The frequency of NUDT15 rs116855232 and its impact on mercaptopurine-induced toxicity in Syrian children with acute lymphoblastic leukemia.

Introduction: Polymorphisms in NUDT15 may result in differences in mercaptopurine-induced toxicity. This study aimed to identify the frequency of the NUDT15 (c.415C>T; rs116855232) polymorphism and investigate the effect of this polymorphism on mercaptopurine-induced toxicity in a population of Syrian patients with childhood acute lymphoblastic leukemia (ALL). Methods: This is a retrospective study that included children with ALL reaching at least 6 months of maintenance therapy. The NUDT15 genotyping was determined using standard targeted sequencing of polymerase chain reaction products. The odds ratio (OR) for the association between toxicity and genotype was evaluated. Results: A total of 92 patients were enrolled. The majority of the patients in the study population were low-risk (63.04%), followed by intermediate-risk (25%), and high-risk (11.96%). There were 5 patients (5.4%) with NUDT15 (c.415C>T; rs116855232) CT genotype, and 1 patient (1.08%) with NUDT15 TT genotype, with allele frequencies of C=0.962 and T=0.038. The mercaptopurine median dose intensity was 100%, 54.69%, and 5% for the genotypes CC, CT, and TT, respectively (P=0.009). Early onset leukopenia was significantly associated with the NUDT15 polymorphism (OR: 6.16, 95% CI: 1.11-34.18, P=0.037). There was no association between the NUDT15 genotype and hepatotoxicity. Conclusion: Approximately 6.5% of the study population exhibited reduced NUDT15 activity. The mercaptopurine dose intensity was considerably low in NUDT15 rs116855232 TT genotype compared with CT and CC. The dosage of mercaptopurine should be adjusted according to the NUDT15 genotype in pediatric patients with ALL.

Improved production of Bacillus subtilis cholesterol oxidase by optimization of process parameters using response surface methodology.

BACKGROUND: Cholesterol oxidase has numerous biomedical and industrial applications. In the current study, a new bacterial strain was isolated from sewage and was selected for its high potency for cholesterol degradation (%) and production of high cholesterol oxidase activity (U/OD600). RESULTS: Based on the sequence of 16S rRNA gene, the bacterium was identified as Bacillus subtilis. The fermentation conditions affecting cholesterol degradation (%) and the activity of cholesterol oxidase (U/OD600) of B. subtilis were optimized through fractional factorial design (FFD) and response surface methodology (RSM). According to this sequential optimization approach, 80.152% cholesterol degradation was achieved by setting the concentrations of cholesterol, inoculum size, and magnesium sulphate at 0.05 g/l, 6%, and 0.05 g/l, respectively. Moreover, 85.461 U of cholesterol oxidase/OD600 were attained by adjusting the fermentation conditions at initial pH, 6; volume of the fermentation medium, 15 ml/flask; and concentration of cholesterol, 0.05 g/l. The optimization process improved cholesterol degradation (%) and the activity of cholesterol oxidase (U/OD600) by 139% and 154%, respectively. No cholesterol was detected in the spectroscopic analysis of the optimized fermented medium via gas chromatography-mass spectroscopy (GC-MS). CONCLUSION: The current study provides principal information for the development of efficient production of cholesterol oxidase by B. subtilis that could be used in various applications.

Inhibition of Pseudomonas aeruginosa quorum sensing by methyl gallate from Mangifera indica.

