N- and s-substituted Pyrazolopyrimidines: A promising new class of potent c-Src kinase inhibitors with prominent antitumor activity.

In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer.

Development of Novel Class of Phenylpyrazolo[3,4-d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies.

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3-24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.

Central nervous system metastasis in a young female patient with primary mediastinal large B-cell lymphoma: A case report and literature review.

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma that originates from a B cell in the thymus. It usually affects young female. Case description: A 30-year-old woman presented with mediastinal mass with history of shortness of breath and chest pain. blood analysis showed low levels of hemoglobin, hematocrit, and mean corpuscular volume and high red cell distribution width. A computed tomography (CT)-guided mediastinal core biopsy disclosed primary mediastinal large B-cell lymphoma (PMLBL) with a nongerminal center phenotype and lung tissue infiltrate. Moreover, after undergoing six cycles of rituximab, cyclophosphamide, hydroxydaunomycin, Oncovin, and prednisone (R-CHOP) chemotherapy and mediastinal radiotherapy, the patient presented with headache and visual disturbance due to multiple supratentorial lesions. Conclusion: Till date, only a few cases of central nervous system (CNS) metastasis have been reported in the literature. Moreover, CNS metastasis of refractory PMBCL is an uncommon event with a poor prognosis. Brain metastases are often the ultimate fatal consequence of many aggressive cancers, so early detection and treatment are important.

Effectiveness of electrical vestibular nerve stimulation on the range of motion in patients with Parkinson's disease.

OBJECTIVES: The present study was undertaken to observe the effectiveness of electrical vestibular stimulation on the range of motion (ROM) in patients with Parkinson's disease (PD). METHODS: The present study was a randomized controlled trial (ClinicalTrials.gov Identifier: NCT04450550). The study participants were assessed at three points of time. After recording baseline cognitive functions, electrical vestibular nerve stimulation was administered to the intervention group and placebo stimulation was administered to the control group for 12 weeks. Post-intervention parameters were recorded after 6 weeks and after 12 weeks after the intervention in both control and intervention groups. A total of 30 cases of PD, including both males and females were recruited in the study by convenient sampling after obtaining written informed consent. All ROM and flexibility measurements were recorded using a universal goniometer and standard protocol with help of an experienced physiotherapist at our hospital. RESULTS: There was a significant improvement in the hip internal and external rotation right and left sides. There was a significant improvement in the hip extension right and left. There was a significant improvement in the ankle plantarflexion left and ankle dorsiflexion right and left followed by the intervention. There was a significant decline in the hip internal rotation on right and left sides. There was a significant decline in the hip extension and ankle dorsiflexion on the left side. CONCLUSIONS: The study results confirm the improvement of motor activities of patients with PD followed by vestibular stimulation. Further detailed studies are recommended to support the application of vestibular stimulation as an alternative therapy in the management of motor functions in patients with PD.

Investigating the structural impacts of a novel missense variant identified with whole exome sequencing in an Egyptian patient with propionic acidemia.

Propionic Acidemia (PA) is an inborn error of metabolism caused by variants in the PCCA or PCCB genes, leading to mitochondrial accumulation of propionyl-CoA and its by-products. Here, we report a 2 year-old Egyptian boy with PA who was born to consanguineous parents. Biochemical analysis was performed using tandem mass spectrometry (MS/MS) on the patient's dried blood spots (DBS) followed by urine examination of amino acids using gas chromatography/mass spectrometry (GC/MS). Molecular genetic analysis was carried out using whole-exome sequencing (WES). The PCCA gene sequencing revealed a novel homozygous missense variant affecting the locus (chr13:100962160) of exon 16 of the PCCA gene, resulting in the substitution of the amino acid arginine with proline at site 476 (p.Arg476Pro). Computational analysis revealed that the novel variant might be pathogenic and attributed to decrease the stability and also has an effect on the biotin carboxylase c-terminal domain of the propionyl carboxylase enzyme. The physicochemical properties analysis using NCBI amino acid explorer study revealed restrictions in the side chain and loss of hydrogen bonds due to the variant. On the structural level, the loss of beta-sheet was observed due to the variant proline, which has further led to the loss of surrounding interactions. This loss of beta-sheet and the surrounding interactions might serve the purpose of the structural stability changes. The current study demonstrates that a combination of whole-exome sequencing (WES) and computational analysis are potent tools for validation of diagnosis and classification of disease-causing variants.

