Although cisplatin has been a pivotal chemotherapy drug in treating patients with various types of cancer for decades, drug resistance has been a major clinical impediment. In general, cisplatin ...exerts cytotoxic effects in tumor cells mainly through the generation of DNA-platinum adducts and subsequent DNA damage response. Accordingly, considerable effort has been devoted to clarify the resistance mechanisms inside tumor cells, such as decreased drug accumulation, enhanced detoxification activity, promotion of DNA repair capacity, and inactivated cell death signaling. However, recent advances in high-throughput techniques, cell culture platforms, animal models, and analytic methods have also demonstrated that the tumor microenvironment plays a key role in the development of cisplatin resistance. Recent clinical successes in combination treatments with cisplatin and novel agents targeting components in the tumor microenvironment, such as angiogenesis and immune cells, have also supported the therapeutic value of these components in cisplatin resistance. In this review, we summarize resistance mechanisms with respect to a single tumor cell and crucial components in the tumor microenvironment, particularly focusing on favorable results from clinical studies. By compiling emerging evidence from preclinical and clinical studies, this review may provide insights into the development of a novel approach to overcome cisplatin resistance.
Background: In modern critical care, extracorporeal membrane oxygenation (ECMO) is crucial in the management of severe respiratory and cardiac failure. Nationwide studies of the relationship between ...hospital volume and outcomes of ECMO use are unavailable.Methods and Results: Using Taiwan’s National Health Insurance Research Database, we identified 11,734 adult patients who received ECMO support in 101 hospitals between January 1, 2001, and December 31, 2017. Outcomes included in-hospital mortality, 1-year mortality, and ECMO-related complications. Cox proportional hazards model, locally estimated scatterplot smoothing, and restricted cubic spline regression were used to analyze the volume–outcome relationship. The overall in-hospital mortality rate was 65.5%, and the 1-year mortality rate was 70.6% in this database. The 101 hospitals were divided into 4 groups based on annual volume. The in-hospital and 1-year mortality rates were significantly lower in the high-volume group (annual volume >40) than in the low-volume group (annual volume <10).Conclusions: For critical care, high-volume hospitals have superior short-term and mid-term outcomes. To make the medical system equitable and reasonable, establishing a rapid and efficient nationwide referral system should be considered.
Oral squamous cell carcinoma (SCC) is a prevalent malignant disease worldwide, especially so in Taiwan. Early- or even preclinical-stage detection is critical for reducing morbidity and mortality ...from oral SCC. Epidemiological and genome association studies are useful for identifying clinicopathological risk factors for preventive, diagnostic, and therapeutic approaches of oral SCC. For advanced oral SCC, effective treatments are critical to prolonging survival and enhancing quality of life. As oral SCC is characteristic of regional invasion with lymph node metastases, understanding the aggressive features of oral SCC, particularly in lymphangiogenesis, is essential for determining effective treatments. Emerging evidence has demonstrated that the tumor microenvironment (TME) plays a pivotal role in tumor growth, invasion, and metastases. Recent clinical successes in immune checkpoint inhibitors either alone or combined with chemotherapy have also supported the therapeutic value of immunotherapy in oral SCC. This review summarizes critical advances in basic knowledge of oral SCC from the perspective of clinicopathological risk factors, molecular tumorigenesis, and the TME. We also highlight our recent investigations on the microbiome, genome association studies, lymphangiogenesis, and immunomodulation in oral SCC. This review may provide new insights for oral SCC treatment by systematically interpreting emerging evidence from various preclinical and clinical studies.
The loss of semaphorin 3A (Sema3A), which is related to endothelial‐to‐mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the ...mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor‐beta (TGF‐β)‐induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF‐β specifically in cardiac tissues (TGF‐β transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF‐β transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF‐β transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment.
Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition ...(EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β–treated human AEECs, cardiac-specific TGF-β–transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β–treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β–transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.
Patients with cirrhosis and acute myocardial infarction (AMI) present dilemma whether dual antiplatelet therapy (DAPT) should be used.
Electronic medical records between 2001-2013 were retrieved from ...Taiwan National Health Insurance Research Database. Patients were excluded for missing information, age <20 years old, history of AMI, liver transplant, autoimmune disease, coagulopathy, taking DAPT 3 months before index date, follow-up <3 months, anticoagulation user, without DAPT, and events of myocardial infarction (MI), ischemic stroke, major bleeding, and heart failure within 3-month of enrollment. Primary outcomes were 1-year all-cause mortality, recurrent MI, major bleeding, and gastrointestinal bleeding.
A total of 150,887 patients with AMI retrieved. After exclusion criteria and propensity score-matching, 914 cirrhotic and 3,656 non-cirrhotic patients with AMI on DAPT were studied. During 1-year follow-up, there was significantly increased mortality in cirrhotic patients compared to non-cirrhotic patients (HR = 1.49, 95% CI = 1.28-1.74). There was significantly decreased recurrent MI in cirrhotic patients compared to non-cirrhotic patients (subdistribution HR SHR = 0.71, 95% CI = 0.54-0.92). However, non-significantly increased major bleeding (SHR = 1.23, 95% CI = 0.87-1.73) and significantly increased gastrointestinal bleeding (SHR = 1.49, 95% CI = 1.31-1.70).