Antipathogenic drugs are a potential source of therapeutics, particularly following the emergence of multiple drug-resistant pathogenic microorganisms in the last decade. The inhibition of quorum sensing (QS) is an advanced antipathogenic approach for suppression of bacterial virulence and dissemination. This study aimed to investigate the inhibitory effect of some Egyptian medicinal plants on the QS signaling system of Pseudomonas aeruginosa. Among the tested plants, Mangifera indica exhibited the highest quorum sensing inhibition (QSI) activity against Chromobacterium violaceum ATCC 12472. Four pure compounds were extracted and identified; of these, methyl gallate (MG) showed the most potent QSI. MG had a minimum inhibitory concentration (MIC) of 512 g/mL against P. aeruginosa strains PAO1, PA14, Pa21, Pa22, Pa23, Pa24, and PAO-JP2. The virulence factors of PAO1, PA14, Pa21, Pa22, Pa23, and Pa24 were significantly inhibited by MG at 1/4 and 1/2 sub-MICs without affecting bacterial viability. Computational insights were performed by docking the MG compound on the LasR receptor, and the QSI behavior of MG was found to be mediated by three hydrogen bonds: Trp60, Arg61, and Thr75. This study indicates the importance of M. indica and MG in the inhibition and modulation of QS and QS-related virulence factors in P. aeruginosa.

The Psychosocial Impact of the COVID-19 Pandemic on Families of Children With Cancer in the Low-income Setting.

The coronavirus disease 2019 (COVID-19) pandemic has had a profound effect on families' psychosocial well-being worldwide. This study aimed to investigate the pandemic's impact on families of children with cancer in a low-income setting in Syria. The study conducted a cross-sectional survey of 50 families of children with cancer receiving treatment at a nongovernmental organization-based pediatric oncology unit in Syria. The survey used the Corona Anxiety Scale (CAS) to assess the pandemic's impact on families' anxiety, and other items to evaluate the financial toxicity of the strict measures implemented during the pandemic's first months. The study's results revealed that the COVID-19 pandemic significantly negatively impacted the psychosocial well-being of families of children with cancer in Syria. Specifically, 22% of families reported a major increase in anxiety levels (CAS of >9), and the majority of families (84%) reported excessive indirect financial costs, including travel and living expenses. The study emphasizes the significant social and psychological impact of the COVID-19 pandemic on families of children with cancer in Syria, highlighting the need for additional psychosocial interventions to mitigate future global health crises or pandemics' impact on this vulnerable population. The interventions should prioritize promoting resilience and adaptive coping strategies.

It is the time for quorum sensing inhibition as alternative strategy of antimicrobial therapy.

Multiple drug resistance poses a significant threat to public health worldwide, with a substantial increase in morbidity and mortality rates. Consequently, searching for novel strategies to control microbial pathogenicity is necessary. With the aid of auto-inducers (AIs), quorum sensing (QS) regulates bacterial virulence factors through cell-to-cell signaling networks. AIs are small signaling molecules produced during the stationary phase. When bacterial cultures reach a certain level of growth, these molecules regulate the expression of the bound genes by acting as mirrors that reflect the inoculum density.Gram-positive bacteria use the peptide derivatives of these signaling molecules, whereas Gram-negative bacteria use the fatty acid derivatives, and the majority of bacteria can use both types to modulate the expression of the target gene. Numerous natural and synthetic QS inhibitors (QSIs) have been developed to reduce microbial pathogenesis. Applications of QSI are vital to human health, as well as fisheries and aquaculture, agriculture, and water treatment. Video Abstract.

2,4-Dichlorophenol biotransformation using immobilized marine halophilic Bacillus subtilis culture and laccase enzyme: application in wastewater treatment.

BACKGROUND: 2,4-Dichlorophenol (2,4-DCP) is a very toxic aromatic compound for humans and the environment and is highly resistant to degradation. Therefore, it is necessary to develop efficient remediation and cost-effective approaches to this pollutant. Microbial enzymes such as laccases can degrade phenols, but limited information is known about immobilized bacterial laccase and their reuse. METHODS: Immobilization of marine halophilic Bacillus subtilis AAK cultures via entrapment and adsorption techniques and degradation of different phenolic compounds by immobilized cells were estimated. Partial purification and immobilization of laccase enzymes were carried out. In addition, the biodegradation of 2,4-DCP and others contaminated by wastewater was investigated. RESULTS: Immobilization of cells and partially purified laccase enzymes by adsorption into 3% alginate increased 2,4-DCP biotransformation compared with free cells and free enzymes. In addition, the reuse of both the immobilized culture and laccase enzymes was evaluated. The highest removal of 2,4-DCP from pulp and paper wastewater samples inoculated by immobilized cells and the immobilized enzyme was 90% and 95%, respectively, at 50 h and 52 h of incubation, compared to free cells and free enzyme. CONCLUSION: The results of this study have revealed the immobilization of a biocatalyst and its laccase enzyme as a promising technique for enhancing the degradation of 2,4-DCP and other toxic phenolic and aromatic compounds. The reuse of the biocatalyst and its laccase enzyme enabled the application of this cost-effective bioremediation strategy.

Methoxyisoflavan derivative from Trigonella stellata inhibited quorum sensing and virulence factors of Pseudomonas aeruginosa.

The number of deaths caused by multidrug-resistant Pseudomonas aeruginosa has risen in the recent decade. The development of quorum sensing inhibition (QSI) is a promising approach for controlling Pseudomonas infection. Therefore, this study mainly aimed to investigate how a plant-source material inhibits QSI to produce an antipathogenic effect for fighting microbial infections. The QSI effect of Trigonella stellata was assessed by using Chromobacterium violaceum ATCC 12472 reporter strain. Trigonella stellata exhibited high QSI activity, and an ethanolic extract of T. stellata was prepared for phytochemical isolation of the most active QSI compound. Nine pure compounds were isolated and identified as kaempferitrin (1), soyasaponin I (2), ß-sitosterol-3-O-glucoside (3), dihydromelilotoside (4), astrasikokioside I (5), methyl dihydromelilotoside (6), (3R, 4S)-4, 2', 4'-trihydroxy-7-methoxy-4'-O-ß-D-glucopyranosylisoflavan (7), (3S, 4R)-4, 2', 4'-trihydroxy-7-methoxyisoflavan (8, TMF), and (+)-D-pinitol (9). These compounds were screened against C. violaceum ATCC 12472, and TMF exhibited a potent QSI. The effect of TMF at sub-minimum inhibitory concentrations (MICs) was assessed against P. aeruginosa virulence factors, including biofilm, pyocyanin formation protease and hemolysin activity. TMF induced significant elimination of QS-associated virulence behavior. In addition, TMF at sub-MICs significantly reduced the relative expression of lasI, lasR, rhlI, and rhlR compared with that in untreated cells. Furthermore, molecular docking was performed to predict structural basis of the QSI activity of TMF. The study demonstrated the importance of T. stellata as a signal modulator and inhibitor of P. aeruginosa pathogenesis.

Psychobiotic Potential of Gamma-Aminobutyric Acid-Producing Marine Enterococcus faecium SH9 from Marine Shrimp.

Psychobiotics are a novel class of probiotics with potential to confer mental wellness via production of neuroactive compounds such as gamma-aminobutyric acid (GABA). The demand for new biological sources of GABA has increased steadily. Therefore, the current study reports the isolation of 17 presumptive lactic acid bacteria (LAB) from marine samples and their screening for GABA synthesis from monosodium glutamate (MSG) using thin-layer chromatography (TLC). The isolate SH9 was selected as a high GABA producing strain. The GABA content of SH9 cell free supernatant (CFS) was quantitatively determined by high performance liquid chromatography (HPLC) to be 0.97 g/L. SH9 was identified biochemically and molecularly as Enterococcus faecium (identity 99%). Moreover, SH9 demonstrated promising probiotic potentials; it gave no signs of hemolysis and could survive at low pH values and high bile salt concentrations. It also exhibited antimicrobial activity against highly pathogenic strains and the ability to grow at 6.5% NaCl. In addition, SH9 CFS showed anti-inflammatory and antioxidant properties. The glutamate decarboxylase (GAD) gene was detected in SH9 by using specific primers. Product of 540 bp was obtained, sequenced, and analyzed (accession number: MW713382). The inferred amino acid sequence was 99.3% identical to Lactobacillus plantarum M-6 gadB gene. The findings of this study suggest that the marine isolate E. faecium SH9 could be used as a novel psychobiotics in the development of GABA rich healthy products.

