The role of TAOK3 in cancer progression and development as a prognostic marker: A pan-cancer analysis study.

The protein kinase TAOK3, belongs to the MAP kinase family, is one of three closely related members, namely TAOK1, TAOK2, and TAOK3. We performed a pan-cancer investigation of TAOK3 across different cancer types, including uterine carcinosarcoma, adenocarcinoma of the stomach and pancreas, and endometrial carcinoma of the uterus, to better understand TAOK3's role in cancer. In at least 16 types of cancer, our findings indicate that TAOK3 expression levels differ considerably between normal and tumor tissues. In addition, our study is the first to identify the oncogenic role of TAOK3 locus S331 and S471 in renal clear cell carcinoma, Glioblastoma Multiforme, hepatocellular carcinoma, Lung adenocarcinoma, and Pancreatic adenocarcinoma, indicating their involvement in cancer progression. In addition, our data analysis indicates that copy number variation is the most prevalent form of mutation in the TAOK3 gene, and that there is a negative correlation between TAOK3 mRNA and DNA promoter methylation. Moreover, our analysis suggests that TAOK3 may serve as a prognostic marker for several kinds of cancer, including Colon adenocarcinoma, renal clear cell carcinoma, Lower Grade Glioma, Lung adenocarcinoma, Mesothelioma, and hepatocellular carcinoma. In addition, our research on signature cancer genes has uncovered a positive association between TAOK3 and SMAD2, SMAD4, and RNF168 in most of the malignancies we have examined. TAOK3 is also correlated with the frequency of mutations and microsatellite instability in four types of cancer. Numerous immune-related genes are closely associated with TAOK3 levels in numerous malignancies. TAOK3 expression is positively correlated with immune infiltrates, which include activated CD4 T cells, CD8 T cells, and type 2T helper cells. Our pan-cancer analysis of TAOK3 provides vital insight into its potential role across a variety of cancer types.

A molecularly imprinted electrochemical sensor for specific and ultrasensitive determination of an aminoglycoside drug: the role of copper ions in the determination.

Herein, a molecularly imprinted polymer (MIP) was fabricated for specific sensing of an aminoglycoside e.g. kanamycin (KANA). Carbon paste modified with a MIP specific to Cu2+-KANA was first introduced. Copper (Cu2+) as a metal ion was used as a signal tracer and an amplifier, producing a current response measured by differential pulse voltammetry (DPV). Introducing the aminoglycoside drug into the solution containing Cu2+ did not affect the current response of the NIP/CPE. Under the optimum conditions, the as-fabricated sensor exhibited an increase in the current response in the range of 0.55-550 nM with a good limit of detection (LOD, S/N = 3) of 161 pM. The sensor exhibited many advantages including high sensitivity and selectivity, good stability and reproducibility, and cost-effectiveness. Moreover, it was successfully applied for the determination of KANA in milk and honey samples with RSD % not more than 3.3%, suggesting the reliability of the as-designed sensor.

Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens.

Cancer cells often depend on multiple pathways for their growth and survival, resulting in therapeutic resistance and the limited effectiveness of treatments. Combination therapy has emerged as a favorable approach to enhance treatment efficacy and minimize acquired resistance and harmful side effects. The murine double minute 2 (MDM2) protein regulates cellular proliferation and promotes cancer-related activities by negatively regulating the tumor suppressor protein p53. MDM2 aberrations have been reported in a variety of human cancers, making it an appealing target for cancer therapy. As a result, several small-molecule MDM2 inhibitors have been developed and are currently being investigated in clinical studies. Nevertheless, it has been shown that the inhibition of MDM2 alone is inadequate to achieve long-term suppression of tumor growth, thus prompting the need for further investigation into combination therapeutic strategies. In this review, possible clinical and preclinical MDM2 combination inhibitor regimens are thoroughly analyzed and discussed. It provides a rationale for combining MDM2 inhibitors with other therapeutic approaches in the management of cancer, taking into consideration ongoing clinical trials that evaluate the combination of MDM2 inhibitors. The review explores the current status of MDM2 inhibitors in combination with chemotherapy or targeted therapy, as well as promising approach of combining MDM2 inhibitors with immunotherapy. In addition, it investigates the function of PROTACs as MDM2 degraders in cancer treatment. A comprehensive examination of these combination regimens highlights the potential for advancing MDM2-inhibitor therapy and improving clinical outcomes for cancer patients and establishes the foundation for future research and development in this promising area of study.

