Enzymatic depletion of l-Met using an engineered human enzyme as a novel therapeutic strategy for melanoma.

Many cancers, including melanoma, have a higher requirement for l-methionine in comparison with noncancerous cells. In this study, we show that administration of an engineered human methionine-γ-lyase (hMGL) significantly reduced the survival of both human and mouse melanoma cells in vitro. A multiomics approach was utilized to identify global changes in gene expression and in metabolite levels with hMGL treatment in melanoma cells. There was considerable overlap in the perturbed pathways identified in the two data sets. Common pathways were flagged for further investigation to understand their mechanistic importance. In this regard, hMGL treatment induced S and G2 phase cell cycle arrest, decreased nucleotide levels, and increased DNA double-strand breaks suggesting an important role for replication stress in the mechanism of hMGL effects on melanoma cells. Further, hMGL treatment resulted in increased cellular reactive oxygen species levels and increased apoptosis as well as uncharged transfer RNA pathway upregulation. Finally, treatment with hMGL significantly inhibited the growth of both mouse and human melanoma cells in orthotopic tumor models in vivo. Overall, the results of this study provide a strong rationale for further mechanistic evaluation and clinical development of hMGL for the treatment of melanoma skin cancer and other cancers.

Combined experimental/computational aspects for the molecular interaction of empagliflozin with bovine serum albumin: Quantification and application to human plasma.

Empagliflozin (EMP) is an oral antihyperglycemic agent for type 2 diabetic patients. The molecular binding of EMP to bovine serum albumin (BSA) was elucidated by a combined experimental/computational approach to fulfil the pharmacokinetics and pharmacodynamics gaps of the cited drug for further development. Fluorescence, synchronous, and three-dimensional fluorescence spectroscopy verified that EMP quenched BSA native fluorescence through a dual static/dynamic mechanism that was further supported by FÓ§rster resonance energy transfer and ultraviolet absorption spectroscopy. Fourier transform infrared spectroscopy revealed the conformational variations in BSA secondary structure induced by EMP. Thermodynamic properties of the BSA-EMP complex were also investigated, and the hydrophobic interactions' role in the binding process was demonstrated by the computed enthalpy (ΔH = 6.558 kJ mol-1 ) and entropy (ΔS = 69.333 J mol-1  K-1 ). Gibbs free energy (ΔG) values were negative at three distinct temperatures, illuminating the spontaneity of this interaction. In addition, molecular docking studies depicted the optimal fitting of EMP to BSA on Site I (sub-domain IIA) through three hydrogen bonds. Additionally, and based on the quenching effect of EMP on BSA fluorescence, this study suggests a simple validated spectrofluorometric method for the quantitation of the studied drug in bulk form and human plasma samples with reasonable recoveries (96.99-103.10%).

Developing a national competency-based curriculum for technical nurses in Egypt.

Nursing in Egypt has evolved over recent decades. Development has accelerated following recent government recognition of the contribution nurses make to healthcare access, quality and delivery. A vision to enhance nursing capacity resulted in a recent mandate requiring all nursing curricula to be competency based. Concurrently, the Educational Development Fund of the Egyptian Cabinet of Ministers drafted a nursing educational plan including a strategy to develop and implement a contextually congruent educational model with proven success comparable to international standards. This report discusses the 4-year curriculum development project designed to upgrade the current technical-level nursing curriculum to a consistent competency-based model. The competency-based educational model will be trialled in 3 technical institutes before nationwide rollout and implementation. Details of the project plan are described, including an overview of curriculum development considerations. This report provides insights for policy-makers and educators embarking on similar health workforce reform and capacity development initiatives.

A novel mesna-based electrochemical sensor embellished with silver nanoparticles for ultrasensitive analysis of modafinil.

