Aging of mesenchymal stem cell in vitro

BACKGROUND: A hot new topic in medical treatment is the use of mesenchymal stem cells (MSC) in therapy. The low frequency of this subpopulation of stem cells in bone marrow (BM) necessitates their in vitro expansion prior to clinical use. We evaluated the effect of long term culture on the senescence of these cells. RESULTS: The mean long term culture was 118 days and the mean passage number was 9. The average number of PD decreased from 7.7 to 1.2 in the 10th passage. The mean telomere length decreased from 9.19 Kbp to 8.7 kbp in the 9th passage. Differentiation potential dropped from the 6th passage on. The culture's morphological abnormalities were typical of the Hayflick model of cellular aging. CONCLUSION: We believe that MSC enter senescence almost undetectably from the moment of in vitro culturing. Simultaneously these cells are losing their stem cell characteristics. Therefore, it is much better to consider them for cell and gene therapy early on

Impact of β-Globin Mutations on Outcome of Matched Related Donor Hematopoietic Stem Cell Transplantation for Patients with β-Thalassemia Major

AbstractThe clinical outcome of hematopoietic stem cell transplantation (HSCT) for patients with β-thalassemia major (β-TM) can be affected by several factors. We investigated the influence of β-globin gene mutation in patients with β-TM on the clinical outcome of HSCT and conducted a prospective study of consecutive β-TM patients who underwent allogeneic HSCT at our center. Among 87 included patients, 62 (71%) had homozygous and 25 (29%) had compound heterozygous β-globin gene mutations. Intervening sequence II-1 appeared to be the most common mutation, with an occurrence rate of 33% in β-globin alleles. With a median follow-up of 12 months, the thalassemia-free survival and overall survival probabilities were 83% (standard error, 4%) and 90% (standard error, 3%), respectively. Overall survival was not found to be associated with the β-globin gene mutation status, but thalassemia-free survival was significantly improved in patients with homozygous mutations compared with patients with compound heterozygous mutations in univariate (91.2% versus 64.0%, P = .009) and multivariable (hazard ratio, 3.83; P = .014) analyses. This is the first report on the impact of β-globin mutation status on the outcome of β-TM after allogeneic HSCT and helps to better illustrate the course and prognosis of β-TM after transplantation

Prognostic factors of survival time after hematopoietic stem cell transplant in acute lymphoblastic leukemia patients: Cox proportional hazard versus accelerated failure time models

<p>Abstract</p> <p>Background</p> <p>The aim of this study is to evaluate the prognostic factors of overall survival (OS) after haematopoietic stem cell transplant (HSCT) in acute lymphoblastic leukaemia (ALL) patients using accelerated failure time (AFT), Cox proportional hazard (PH), and Cox time-varying coefficient models.</p> <p>Methods</p> <p>206 patients were enrolled after HSCH in Shariati Hospital between 1993 and 2007. There was evidence of marked departures from the proportional hazards assumption with two prognostic factors, relapse and chronic graft-versus-host disease (cGVHD) (P < .001). Performance among AFT and Cox's models was assessed using explained variation and goodness of fit methods. Discrimination among the exponential, Weibull, generalized gamma (GG), log-logistic, and lognormal distributions was done using maximum likelihood and Akaike information criteria.</p> <p>Results</p> <p>The 5-year OS was 52% (95%CI: 47.3–56.7). Peak mortality hazard occurred at months 6–7 after HSCT followed by a decreasing trend. In univariate analysis, the data was better fitted by GG distribution than by other distributions. Univariate analysis using GG distribution showed a positive association between OS with acute graft-versus-host disease (aGVHD) (P = .021), no relapse (P < .001), cGVHD (P < .001), neutrophil recovery (P < .001) and platelet recovery (P < .001). Based on Cox PH models; however cGVHD and relapse were the predictive factors of OS (P < .001). Multivariate analysis indicated that, OS is related to relapse (P < .001) and platelet recovery (P = .037), where predictive power of Weibull AFT models was superior to Cox PH model and Cox with time-varying coefficient (R²= 0.46 for AFT, R²= .21 for Cox PH and R²= .34 for Cox time-varying coefficient). Cox-Snell residual shows Weibull AFT fitted to data better than other distributions in multivariate analysis.</p> <p>Conclusion</p> <p>We concluded that AFT distributions can be a useful tool for recognizing prognostic factors of OS in acute lymphoblastic leukemia patients.</p

Efficacy and Safety of the Irinotecan, Capecitabine, and Oxaliplatin (IOX) Regimen in Metastatic Gastric Cancer: A Single Arm Phase II Trial