Suggested Sustainable Medical and Environmental Uses of Melanin Pigment From Halotolerant Black Yeast Hortaea werneckii AS1.

The marine ecosystem is a complex niche with unique environmental circumstances. Microbial communities from the sea are one of the main origins of compounds with tremendous capabilities. Marine yeasts have the ability to produce secondary metabolites that are architecturally distinct from those found in terrestrial species. Melanin pigment synthesized by marine halotolerant black yeast Hortaea werneckii AS1 isolated from Mediterranean salt lakes in Alexandria, Egypt was found to exert a radical scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) with an IC50 of 61.38 µg/ml. Furthermore, it showed no cytotoxicity toward human skin fibroblast cell line (HSF) with an IC50 value above 0.1 mg/ml. The antimicrobial capability of the pigment was revealed against the tested number of bacterial and fungal strains with the highest inhibition zone of 25 mm against Aeromonas sp. and a growth inhibition percentage up to 63.6% against Aspergillus niger. From an environmental impact point of view, the pigment disclosed a heavy metal removal efficiency of 85.7, 84.8, and 81.5% for Pb2+, Cd2+, and Ni2+, respectively, at 100 mg/L metal concentration. The previously mentioned results suggested melanin from H. werneckii AS1 as a promising biocompatible candidate in various medical, cosmetics, pharmaceutical, and environmental applications.

Optimization of melanin pigment production from the halotolerant black yeast Hortaea werneckii AS1 isolated from solar salter in Alexandria.

BACKGROUND: Melanins are one of the magnificent natural pigments synthesized by a wide range of microorganisms including different species of fungi and bacteria. Marine black yeasts appear to be potential prospects for the synthesis of natural melanin pigment. As a result, the goal of this research was to isolate a marine black yeast melanin-producing strain and improve the culturing conditions in order to maximize the yield of such a valuable pigment. RESULTS: Among five locally isolated black yeast strains, the only one that demonstrated a potent remarkable melanin pigment production was identified using ITS rDNA as Hortaea werneckii AS1. The extracted pigment's physiochemical characterization and analytical investigation with Ultraviolet-Visible (UV) spectrophotometry, Fourier Transform-Infrared spectroscopy (FTIR), and Scanning Electron Microscope (SEM) confirmed its nature as a melanin pigment. The data obtained from the polynomial model's maximum point suggested that CaCl2, 1.125 g/L; trace element, 0.25 ml/L; and a culture volume 225 mL/500 mL at their optimal values were the critical three elements impacting melanin production. In comparison with the baseline settings, the response surface methodology (RSM) optimization approach resulted in a 2.0 - fold improvement in melanin output. CONCLUSIONS: A maximum melanin yield of 0.938 g/L proved the halotolerant H. werneckii AS1 potentiality as a source for natural melanin pigment synthesis 'when compared to some relevant black yeast strains' and hence, facilitating its incorporation in a variety of pharmaceutical and environmental applications.

Quorum Sensing Inhibiting Activity of Cefoperazone and Its Metallic Derivatives on Pseudomonas aeruginosa.