Modafinil (MOD) is a CNS stimulant used for the treatment of narcolepsy, shift work sleep disorder, excessive daytime sleepiness, and post-COVID 19 neurological symptoms. In the literature, there is no report of square wave voltammetric (SWV) methods being used for the determination of MOD. This study describes, for the first time, the construction and evaluation of the analytical performance of a novel sensor for ultrasensitive SWV detection of MOD. The sensor was constructed by integration of silver nanoparticles (AgNPs) on Mesna (MSN) layers over a pencil graphite electrode (PGE) surface. The interface and morphological characteristics of the fabricated AgNPs@MSN/PGE sensor were investigated via cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). This sensor was found to enhance the electro-oxidation of MOD. The combination of AgNPs@MSN/PGE with SWV enabled the determination of MOD in its bulk form and in pharmaceutical and biological matrices at the nanomolar scale (LOD = 28.59 nM) with excellent recoveries. This study represents the first report describing an electrochemical procedure for MOD detection in human plasma. The established SWV method was also validated, and the results were consistent with ICH criteria. Finally, the presented SWV procedure provides a facile, sensitive, rapid, and cost-effective approach compared to other existing methods.

One Anastomosis Gastric Bypass (OAGB) with a 150-cm Biliopancreatic Limb (BPL) Versus a 200-cm BPL, a Systematic Review and Meta-analysis.

This is a systematic review and meta-analysis that assessed the impact of performing OAGB with a 150-cm BPL versus a 200-cm BPL concerning weight loss, comorbidities remission, and adverse nutritional effects. The analysis included studies that compared patients who underwent OAGB with a 150-cm BPL and 200-cm BPL. Eight studies were eligible for this review after searching in the EMBASE, PubMed central database, and Google scholar. The pooled analysis revealed favoring the 200-cm BPL limb length for weight loss, with a highly significant difference in the TWL% (p=0.009). Both groups showed comparable comorbidities remission. Significantly higher ferritin and folate deficiency rates were found in the 200-cm BPL group. Considering a 200-cm BPL when performing OAGB delivers a better weight loss outcome than a 150-cm BPL, which is at the expense of a more severe nutritional deficiency. No significant differences were found regarding the comorbidities' remission.

Development of High Dietary Fibre-Enriched Cupcake Using Pomegranate Peel Powder.

The effect of substituted wheat flour with pomegranate peel powder (PPP) at different ratios 5, 10, 15, and 20% on chemical composition, physical properties, color appearance, staling, and the sensory evaluation of the high-fibre cupcake was evaluated. The obtained results revealed that a slight increase in ash of cake samples with all levels of PPP was found. The highest value of ash was 1.92% given by cupcakes with 20% PPP. It was observed that a gradual significant (p ≤ 0.05) increase in dietary fibre of prepared cupcakes with PPP compared to control cake. The dietary fibre values ranged from 2.73% for the control cake to 17.00% with 20% of PPP; it may be due to the high content of ash and dietary fibre in PPP. Also, using PPP in cupcake manufacturing had a lowered effect on their volume and specific volume, where control cupcake recorded 48.00 cm3 and 1.40 cm3/g for volume and specific volume, respectively. In addition, a gradual significant (p ≤ 0.05) decrease in L value (lightness) with incorporated different levels of PPP was found. The control cupcake had the highest lightness value (65.97) with a significant (p ≤ 0.05) increase compared to all other cupcake samples that ranged between 37.67 and 30.18 by 5% and 20% of PPP, respectively. The results indicated that the highest value of taste was 18.75, which was given by cupcake with 5% PPP. While increasing the percentage of PPP in cupcake, the taste is less acceptable by panelists, and perhaps, this decreases in taste due to the high ratio of fibre in PPP. The highest staling was given by cupcake replaced with PPP at 20% after the ninth day of storage. Finally, it can be concluded that PPP can be used in cupcake production to raise its dietary fibre and mineral content up to a substitution rate of 10% PPP while retaining acceptable organoleptic properties.

Development and validation of a novel evaporation setup-assisted TLC method with fluorescence detection for determination of flibanserin in pharmaceutical and biological samples.