Background: Gastric cancer is one of the most common malignancies worldwide with a high case mortality rate. In metastatic gastric cancer, a proper combination of chemotherapy could increase the survival rate. The goal of this study is to evaluate the efficacy and safety of the combination regimen of irinotecan, oxaliplatin, and Xeloda in metastatic gastric cancer. Methods: A total of 45 patients with metastatic gastric cancer and good performance status according to the Eastern Cooperative Oncology Group (score: 0-1) received the irinotecan, oxaliplatin, and Xeloda chemotherapy regimen. Demographic data, responses to treatment, and adverse effects were gathered for all cases. Overall survival and progression-free survival rates for patients were calculated using the Kaplan-Meier estimate. Results: Patients’ mean age was 58.3 ± 11.3 years (range: 24-81). There were 73.4% male patients and 26.6% female patients. Anorexia and weight loss were the most common symptoms. Overall response rate was 50%. The majority of toxicities were anemia, nausea and vomiting (grades 1 and 2), diarrhea (grades 1 and 2), neutropenia, alopecia, and hand and foot syndrome. The one-year progression-free survival rate was 31.5 ± 7.5%, whereas the twoyear progression-free survival rate was zero. The one-year overall survival rate was 34.91 ± 8.5%. Patients had a two-year overall survival rate of 7.7 ± 6.6%. Diffuse type cancer was linked to an inferior outcome. Conclusion: Regardless of our limited number of patients, this combination could be a suitable regimen for metastatic gastric cancer in terms of low toxicity, acceptable response rate, and survival results

Three doses of a recombinant conjugated SARS-CoV-2 vaccine early after allogeneic hematopoietic stem cell transplantation: predicting indicators of a high serologic response—a prospective, single-arm study

BackgroundAllogeneic hematopoietic stem cell transplant (allo-HSCT) recipients must be vaccinated against SARS-CoV-2 as quickly as possible after transplantation. The difficulty in obtaining recommended SARS-CoV-2 vaccines for allo-HSCT recipients motivated us to utilize an accessible and affordable SARS-CoV-2 vaccine with a recombinant receptor-binding domain (RBD)–tetanus toxoid (TT)-conjugated platform shortly after allo-HSCT in the developing country of Iran.MethodsThis prospective, single-arm study aimed to investigate immunogenicity and its predictors following a three-dose SARS-CoV-2 RBD–TT-conjugated vaccine regimen administered at 4-week (± 1-week) intervals in patients within 3–12 months post allo-HSCT. An immune status ratio (ISR) was measured at baseline and 4 weeks (± 1 week) after each vaccine dose using a semiquantitative immunoassay. Using the median ISR as a cut-off point for immune response intensity, we performed a logistic regression analysis to determine the predictive impact of several baseline factors on the intensity of the serologic response following the third vaccination dose.ResultsThirty-six allo-HSCT recipients, with a mean age of 42.42 years and a median time of 133 days between hematopoietic stem cell transplant (allo-HSCT) and the start of vaccination, were analyzed. Our findings, using the generalized estimating equation (GEE) model, indicated that, compared with the baseline ISR of 1.55 [95% confidence interval (CI) 0.94 to 2.17], the ISR increased significantly during the three-dose SARS-CoV-2 vaccination regimen. The ISR reached 2.32 (95% CI 1.84 to 2.79; p = 0.010) after the second dose and 3.87 (95% CI 3.25 to 4.48; p = 0.001) after the third dose of vaccine, reflecting 69.44% and 91.66% seropositivity, respectively. In a multivariate logistic regression analysis, the female sex of the donor [odds ratio (OR) 8.67; p = 0.028] and a higher level donor ISR at allo-HSCT (OR 3.56; p = 0.050) were the two positive predictors of strong immune response following the third vaccine dose. No serious adverse events (i.e., grades 3 and 4) were observed following the vaccination regimen.ConclusionsWe concluded that early vaccination of allo-HSCT recipients with a three-dose RBD–TT-conjugated SARS-CoV-2 vaccine is safe and could improve the early post-allo-HSCT immune response. We further believe that the pre-allo-HSCT SARS-CoV-2 immunization of donors may enhance post-allo-HSCT seroconversion in allo-HSCT recipients who receive the entire course of the SARS-CoV-2 vaccine during the first year after allo-HSCT

The combination of arsenic, interferon-alpha, and zidovudine restores an “immunocompetent-like” cytokine expression profile in patients with adult T-cell leukemia lymphoma

BACKGROUND: HTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN. RESULTS: Here we assessed Th1/Th2/T(reg) cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. ATL patients at diagnosis displayed a T(reg)/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4(+)CD25(+) cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4(+)CD25(+) cells. Finally, IL-10 transcript level negatively correlated with clinical response at Day 30. CONCLUSIONS: The observed shift from a T(reg)/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections