Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells

Senotherapeutics are new drugs that can modulate senescence phenomena within tissues and reduce the onset of age-related pathologies. Senotherapeutics are divided into senolytics and senomorphics. The senolytics selectively kill senescent cells, while the senomorphics delay or block the onset of senescence. Metformin has been used to treat diabetes for several decades. Recently, it has been proposed that metformin may have anti-aging properties as it prevents DNA damage and inflammation. We evaluated the senomorphic effect of 6 weeks of therapeutic metformin treatment on the biology of human adipose mesenchymal stromal cells (MSCs). The study was combined with a proteome analysis of changes occurring in MSCs’ intracellular and secretome protein composition in order to identify molecular pathways associated with the observed biological phenomena. The metformin reduced the replicative senescence and cell death phenomena associated with prolonged in vitro cultivation. The continuous metformin supplementation delayed and/or reduced the impairment of MSC functions as evidenced by the presence of three specific pathways in metformin-treated samples: 1) the alpha-adrenergic signaling, which contributes to regulation of MSCs physiological secretory activity, 2) the signaling pathway associated with MSCs detoxification activity, and 3) the aspartate degradation pathway for optimal energy production. The senomorphic function of metformin seemed related to its reactive oxygen species (ROS) scavenging activity. In metformin-treated samples, the CEBPA, TP53 and USF1 transcription factors appeared to be involved in the regulation of several factors (SOD1, SOD2, CAT, GLRX, GSTP1) blocking ROS

Outcomes and treatment strategies for autoimmunity and hyperinflammation in patients with RAG deficiency

BACKGROUND: While autoimmunity and hyperinflammation secondary to recombinase activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. The majority of patients (55.6%) presented with more than one autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP) and autoimmune neutropenia (AN), respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in the majority of cases (64.7%, 73.7%, and 71.4% for AIHA, ITP, and AN, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multi-lineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management

Diagnostic Accuracy of a New Urinalysis System, DongJiu, for Diagnosis of Urinary Tract Infection

Objectives. The microscopic and chemical analysis of urine is essential for the diagnosis of patients with urinary tract infections (UTI). Quantitative urine culture is the 'gold standard' method for the diagnosis of UTI, but it is labour-intensive and time consuming. The DongJiu 8602 is a new automated urinalysis system with dipstick and microscopy testing. The aim of this study was to evaluate the analytical and diagnostic performance of DongJiu 8602 in comparison to urine culture as the reference method. Methods. This retrospective study included 3970 urine samples, with a preliminary diagnosis of UTI and for which both urine analysis and urine culture were requested. Cut-off values for bacteria and white blood cells (WBCs) were determined by comparing the results with urine cultures. The cut-off values by the receiver operating characteristic (ROC) curve technique, sensitivity, and specificity were calculated for microscopy and dipstick parameters (nitrite and leukocyte esterase). Results. Among the 3970 urine specimens submitted for culture, 3275 cultures (82.5%) were negative, and 695 were (17.5%) positive. The best cut-off values obtained from ROC analysis were 13/mu L for bacteriuria (sensitivity: 31.1%, specificity: 91.8%), and 31/mu L for WBCs (sensitivity: 48.6%, specificity: 85.9 %). We observed no significant difference between the area under the curves (AUC) of microscopy and dipstick parameters (p>0.05). Conclusion. According to our data, performances of microscopic and dipstick parameters of DongJiu 8602 were not satisfactory. Although, analytical sensitivity was improved slightly with combined assessment of microscopic and dipstick results for the lack of UTI, it did not achieve expected levels

HEMATOPOIETIC STEM CELL TRANSPLANTATION IN REFRACTORY OR RECURRENT LYMPHOMAS OF CHILDREN AND ADOLESCENTS: A MULTICENTER SURVEY OF TURKISH PEDIATRIC BMT STUDY GROUP

40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation -- MAR 30-APR 02, 2014 -- Milan, ITALYWOS: 000359941901154…European Grp Blood & Marrow Transplanta

Outcome of autologous hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory Hodgkin's lymphoma

