Mohamed A. M. Ali

Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. The hallmark of CML is a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, t(9; 22)(q34; q11), creating a derivative 9q+ and a shortened 22q–. The latter, known as the Philadelphia (Ph) chromosome, harbors the breakpoint cluster region-abelson (BCR-ABL) fusion gene, encoding the constitutively active BCR-ABL tyrosine kinase that is necessary and sufficient for initiating CML. The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of CML remains a flagship for molecularly targeted therapy in cancer. TKIs have changed the clinical course of CML; however, some patients nonetheless demonstrate primary or secondary resistance to such therapy and require an alternative therapeutic strategy. Therefore, the assessment of early response to treatment with TKIs has become an important tool in the clinical monitoring of CML patients. Although mutations in the BCR-ABL have proven to be the most prominent mechanism of resistance to TKIs, other mechanisms—either rendering the leukemic cells still dependent on BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling—have been identified. This article provides an overview of the current understanding of CML pathogenesis; recommendations for diagnostic tools, treatment strategies, and management guidelines; and highlights the BCR-ABL-dependent and -independent mechanisms that contribute to the development of resistance to TKIs.

Novel Pyrazolo[3,4-b]pyridine Derivatives: Synthesis, Characterization, Antimicrobial and Antiproliferative Profile.

Three novel series of pyridine derivatives, namely Schiffs bases, 4-thiazolidinones and azetidin-2-ones bearing pyrazolo[3,4-b]pyridine moiety, have been synthesized. The chemical structures of the synthesized compounds were characterized. The compounds were tested for their antimicrobial activity using the agar well diffusion and broth macrodilution methods. The compounds were also evaluated for their antiproliferative activity using the sulforhodamine B (SRB) assay. The majority of the tested compounds exhibited slight to high antimicrobial activity against the test microorganisms with minimum inhibitory concentrations (MICs) of 0.12-62.5 µg/mL when compared to that of 3 standard antimicrobial agents (Ampicillin, 0.007-0.03 µg/mL; Gentamicin; 0.015-0.24 µg/mL; and Amphotericin B, 0.03-0.98 µg/mL). Compound (7b) was found to be nearly as active as the standard antimicrobial drug Amphotericin B against Fusarium oxysporum fungal strain with MIC of 0.98 µg/mL. Some of the test compounds showed remarkable cytotoxic activities against Hep G2 (hepatocellular carcinoma) cells (IC50=0.0158-71.3 µM) in comparison to the standard anticancer drug doxorubicin (IC50=0.008 µM). Among the compounds tested, (5), (6a), (6b), (7b), and (10) exhibited antiproliferative potency (IC50=0.0001-0.0211 µM) that was found to be better than that of doxorubicin (IC50=0.099 µM) against MCF7 (breast adenocarcinoma) cells. In particular, (7b) displayed the highest significant antiproliferative efficacy against both Hep G2 and MCF7 cell lines showing IC50 values of 0.0158 µM and 0.0001 µM, respectively. Our findings suggest that the synthesized compounds may be promising candidates as novel antimicrobial and antiproliferative agents.

Presepsin is an early monitoring biomarker for predicting clinical outcome in patients with sepsis.

Despite their undoubted helpfulness in diagnosing sepsis, increased blood C-reactive protein (CRP) and procalcitonin (PCT) levels have been described in many noninfectious conditions. Presepsin is a soluble fragment of the cluster of differentiation 14 involved in pathogen recognition by innate immunity. We aimed to investigate the diagnostic and prognostic performance of presepsin in comparison to PCT and CRP in patients presenting with systemic inflammatory response syndrome (SIRS) and suspected sepsis. Seventy-six subjects were enrolled in this study, including 51 patients with SIRS as well as 25 healthy subjects. Plasma presepsin, PCT and CRP levels were serially measured on admission and at days 1, 3, 7 and 15. Presepsin and PCT yielded similar diagnostic accuracy, whereas presepsin performed significantly better than CRP. Presepsin and PCT showed comparable performance for predicting 28-day mortality, and both biomarkers performed significantly better than CRP. In septic patients, presepsin revealed earlier concentration changes over time when compared to PCT and CRP. Presepsin and PCT could differentiate between septic and non-septic patients with comparable accuracy and both biomarkers showed similar performance for predicting 28-day mortality. Early changes in presepsin concentrations might reflect the appropriateness of the therapeutic modality and could be useful for making effective treatment decisions.

Ellagic and ferulic acids alleviate gamma radiation and aluminium chloride-induced oxidative damage.