A specific and sensitive thin layer chromatographic method coupled with fluorescence detection for determination of flibanserin (FLN) that treats woman hypoactive sexual desire disorder was developed. The proposed method depends on the enhancement of FLN native fluorescence intensity via the exposure of the developed TLC plate to concentrated hydrochloric acid vapors. Herein, an evaporation setup needed for HCl vapors exposure step was designed for the first time to ensure a uniform distribution of the vapors throughout the developed bands on the plate. Chloroform: methanol (9.5: 0.5, v/v) was the optimum mobile phase that gave a compact band (Rf= 0.44 ± 0.02) using TLC aluminium plates precoated with silica gel G 60F254 as a stationary phase. After exposure of the developed TLC plate to HCl vapors, the FLN bands emission intensities were measured after excitation at 275 nm. Conferring ICH guidelines, the linearity range was 20.0 - 1500.0 ng/band with a good linear relationship (r= 0.9998). Detection and quantitation limits were 5.12 and 15.50 ng/band, respectively. Also, the method was validated for accuracy, precision, robustness, specificity and selectivity. Statistical analysis verified the suitability of the proposed method for estimation of FLN in tablets and in human plasma with acceptable recoveries (98.07-101.45%).

Anti-Obesity Effects of Formulated Biscuits Supplemented with Date's Fiber; Agro-Waste Products Used as a Potent Functional Food.

Superabundant date fruit production in Al-Qassim in the Kingdom of Saudi Arabia (KSA), a plentiful region for producing date syrup resulting in massive amounts of date fiber (DF), causes environmental issues with what is considered dietary waste. However, no food producer or researcher has thought of the valorization of DF by extracting the crude polysaccharides that can be converted to nanoparticles (flours) to increase its functional group and enhance its functionality. Using the DF was the primary goal, with the new biscuits used within the current study investigated as a potent integrated approach for controlling obesity levels and its effects. Obesity is one of the most important human problems worldwide, connected to many metabolic diseases, e.g., diabetes mellitus and cardiovascular disease. Its prevalence has recently increased among Saudi children and adolescents. An investigation of the biological effects of the formulated products was carried out by feeding the formulated biscuits with different DF levels (5, 10 and 15%) to obese albino rats, in addition to positive and negative control groups, to evaluate the effect of a reduced calorie product on controlling their body weight and health stats (lipid profile, blood sugars, kidney and liver functions). The collected data showed that the most positive results were obtained from rats fed diets supplemented with 10% DF biscuits. All TCHO, TrGs, HDL, and HDL were decreased to the best levels in this group compared to the positive control group (148.23, 145.30, 37.50, and 81.67 vs. 238.37, 199.07, 62.57, and 135.99, respectively). To conclude, DF supplementation presented anti-obesity properties in animal models; however, more epidemiological trials are needed.

Towards understanding of the interaction of certain carbapenems with protein via combined experimental and theoretical approach.

The interactions of the recent carbapenems; ertapenem (ERP) and meropenem (MRP); with serum albumin (SA) were closely investigated by a combined spectrofluorometric experimental and theoretical approach. The approach is based on the quenching of fluorescence intensity of bovine serum albumin (BSA) upon binding with different carbapenems. The quenching was observed at λem 333-340 nm after excitation at 280 nm. Mechanism of interaction was found to be static quenching through hydrophobic and H-bonding interactions and confirmed with molecular docking using MOE software. Binding constant, binding number were estimated for both MRP and ERP. Thermodynamic parameters including entropy change (ΔS), enthalpy change (ΔH) and free energy change (ΔG) were calculated at three different temperatures. Moreover, BSA configuration during binding was investigated via synchronous and 3D spectrofluorimetry. Förster resonance energy transfer calculated (FRET), integration interval (J) and distance (ro) between BSA and the studied drugs were calculated to confirm the static quenching.

Can botulinum toxin help in managing children with functional constipation and obstructed defecation?

