Oxaliplatin-associated shock in stage III colorectal cancer patients: real-world evidence in Taiwan.

Background: Oxaliplatin-associated shock (referred to as shock) is a rare but life-threatening adverse event. Objectives: This pioneering cohort study aimed to quantitatively investigate the association between oxaliplatin use and shock in patients with stage III colorectal cancer (CRC), identify potential independent risk factors for shock, and assess the cycle-to-shock during oxaliplatin treatment. Design: The study utilized a nested case-control (NCC) design to assess the association between oxaliplatin and shock and employed a case-crossover approach to address unmeasured confounders. Methods: All newly diagnosed stage III CRC patients were identified from the CRC Health Database (2012-2016). Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for oxaliplatin's link to shock incidence. Results: Among 6932 oxaliplatin recipients, 331 suffered shock. In all, 3309 controls were selected via risk-set sampling for the shock cases. Oxaliplatin use is associated with a doubled risk of shock (adjusted OR: 2.08, 95% CI: 1.23-3.52). Two independent risk factors were male sex (adjusted OR: 1.33, 95% CI: 1.05-1.69) and heart diseases (adjusted OR: 1.65, 95% CI: 1.17-2.32). The case-crossover analysis revealed a more than fourfold risk (OR: 4.4, 95% CI: 1.67-11.62). In total, 22 of 331 shock cases were exposed to oxaliplatin within 2 days of shock onset, with a median cycle-to-shock time at the seventh cycle. Conclusion: Oxaliplatin use significantly increased shock risk in stage III CRC patients. Male sex and heart disease are two independent risk factors.

This pioneering study identified potential independent risk factors and the cycle-to-shock of oxaliplatin-associated shock which is a rare but life-threatening adverse event Why was the study done? Oxaliplatin-induced anaphylactic shock (referred to as shock) is a rare but life-threatening adverse event which is a harmful and undesirable experience associated with medical care in a patient. What did the researchers do? This pioneering cohort study aimed to quantitatively investigate the association between oxaliplatin use and shock in patients with stage III colorectal cancer (CRC), identify potential independent risk factors for shock and assess the cycle-to-shock during oxaliplatin treatment. All newly diagnosed stage III CRC patients were identified from the CRC Health Database (2012­2016). The study utilized a nested case-control (NCC) design to assess the association between oxaliplatin and shock and employed a case-crossover approach to address unmeasured confounders. Conditional logistic regression was used to quantify the association between oxaliplatin and shock incidence. What did the researchers find? Among 6,932 oxaliplatin recipients, 331 suffered shock. 3,309 controls were selected via risk-set sampling for the shock cases. Oxaliplatin use is associated with a doubled risk of shock. Independent risk factors were male sex and heart diseases. The risk of shock was 33% higher for males and 65% higher for people with heart diseases compared to females and those without heart diseases. The case-crossover analysis revealed a more than four-fold risk of shock of oxaliplatin. Twenty-two of 331 shock cases were exposed to oxaliplatin within two days before the shock onset. The median cycle-to-shock time is at the seventh cycle. What do the findings mean? Oxaliplatin use significantly increased shock risk in stage III CRC patients. Male sex and having heart diseases are two independent risk factors.

Influence of antipsychotic medications on hyperlipidemia risk in patients with schizophrenia: evidence from a population-based cohort study and in vitro hepatic lipid homeostasis gene expression.

Introduction: Schizophrenia increases the risk of mortality and cardiovascular disease (CVD) risk. However, the correlation between antipsychotics (APs) and CVD remains controversial. Hyperlipidemia is a significant risk factor for CVD. Methods: We conducted a nationwide population-based retrospective cohort study to investigate the effects of APs on the risk of hyperlipidemia and lipid homeostasis gene expression. We used data from the Longitudinal Health Insurance Database of Taiwan on new-onset schizophrenia patients and a comparison cohort without schizophrenia. We used a Cox proportional hazards regression model to analyze the differences in hyperlipidemia development between the two cohorts. Furthermore, we examined the effects of APs on the hepatic expression of lipid homeostasis-related genes. Results: After adjusting for potential interrelated confounding factors, the case group (N = 4,533) was found to have a higher hyperlipidemia risk than the control cohort (N = 4,533) [adjusted hazard ratio (aHR), 1.30, p < 0.001]. Patients with schizophrenia without APs had a significantly higher risk of hyperlipidemia (aHR, 2.16; p < 0.001). However, patients receiving APs had a significantly lower risk of hyperlipidemia than patients not receiving APs (all aHR ≤ 0.42, p < 0.001). First-generation antipsychotics (FGAs) induce the expression of hepatic lipid catabolism genes in an in vitro model. Discussion: Patients with schizophrenia had a higher risk of hyperlipidemia than controls; however, compared with non-treated patients, AP users had a lower risk of hyperlipidemia. Early diagnosis and management of hyperlipidemia may help prevent CVD.