The last decade has witnessed a massive increase in the rate of mortalities caused by multidrug-resistant Pseudomonas aeruginosa. Therefore, developing new strategies to control virulence factors and pathogenicity has received much attention. One of these strategies is quorum sensing inhibition (QSI) which was developed to control Pseudomonas infection. This study aims to validate the effect of one of the most used ß-lactam antibiotics; cefoperazone (CFP) and its metallic-derivatives on quorum sensing (QS) and virulence factors of P. aeruginosa. Assessment of quorum sensing inhibitory activity of CFP, cefoperazone Iron complex (CFPF) and cefoperazone Cobalt complex (CFPC) was performed by using reporter strain Chromobacterium violaceum ATCC 12472. Minimal inhibitory concentration (MIC) was carried out by the microbroth dilution method. The influence of sub-MICs (1/4 and 1/2 MICs) of CFP, CFPF and CFPC on virulence factors of P. aeruginosa was evaluated. Data was confirmed on the molecular level by RT-PCR. Also, molecular docking analysis was conducted to figure out the possible mechanisms of QSI. CFP, CFPF, and CFPC inhibited violacein pigment production of C. violaceum ATCC 12472. Sub-MICs of CFP (128- 256 µg/mL), and significantly low concentrations of CFPC (0.5- 16 µg/mL) and CFPF (0.5- 64 µg/mL) reduced the production of QS related virulence factors such as pyocyanin, protease, hemolysin and eliminated biofilm assembly by P. aeruginosa standard strains PAO1 and PA14, and P. aeruginosa clinical isolates Ps1, Ps2, and Ps3, without affecting bacterial viability. In addition, CFP, CFPF, and CFPC significantly reduced the expression of lasI and rhlI genes. The molecular docking analysis elucidated that the QS inhibitory effect was possibly caused by the interaction with QS receptors. Both CFPF and CFPC interacted strongly with LasI, LasR and PqsR receptors with a much high ICM scores compared to CFP that could be the cause of elimination of natural ligand binding. Therefore, CFPC and CFPF are potent inhibitors of quorum sensing signaling and virulence factors of P. aeruginosa.

Treatment-induced cerebral sinus venous thrombosis in childhood acute lymphoblastic malignancies: New risk factors to consider.

BACKGROUND: Cerebral sinus venous thrombosis (CSVT) is one of the many side effects encountered during acute lymphoblastic leukemia (ALL) therapy. Due to the rarity of cases, lack of data, and consensus management, no recommendations exist to target the population at risk. METHODS: This is a retrospective chart review of 229 consecutive patients diagnosed with ALL with an age range of 1-21 years, treated at the Children's Cancer Center of Lebanon between October 2007 and February 2018. RESULTS: The incidence of CSVT was 10.5%. Using univariate analysis, increased risk of CSVT was observed with male gender, age >10 years, T-cell immunophenotype, intermediate/high-risk disease, maximum triglyceride (TG) level of >615 mg/dl, presence of mediastinal mass, and larger body surface area (BSA). With multivariate analysis, the only statistically significant risk factors were maximum TG level, BSA, presence of mediastinal mass, and risk stratification (intermediate/high risk). CONCLUSION: Our study was able to unveil TG level of >615 mg/dl, mediastinal mass, and a larger BSA as novel risk factors that have not been previously discussed in the literature.

The Inhibitory Effect of Wheat Husks Addition on Aflatoxins Production by Aspergillus flavus in Liquid Culture With Various Wheat Compositions as Carbon Sources.

Wheat may be infected by the aflatoxigenic mold Aspergillus flavus during pre- and post-harvest activities. Control strategies reported to manage aflatoxin contamination of wheat are expensive and require extensive testing to verify the absence of toxic secondary metabolites or newly formed compounds. The objective of this study was to develop an in vitro new control strategy based on assessing the influence of wheat husks on aflatoxin production by A. flavus in liquid culture. The results showed that aflatoxin production is significantly influenced by the existence of husks in the wheat forms used as carbon substrates according to the following order: full wheat grains < half-crushed wheat grains < wheat flour 82% < wheat flour 72%. By applying a fractional factorial design and a response surface methodology, maximum aflatoxin production (2.567 ng/mg) was predicted when wheat flour 72% (39 g/l) as a carbon source, yeast extract (5 g/l), and a 75-ml medium volume/250 ml flask were utilized. At this optimized condition, after addition of wheat husk extract, the growth and synthesis of aflatoxins of A. flavus were repressed by 74.85 and 98.72%, respectively. This finding paves the way to examine the antifungal potential of wheat husk constituents and to compare their efficacy with thyme, cinnamon, sweet basil, and coriander essential oils, which possess antimycotic activities. Accordingly, the wheat husk component SiO2 showed the highest growth inhibition (67.04%) and reduction of A. flavus aflatoxins (82.67%). These results are comparable to those obtained from various examined antimycotic essential oils.

