Mohammad Ahmad Bani-Ahmad

Introduction: Tumor neovascularization, an essential requirement for malignant disease progression and metastasis, depends on the dysregulation of pro-angiogenic and anti-angiogenic activities. This study aimed to investigate the utilization of circulatory angiopoietins (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF-A and VEGF-C), and basic fibroblast growth factor (bFGF) as a prognostic tool for acute myeloid leukemia (AML).Material and methods: Twenty-four AML patients who were under chemotherapeutic intervention were included. Patients’ relapse status, responsiveness to chemotherapy, and remission status were obtained from their medical profiles. For comparative purposes, fifteen healthy subjects were included. Serum levels of growth factors were measured.Results: As compared to control subjects, AML patients had significantly lower average levels of Ang-1 (170.8 ±12.7 versus 59.2 ±12.5 ng/ml) and VEGF-A (56.0 ±13.1 versus 98.6 ±11.9 ng/dl) that coincide with a higher average level of Ang-2 (18.5 ±4.1 ng/ml versus 7.5 ±0.8 ng/ml). Spearman’s correlation analysis defined a significant association of sAng-1 and sAng-2 with patients’ response to chemotherapy ( = 0.488) and remission status ( = 0.476), respectively. According to the receiver operating characteristic (ROC) curve, downregulation of Ang-1 has good predictivity for poor responsiveness to chemotherapy (AUC = 0.781, p < 0.05) while upregulation of sAng-2 has good predictivity for failed remission status (AUC = 0.779, p < 0.05).Conclusions: In the context of AML, dysregulated circulatory levels of Ang-1 and Ang-2 are suggested prognostic markers to provide useful predictivity of patients’ adverse responsiveness to chemotherapy and remission status, respectively.

Objectives: The contribution of pancreatic secretions in iron metabolism has been elucidated, but the clinical outcomes of iron deficiency on pancreatic function are debatable. This study aimed to investigate the modulation of euglycemic endocrine and exocrine pancreatic excretions in response to variations in iron availability. Subjects and Methods: Serum levels of insulin, glucagon, insulin-to-glucagon ratio (IGR), and amylase were determined in 170 adult subjects with variable levels of serum iron. Results: Control (n = 46) and iron-deficient (n = 124) subjects had significant differences (p < 0.001) in their average levels of insulin (68.7 ± 0.5 vs. 100.0 ± 2.0 pmol/dL), glucagon (17.9 ± 0.6 vs. 10.8 ± 0.8 pmol/dL), IGR (4.0 ± 0.1 vs. 19.5 ± 2.1), and amylase (29.7 ± 0.9 vs. 17.5 ± 0.2). The upregulation of serum insulin levels increases proportionally and gradually to the extent of iron deficiency as compared to an abrupt downregulation of serum levels of glucagon and amylase. A significant association was observed between serum iron and IGR (r = −0.645, p < 0.001) and amylase levels (r = 0.653, p < 0.001). The receiver operating characteristic curve analysis defines an excellent predictivity of the reduced serum iron level to discriminate subjects with upregulated IGR and amylase levels with area under curves of 0.938 and 0.905, respectively. Conclusion: Iron deficiency is associated with an adaptive modulation of euglycemic endocrine and exocrine secretions that is consistent with a status of insulin resistance.

This article aims to synthesize the existing literature on the implementation of public policies to incentivize the development of treatments for rare diseases, (diseases with very low prevalence and therefore with low commercial interest) otherwise known as orphan drugs. The implementation of these incentives in the United States (US), Japan, and in the European Union (EU) seems to be related to a substantial increase in treatments for these diseases, and has influenced the way the pharmaceutical research & development (R&D) system operates beyond this policy area. Despite the success of the Orphan Drug model, the academic literature also highlights the negative implications that these public policies have on affordability and access to orphan drugs, as well as on the prioritization of certain disease rare areas over others. The synthesis focuses mostly on the United States’ Orphan Drug Act (ODA) as a model for subsequent policies in other regions and countries. It starts with a historical overview of the creation of the term “rare diseases”, continues with a summary of the evidence available on the US ODA’s positive and negative impacts, and provides a summary of the different proposals to reform these incentives in light of the negative outcomes described. Finally, it describes some key aspects of the Japanese and European policies, as well as some of the challenges captured in the literature related to their impact in Low- and Middle-Income Countries (LMICs).

In the context of iron deficiency anemia, central dopamine, serotonin, and brain-derived neurotrophic factor (BDNF) are intensively investigated. However, peripheral isoforms are poorly investigated. This study aimed to investigate the modulation of plasma levels of dopamine, serotonin, and BDNF among children with iron deficiency anemia. A total of seventy-three iron-deficient (n=38) and iron-sufficient (n=35) children were included in the study. Twenty-nine subjects were showing clinical presentations and were diagnosed with iron deficiency anemia and forty-four were asymptomatic normal children. Plasma levels of dopamine, serotonin, and brain-derived neurotrophic factor were determined by enzyme-linked immunosorbent assay. As compared to corresponding levels among control subjects, Anemic subjects were having significantly higher plasma dopamine and lower plasma brain-derived neurotrophic factor levels. A significant linear and monotonic association of plasma dopamine and brain-derived neurotrophic factor with hemoglobin concentration (r=-0.520, P < 0.001 and ρ = 0.411, P = 0.001), respectively. Furthermore, there were significantly higher plasma serotonin levels among iron-deficient subjects with a significant inverse linear association with serum ferritin levels (r = -0.337, P = 0.005). Iron deficiency anemia is associated with the modulation of peripheral dopamine, serotonin, and brain-derived neurotrophic factor. Upregulation of dopamine and downregulation of brain-derived neurotrophic factor are correlated to the anemic status. The upregulation of plasma serotonin levels is iron-dependent and, probably, is attributed to the impairment of its metabolic fate. Further investigation is required to explore the pathophysiological and clinical association of these peripheral biomolecules in the context of iron deficiency anemia. (www.actabiomedica.it)

Away from hemorheological properties, the effect of heroin addiction on erythrocytes is poorly investigated. This study aimed to investigate the oxidative impacts of heroin administration on erythrocytes. Study subjects included chronic intravenous heroin addicts and control subjects. Hematological analysis and redox parameters were measured, including serum concentration of methemoglobin ([MethHb]), serum glutathione peroxidase-1 ([GPX-1]), serum glutathione peroxidase (GPX) activity, erythrocytic protein carbonyl content, and oxidized to reduced glutathione (GSSG/GSH) ratio. Hematological analysis revealed that addicts had a significantly higher red cell distribution width, consistent with the mild anisocytosis and poikilocytosis of erythrocytes. As compared to control subjects, significantly higher levels of serum [Met-Hb], [GPX-1], and GPX activity ( ) were reported among addicted subjects. A significant association between [MetHb] and GPX activity was observed with r = 0.764 ( ). Furthermore, significantly higher erythrocytic protein carbonyl contents and GSSG/GSH ratio were evident among heroin addicts ( ) that were significantly associated with r = 0.429 ( ). Results demonstrate preliminary evidence that heroin addiction is implicated in impaired redox status of erythrocytes. Considering the pharmacokinetics of heroin, erythrocytic antioxidant mechanisms, and turnover rate, further investigation is required to evaluate the extent and clinical outcomes, especially upon over-dose administration.

Introduction: Illicit drugs abuse is associated with several clinical life-threatening consequences that are primarily mediated by oxidative damage to multiple cellular components with a subsequent cellular dysfunction and death. Primarily, this study aimed to investigate oxidative stress to protein and lipid components of circulatory platelets among chronic heroin and hashish addicts. Methods: Platelet lysates were prepared from 20 chronic intravenously administrated heroin addicts and 20 chronic smoked hashish addicts. For comparative purposes, two control groups of 20 cigarette smokers and 20 nonsmokers were included in the study. Oxidative stress to platelet’s proteins and lipids was investigated using carbonyl group contents assay and thiobarbituric acid reactive substances (TBARS) assay, respectively. Results: In comparison to control groups, carbonyl group contents and TBARS concentration were significantly higher among heroin addicts but not among hashish addicts. Both of these markers were significantly correlated to the duration of addiction but not to the daily administrated dose. While in regard of the timing of the latest administrated dose (TLAD), only carbonyl group contents were significantly correlated to the TLAD. Conclusions: Considering the contribution of drug’s route of administration, drug’s pharmacokinetics, and kinetics of circulatory platelet, we concluded that chronic heroin addiction is associated with significant levels of oxidative stress to platelet’s proteins and lipids. Due to the high proteomic contents of platelets, protein’s oxidative stress is more prominent compared to lipids. Chronic hashish smoking is not associated with significant levels of oxidative stress in platelet’s proteins and lipids.

Background: Wilms tumor (WT1) and p53 proteins were identified in the pathogenesis of several malignancies, including hematological malignancies. As a result of their interaction and diverse context-specific functions, this study aimed to emphasize the diagnostic and prognostic impacts of WT1 and p53 expression in acute myeloid leukemia (AML). Methods: Twelve bone marrow (BM) biopsies were obtained from AML patients who were diagnosed in accordance with the French-American-British diagnostic criteria. For comparative purposes, nine normal BM biopsies were included. The expression rate of WT1 and p53 were determined by an immunohistochemistry assay. Results: A significantly higher (p < 0.005) and strongly correlated (p = 0.855, p = 0.001) expression rates of WT1 and p53 were observed in the BM of AML patients in comparison to control BM. Furthermore, relapsed AML patients had significantly higher expression of WT1, but not p53, when compared to newly diagnosed patients. In regard of patient's responsiveness to chemotherapy, no significant difference was reported between good and poor responders. However, the relative ratio of p53 to WT1 expression was evidently correlated to the responsiveness groups (p < 0.05), where the ratio was observed to be significantly higher among poor responders. Poor responders were characterized by a statistically significant and dominant p53 expression (p53/WT1 > 1.0) while both good responding patients and control subjects had a dominant WT1 expression (p53/WT1 < 1.0). Conclusions: The enhanced expression levels of WT1 and p53 proteins in the BM of AML patients is supportive of their intermediate role in the pathogenesis of the disease. WT1 expression rate may encompass a negative prognostic value of the disease. Furthermore, the ratio of p53/WT expression may serve as a hallmark of the patient's responsiveness to chemotherapy, where a dominant WT1 expression may reveal good responsiveness to chemotherapy. Herein, we are proposing a kinetic model where the p53/WT1 ratio might be useful as a laboratory approach to evaluate the prognostic value of AML including the patient's responsiveness to chemotherapeutic regimen.