Mohamed Mabed

Mesenchymal stem cell-based therapy for the treatment of type 1 diabetes mellitus.

The pathophysiology of Type 1 diabetes (T1D) appears largely related to an innate defect in the immune system culminating in a loss of self tolerance and destruction of the insulin producing β-cells. Currently, there is no definitive cure for diabetes. Insulin injection does not mimic the precise regulation of β-cells on glucose homeostasis, leading long term to the development of complications. Other therapeutic approaches therefore, are necessary and cell therapy is thought to be a possible approach. In this sense, mesenchymal stem cells (MSCs) can offer a promising possibility that deserves to be explored. MSCs are multipotent non-hematopoietic progenitor cells. Their therapeutic potentials have recently been brought into the spotlights of many fields of research. Although the regenerative capabilities of MSCs have been a driving force to initiate studies testing their therapeutic effectiveness, their immunomodulatory properties have been equally exciting. MSCs possess specific immunomodulatory properties that would appear capable of disabling immune dysregulation that leads to β-cell destruction in T1D. Furthermore, MSCs can be sequentially cultured in specially defined conditions and their differentiation extends toward the β-cell phenotype and the formation of insulin producing cells (IPCs). To date, the role of MSCs in T1D remains completely unexplored. We herein summarize multiple strategies that have been proposed and tested for its potential therapeutic benefit for T1D.

Thrombopoietin (TPO) Levels in Hepatic Patients with Thrombocytopenia

Abstract Thrombocytopenia is a common problem complicating the course of liver disease. One of the postulated mechanisms in chronic liver disease is impaired production of the hormone, thrombopoietin (TPO). The aim of present study was to evaluate the role of TPO on the occurrence of thrombocytopenia. Serum TPO levels was determined by ELISA in 40 patients with liver disease (11 seropositive with hepatitis C; 10 with mixed liver cirrhosis; 19 with bilharzial hepatic fibrosis), plus 14 normal healthy subjects as a control group. The sTPO levels were unevenly distributed among the liver disease subgroups being the highest in the group with HCV (median 1232.0, range 154.7-2042.0 pg/ml) followed by the mixed cirrhosis group (556.5; 342.0-1497.0 pg/ml) and lowest among the bilharzial hepatic fibrosis group (130.0; 22.0-204.0 pg/ml) ( P <0.01). While sTPO levels in HCV and cirrhotic group were significantly higher when compared to the control group (97.0; 19.0-377.0 pg/ml), those in the Bilharzial hepatic fibrosis group were not significantly elevated ( P > 0.05). There is significant negative correlation between sTPO levels and spleen size ( R =−0.3, P =0.043); but there was no correlation with platelet count ( R =0.09, P >0.05). In addition, sTPO levels were significantly higher in patients with platelet counts ≥60×10 9 /l as compared to those with platelet counts <60×10 9 /l ( P =0.04). Using the receiver operating curve (ROC) at sTPO cut off value ≥ vs. < 368 ng/ml, most of HCV and cirrhotic patients had higher sTPO levels (81.8 and 80.0%, respectively), while all Bilharzial hepatic fibrosis group (100%) had lower sTPO levels. In conclusion, sTPO levels had no role in the occurrence of thrombocytopenia in liver disease patients and other factors appear to be more important. It also appears that the mechanism controlling sTPO levels might be different in cirrhotic patients compared to Bilharzial hepatic fibrosis patients.

Cyclin D1 expression in acute leukemia

Abstract Background: Disorders of the cell cycle regulatory machinery play a key role in the pathogenesis of cancer. Over expression of cyclin D1 protein has been reported in several solid tumors and certain lymphoid malignancies, but little is known about the involvement of cyclin D1 in acute leukemia. Patients and methods: In this study, we analyzed the expression of cyclin D1 at protein level in, 40 newly diagnosed patients with acute myeloid leukemia (AML), 10 patients with acute lymphoblastic leukemia (ALL), and 11 normal controls using flow cytometry. Results: The expression of cyclin D1 was not significantly different in AML group as compared to normal controls. On the other hand, over expression of cyclin D1 was evident in ALL group (4/10) as compared to that in healthy control. The ALL cases with cyclin D1 over expression were significantly correlated to blast cell counts in the peripheral blood and bone marrow (BM) but not with hemoglobin level, WBC, and platelets count. The ALL group with lymphadenopathy and organomegaly express significantly higher cyclin D1 over expression as compared to those without. Conclusion: The biological value of cyclin D1 over expression might be different in AML and ALL.

Chlorambucil Plus Theophylline vs Chlorambucil Alone as a Front Line Therapy for B-Cell Chronic Lymphatic Leukemia

B-cell chronic lymphatic leukemia (B-CLL) has emerged as a prototype of malignancies characterized by a defective apoptosis that leads to a progressive accumulation of monoclonal B cells in the bone marrow, lymphoid tissues and peripheral blood. Chlorambucil, an aromatic derivative of nitrogen mustards, is the most common treatment for chronic lymphatic leukemia (CLL). The response rate with its use is 40 to 60%, with 3 to 10% only of patients achieving a complete response (CR). To improve response rates, chlorambucil has been combined with steroids or other agents. Theophylline, a methylxanthine commonly used as a treatment for asthma, has been shown to induce apoptosis in CLL cells both in vitro and in vivo. Chlorambucil induces apoptosis in CLL cells as well and synergy has been shown between the two drugs without affecting the normal B lymphocytes. The aim of this work was to evaluate the potential utility of this combination as a therapeutic modality for B-CLL. A total of 210 B-CLL patients were recruited and randomized to receive either chlorambucil in an oral dose of 0.1 mg/kg/day indefinitely (109 patients) or chlorambucil 0.1 mg/kg/day plus theophylline 200 mg bid, orally (101 patients). The main endpoints were overall survival from the time of randomization, disease status after 9 months and time to disease progression. After 9 months of treatment, clinical and hematological remission was achieved in 14 patients (12.8%) in the chlorambucil group, compared to 26 (25.7%) in the chlorambucil plus theophylline group (P value 0.01). Partial remission was observed for 38 patients (34.9%) in the chlorambucil group and 36 patients (35.7%) in the chlorambucil plus theophylline group. In patients treated with chlorambucil alone, the median progression-free survival (PFS) was 30 months and in patients treated with chlorambucil plus theophylline it was 44 months. Probabilities of PFS at 24 months for the chlorambucil-treated patients were 59% and 85% for the chlorambucil plus theophylline-treated patients. The difference was statistically significant (P = 0.006). The 3-year and 5-year overall survival rates were, respectively 75% and 38% in the chlorambucil group as opposed to 76% and 46% in the chlorambucil plus theophylline group. The median survival time was 55 months in the chlorambucil group and 56 months in the chlorambucil plus theophylline group. Forty-nine patients died in the chlorambucil group compared to 44 patients in the chlorambucil plus theophylline group (P = 0.371). The trial has demonstrated that adding theophylline to the standard treatment of B-CLL significantly increases effectiveness of treatment in terms of tumor response and time to disease progression. It could not improve the overall survival. Treatment with theophylline does not compromise quality of life or add significant toxicity. As newer drugs have recently become available for treating patients with CLL like fludarabine, further trials are needed to evaluate the effect of combining theophylline with these drugs.

Potential utility of antineoplaston A-10 levels in breast cancer

Antineoplastons, first described by Burzynski, are naturally occurring peptides and amino acid derivatives, which control neoplastic growth. Antineoplaston A-10 (3-phenylacetyl amino-2, 6-pepridinedione) is the first chemically identified antineoplaston. Here we describe the potential utility of antineoplaston A-10 as a predictive test for breast cancer. Antineoplaston A-10 level was measured in the urine of 31 breast cancer patients and 17 normal women using high performance thin layer chromatography (HPTLC). Significantly lower antineoplaston A-10 levels were detected among patients with breast cancer with a P value <0.001. These data suggest a strong inverse association of urinary antineoplaston A-10 level with breast cancer. Such finding was the stimulus for further investigations of antineoplaston A-10 levels in some benign as well as other malignant diseases to determine the utility of this approach as a predictive test for women who are at risk of developing breast cancer.

Immune modulatory potentials of antineoplaston A-10 in breast cancer patients

Antineoplastons are naturally occurring cytodifferentiating agents. Chemically, they are medium and small sized peptides, amino acid derivatives and organic acids, which exist in blood, tissues and urine. Antineoplaston A-10 (3-phenylacetylamino-2,6-piperidinedione) is the first chemically identified antineoplaston. Previously we have shown a strong inverse association of urinary antineoplaston A-10 with breast cancer. This study is designed to evaluate neutrophil apoptosis in patients with breast cancer at time of diagnosis and to correlate urinary antineoplaston A-10 levels with neutrophil apoptosis and to describe the direct effect of A-10 in vitro on neutrophil apoptosis in breast cancer patients. The participants were patients with a histologically confirmed diagnosis of breast cancer. Only those cases without previous treatment for breast cancer were included. Neutrophil apoptosis was assessed in breast cancer patients both morphologically and by DNA fragmentation and studied relative to healthy controls. Antineoplaston A-10 was measured using high performance liquid chromatography in urine samples collected from the patients. Urine samples from normal women served as controls. Direct effect of antineoplaston A-10 on neutrophil apoptosis was tested in vitro after adding A-10 at a concentration of 10 ng/ml to the cellular suspensions of breast cancer patients. Non-treated samples served as controls. Significantly higher neutrophil apoptosis levels were detected among patients with breast cancer with a P value <0.001. Urinary antineoplaston A-10 level is significantly negatively correlated with high apoptosis levels (P<0.0001). In vitro, antineoplaston A-10 was found to inhibit significantly the neutrophil apoptosis with a P value <0.0001. These findings confirm the presence of immune defects among patients with breast cancer and such results should stimulate the development of new strategies to induce and augment immunity for the treatment of breast cancer. Antineoplaston A-10 may provide rational basis for designing trials to employ its immune modulatory potentials as adjuvant therapy in breast cancer patients.

The Potential Utility of Bone Marrow or Umbilical Cord Blood Transplantation For the Treatment of Type I Diabetes Mellitus

The pathology of type 1 diabetes mellitus (T1D) involves the autoimmune destruction or malfunction of pancreatic β cells, leading to a lack of insulin. The absence of insulin is life-threatening, necessitating daily hormone injections from an exogenous source. Insulin injections do not adequately mimic the precise regulation of β cells on glucose homeostasis, however, eventually leading to complications in diabetic patients. There currently is no definitive cure for T1D. Pancreas transplantation, although quite successful, is an invasive intervention that is restricted to patients with advanced complications, requires constant immunosuppression, and is severely limited by donor availability. Recent progress in human islet cell isolation and immunosuppressive protocols has restored euglycemia in patients who received islet cells from 2 or 3 pancreas donors. However, because of the scarcity of cadaver pancreata and the low yield of islet cells obtained by the procedure, not all patients have access to this surgical intervention. Thus, other therapeutic approaches are needed to arrest immune aggression, preserve β cell mass, and provide efficient replacement. In this sense, bone marrow and umbilical cord blood transplantation are promising possibilities that merit exploration. In this review, we summarize multiple strategies that have been proposed and tested for potential therapeutic benefit in patients with T1D.

Increased expression of costimulatory molecules CD86 and sCTLA-4 in patients with acute lymphoblastic leukemia

Abstract We herein evaluate the role of the B7-family molecule CD86 and the Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) as a possible immunopathogenic factors in patients with ALL. The results of 60 patients with de novo ALL were compared to 40 controls. A significant statistical difference between CD86 expression and sCTLA-4 levels in patients versus their controls has been detected. During follow up period of 28 months, patients suffered from relapse (16 patients) had significantly higher CD86 expression and sCTL-4 levels compared to those remained in complete remission (44 patients) (p = 0.005 and 0.03 respectively). Patients who died from the disease (9 patients) showed significantly higher CD 86 expression and sCTLA-4 levels than surviving patients (51 patients) (p = 0.004 and 0.01 respectively). In conclusion, the higher levels of sCTLA-4 and CD86 in B-ALL patients might be candidate parameters for poor prognosis and may serve to refine treatment stratification with intensification of therapy in those patients prone to relapse.

Autoimmune Hemolytic Anemia in a Patient with Acute Myelomonocytic Leukemia

Autoimmune hemolytic anemia (AIHA) has been described in patients with lymphoid neoplasm with an etiologic relationship between the emergence of autoantibodies and lymphocyte dysfunction. Autoimmune disorders are less to develop in patients with other neoplasm like chronic myeloid leukemia, myelodysplastic syndrome or acute myeloid leukemia. Few reports have been documented the development of immune hemolytic anemia in patients with acute myeloid leukemia. We herein, present the case of de novo acute myelomonocytic leukemia associated with autoimmune hemolytic anemia. The patient has no previous medical history of anemia and Hb level at presentation was normal. She received chemotherapy containing Adriamycin plus Cytarabine. She showed marked improvement of anemia after steroid therapy with subsidence of all the clinical and laboratory manifestations of hemolysis when the patient went into remission. AIHA should be considered as one cause of anemia in

Anticardiolipin antibodies in proliferative diabetic retinopathy: An additional risk factor.

PURPOSE To report the prevalence of anticardiolipin antibodies in patients with proliferative diabetic retinopathy (PDR) having high-risk criteria (HRC). METHODS Diabetic patients having PDR with HRC and diabetics free of retinopathy were compared for the presence of anticardiolipin antibodies. RESULTS Among the 34 patients, 6 (17.7%) of diabetics having PDR with HRC were positive for anticardiolipin antibodies. There was no significant association of aCL antibodies with sex or type of diabetes. Using Pearsons correlation test, no significant associations of aCL antibodies with duration of diabetes or age of patients were found. All patients who were positive for anticardiolipin antibodies had PDR with HRC. The difference was statistically significant. CONCLUSION Presence of anticardiolipin antibodies may represent an additional risk factor for PDR.