Impact of the coronavirus disease 2019 (COVID-19) pandemic on pediatric oncology care in the Middle East, North Africa, and West Asia region: A report from the Pediatric Oncology East and Mediterranean (POEM) group.

BACKGROUND: Childhood cancer is a highly curable disease when timely diagnosis and appropriate therapy are provided. A negative impact of the coronavirus disease 2019 (COVID-19) pandemic on access to care for children with cancer is likely but has not been evaluated. METHODS: A 34-item survey focusing on barriers to pediatric oncology management during the COVID-19 pandemic was distributed to heads of pediatric oncology units within the Pediatric Oncology East and Mediterranean (POEM) collaborative group, from the Middle East, North Africa, and West Asia. Responses were collected on April 11 through 22, 2020. Corresponding rates of proven COVID-19 cases and deaths were retrieved from the World Health Organization database. RESULTS: In total, 34 centers from 19 countries participated. Almost all centers applied guidelines to optimize resource utilization and safety, including delaying off-treatment visits, rotating and reducing staff, and implementing social distancing, hand hygiene measures, and personal protective equipment use. Essential treatments, including chemotherapy, surgery, and radiation therapy, were delayed in 29% to 44% of centers, and 24% of centers restricted acceptance of new patients. Clinical care delivery was reported as negatively affected in 28% of centers. Greater than 70% of centers reported shortages in blood products, and 47% to 62% reported interruptions in surgery and radiation as well as medication shortages. However, bed availability was affected in <30% of centers, reflecting the low rates of COVID-19 hospitalizations in the corresponding countries at the time of the survey. CONCLUSIONS: Mechanisms to approach childhood cancer treatment delivery during crises need to be re-evaluated, because treatment interruptions and delays are expected to affect patient outcomes in this otherwise largely curable disease.

Isolated Central Nervous System Relapse Following Treatment Reduction in Low-risk Acute Lymphoblastic Leukemia at the Children's Cancer Center of Lebanon.

The aim of this trial was to decrease the incidence of life-threatening infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy. This was a prospective, nonrandomized trial of low-risk acute lymphoblastic leukemia patients 1 to 18 years of age who were treated at the Children's Cancer Center of Lebanon (CCCL). Patients consecutively diagnosed between 2002 and 2013 were divided into groups 1 and 2 receiving total dexamethasone doses of 1144 and 618 mg/m, respectively. A total of 84 patients were assigned to group 1 and 33 patients to group 2. The 5-year cumulative incidence of isolated central nervous system relapse increased from (n=0% [95% confidence interval: 0%-4.4%]) in group 1 to 9.1% [95% confidence interval: 3%-23%]; P=0.021) in group 2. Decreasing cumulative dose of dexamethasone for low-risk childhood acute lymphoblastic leukemia patients aiming to avoid serious viral infections led to a significant increase in isolated central nervous system relapse.

Clinical Prognostic Factors and Outcome in Pediatric Osteosarcoma: Effect of Delay in Local Control and Degree of Necrosis in a Multidisciplinary Setting in Lebanon.