AIM Ionizing radiation interacts with biological systems through the generation of free radicals, which induce oxidative stress. Aluminium (Al) can negatively impact human health by direct interaction with antioxidant enzymes. Ellagic acid (EA) and Ferulic acid (FA) are plant polyphenolic compounds, have gained attention due to their multiple biological activities. To date, no studies investigating the antioxidant effect of EA/FA in a model involving both γ radiation and aluminium chloride (AlCl3) have been reported. Herein, we investigated the protective effect of EA and FA against oxidative stress induced by γ radiation and AlCl3 in rats. METHODS Rats were divided into thirteen groups: a negative control group, 3 positive control groups (γ-irradiated, AlCl3-treated and γ-irradiated+AlCl3-treated) and 9 groups (3 γ-irradiated, 3 AlCl3-treated and 3 γ-irradiated+AlCl3-treated) treated with EA and/or FA. Liver function and lipid profile were assessed. Levels of lipid peroxidation, protein oxidation and endogenous antioxidants as well as the concentrations of copper, iron and zinc were estimated in liver tissue homogenate. Furthermore, liver tissue sections were histologically examined. RESULTS Oral administration of EA and/or FA resulted in 1) amelioration of AlCl3 and/or γ-radiation-induced hepatic function impairment, dyslipidemia and hepatic histological alterations; 2) reduction in liver MDA and PCC levels; 3) elevation of liver CAT, GPx and SOD activity as well as GSH level; 4) elevation in liver Cu concentrations which was accompanied by a reduction in Fe and Zn concentrations. CONCLUSIONS Oral administration of EA and/or FA may be useful for ameliorating γ radiation and/or AlCl3-induced oxidative damage.

Value of vanin-1 assessment in adult patients with primary immune thrombocytopenia

Abstract The diagnosis of primary immune thrombocytopenia (ITP) is clinical and cannot be established by any specific laboratory assay. Perhaps the best diagnostic study is assessment of the patient’s response to ITP therapy. Oxidative stress-related pathways were among the most significant chronic ITP-associated pathways. Overexpression of VNN1 gene, an oxidative stress sensor in epithelial cells, was most strongly associated with progression to chronic ITP. To address this issue, we tested the hypothesis that blood vanin-1 protein level could distinguish between chronic responders and non-responders ITP patients as well as between ITP patients and healthy controls. Vanin-1 protein levels were determined in peripheral blood leukocytes of 80 adult subjects (16 newly diagnosed ITP patients, 24 chronic responders ITP patients, 24 chronic non-responders ITP patients and 16 healthy controls) by enzyme-linked immunesorbent assay (ELISA). Blood vanin-1 protein levels were lower in controls (median = 18.39 ng) than in ITP patients (median = 58.78 ng) with a highly significant p value (p < 0.001). Vanin-1 levels were highly significantly elevated in newly diagnosed ITP patients (median = 188.62 ng) in comparison to chronic responders (median = 26.90 ng) and chronic non-responders (median = 73.87 ng). Vanin-1 level at a cut-off value of >20.73 ng was found to be 100% sensitive and 93.7% specific in discriminating between newly diagnosed ITP patients and healthy controls. Vanin-1 level was found to be 100% sensitive and 100% specific in differentiating between responders and non-responders with a cut-off value of ≤34.5 ng. Our results suggest that vanin-1 can distinguish between chronic responders and non-responders ITP patients as well as between newly diagnosed ITP patients and healthy controls. These findings demonstrate that vanin-1 may contribute to the pathogenesis of ITP, indicating that vanin-1 is an important target for further investigation.

Diagnostic utility of BNP, corin and furin as biomarkers for cardiovascular complications in type 2 diabetes mellitus patients.

Abstract Context: The number of patients with type 2 diabetes mellitus (T2DM) is progressively increasing, and diabetic cardiovascular complications have become a public health problem. Brain or B-type natriuretic peptide (BNP) is a cardiac hormone synthesized as a pre-pro-peptide. pro-BNP is produced by cleaving the signal peptide then two proprotein convertases, corin and furin cleave pro-BNP to form a biologically active hormone. Two corin single nucleotide polymorphisms (SNPs) have been reported to alter corin protein conformation and impair its biological activity. Objective: We aimed to investigate the potential role of corin and furin in comparison to BNP as biomarkers for predicting cardiovascular complications in T2DM patients. The association of corin gene SNPs with corin levels was also examined. Methods: Seventy-five subjects were recruited in this study, including 25 T2DM patients with complications, 25 T2DM patients without complications as well as 25 healthy subjects. Plasma BNP, corin and furin levels were measured using enzyme-linked immunosorbent assays. Two corin SNPs were genotyped using allele specific oligonucleotide-polymerase chain reaction. Results: Both furin and BNP were found to be more sensitive than corin (80% versus 56%, p = 0.008), whereas furin showed higher specificity when compared to BNP (96% versus 84%, p = 0.041) and corin (96% versus 64%, p < 0.0001) in predicting cardiovascular complications in T2DM patients. Corin SNPs are not associated with corin levels, neither in the entire study cohort nor in the subgroup of T2DM patients with cardiovascular complications (p > 0.05). Conclusions: Furin may be useful, either alone or in combination with other biomarkers, for cardiovascular risk stratification assessment in T2DM patients.

