Impact of CYP2D6*2A, CYP2D6*4 and CYP3A5*3 genetic polymorphisms on Bisoprolol peak concentration and clinical response in acute coronary syndrome patients.

AIMS: Acute coronary syndrome (ACS) represents a major cause of death. Bisoprolol is commonly used in the management of ACS. This study aims to investigate the impact of CYP2D6*2A, CYP2D6*4 and CYP3A5*3 genetic polymorphisms on pharmacokinetics and clinical response of bisoprolol in ACS patients. METHODS: This is an open-label cohort study that included 127 ACS patients and studied the effect of CYP3A5*3, CYP2D6*2A and CYP2D6*4 genotyping using real-time polymerase chain reaction on steady state bisoprolol plasma peak concentration analysed by high performance liquid chromatography-fluorescence detector. RESULTS: Regarding CYP3A5*3, the mean peak bisoprolol concentration for CC, CT and TT genotypes were 4.25 ± 1.20, 3.93 ± 1.10 and 1.79 ± 0.69 ng/mL, respectively (P < .001). Higher systolic (126 ± 5.47 mmHg), diastolic blood pressure (82 ± 2.73 mmHg) and heart rate (97.80 ± 3.03 beats/min) were also observed in CYP3A5*3 TT carriers (P < .05). In CYP2D6*2A, the peak concentration of bisoprolol was lower in CC carriers (3.54 ± 1 ng/mL) compared to GG (4.38 ± 1.25 ng/mL) and GC carriers (4.07 ± 1.29 ng/mL, P = .019). In CYP2D6*4, the mean bisoprolol peak concentration in CC carriers was 3.98 ± 1.31 ng/mL, which was lower than T allele carriers (4.5 ± 0.8, P = .02). No differences in heart rate, systolic, diastolic blood pressure or bisoprolol dose were observed among CYP2D6*2A or CYP2D6*4 variants. Smokers exhibited lower bisoprolol peak concentration (3.96 ± 1.2 ng/mL) compared to nonsmokers (4.55 ± 1.34 ng/mL, P = .037). CONCLUSION: There is an association between CYP3A5*3, CYP2D6*4, CYP2D6*2A variants and bisoprolol peak concentration, which may serve as a guide in the future in choosing the optimum dose of bisoprolol in ACS patients.

Alveolar cleft reconstruction using bone marrow aspirate concentrate and iliac cancellous bone: A 12-month randomized clinical study.

OBJECTIVE: This study aimed to compare the bone density and volume in patients with alveolar cleft reconstructions utilizing bone marrow aspirate concentrate with iliac graft versus iliac graft alone. MATERIAL AND METHODS: Thirty-six patients with unilateral alveolar cleft were randomly allocated into either an intervention group receiving an iliac bone graft mixed with bone marrow concentrate or a control group receiving an iliac bone graft. Cone beam CT was obtained preoperative, 6 and 12 months postoperatively to assess the bone density of the graft and bone volume of the alveolar defect, and then, the bone loss ratio was calculated. RESULTS: Bone volume and bone density demonstrated a statistically significant increase in the intervention group at 6 and 12 months. In contrast, the bone loss ratio decreased significantly in the intervention group throughout the follow-up period. CONCLUSION: A combination of bone marrow concentrate and iliac cancellous bone in alveolar cleft reconstruction may improve bone densities and volume in addition to decreasing graft loss rate. CLINICAL SIGNIFICANCE: Using of bone marrow aspirate concentrate will decrease the amount of the graft needed and decrease the ratio of bone loss at the grafted site by the time. Trial registration ClinicalTrials.org ( NCT04414423 ) 4/6/2020.

Polymorphic renal transporters and cisplatin's toxicity in urinary bladder cancer patients: current perspectives and future directions.

Urinary bladder cancer (UBC) holds a potentially profound social burden and affects over 573,278 new cases annually. The disease's primary risk factors include occupational tobacco smoke exposure and inherited genetic susceptibility. Over the past 30 years, a number of treatment modalities have emerged, including cisplatin, a platinum molecule that has demonstrated effectiveness against UBC. Nevertheless, it has severe dose-limiting side effects, such as nephrotoxicity, among others. Since intracellular accumulation of platinum anticancer drugs is necessary for cytotoxicity, decreased uptake or enhanced efflux are the root causes of platinum resistance and response failure. Evidence suggests that genetic variations in any transporter involved in the entry or efflux of platinum drugs alter their kinetics and, to a significant extent, determine patients' responses to them. This review aims to consolidate and describe the major transporters and their polymorphic variants in relation to cisplatin-induced toxicities and resistance in UBC patients. We concluded that the efflux transporters ABCB1, ABCC2, SLC25A21, ATP7A, and the uptake transporter OCT2, as well as the organic anion uptake transporters OAT1 and OAT2, are linked to cisplatin accumulation, toxicity, and resistance in urinary bladder cancer patients. While suppressing the CTR1 gene's expression reduced cisplatin-induced nephrotoxicity and ototoxicity, inhibiting the expression of the MATE1 and MATE2-K genes has been shown to increase cisplatin's nephrotoxicity and resistance. The roles of ABCC5, ABCA8, ABCC10, ABCB10, ABCG1, ATP7B, ABCG2, and mitochondrial SLC25A10 in platinum-receiving urinary bladder cancer patients should be the subject of further investigation.