Tangeretin and 4'-demethyltangeretin prevent damage to mouse hepatocytes from oxidative stress by activating the Nrf2-related antioxidant pathway via an epigenetic mechanism.

Polymethoxyflavones (PMFs) in citrus fruits have a variety of biological activities, including antioxidant, anti-inflammatory, anticancer, and anti-atherosclerotic effects. The liver is the major detoxifying organ of the human body; however, factors such as acetaminophen (APAP) overdose may increase oxidative stress in liver cells and lead to severe liver failure. In this study we examined the effects of tangeretin (TAN), a common citrus PMF, and its metabolite 4'-demethyltangeretin (4'-OH-TAN) on activation of the Nrf2 antioxidant system in mouse AML-12 hepatocytes through regulation by epigenetic mechanisms. The ability of TAN and 4'-OH-TAN to inhibit APAP-induced hepatotoxicity was also evaluated. The results showed that TAN and 4'-OH-TAN significantly increased the mRNA and protein levels of Nrf2 and Nrf2-mediated antioxidant and detoxifying enzymes (UGT1A, HO-1, and NQO1) in AML-12 cells. TAN and 4'-OH-TAN also suppressed protein expression of histone deacetylases (HDACs) and DNA methyltransferases (DMNTs) and reduced DNA methylation of the nrf2 promoter. Furthermore, TAN and 4'-OH-TAN prevented APAP-induced injury and inhibited APAP-induced ROS generation in AML-12 cells. Based on these results, we conclude that TAN and 4'-OH-TAN may increase the antioxidant capacity of liver cells by regulating epigenetic alteration to activate the Nrf2-related antioxidant system, thereby preventing liver cells from being damaged by APAP-induced oxidative stress.

Survival outcomes of beta-blocker usage in HER2-positive advanced breast cancer patients: a retrospective cohort study.

Background: Clinical trials investigating the effects of beta-blockers (BBs) on cancer are underway. Evidence from preclinical research suggests that BBs could serve as anticancer agents and immune boosters. There is conflicting evidence regarding the effect of BB use on clinical outcomes in patients with breast cancer. Objectives: The study aimed to determine whether BB use is associated with progression-free survival (PFS) and overall survival (OS) in patients receiving anti-human epidermal growth factor receptor 2 (HER2) treatment for advanced breast cancer. Design: Retrospective hospital-based study. Methods: The participants enrolled were breast cancer patients with advanced HER2-positive status who initiated trastuzumab monotherapy or concomitant therapy with trastuzumab and any dose of BB. The patients were enrolled between January 2012 and May 2021 and divided into three groups based on whether they received a BB or not in the therapeutic regimen: BB-/trastuzumab+, BB+ (non-selective)/trastuzumab+, and BB+ (selective)/trastuzumab+. PFS and OS were the primary and secondary endpoints, respectively. Results: The estimated median PFS in the BB-/trastuzumab+, BB+ (non-selective)/trastuzumab+, and BB+ (selective)/trastuzumab+ groups was 51.93, 21.50, and 20.77 months, respectively. The corresponding OS was 56.70, 29.10, and 27.17 months. The intergroup differences in these durations were significant. Both PFS [adjusted hazard ratio (HR): 2.21, 95% confidence interval (CI): 1.56-3.12; p < 0.001]) and OS (adjusted HR: 2.46, 95% CI: 1.69-3.57; p < 0.001) were worse when BBs were used. Conclusion: Our study provides important evidence that BB use potentially has a negative effect on patients with HER2-positive advanced breast cancer. Nevertheless, despite the study's results, cardiovascular disease (CVD) should be appropriately treated in patients with HER2-positive advanced breast cancer. Other types of drugs can be used to treat CVD, but BB use should be avoided. Large real-world database and prospective studies should be conducted to validate the results of this study.