Extracellular miR-145, miR-223 and miR-326 expression signature allow for differential diagnosis of immune-mediated neuroinflammatory diseases

BACKGROUND Although misdiagnosis of neuromyelitis optica spectrum disorder (NMOSD) with neuropsychiatric systemic lupus erythematosus (NPSLE) or multiple sclerosis (MS) is not infrequent, reliable biomarkers remains an unmet need. Extracellular microRNAs (miRNAs) represent a worthy avenue to identify biomarkers for differential diagnosis. We aimed to explore the potential role of some selected circulating miRNAs as biomarkers for the differential diagnosis in immune-mediated neuroinflammatory diseases. METHODS A total of 80 subjects were enrolled in the present study, including 37 patients with MS (relapsing-remitting MS [RRMS; n=18] and secondary progressive MS [SPMS; n=19]), 10 patients with NMOSD and 10 patients with NPSLE as well as 23 healthy subjects. Serum expression levels of three selected miRNAs (miR-145, miR-223 and miR-326) were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Whole blood expression levels of cellular immune response-relevant target genes, including signaling mother against decapentaplegic peptide 3 (SMAD3) and specificity protein 1 (SP1), were also measured using qRT-PCR. RESULTS In comparison to healthy subjects, only miR-145 and miR-223 were significantly up-regulated in MS patients, whereas, all the analyzed miRNAs revealed insignificant upregulation in NMOSD patients. All the examined miRNAs were significantly down-regulated in NPSLE patients compared to healthy subjects. miR-145, miR-223 and miR-326 expression profile is a promising diagnostic biomarker for MS and NPSLE, but not for NMOSD. This expression profile is capable of differentiating not only among MS, NMOSD and NPSLE, but also between RRMS and SPMS. CONCLUSION Specific circulating miRNAs expression signature may have the potential to differentially diagnose immune-mediated neuroinflammatory diseases.

Rectal misoprostol for myomectomy: A randomised placebo-controlled study

Uterine leiomyomas are the most common benign tumours in women. Misoprostol, which is widely used in the treatment and prevention of postpartum haemorrhage in obstetrics, may decrease intra‐operative bleeding in abdominal myomectomies when haemorrhage constitutes a challenging problem.

Successes and failures of uterine leiomyoma drug discovery

ABSTRACT Introduction: To-date, the only cure for symptomatic uterine fibroids (UFs) is surgical intervention. However, surgery may eliminate the hope of future pregnancies; moreover, the intrinsic risks of surgery make it a less favorable to women with UFs. Because of this, conservative medical therapies have become an attractive and prior option for those women. Leuprolide acetate (LA), a gonadotropin-releasing hormone (GnRH) agonist, is the only pharmacological agent currently approved for the short-term and pre-operative management of symptomatic UFs in the USA. Areas covered: This systematic review covers the successes and failures of prominent drugs that have been researched for UFs in the past and agents that have shown promise in recent clinical trials. The most recent clinical trials and advances in drug therapy are presented in a comprehensive overview outlining the direction UF drug discovery is heading. Expert opinion: Experts in the field are already on the forefront leading the responsibility to uncover potential drugs as long term fertility friendly viable options for non-invasive treatment/prevention of UFs. Indeed, a shift in the UF management is expected in the future.

Reliability Assessment and Economic Evaluation of Offshore Wind Farm Using Stochastic Probability

This paper shortly introduced the electric power transmission system for offshore wind farms (OWF). The transmission system components are demonstrated. Each component cost and reliability are studied and tabulated. An evaluation of the transmission system reliability of OWF is performed to increase the dependence on the OWF as a power source in the future. Reliability assessment is performed on a proposed site in Zafarana, Egypt and results are tabulated and simulated for different distances from the shore. The cost of the transmission system is studied using the stochastic probability method; optimization is performed on the investment cost, unavailability cost, and ohmic cost losses. Optimization results on the proposed site are done using different electrical power transmission system schemes. Losses due to the wind unavailability and ohmic losses are studied and simulated.