Impact of HOXB4 and PRDM16 Gene Expressions on Prognosis and Treatment Response in Acute Myeloid Leukemia Patients.

Introduction: Acute myeloid leukemia (AML) is the most common type of leukemia among adults and is characterized by various genetic abnormalities. HOXB4 and PRDM16 are promising markers of AML. Our objective is to assess the potential roles of HOXB4 and PRDM16 as prognostic and predictive markers in newly diagnosed AML patients and determine the correlation between their expressions and other prognostic markers as FLT3-ITD, NPM1 exon 12 mutations, response to treatment, and patient's survival. Methods: This study included 83 de novo AML adult patients. All patients were subjected to clinical, morphological, cytochemical, and molecular analysis to detect HOXB4 and PRDM16 gene expressions and FLT3-ITD, NPM1 exon 12 mutations. Results: The results showed that a low expression of HOXB4 was found in 31.3% of AML patients, whereas a high expression of PRDM16 was evident in 33.8% of AML patients. FLT3-ITD mutations were detected in 6 patients (7.2%), while NPM1 exon 12 mutations were detected in 7 patients (19.4%) out of 36 patients with intermediate genetic risk. Out of the 50 patients who achieved complete remission (CR), relapse occurred in 16% of the cases. Low expression of HOXB4 and high expression of PRDM16 were associated with CR of 32% and 28%, respectively, and a short overall survival (OS) and disease-free survival (DFS). Conclusion: Further larger study should be conducted to verify that high PRDM16 and low HOXB4 gene expressions could be used as a poor prognostic predictor for AML. The correlation between PRDM16 and HOXB4 gene expressions and FLT3-ITD and NPM1 exon 12 mutations might have a role on CR, relapse, OS, and, however, this should be clarified in analysis with a larger number of samples.

Epigenetic restoration and activation of ERß: an inspiring approach for treatment of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and HER2-targeted therapies ineffective. TNBC is typically treated with cytotoxic chemotherapy followed by surgery. Targeting epigenetic modifications could potentially be a new effective TNBC target therapy. The aim of this study is to examine the effects of epigenetic drugs, decitabine as DNA methyltransferase inhibitor (DNMTI) and vorinostat as histone deacetylase inhibitor (HDACI), and the ERß agonist DPN on ERα and ERß re-expressions in the MDA-MB-231 cells as a model of TNBC. METHODS: Using MTT assay, the IC50 of decitabine, vorinostat, and DPN on MDA-MB-231 cells were determined. The effects of all drugs alone or in combinations on MDA-MB-231 cells were evaluated. qRT-PCR was used to determine ERα & ERß gene expression. Caspase-3 activity and the protein expression levels of VEGF, Cyclin D1, and IGF-1 were assessed. RESULTS: Both ERα and ERß mRNA were re-expressed in different high levels in all treated groups, especially in the triple therapy group compared with control. Significantly, the triple drugs therapy showed the lowest levels of VEGF, Cyclin D1, and IGF-1 and the highest level of Caspase-3 activity, indicating a possible antitumor effect of ERß activation through decreasing proliferation and angiogenesis and increasing apoptosis in MDA-MB-231 cells. CONCLUSIONS: The antiproliferative effect of ERß could be retained when co-expressed with Erα using a powerful epigenetic combination of Decitabine and vorinostat with DPN.

Evening Primrose Oil Enhances Tamoxifen's Anticancer Activity against Breast Cancer Cells by Inducing Apoptosis, Inhibiting Angiogenesis, and Arresting the Cell Cycle.

