT3 in MDS samples when compared to healthy controls and importantly, found that increased STAT3 expression was predictive of significantly adverse prognosis (P value < 0.01, median survival of 2.6 years compared to 5.8 years for group with lower STAT3). Clinical correlations revealed that MDS patients with higher STAT3 expression in stem/progenitor cells were significantly more anemic (Mean Hgb 9.4gm/dl vs 10.2gm/dl, P=0.002) and had higher blast counts (Mean Blast Count 7.1% vs 5.3%, P=0.02), further demonstrating STAT3 to be an adverse prognostic marker in MDS. To functionally determine the role of STAT3 in MDS/AML pathogenesis, we used AZD9150, a Gen 2.5 Antisense Oligonucleotide (ASO) specific inhibitor of STAT3 (Hong et al, SciTM, 2015). This ASO has recently demonstrated safety and single-agent antitumor activity in patients with refractory lymphoma in a phase 1 dose-escalation study. We evaluated its efficacy in multiple leukemic cell lines and primary MDS/AML samples and used an inactive structural analogue oligonucleotide as control. AZD9150 treatment led to significantly decreased viability in numerous AML and MDS derived cell lines. (N=7, P < 0.01). Loss of viability was accompanied by dose dependent increase in apoptosis in leukemic cells. Specific inhibition of STAT3, but not STAT5, was seen in AZD9150 treated leukemic cells in luciferase reporter assays. AZD9150 treatment also led to decreased expression of important oncogenic downstream genes including not only STAT3 itself, but also IL8, IL6, CXCR2 and others. In vivo studies using a leukemia xenograft model in NSG mice demonstrated that treatment with AZD9150 at 50mg/kg/day led to significantly improved survival compared to control oligonucleotide (p-value: 0.004). It is generally challenging to show uptake of oligonucleotide-based therapeutics by primary cancer samples. Here, we treated healthy stem cells and AML primary patient samples with AZD 9150 and determined by intracellular flow cytometry that the ASO were readily taken up by primary patient- or cord blood-derived HSCs, myeloid progenitors and lymphocytes in a time and dose-dependent manner. We then treated a cohort of MDS and AML primary samples (N= 7) with AZD9150 or control and found qualitatively decreased leukemic colony growth, enhanced erythroid colony formation, and increased myeloid differentiation following STAT3 inhibition. In conclusion, we demonstrate that STAT3 is upregulated in highly purified stem and progenitor cells in MDS and AML and is an adverse prognostic marker. Importantly, a clinically applicable oligonucleotide inhibitor of STAT3 shows preclinical in vitro and in vivo efficacy in MDS and AML models, thereby providing a rationale for further development and clinical testing in MDS and AML. Supported by LLS Disclosures No relevant conflicts of interest to declare.
Background: Hepatorenal syndrome is a clinical condition that occurs in patients with chronic liver disease, advanced liver cell failure and portal hypertension characterized by impaired renal function Various variables were studied between survivor and non-survivor groups to detect possible predictors of non-survival. Objective: This study aims to assess outcome of hepatorenal syndrome in Sohag University Hospitals and discover possible predictors of non-survival in these patients. Materials & Methods : This study included 50 patient attented Sohag University hospital from 1 / 4 / 2017 till 1 / 10 / 2017 and Who agreed to share in the study and fulfilling the criteria of hepatorenal syndrome were be studied prospectively to observe clinical outcome Various variables were studied between survivor and non-survivor groups to detect possible predictors of non-survival in hepatorenal syndrome. The diagnosis for cirrhosis was based on history, examination, liver function test, and abdominal ultrasound. In all patients history of jaundice, fever, abdominal pain, abdominal distension, deceased urine output and GIT bleeding was taken. diagnosis of hepatorenal syndrome was according to the International Ascites club criteria (inclusion criteria).Study was divided into 2 groups, survivors and non-survivors. Results: the study shows 14 patients (28%) were survivors, but the remaining 36 patients were non-survivors (72%). the possible predicting factors of mortality included were male sex,having tense ascites, having SBP,hepatic encephalopathy being child score C, type I HRS,with high level ofserum creatinine and urea,low level of serum albumin. These factors were be subjected to multivariate regression analysis.
Background: Patients with End stage renal disease (ESRD) suffer from recurrent gastrointestinal bleeding episodes with superficial mucosal inflammatory lesions. Lesions are more frequent in those who were in advanced stage of CKD and those undergoing dialysis.
Background: Postoperative Endophthalmitis is a rare complication after intraocular surgeries. However, it remains one of the most devastating complications following cataract surgery because of its poor prognosis. We describe the effects of antibiotic prophylaxis on the incidence of postoperative endophthalmitis after cataract surgery, particularly phacoemulsification. Aim of the work: To identify risk factors of acute endophthalmitis and describe the effects of antibiotic prophylaxis on the incidence of postoperative endophthalmitis after phacoemulsification surgery. Methods: A prospective randomized cataract surgery study recruited 300 patients; 150 patients who received just intracameral vigamox at the end of surgery without topical antibiotics before surgery and 150 patients who received both intracameral vigamoxas well as topical perioperative vigamox which either just half an hour before surgery or three days preceding surgery. We took a conjunctival swab before and after vigamox administration in order to detect the type of conjunctival flora in the Libyan population as well as the effect of the vigamox on the conjunctival flora by using Phoenix-BD machine. In total we collected 166 specimens (83 patients). Results: In all groups no acute post-operative endophthalmitis was reported. Conclusions: The study was based on intracameral Moxifloxacin at the end of surgery with and without topical antibiotics drops administration. The incidence of postcataract endophthalmitis was not reported in our study after using intracameral antibiotics, as it seems to be effective in preventing endophthalmitis after cataract surgery.
Background: Coronary artery disease (CAD) has been proven to be causally associated to genetically defined and metabolically produced changes in lipid metabolism, as seen in numerous kinds of dyslipidemia. Objective:The aim of the present study was to assess the lipid profile in patients with chronic coronary syndrome. Patients and Methods: A hospital based cross-sectional study was conducted at Sohag University Hospital and included 100 patients with chronic coronary syndrome. The examined if our patients could achieve the target lipid profile level of their group according to 2019 ESC/EAS Guidelines for the management of dyslipidaemia. History of CAD and family history were taken. Clinical presentation and body mass index (BMI) were assessed. Finally, lifestyle, drug history (lipid lowering drug, anti HTN drug and anti-platelets drugs), dietary intake assessment and physical exercise were evaluated. Results: Patients had a mean HDL-C level of 39.4 91mg/dL, a mean total cholesterol level of 188.91mg/dL, a mean LDL-C level of 119.67mg/dL and a mean triglyceride level of 149.15mg/dL. HDL-C was significantly lower for nonstatin therapy group compared to statin therapy group (P<0.001), while triglycerides and vLDL were significantly higher non-statin therapy group compared to statin therapy group (P<0.001). Only 8% of patients achieved target LDL-C according to 2019 ESC/EAS guidelines. Conclusion:Most of patients at Sohag University Hospital are not reaching the target LDL-C. Thus, more strict application of guidelines and investigating the predisposing factors for uncontrolled lipid profile, especially in patients with CAD, are urgently needed.
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