Prevalence of pharmacological and non-pharmacological coping mechanisms for anxiety management during the COVID-19 pandemic: investigating the transition to online learning among medical students.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic had a devastating effect on college students worldwide. Here, the authors aimed to determine the prevalence of anxiety and its related coping strategies, provide a theoretical basis for understanding self-prescription, and identify the factors contributing to stress and anxiety in medical students during the pandemic. METHODS: The authors conducted a cross-sectional study among medical students in Saudi Arabia from September to November 2020. They assessed anxiety using the GAD-7 scale based on seven core symptoms. The authors also examined perceived psychological stress using a single-item measure of stress, the factors contributing to stress during the transition to online learning and examinations, and related coping strategies. The Statistical Package for Social Sciences (SPSS) version 26.0 was used to examine the data for both descriptive and inferential analyses. Chi-square test, one-way ANOVA, and univariate linear regression were used to test the research hypotheses. RESULTS: The authors collected and analyzed data from 7116 medical students distributed across 38 medical colleges. Among them, 40% reported moderate to severe anxiety symptoms. Pre-clinical and female students experienced more stress than clinical and male students. 12.19% (n = 868) of respondents reported using medication during their college years. Among those, 58.9% (n = 512) had moderate to severe anxiety, and the most commonly used drug was propranolol (45.4%, n = 394). Among the studied sample, 40.4% (n = 351) decreased their medication use after switching to online teaching. Most students used these medications during the final exam (35.8%, n = 311) and before the oral exam (35.5%, n = 308). In terms of coping strategies, males were much more likely to use substances than females, who mainly resorted to other strategies. CONCLUSIONS: This study provides a national overview of the impact of COVID-19 on the mental health of medical students. The results indicated that the pandemic is associated with highly significant levels of anxiety. These findings can provide theoretical evidence for the need for supportive psychological assistance from academic leaders in this regard.

Evaluation of antitumor effects of VEGFR-2 inhibitor F16 in a colorectal xenograft model.

OBJECTIVES: Colorectal cancer (CRC) is the third most prevalent type of cancer in the United States. The treatment options for cancer include surgery, chemotherapy, radiation, and/or targeted therapy, which show significant improvement in overall survival. Among the various available treatments, antagonizing VEGF/VEGFR-2 pathways have shown effectiveness in limiting colorectal cancer growth and improving clinical outcomes. In this regard, we hypothesized that F16, a novel VEGFR-2 inhibitor, would control colorectal cancer growth by blocking the VEGFR-2 singling pathway in both in vitro and in vivo conditions. Therefore, the current study was aimed to analyze the efficacy of F16 on the growth of Colo 320DM cells under in vitro and in vivo conditions. RESULTS: Human RT2 profiler PCR array analysis results clearly showed that angiogenesis and anti-apoptosis-related gene expressions were significantly reduced in HUVEC cells after F16 (5 µM) treatment. In addition, Western blot results revealed that F16 attenuated the downstream signaling of the VEGFR-2 pathway in HUVEC cells by up-regulating the p53 and p21 levels and down-regulating the p-AKT and p-FAK levels. Accordingly, F16 confirmed potent cytotoxic effects against the cell viability of Colo 320DM tumors, with an IC50 value of 9.52 ± 1.49 µM. Furthermore, treatment of mice implanted with Colo 320DM xenograft tumors showed a significant reduction in tumor growth and increases in survival rate compared to controls. Immunohistochemistry analysis of tumor tissues showed a reduction in CD31 levels also in F16 treated groups. CONCLUSIONS: These results justify further evaluation of F16 as a potential new therapeutic agent for treating colorectal cancers.

Ultrasensitive and selective molecularly imprinted electrochemical oxaliplatin sensor based on a novel nitrogen-doped carbon nanotubes/Ag@cu MOF as a signal enhancer and reporter nanohybrid.