Immunohistochemical Study Using Monoclonal VE1 Antibody Can Substitute the Molecular Tests for Apprehension of BRAF V600E Mutation in Patients with Non-small-Cell Lung Carcinoma.

In patients with non-small-cell lung carcinoma (NSCLC), the analysis of BRAF V600E mutation has become more and more applied since the introduction of many mutation-targeted medications. In this regard, the advantage of immunohistochemistry (IHC) as a reliable diagnostic test substitute to other molecular studies has not been approved yet. Objective. To examine the dependability of using immunohistochemical method utilizing monoclonal VE1 antibody in the detection of BRAF V600 E mutation in patients with non-small-cell lung carcinoma and compare the results there with that of polymerase chain reaction (SSCP-PCR). Materials and Methods. We retrospectively identified 53 patients of whom their histopathological diagnosis was non-small-cell carcinoma of different types. Evaluation of BRAF V600E mutation was assessed using polymerase chain reaction (SSCP-PCR) and IHC using VE1 antibody. This approach was applied to all cases under the study. Results. Among the 53 NSCLC samples, only 5 (9.3%) cases harbored BRAF V600E mutation, 80% were of adenocarcinoma type, and the rest (20%) was of squamous cell carcinoma. IHC analysis for VE1 was positive in 4 out of 5 (80%) BRAF-mutated tumors and negative in all nonmutated BRAF V600 E NSCLC. Conclusion. Our results revealed that VE1 antibody IHC analysis is a promising technique that can be used to detect BRAF V600-mutated NSCLC with relatively high specificity and sensitivity and might become a potential alternative to the current molecular biological methods that are in use for this purpose.

Validation of the Virga GFR equation in a renal transplant population.

BACKGROUND: Virga and colleagues derived a glomerular filtration rate (GFR) equation which demonstrated a superior performance over Cockcroft-Gault (C-G) and modified diet in renal disease-isotope dilution mass spectrometry (MDRD-IDMS) formulas in chronic kidney disease (CKD) patients. AIM: To validate the performance of the Virga equation on 103 renal transplant patients. METHODS: We compared the performances of the MDRD-IDMS, C-G and Virga equations using inulin clearance as a reference test. Error, accuracy, relative accuracy, precision, scatter, and coefficient of variance of each equation were tested. RESULTS: The mean absolute percentage error in estimated GFR by the new equation was 39.8 +/- 36.34% (mean +/- SD). Relative accuracy at 10, 30 and 50% range were 18.44, 48.54 and 73.78%, respectively. It has a bias of 0.09 +/- 0.169 and a precision of 19.69. Inulin clearance (GFR) in stages 1-4 were 106.19 +/- 14.11, 71.17 +/- 7, 42.37 +/- 8.40 and 22.92 +/- 3.48 ml/min/1.73 m(2), respectively. Comparative statistics in the overall population and in patients with transplant CKD stage 3T showed that the MDRD-IDMS equation had better accuracy. The performance of MDRD-IDMS over the Virga equation was clearly superior for males. In patients with CKD stage 2T, the Virga equation showed superiority over MDRD-IDMS. In the overall and subpopulations, the Virga equation performed better than the C-G equation. CONCLUSION: Among renal transplant patients, the results suggest that the best GFR estimate is probably obtained using the MDRD-IDMS equation in moderate kidney failure whilst the Virga formula was superior to MDRD-IDMS for patients with mild kidney failure. As in untransplanted patients, estimating GFR with the MDRD-IDMS equation is not advisable in the range of normal renal function because of its known underestimation of renal function.