BACKGROUND: Functional constipation (FC) is a common pediatric healthcare problem worldwide. Obstructed defection syndrome (ODS) is frequently presented with an inability to coordinate the bowel movement with pelvic floor muscles. Botulinum toxin (BT) intraanal sphincteric injection can improve the obstructed defecation by relaxing the anal sphincter and reducing the required force to propel the stools. PURPOSE: This study aimed to compare the changes in Rintala scores (as a mean of assessing defecatory function), in children with FC and ODS, managed by BT injection, bowel management program (BMP), and senna based laxatives (SBL), versus a control group managed by BMP and SBL only. METHODS: Prospective randomized controlled study, started at December 2017 on 40 pediatric patients, divided into 2 equal groups (group A: managed by BMP and SBL, group B: like group A with once intraanal sphincteric BT injection) suffering from FC, ODS, with contrast enema showing persistence of ≤90 rectoanal angle (RAA) even with trials of defecation. Patients were excluded if they have neuromuscular abnormalities, hypothyroidism, previous colorectal or anal surgery. Rintala score was assessed before treatment, at 2 months, and 6 months after management. RESULTS: The study included 18 females (45%) and 22 males (55%). Group A had equal gender distribution and mean age of 6.9 years, while group B had 12 males with mean age of 7.35 years. The mean follow up period was 11.35 months in group A and 11.6 months in group B. Mean Rintala scores of both groups at initial presentation, 2 months and 6 months follow up were: group A: 9.10, 9.40, 10.90; group B: 9.30, 10.70, 11.05 respectively, and showed no statistically significant difference (p value: 0.884, 0.294, 0.923 respectively). No complications were detected from BT injection like allergic reactions, neuromuscular urinary or lower limbs disturbances. CONCLUSION: Intraanal sphincteric injection of botulinum toxin by the mentioned technique and dose, did not result in additional defecatory functional improvement (when assessed by Rintala score) over the routine protocol (using bowel management program and laxatives) of managing functional constipation with obstructed defecation. ANNOUNCEMENT: a preliminary report of this work was presented in the 34th Egyptian pediatric surgery association (EPSA) meeting in Cairo in November 2019. TYPE OF STUDY: Treatment/prospective study. LEVEL OF EVIDENCE: Level I.

Predictors of outcome of pleurodesis in patients with malignant pleural effusion: a systematic review and meta-analysis.

Objectives: Pleurodesis is an important management option to palliate breathlessness in patients with malignant pleural effusion (MPE). This systematic review aimed to examine available literature for studies investigating factors that predict pleurodesis outcome.Methods: The healthcare databases advanced search (HDAS) Medline and Embase in addition to Cochrane Database of Systematic Reviews were searched on for publications reporting on pleurodesis for MPE in English language. All study types reporting previously unpublished data on predictors of pleurodesis success were included. Thirty-four studies involving 4626 patients were included in the systematic review.Results: The most common pleurodesis agent used was talc which was used in 27 studies. Meta-analyses demonstrated that the strongest predictors of pleurodesis success were higher pleural fluid pH, smaller volume of effusion pre-pleurodesis and full lung re-expansion post effusion drainage. Shorter duration of tube drainage, higher pleural fluid glucose, lower LDH, and lower pleural tumor burden all seem to favor pleurodesis success, but with considerable statistical heterogeneity between studies. Available data do not suggest that chest tube size affects pleurodesis outcome.Conclusion: Overall, available results are difficult to interpret due to evidence quality. Prospective studies are needed to further explore these factors.Protocol registration: CRD42018115874 (Prospero database of systematic reviews).

Poly (bromocresol green) flakes-decorated pencil graphite electrode for selective electrochemical sensing applications and pharmacokinetic studies.

A square wave voltammetric method for selective determination of meropenem (MRP) and ertapenem (ERP) was developed using pencil graphite electrode modified with poly (bromocresol green) (PGE/PBCG). The modified electrode film was characterized by scanning electron microscopy and electro-chemical impedance spectroscopy. Under the optimized conditions, the prepared electrode has good linearity over concentration range 1.0-60.0 and 0.3.0-75.0 µM for MRP and ERP, respectively. The developed method was validated according to ICH guidelines. In addition, the diffusion co-efficients of MRP and ERP were estimated to be 1.24 × 10-6 and 9.09 × 10-6 cm2 s-1, respectively using chronoamperometric technique. The developed method was highly sensitive and selective for the determination of MRP or ERP in the presence of their corresponding open beta-lactam ring degradation products. Consequently, it was successfully utilized for in-vitro and in-vivo applications in spiked and real plasma samples of healthy rabbits for their pharmacokinetic studies. Furthermore, the method was applied for the assay of the available dosage forms of both drugs.