A sensitive and selective molecular imprinted polymeric network (MIP) electrochemical sensor is proposed for the determination of anti-cancer drug oxaliplatin (OXAL). The polymeric network [poly(pyrrole)] was electrodeposited on a glassy carbon electrode (GCE) modified with silver nanoparticles (Ag) functionalized Cu-metal organic framework (Cu-BDC) and nitrogen-doped carbon nanotubes (N-CNTs). The MIP-Ag@Cu-BDC /N-CNTs/GCE showed an observable reduction peak at -0.14 V, which corresponds to the Cu-BDC reduction. This peak increased and decreased by eluting and rebinding of OXAL, respectively. The binding constant between OXAL and Cu-BDC was calculated to be 3.5 ± 0.1 × 107 mol-1 L. The electrochemical signal (∆i) increased with increasing OXAL concentration in the range 0.056-200 ng mL-1 with a limit of detection (LOD, S/N = 3) of 0.016 ng mL-1. The combination of N-CNTs and Ag@Cu-BDC improves both the conductivity and the anchoring sites for binding the polymer film on the surface of the electrode. The MIP-based electrochemical sensor offered outstanding sensitivity, selectivity, reproducibility, and stability. The MIP-Ag@Cu-BDC /N-CNTs/GCE was applied to determine OXAL in pharmaceutical injections, human plasma, and urine samples with good recoveries (97.5-105%) and acceptable relative standard deviations (RSDs = 1.8-3.2%). Factors affecting fabrication of MIP and OXAL determination were optimized using standard orthogonal design using L25 (56) matrix. This MIP based electrochemical sensor opens a new venue for the fabrication of other similar  sensors and biosensors.

Matrix Metalloproteinases: A challenging paradigm of cancer management.

Matrix metalloproteinases (MMPs) are members of zinc-dependent endopeptidases implicated in a variety of physiological and pathological processes. Over the decades, MMPs have been studied for their role in cancer progression, migration, and metastasis. As a result, accumulated evidence of MMPs incriminating role has made them an attractive therapeutic target. Early generations of broad-spectrum MMP inhibitors exhibited potent inhibitory activities, which subsequently led to clinical trials. Unexpectedly, these trials failed to meet the desired goals, mainly due to the lack of efficacy, poor oral bioavailability, and toxicity. In this review, we discuss the regulatory role of MMPs in cancer progression, current strategies in targeting MMPs for cancer treatment including prodrug design and tumor imaging, and therapeutic value of MMPs as biomarkers in breast, lung, and prostate cancers.

Continued elevation of creatinine and uric acid in a male athlete: A case report.

Whey protein and other protein-fortified supplements are frequently consumed as nutritional supplements to aid in muscle hypertrophy and myogenesis. This case presents a 36-year-old athletic male with elevated creatinine and uric acid levels during routine laboratory evaluation. The patient had no history of kidney disease, diabetes, or hypertension. It was revealed that the patient had been regularly consuming whey protein as a dietary supplement for 2 months. Given the potential association between the elevated creatinine and uric acid levels and the use of whey protein, the patient was advised to discontinue the supplement. The patient then switched to protein-fortified milk to mitigate the possible harmful connection between the dietary intake and the laboratory findings. However, despite the dietary change, the increased levels of creatinine and uric acid persisted. This observation suggests that the elevated levels may be attributed to chronic whey protein consumption along with high-protein dietary consumption.

Assessing the Impact of COVID-19 Vaccines on Sickle Cell Anaemia Patients: A Comparative Analysis of Biochemical and Haematological Parameters.