PURPOSE: Outcomes in pediatric osteosarcoma have dramatically improved over the past few decades, with overall survival rates of 70% and 30% for patients with localized and metastatic disease, respectively. PATIENTS AND METHODS: We retrospectively reviewed clinical characteristics and outcomes of 38 patients treated between 2001 and 2012 at a single institution in Lebanon. All patients received a uniform three-drug chemotherapy regimen consisting of cisplatin, doxorubicin, and methotrexate. Ifosfamide and etoposide were added to the adjuvant treatment regimen in case of metastatic disease and/or poor degree of tumor necrosis (< 90%). RESULTS: After a median follow-up of 61 months (range, 8 to 142 months), patients with localized disease had 5-year overall and event-free survival rates of approximately 81% and 68%, respectively, whereas for metastatic disease, they were approximately 42%. The most common primary site was the long bones around the knee (n = 34; 89.5%). Six patients (15.8%) had metastatic disease to lungs, and three (7.9%) had synchronous multifocal bone disease with lung metastases. Adverse prognostic factors included nonlower extremity sites, metastasis, poor degree of necrosis, and delay of more than 4 weeks in local control. In bivariable analysis, only degree of necrosis was a prognostic predictor for survival and disease recurrence. CONCLUSION: Treatment of pediatric osteosarcoma in a multidisciplinary cancer center in Lebanon resulted in survival similar to that in developed countries. Delay in local control was associated with worse outcome. The only statistically significant inferior outcome predictor was poor degree of necrosis at the time of local control.

Genetic polymorphisms in candidate genes are not associated with increased vincristine-related peripheral neuropathy in Arab children treated for acute childhood leukemia: a single institution study.

OBJECTIVE: The aim of this study was to evaluate the potential association between candidate genetic polymorphisms and vincristine-related peripheral neuropathy in Arab children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: This is a retrospective evaluation of 133 Arab children treated for ALL at the Children's Cancer Center of Lebanon. Incidence and severity of, as well as the timing (in weeks) at which grade 2 or higher peripheral neuropathy occurred were recorded. Genotyping for ABCB1 (rs1045642), ABCB1 (rs1128503), ABCC2 (rs717620), CEP72 (rs924607), ETAA1 (rs17032980), and MTNR1B (rs12786200) was performed. RESULTS: A total of 26 (19.5%) individuals developed peripheral neuropathy, three of which occurred during the induction phase. No statistically significant associations were revealed for any of the polymorphisms with either incidence of vincristine-related toxicity, toxicity severity, or time to the first episode of grade 2 or higher vincristine-related peripheral neuropathy. CONCLUSION: This study presents the first pharmacogenetic analysis of vincristine-related peripheral neuropathy in children with ALL in an Arab country. We have shown that genetic polymorphisms in candidate genes are not associated with peripheral neuropathy secondary to chronic therapy with high-dose vincristine (2 mg/m) during the continuation phase. Concerning CEP72, our results are in line with the findings from the St Jude cohort of children treated for ALL with higher vincristine doses during chronic treatment. Larger high-throughput genetic analyses may be warranted to evaluate variants in other candidate genes such as CYP3A5 and reveal new nonpreviously reported alleles that may be peculiar to this region of the world.

Production of di-(2-ethylhexyl) phthalate by Bacillus subtilis AD35: Isolation, purification, characterization and biological activities.

The emergence of extensive antibiotics resistant bacteria increased the demands for finding out new sources of antimicrobial agents. Marine niches were reported to be rich in many competent producers of significant bioactive compounds. On the course of screening program for new antimicrobials, a Bacillus strain was isolated from Alexandria sea shores, Egypt. According to the morphological, cultural and biochemical characteristics, 16S rRNA sequence analysis and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS), the strain was identified as Bacillus subtilis and designated as B. subtilis AD35. One phthalate derivative namely Di-(2-ethylhexyl) phthalate (DEHP) was purified from the crude extract of B. subtilis AD35 by high performance liquid chromatography (HPLC) and the structural elucidation of this compound was confirmed on the basis of gas chromatography-mass spectroscopy (GC-MS), Fourier infrared spectroscopy (FT-IR) and UV spectrum. The results of MIC of the purified DEHP were as follow: 16 µg/ml (Salmonella typhimurium), 32 µg/ml (Methicillin resistant Staphylococcus aureus, MRSA), 0.25 µg/ml (Listeria monocytogenes), 0.5 µg/ml (Aeromonas hydrophila), 8 µg/ml (Staphylococcus aureus), 4 µg/ml (Staphylococcus epidermidis), 4 µg/ml (Escherichia coli), and 8 µg/ml (Pseudomonas aeruginosa). DEHP produced by B. subtilis AD35 up to a concentration of 2500 µg/ml exhibited no cytotoxic effect against normal Vero cells. In addition, it did not show an antiviral activity against HAV or a significant growth inhibitory effect toward human colorectal adenocarcinoma and human mammary gland adenocarcinoma cell-lines.