BACKGROUND: Despite advancements in cancer treatment, breast cancer (BC) is still one of the leading causes of death among women. The majority of anti-breast-cancer medications induce serious side effects and multidrug resistance. Although several natural compounds, such as evening primrose oil (EPO), have been shown to have anticancer properties when used alone, their combination with the anticancer medicine tamoxifen (TAM) has yet to be investigated. The present study aimed to investigate the anticancer efficacy of EPO, alone or in combination with TAM, in the BC cell lines MCF-7 and MDA-MB-231, as well as to elucidate the mechanism of action. METHODS: The MTT assay was used to investigate the cytotoxic effect of EPO on the two cell lines, and we discovered an acceptable IC50 that was comparable to TAM. The ELISA, qRT-PCR, flow cytometry and colorimetric techniques were used. RESULTS: The combination of EPO and TAM suppressed the VEGF level, VEGF gene expression and Cyclin D1 signaling pathways, arrested the cell cycle, and induced the apoptotic signaling pathways by increasing the Bax/Bcl-2 ratio and caspase 3 activity; this revealed significant anti-tumor activity. CONCLUSIONS: The most significant finding of this study was the confirmation of the anticancer activity of the natural product EPO, which potentiated the activity of the anticancer drug TAM against MCF-7 and MDA-MB-231 BC cell lines through the induction of apoptosis, inhibiting angiogenesis and halting cell proliferation.

Attenuative Effects of Fluoxetine and Triticum aestivum against Aluminum-Induced Alzheimer's Disease in Rats: The Possible Consequences on Hepatotoxicity and Nephrotoxicity.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurological illness that causes considerable cognitive impairment. Hepatic and renal dysfunction may worsen AD by disrupting ß-amyloid homeostasis at the periphery and by causing metabolic dysfunction. Wheatgrass (Triticum aestivum) has been shown to have antioxidant and anti-inflammatory properties. This work aims to study the effect of aluminum on neuronal cells, its consequences on the liver and kidneys, and the possible role of fluoxetine and wheatgrass juice in attenuating these pathological conditions. METHOD: Rats were divided into five groups. Control, AD (AlCl3), Fluoxetine (Fluoxetine and AlCl3), Wheatgrass (Wheatgrass and AlCl3), and combination group (fluoxetine, wheatgrass, and AlCl3). All groups were assigned daily to different treatments for five weeks. CONCLUSIONS: AlCl3 elevated liver and kidney enzymes, over-production of oxidative stress, and inflammatory markers. Besides, accumulation of tau protein and Aß, the elevation of ACHE and GSK-3ß, down-regulation of BDNF, and ß-catenin expression in the brain. Histopathological examinations of the liver, kidney, and brain confirmed this toxicity, while treating AD groups with fluoxetine, wheatgrass, or a combination alleviates toxic insults. CONCLUSION: Fluoxetine and wheatgrass combination demonstrated a more significant neuroprotective impact in treating AD than fluoxetine alone and has protective effects on liver and kidney tissues.

Correlation Study on HLA-DR and CD117 (c-Kit) Expressions: Its Prognosis and Treatment Response in Acute Myeloid Leukemia Patients.

INTRODUCTION: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. HLA-DR and CD117 (c-Kit) are important diagnostic markers of AML. Our objective is to determine the prognostic significance of HLA-DR and CD117 expressions in newly diagnosed AML patients and determine the correlation between HLA-DR and CD117 expressions and other prognostic markers such as cytogenetic abnormalities, FLT3-ITD, response to treatment, and patient's survival. METHODS: This study included 100 newly diagnosed AML patients. All patients were subjected to clinical, morphological, cytochemical, cytogenetic analysis, molecular genetic analysis to detect FLT3-ITD, and Flowcytometric detection of HLA-DR, CD117, and CD 34. RESULTS: The results showed that HLA-DR expression was found in 75 patients (77.3%), while CD117 expression was found in 63 patients (64.9%). Patients with HLA-DR expression showed significantly higher mean Hb concentration, significantly higher platelet count, associated with AML-FAB subtypes (M0, M1, and M2), CD34 expression, and favorable cytogenetic group. M3 subtype was significantly associated with HLA-DR-ve. While patients with CD117 expression showed significantly lower platelets count. Double positive patients (HLA-DR+ve/CD117+ve) showed significant association with the intermediate cytogenetic group, while double-negative patients (HLA-DR-ve/CD117-ve) were associated with the favorable and intermediate cytogenetic group and either positive (HLA-DR+ve /CD117-ve or HLA-DR-ve/CD117+ve) associated with poor cytogenetic groups. FLT3-ITD expression had significantly worse overall survival. CONCLUSION: The current study suggested that the expression of CD117 and HLA-DR may be a prognostic marker in AML, as they are associated with M0, M1, and M2 FAB subtypes; moreover, patients with combined HLA-DR and CD117 positive expression are associated with CD34 expression and intermediate cytogenetic group.

Ameliorative effect of gossypin against gentamicin-induced nephrotoxicity in rats.