In cirrhotic patients with AMI, DAPT offers benefit with decreased recurrent MI at the expense of increased gastrointestinal bleeding.
Background
Whether non–vitamin K antagonist oral anticoagulants (NOACs) are superior to warfarin among Asians with nonvalvular atrial fibrillation remains unclear.
Methods and Results
In this ...nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, there were 5843, 20 079, 27 777, and 19 375 nonvalvular atrial fibrillation patients taking apixaban, dabigatran, rivaroxaban and warfarin, respectively, from June 1, 2012 to December 31, 2016. Propensity‐score weighting was used to balance covariates across study groups. Patients were followed until the first occurrence of any efficacy or safety outcome or the end date of study. Hazard ratios (95% confidence intervals) comparing apixaban, dabigatran, and rivaroxaban with warfarin were: ischemic stroke/systemic embolism (IS/SE), 0.55 (0.43–0.69), 0.82 (0.68–0.98), and 0.81 (0.67–0.97); major bleeding, 0.41 (0.31–0.53), 0.65 (0.53–0.80), and 0.58 (0.46–0.72); and all‐cause mortality, 0.58 (0.51–0.66), 0.61 (0.54–0.68), and 0.57 (0.51–0.65). A total of 3623 (62%), 17 760 (88%), and 26 000 (94%) patients were taking low‐dose apixaban (2.5 mg twice daily), dabigatran (110 mg twice daily), and rivaroxaban (10–15 mg once daily), respectively. Similar to all‐dose NOACs, all low‐dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. In contrast to other standard‐dose NOACs, apixaban was associated with lower risks of IS/SE (0.45 0.31–0.65), major bleeding (0.29 0.18–0.46), and mortality (0.23 0.17–0.31) than warfarin.
Conclusions
All NOACs were associated with lower risk of IS/SE, major bleeding, and mortality compared with warfarin in the largest real‐world practice among Asians with nonvalvular atrial fibrillation. All low‐dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. Standard‐dose apixaban caused a lower risk of IS/SE, major bleeding, and mortality compared with warfarin.
Abstract
Objectives
Observational studies have demonstrated associations between gout and hypertension, but whether they are causal remains unclear. Our work aims to assess the causal relationship ...between gout and hypertension.
Methods
We obtained genetic information from the Taiwan Biobank, including 88,347 participants and 686,439 single-nucleotide polymorphisms (SNPs). A novel model of Mendelian randomisation (MR) with coarsened exposures was used to examine the causality between the liability of gout on hypertension and vice versa, using 4 SNPs associated with gout and 10 SNPs associated with hypertension after removal of SNPs associated with measured confounders. The binary exposure (gout/hypertension) can be considered a coarsened approximation of a latent continuous trait. The inverse-variance weighted (IVW) and polygenic risk score (PRS) methods were used to estimate effect size. The MR analysis with coarsened exposures was performed with and without adjustments for covariates.
Results
Of the 88,347 participants, 3253 (3.68%) had gout and 11,948 (13.52%) had hypertension (men, 31.9%; mean age 51.1 SD, 11.1 years). After adjusting to measured confounders, MR analysis with coarsened exposures showed a significant positive causal effect of the liability of gout on hypertension in both the IVW method (relative risk RR, 1.10; 95% confidence interval CI, 1.03–1.19;
p
= 0.0077) and the PRS method (RR, 1.10; 95% CI, 1.02–1.19;
p
= 0.0092). The result of causality was the same before and after involving measured confounders. However, there was no causal effect of the liability of hypertension on gout.
Conclusions
In this study, we showed that the liability of gout has a causal effect on hypertension, but the liability of hypertension does not have a causal effect on gout. Adequate management of gout may reduce the risk of developing hypertension.
Background:Patients are prone to permanent pacemaker implantation (PPM) after valve surgery, yet current data on the effects of postoperative PPM are scarce and large-scale studies are lacking. The ...aim of this study was to determine rates and long-term outcomes of PPM after cardiac valve surgery.Methods and Results:A total of 24,014 patients who received valve surgery from 2000 to 2013 were identified from the Taiwan National Health Insurance Research Database. The number of valve surgeries and the proportion of PPM implantations after valve surgery increased (P<0.001). After 1 : 5 propensity score matching, 602 and 3,010 patients were categorized to the PPM and non-PPM groups, respectively. Late outcomes included all-cause mortality, cardiovascular death, sepsis, and readmission due to any cause. The mean follow up was 4.3 years. PPM was associated with a higher all-cause mortality rate (33.6% vs. 29.8%; hazard ratio HR, 1.14; 95% confidence interval CI, 0.98–1.32), though not significant at the threshold of P<0.05. PPM was also associated with higher all-cause mortality rates in subgroups that received mitral valve (MV) replacement surgery, combined aortic valve replacement (AVR) with MV surgeries, and combined AVR with tricuspid valve surgeries.Conclusions:The PPM rate after valve surgery is increasing, and is associated with short-term adverse effects. Patients with PPM may have a higher long-term mortality rate.
Non-vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk.
To assess the association between use of ...NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation.
Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016.
NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin.
Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score.
Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years SD, 10.8; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 99% CI, 9.76-18.13); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 99% CI, 80.96-195.97); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 99% CI, 1.59-72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 99% CI, 32.18-72.44; P < .01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone.
Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the use of NOACs alone, was associated with increased risk of major bleeding. Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs.
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