Use of beta-blockers for cancer therapy Summary: Background • Evidence from preclinical research suggests that beta-blockers (BBs) could serve as anticancer agents and immune boosters. • Beta-blockers could therefore be a potential therapy for cancers. • Trastuzumab is a drug that affects the overall survival (OS) and progression-free survival (PFS) of patients with HER2-positive breast cancer by binding to the extracellular domain of HER2. • This study investigates the effect of BBs on trastuzumab therapy in patients with advanced breast cancer. Method • This retrospective study was conducted between January 2012 and May 2021. • Patients with HER2-positive advanced breast cancer who were treated using trastuzumab monotherapy or trastuzumab concomitantly with any dose of a BB were recruited and divided into three groups. • One group received only the trastuzumab (BB−/trastuzumab+), another group received both BB+ (non-selective) and trastuzumab [BB+ (non-selective)/trastuzumab+], and the third group received both BB+ (selective) and trastuzumab [BB+ (selective)/trastuzumab+]. • The PFS and OS were determined and compared between the treatment groups. Results • We enrolled 221 patients (mean age: 56.1 ± 11.1 years) in the study. • The estimated median PFS and OS were significantly lower in the BB+ (non-selective)/trastuzumab+ and BB+ (selective)/trastuzumab+ groups than in the BB−/trastuzumab+ group. • The use of BBs was associated with worse PFS and OS in patients with HER2-positive advanced breast cancer. Conclusion • Trastuzumab treatment was independently associated with poorer PFS and OS for patients who used BB prior to initiating trastuzumab therapy for advanced HER2-positive breast cancer. • BB use potentially has a negative effect on patients with HER2-positive advanced breast cancer. • Future studies with larger sample sizes are needed to validate our findings.

Survival Outcomes of Calcium Channel Blocker Therapy in Patients With Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor Inhibitors: A Retrospective Study.

BACKGROUND: Non-cancer drugs are currently being repurposed for cancer treatment. Mounting evidence highlights the influence of calcium channels on tumorigenesis and progression. Hence, inhibition of calcium signaling may be a promising cancer treatment strategy. OBJECTIVE: In this study, we aimed to examine whether calcium channel blockers (CCBs) affect the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). DESIGN: We conducted a retrospective analysis. METHODS: In this study, conducted between January 2009 and June 2021, patients with NSCLC treated with erlotinib, or gefitinib for at least 1 week were enrolled and divided into 2 groups: CCBs-/EGFR-TKIs+ and CCBs+/EGFR-TKIs+, depending on whether they received CCB therapy. Progression-free survival (PFS) and overall survival (OS) were determined as the primary and secondary endpoints, respectively. RESULT: : The estimated median PFS and OS for the CCBs-/EGFR-TKIs+group were 7.70 and 12.17 months, respectively, and they were significantly different from those of the CCBs+/EGFR-TKIs+ group (10.43 and 18.07 months, respectively). CCB use was associated with improved PFS (adjusted hazard ratios [HR] 0.77, 95% confidence interval [CI]: 0.61-0.98; P = .035) and OS (adjusted HR 0.66, 95% CI: 0.51-0.84; P < .001). CONCLUSION: Calcium channels have been implicated in cancer pathogenesis. Our findings revealed the potential additive anticancer effects of CCBs when used concomitantly with EGFR-TKIs. However, study limitations, including the retrospective nature and small number of patients, necessitate large-scale prospective studies on the therapeutic potential of CCB as an adjunctive therapy with EGFR-TKIs in patients with NSCLC.

Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation.

Introduction: A potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship. Methods: We extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated. Results: After adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ. Discussion: Our study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM.

Clinical impact of tetracyclines and/or proton pump inhibitors on the efficacy of epidermal growth factor receptor inhibitors in non-small cell lung cancer: a retrospective cohort study.