AIM: Gentamicin (GEN) is an aminoglycoside antibiotic employed in treatment of life-threatening gram-negative infections, but one of its major side effects is the induction of nephrotoxicity. Therefore, the aim of this work was to scrutinize the possible protective effect of gossypin against GEN-induced nephrotoxicity. METHOD: Rats were randomly divided into four groups. First group served as a control, second group was injected with gossypin (10mg/kg, orally) for 7days, third group was injected with GEN (80mg/kg, i.p.) and the fourth group was co-treated with GEN and gossypin for 7days. KEY FINDING: GEN-treated group showed kidney dysfunction as proteinuria excretion rate, podocalyxin excretion rates, renal monocyte chemoattractant protein-1 (MCP-1), blood urea nitrogen (BUN) and plasma creatinine were significantly increased as well as tubular degeneration occur. The significant decrease in renal reduced glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities and an increase in thiobarbituric acid reactive substances (TBARs) level, indicated that GEN-induced nephrotoxicity through oxidative stress reactions. Also, GEN up-regulated both gene expression and renal levels of inflammatory cytokines TNF-α and IL-6. On the other hand, concurrent treatment of gossypin plus GEN protected kidney tissues against nephrotoxic effects of GEN through elevated levels of renal GSH, SOD and CAT activities while decreased in renal TBARs level. In addition, gossypin down-regulated gene expression and renal levels of inflammatory cytokines TNF-α and IL-6 induced by GEN. SIGNIFICANCE: This study revealed that gossypin exerts protection against nephrotoxicity induced by gentamicin via its antioxidant activity.

ERCC1 and ERCC2 as predictive biomarkers to oxaliplatin-based chemotherapy in colorectal cancer patients from Egypt.

BACKGROUND: The impact of Excision repair cross-complementation group 1 (ERCC1) and group 2 (ERCC2) expression levels on the efficacy of oxaliplatin-based chemotherapy is still controversial. The present study was conducted to determine the predictive value of these molecular biomarkers in stage III and IV colorectal cancer (CRC) patients receiving oxaliplatin (OX)-based chemotherapy as first-line treatment. METHODS: The study included 80 CRC patients who received first line oxaliplatin based chemotherapy The expression levels of ERCC1 and ERCC2-mRNA and proteins were determined in the primary tumors by quantitative real time reverse transcription polymerase chain reaction(RT-qPCR) and immunohistochemistry (IHC); respectively. The results of mRNA expression were correlated with patients' characteristics, response to treatment, overall- and event free survival (OS & EFS). RESULTS: Sixty four out of the 80 patients were legible for assessment of ERCC1 and ERCC2 expression. The cut-off levels of ERCC1and ERCC2-RNA were 3.8×10-3& 4.6×10-3; respectively. Reduced ERCC1 and ERCC2 RNA expressions were detected in 50 (78.1%) and 48 (75%) cases, respectively whereas reduced proteins were detected in 48 cases (75%) for ERCC1 and ERCC2. After The median follow up period was 30.5months (range: 7-104months), Patients with low mRNAERCC1levels showed significantly longer OS (p=0.011) and EFS (p˂0.001). However, no significant relation was found between ERCC2 levels and OS or EFS. In multivariate analysis performance status (PS), stage of the disease and ERCC1-mRNA expression were independent prognostic factors for EFS whereas tumor histology and stage of the disease were independent factors for OS. CONCLUSIONS: ERCC1 expression levels may help in selecting patients who benefit from oxaliplatin chemotherapy in stage III & IV CRC. Further large trials are needed to validate these data.

Inverse horse-shoe technique for the phacoemulsification of posterior polar cataract.

OBJECTIVE: To study a new technique of controlled hydrodelineation followed by viscodelineation and viscodissection during phacoemulsification in eyes with posterior polar cataracts and to report its effectiveness in preserving the posterior capsule. DESIGN: Prospective interventional study. PARTICIPANTS: Twenty-eight eyes of 22 patients with posterior polar cataracts. METHODS: All patients underwent phacoemulsification under topical anaesthesia with controlled hydrodelineation, viscodelineation, and viscodissection with minimal stress on the posterior capsule. Hydrodissection was not done. The preoperative complications and visual outcome were recorded. RESULTS: The mean follow-up time was 8 months (range 2-24 months). Posterior capsule rupture occurred only in 2 eyes (7.1%); neither of the 2 had any vitreous prolapse, so anterior vitrectomy was not required. Mean visual acuity improved significantly after surgery (p = 0.0001, paired t test). The causes of the low postoperative visual acuity were amblyopia in 3 eyes (10.7%) and age-related macular degeneration in 1 (3.6%). CONCLUSIONS: This inverse horse-shoe technique of controlled viscodelineation and viscodissection markedly reduced the risk of posterior capsule rupture. Moreover, if it occurred, the anterior vitreous face remained intact, so the IOL could be implanted in the sulcus without resorting to anterior vitrectomy.