The coronavirus disease 2019 (COVID-19) vaccines have been developed to help prevent the spread of the virus infections. The COVID-19 vaccines, including Pfizer, Moderna, and AstraZeneca, have undergone rigorous testing and have demonstrated both safety and effectiveness. Extensive evidence supports their effectiveness in preventing severe illness, hospitalization, and mortality associated with COVID-19 infection. The administration of COVID-19 vaccines can directly affect hematological and biochemical parameters, with reported cases showing an association with thrombosis and thrombocytopenia. Therefore, it was hypothesized that COVID-19 vaccines may also influence hematological and biochemical markers in sickle cell patients. This study aimed to investigate the side effects of COVID-19 vaccines on sickle cell patients, providing a comprehensive evaluation of hematological and biochemical parameters. To our knowledge, this is the first study of its kind conducted in Saudi Arabia. The study included the evaluation of Pfizer and Oxford-AstraZeneca vaccines in sickle cell patients, measuring key parameters. Our findings revealed varying impacts of both vaccines on the ALT, AST, and CRP levels. Notably, CRP and ALT exhibited potential as indicators for renal disease, diabetes, and arthritis. However, further investigations are necessary to uncover the underlying mechanisms that drive these observed differences and comprehend their clinical implications for this vulnerable patient population. The unique nature of our study fills a crucial research gap and underscores the need for additional research in this area.

Preparation and Evaluation of Nanoemulsion of Citronella Essential Oil with Improved Antimicrobial and Anti-Cancer Properties.

The development of new pharmaceutical solutions for treating various diseases results from a growing understanding of the benefits of using essential oils. One of the most often used volatile materials among essential oils is the oil of the citronella plant, termed citronella essential oil (CITEO), which has potential for use in food and medicine. Its wide use is limited due to lipophilicity, high volatility and poor physicochemical stability. With this background, the present study aims to evaluate the properties of CITEO-nanoemulsion (CITEO-NE) by analyzing its antimicrobial activities against Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) and its anticancer activity against, human skin adenocarcinoma cell line (A431). The CITEO-NE was prepared and evaluated for the size range of 130 ± 5 nm, polydispersity index (PDI) of 0.127 and zeta potential -12.6 mV. The percentage % of entrapment efficiency (%EE) of nanoemulsions loaded with CIT was very high at the beginning of the study, at 95.5 ± 4.775%. The MIC was observed to be 500 µg/mL for CITEO and 250 µg/mL for CITEO-NE against S. aureus and 250 µg/mL for CITEO and 125 µg/mL for CITEO-NE against C. albicans. The time-kill assay also suggests the effectiveness of CITEO-NE against the test pathogens as a novel alternative therapy. The IC50 values of CITEO and CITEO-NE exhibited significant cytotoxic properties against the A431 cell line, with 41.20 µg/mL and 37.71 µg/mL, respectively. Hence, our findings revealed that encapsulation of CITEO increased the pharmacological properties.

Evaluation of anti-angiogenic agent F16 for targeting glioblastoma xenograft tumors.

Glioblastoma Multiforme (GBM) is one of the most aggressive and lethal types of all cancers, with an average 5-year survival rate of 5%. Since GBM tumors are highly vascularized tumors, and their growth is angiogenesis-dependent, antagonizing tumor angiogenesis by using angiogenesis inhibitors were considered as one of the promising approaches. In this context, intensive preclinical evaluation of a novel small molecule named F16 has exhibited potent anti-angiogenic and anti-tumor activities by selectively antagonizing Vascular Endothelial Growth Factor Receptor (VEGFR). Also, recent pharmacokinetic evaluation of F16 with tissue distribution analysis has shown that this molecule is transported across the blood-brain barrier (BBB) and accumulates in the brain regions with no signs of neurotoxicity. Therefore, further studies were conducted to determine the efficacy of F16 in delaying glioblastoma progression via inhibiting tumor angiogenesis. Our in vitro studies have clearly demonstrated the ability of F16 to inhibit migration and invasion of U87MG cells and also confirmed a potent cytotoxic effect against these cells in comparison to Temozolomide (TMZ). Our in vivo studies with the subcutaneously implanted (s.c.) xenograft tumor model and in vitro studies have clearly demonstrated the ability of F16 to delay tumor growth and inhibit migration and invasion.

Nitrogen doped graphene quantum dots based on host guest interaction for selective dual readout of dopamine.