PubMedID: 26346042This study evaluates the outcome of 66 pediatric patients with rrHL who underwent autoHSCT. Twenty-nine patients experienced early relapse, and 19 patients experienced late relapse. Of 18 newly diagnosed with HL, 13 were primary refractory disease and five had late responsive disease. At the time of transplantation, only 68% of the patients were chemosensitive. The majority of patients received BCNU + etoposide + ara-C + melphalan for conditioning (45/66), and peripheral blood (56/66) was used as a source of stem cells. After a median follow-up period of 39 months, 46 patients were alive. At five yr, the probabilities of OS, EFS, the relapse rate, and the non-relapse mortality rate were 63.1%, 54.3%, 36.4%, and 9.1%, respectively. The probability of EFS in chemosensitive and chemoresistant patients at five yr was 72.3% and 19%, respectively (p < 0.001). Multivariate analysis showed that chemoresistant disease at the time of transplantation was the only factor predicting limited both OS (hazard ratio = 4.073) and EFS (hazard ratio = 4.599). AutoHSCT plays an important role for the treatment of rrHL in children and adolescents, and survival rates are better for patients with chemosensitive disease at the time of transplantation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Evaluation of risk factors and outcomes of invasive fungal infections in the first six months after allogeneic hematopoietic stem cell transplantation in pediatric acute leukemia: A Turkish multicenter study

41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation -- MAR 22-25, 2015 -- Istanbul, TURKEYWOS: 000351632903148…European Soc Blood & Marrow Transplanta

Reduction in serum paraoxonase level in newborns with hyperbilirubinemia as a marker of oxidative stress

Objective: Indirect bilirubin exerts an antioxidant effect when increased mildly. This study aimed to investigate whether increased bilirubin levels lead to an oxidant effect in newborns with hyperbilirubinemia requiring phototherapy.Patients and methods: The study included 30 term newborn infants aged 0-7 days with indirect hyperbilirubinemia requiring phototherapy and no comorbid disease as the study group. In addition, 30 term healthy newborn infants aged 0-7 days without indirect hyperbilirubinemia were employed as a control group. Serum triglyceride, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), serum paraoxonase (PON) levels and malondialdehyde (MDA) levels were compared between the groups.Results: Serum MDA, total bilirubin, and LDL and HDL levels were significantly higher and the serum PON level was significantly lower, in the study group compared with the controls (p <0.05).Conclusion: In newborns with hyperbilirubinemia requiring phototherapy, an increased bilirubin level causes oxidative stress by decreasing the level of serum PON and increasing the level of MDA

Apelin-13: A Promising Biomarker for Age-Related Macular Degeneration?

Purpose: To investigate the value of serum apelin-13 levels in patients with age-related macular degeneration (AMD). Methods: Patients with dry-type AMD, patients with treatment-naive neovascular-type AMD, and healthy controls were included in this study. Diagnoses were confirmed on detailed fundus examination, optical coherence tomography (OCT), and fundus fluorescein angiography (FFA). Central foveal thickness and subfoveal choroidal thickness were evaluated. Both serum apelin-13 and vascular endothelial growth factor (VEGF) levels were measured by a competitive enzyme-linked immunosorbent assay (ELISA) principle. Results: A total of 84 subjects, i.e., 24 in the dry-type AMD group (group 1), 27 in the neovascular-type AMD group (group 2), and 33 in the control group (group 3) were included in the study. Mean best-corrected visual acuity (BCVA) was 76 +/- 4.5, 48.4 +/- 16.3, and 83.4 +/- 3.09 ETDRS letters in group 1, 2, and 3, respectively. The level of serum VEGF was 44.11 +/- 26.14, 56.53 +/- 53.77, and 61.47 +/- 41.62 pg/mL in groups 1, 2, and 3, respectively (p = 0.553, p = 0.286, and p = 0.896, respectively). The level of serum apelin-13 was 586.47 +/- 167.56, 622.18 +/- 324.52, and 379.31 +/- 171.96 pg/mL in groups 1, 2, and 3, respectively (p = 0.847, p = 0.04, and p <= 0.001, respectively). There was a negative correlation between the level of serum apelin and visual acuity (VA) and choroidal thickness. Conclusion: Serum apelin-13 levels were higher in both dry-type and neovascular-type AMD patients than in controls. Further studies demonstrating the relationship of the level of serum apelin-13 and AMD are needed