Statistically optimized ceftriaxone sodium biotransformation through Achromobacter xylosoxidans strain Cef6: an unusual insight for bioremediation.

The present study underlines a unique promising approach toward efficient biotransformation of ceftriaxone sodium (Ceftx), a highly frequent prescribed cephalosporin antibiotic, by a newly bacterium namely Achromobacter xylosoxidans strain Cef6 isolated from Ceftx contaminated raw materials in pharmaceutical industries. A three step sequential statistical-mathematical approach (Plackett-Burman design [PBD], Central Composite Design [CCD], and ridge-canonical analyses) was anticipated to optimize the biotransformation process. Ceftx concentration and medium volume: bottle volume ratio, two key determinants, significantly (p < 0.05) affected the process outcome deduced by regression analysis of PBD' data. CCD and ridge-canonical analyses localized the optimal levels of Ceftx concentration and medium volume: 250 ml bottle volume ratio to be 0.39 and 7.973 g Ceftx/L modified tryptic soy broth achieving Ceftx biotransformation (100%) after 39 h under aerobic static conditions at 30 °C, irrespectively deduced via HPLC analysis. Impressively, only one of five Ceftx byproducts was detected by the end of the biotransformation process. To the best of authors' knowledge, this is the first report addressing a detailed study regarding efficient biotransformation of Ceftx by single bacterium not bacterial consortium under aerobic conditions. Present data would greatly encourage applying this approach for decontamination of some Ceftx contaminated environmental sites.

Cerebral sinus venous thrombosis during childhood acute lymphoblastic leukemia therapy: Risk factors and management.

BACKGROUND: Cerebral sinus venous thrombosis (CSVT) is a rare but serious complication of childhood acute lymphoblastic leukemia (ALL) therapy. No available consensus exists regarding its risk factors and appropriate management due to the rarity of cases. PROCEDURES: Out of 209 ALL patients aged 1-21 years treated at the Children's Cancer Center of Lebanon between May 2002 and May 2015, 13 developed CSVT during therapy. Patient characteristics, clinical management, and outcomes were studied. RESULTS: The incidence of CSVT was 6.2% (95% confidence interval [CI]: 3.4-10.4). Using univariate analysis, increased risk of CSVT was observed with age >10 years (odds ratio [OR]: 3.56, 95% CI: 1.13-11.2), T-cell immunophenotype (OR: 4.14, 95% CI: 1.16-14.7), and intermediate/high risk disease (OR: 3.4, 95% CI: 1.03-11.7). The only statistically significant risk factor by multivariate analysis was the treatment as per the intermediate-/high-risk protocol (HR: 15.6, 95% CI: 1.43-171.3). Most cases (77%) occurred in the postinduction phases of treatment while receiving a combination of asparaginase and dexamethasone rather than prednisone. Treatment with low molecular weight heparin (LMWH) for a minimum of 3 months and until significant radiological improvement is observed resulted in 100% survival rate. All but one patient had complete neurological recovery. CONCLUSIONS: CSVT is an important complication of childhood ALL therapy. Postinduction combined asparaginase and dexamethasone intensive treatment for intermediate-/high-risk patients was the most important risk factor. Treatment with LMWH for a minimum of 3 months, and until asparginase therapy is over, with major radiological improvement seems to be effective and feasible.