Herein, yellow emissive nitrogen doped graphene quantum dots (N@GQDs) were prepared by a novel advanced thermal driven oxidation. The N@GQDs was functionalized with ß-cyclodextrin (ß-CD) to improve its catalytic performance towards dopamine (DA) detection. The ß-CD/N@GQDs exhibited strong fluorescence at λem. = 550 nm after excitation at 460 nm with a quantum yield of 38.6%. The ß-CD/N@GQDs showed good peroxidase like activity via catalyzing the oxidation of tetramethylbenzidine (TMB) in presence of H2O2 to form blue colored product at λmax = 652 nm. In the colorimetric assay of DA, the detection based on the oxidation of TMB by H2O2 in presence of ß-CD/N@GQDs as a catalyst. Then, the color of the blue oxidized TMB (oxTMB) product was reduced by addition of DA. While the fluorometric detection of DA based on the "inner filter effect" of the overlapped emission spectrum of ß-CD/N@GQDs with the absorption spectrum of oxTMB, where, addition of DA reduces oxTMB to TMB and restores the fluorescence intensity of ß-CD/N@GQDs. Under the optimized conditions, the colorimetric method achieved linearity range of 0.12-7.5 µM and LOD (S/N = 3) of 0.04 µM, while the fluorometric method achieved linearity range of 0.028-1.5 µM and LOD (S/N = 3) of 0.009 µM. The peroxidase like activity of ß-CD/N@GQDs was used to detect DA in human plasma and serum samples with good % recoveries. The colorimetric and fluorometric methods exhibited good sensitivity and selectivity toward DA detection.

Focal Adhesion Kinase in Ovarian Cancer: A Potential Therapeutic Target for Platinum and Taxane-Resistant Tumors.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which is an essential player in regulating cell migration, invasion, adhesion, proliferation, and survival. Its overexpression and activation have been identified in sixty-eight percent of epithelial ovarian cancer patients and this is significantly associated with higher tumor stage, metastasis, and shorter overall survival of these patients. Most recently, a new role has emerged for FAK in promoting resistance to taxane and platinum-based therapy in ovarian and other cancers. The development of resistance is a complex network of molecular processes that make the identification of a targetable biomarker in platinum and taxane-resistant ovarian cancer a major challenge. FAK overexpression upregulates ALDH and XIAP activity in platinum-resistant and increases CD44, YB1, and MDR-1 activity in taxaneresistant tumors. FAK is therefore now emerging as a prognostically significant candidate in this regard, with mounting evidence from recent successes in preclinical and clinical trials using small molecule FAK inhibitors. This review will summarize the significance and function of FAK in ovarian cancer, and its emerging role in chemotherapeutic resistance. We will discuss the current status of FAK inhibitors in ovarian cancers, their therapeutic competencies and limitations, and further propose that the combination of FAK inhibitors with platinum and taxane-based therapies could be an efficacious approach in chemotherapeutic resistant disease.

MDM2 Overexpression Modulates the Angiogenesis-Related Gene Expression Profile of Prostate Cancer Cells.

The Murine Double Minute 2 (MDM2) amplification or overexpression has been found in many tumors with high metastatic and angiogenic ability. Our experiments were designed to explore the impact of MDM2 overexpression, specifically on the levels of angiogenesis-related genes, which can also play a major role in tumor propagation and increase its metastatic potential. In the present study, we have used the human angiogenesis RT² profiler PCR array to compare the gene expression profile between LNCaP and LNCaP-MST (MDM2 transfected) prostate cancer cells, along with LNCaP-MST cells treated with Nutlin-3, an MDM2 specific inhibitor. As a result of the overexpression of MDM2 gene in LNCaP-MST (10.3-fold), Thrombospondin 1 (THBS1), Tumor necrosis factor alpha (TNF-α) and Matrix metallopeptidase 9 (MMP9) were also found to be significantly up-regulated while genes such as Epiregulin (EREG), Tissue inhibitor of metalloproteinases 1 (TIMP1) were down-regulated. Also, we determined the total MMP activity and MMP9 expression in LNCaP, LNCaP-MST and SJSA-1 cells. Our results indicated that MDM2 level is positively correlated with MMP activity and MMP9 secretion. Our findings offer strong supporting evidence that MDM2 can impact growth and metastatic potential of cancer cells through tilting the balance towards pro-angiogenic mechanisms.