BACKGROUND: This retrospective cohort study examined the impact of tetracyclines (TCs) and proton pump inhibitors (PPIs) alone or in combination on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with NSCLC treated with gefitinib or erlotinib for at least 1 week between January 2009 and October 2021 were enrolled and divided into four groups based on the presence/absence of TC and/or PPI in the therapeutic regimen: TC-/PPI-, TC + /PPI-, TC-/PPI + , TC + /PPI + . Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively. RESULTS: The estimated median PFS and OS of 347 included patients with NSCLC were 8.57 (95% confidence interval [CI]: 7.66-9.48) months and 13.10 (95% CI: 11.03-15.17) months, respectively. Co-administration of EGFR-TKIs with PPIs decreased the PFS and OS, while that with TCs improved the PFS and OS. However, the concomitant use of EGFR-TKIs, TCs, and PPIs yielded survival rates similar to that of EGFR-TKI therapy alone. CONCLUSIONS: The administration of EGFR-TKIs with other drugs poses a challenge in managing patients with NSCLC. Therefore, reassessing the indications and necessity of TC or PPI therapy is essential for patients receiving erlotinib or gefitinib. The benefits and risks of possible discontinuation due to the clinical relevance of this interaction should be considered.

Computer-aided discovery, design, and investigation of COVID-19 therapeutics.

Coronavirus disease 2019 (COVID-19) pandemic is currently the most serious public health threat faced by mankind. Thus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, is being intensively investigated. Several vaccines are now available for clinical use. However, owing to the highly mutated nature of RNA viruses, the SARS-CoV-2 is changing at a rapid speed. Breakthrough infections by SARS-CoV-2 variants have been seen in vaccinated individuals. As a result, effective therapeutics for treating COVID-19 patients is urgently required. With the advance of computer technology, computational methods have become increasingly powerful in the biomedical research and pharmaceutical drug discovery. The applications of these techniques have largely reduced the costs and simplified processes of pharmaceutical drug developments. Intensive and extensive studies on SARS-CoV-2 proteins have been carried out and three-dimensional structures of the major SARS-CoV-2 proteins have been resolved and deposited in the Protein Data Bank. These structures provide the foundations for drug discovery and design using the structure-based computations, such as molecular docking and molecular dynamics simulations. In this review, introduction to the applications of computational methods in the discovery and design of novel drugs and repurposing of existing drugs for the treatments of COVID-19 is given. The examples of computer-aided investigations and screening of COVID-19 effective therapeutic compounds, functional peptides, as well as effective molecules from the herb medicines are discussed.

Impact of Inflammatory Bowel Disease (IBD) and IBD Medications on Risk of Hyperlipidemia and in vitro Hepatic Lipogenic-Related Gene Expression: A Population-Based Cohort Study.

Patients with inflammatory bowel disease (IBD) present a higher risk of developing cardiovascular diseases (CVDs) due to chronic inflammation, which plays an essential role in atherogenesis. Hyperlipidemia is another risk factor for CVDs; however, the association between IBD, IBD medications, and hyperlipidemia remains controversial. We conducted a nationwide, population-based, retrospective, cohort study to examine the effect of IBD and IBD medications on the risk of developing hyperlipidemia. The effects of IBD medications on the expression of lipogenesis-related hepatic genes were also evaluated. We obtained data from the Longitudinal Health Insurance Database of Taiwan from patients with new-onset IBD and a comparison cohort of patients without IBD. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing hyperlipidemia between the two cohorts. We also examined the influence of IBD medications on the expression of lipogenesis-related hepatic genes. After adjusting for comorbidities and confounding factors, the case group (N = 14,524) had a higher risk for hyperlipidemia than the control group (N = 14,524) [adjusted hazards ratio (aHR), 2.18]. Patients with IBD that did not receive IBD medications exhibited a significantly higher risk of hyperlipidemia (aHR, 2.20). In those treated with IBD medications, the risk of developing hyperlipidemia was significantly lowered than those without such medications (all aHR ≤ 0.45). Gene expression analysis indicated that IBD medications downregulated the expression of lipogenesis-related genes. Screening blood lipids in IBD patients is needed to explore the specific role and impact of IBD medications in the development of CVD.