The Association Between Antidepressant Use and Drug-Induced Liver Injury: A Nationwide, Population-Based Case-Control Study in Taiwan.

BACKGROUND AND OBJECTIVE: The complex risk factors of liver injury have prevented the establishment of causal relationships. This study aimed to explore the effects of antidepressant class, cumulative days of medication exposure, presence of comorbidities, and the use of confounding drugs on the risk of antidepressant-induced liver injury. METHODS: The population-based case-control study sample included individuals registered on the Taiwan National Health Insurance Database between 2000 and 2018. Hospitalized patients with suspected drug-induced liver injury were considered as cases, while control subjects were matched 1:1 by age, gender, and index date (the first observed diagnosis of liver injury). Multivariable regression models were performed to evaluate the association between antidepressants and liver injury. RESULTS: The findings showed that antidepressant users exhibited a higher risk of liver injury (adjusted odds ratio [aOR] 1.16, 95% confidence interval [CI] 1.12-1.20), particularly those prescribed non-selective serotonin reuptake inhibitors (NSRIs; aOR 1.05; 95% CI 1.01-1.10), selective serotonin reuptake inhibitors (SSRIs; aOR 1.22; 95% CI 1.16-1.29), serotonin-norepinephrine reuptake inhibitors (SNRIs; aOR 1.18; 95% CI 1.13-1.24), and others (aOR 1.27; 95% CI 1.14-1.42). Moreover, cases exhibited a more significant proportion of antidepressant usage and longer durations of treatment compared with controls. The risk of liver injury was higher in the first 30 days of use across all classes of antidepressants (aOR 1.24; 95% CI 1.18-1.29). CONCLUSION: SSRIs or SNRIs are commonly used to treat depression and other psychological disorders, and consideration of their potential effects on the liver is essential.

Impact of the implementation of the Intelligent Antimicrobial System (iAMS) on clinical outcomes among patients with bacteraemia caused by methicillin-resistant Staphylococcus aureus.

OBJECTIVES: This study aimed to investigate the clinical impact of the Intelligent Antimicrobial System (iAMS) on patients with bacteraemia due to methicillin-resistant (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA). METHODS: A total of 1008 patients with suspected SA infection were enrolled before and after the implementation of iAMS. Among them, 252 with bacteraemia caused by SA, including 118 in the iAMS and 134 in the non-iAMS groups, were evaluated. RESULTS: The iAMS group exhibited a 5.2% (from 55.2% to 50.0%; P = 0.96) increase in the 1-year survival rate. For patients with MRSA and MSSA compared to the non-iAMS group, the 1-year survival rate increased by 17.6% (from 70.9% to 53.3%; P = 0.41) and 7.0% (from 52.3% to 45.3%; P = 0.57), respectively, both surpassing the rate of the non-iAMS group. The iAMS intervention resulted in a higher long-term survival rate (from 70.9% to 52.3%; P = 0.984) for MRSA patients than for MSSA patients. MRSA patients experienced a reduced length of hospital stay (from 23.3% to 35.6%; P = 0.038), and the 45-day discharge rate increased by 20.4% (P = 0.064). Furthermore, the intervention resulted in a significant 97.3% relative decrease in near miss medication incidents reported by pharmacists (P = 0.013). CONCLUSIONS: Implementation of iAMS platform improved long-term survival rates, discharge rates, hospitalization days, and medical cost (although no significant differences were observed) among patients with MRSA bacteraemia. Additionally, it demonstrated significant benefits in ensuring drug safety.

Efficacy of Warfarin Therapy Guided by Pharmacogenetics: A Real-world Investigation Among Han Taiwanese.

PURPOSE: The anticoagulation activity of warfarin in populations with CYP2C9, VKORC1, and CYP4F2 variants differs between individuals and is correlated with poor international normalized ratio (INR) control. Pharmacogenetics-guided warfarin dosing has been successfully developed for patients with genetic variations in recent years. However, few real-world data have been used to investigate the INR and warfarin dosage and the time to target INR. This study examined the largest collection of genetic and clinical real-world data related to warfarin to provide further evidence supporting the benefits of pharmacogenetics in clinical outcomes. METHODS: We retrieved a total of 69,610 INR-warfarin records after the index date from 2,613 patients in the China Medical University Hospital database between January 2003 and December 2019. Each INR reading was obtained from the latest laboratory data after the hospital visit date. Patients with a history of malignant neoplasms or pregnancy before the index date were excluded, as were patients without data on INR measurements after the fifth day of prescription, genetic information, or gender variables. The primary outcomes were the INR and warfarin dosage during days 7, 14, 28, 56, and 84 after prescription. The secondary outcome was the time required to reach the INR ranges of 1.5 to 3.0 and >4.0. FINDINGS: A total of 59,643 INR-warfarin records from 2188 patients were retrieved. The average INR was higher for homozygous carriers of the minor allele at CYP2C9 and VKORC1 during the first 7 days (1.83 [1.03] [CYP2C9*1] and 2.46 [1.44] [CYP2C9*3], P < 0.001; 1.39 [0.36] [rs9923231 G/G], 1.55 [0.79] [rs9923231 G/A], and 1.96 [1.13] [rs9923231 A/A], P < 0.001) than for the wild-type allele. These patients with variants required lower warfarin doses than those with the wild-type allele during the first 28 days. CYP4F2 variant patients seemed to require higher doses of warfarin than those in the wild-type group; however, no significant difference in the average INR was observed (1.95 [1.14] [homozygous V433 carriers], 1.78 [0.98] [heterozygous V433M carriers], and 1.66 [0.91] [homozygous M433 carriers], P = 0.016). IMPLICATIONS: Our study indicates that genetic variants in the Han population may enhance warfarin responsiveness, which holds clinical relevance. An increased warfarin dosage was not linked to a shorter time to therapeutic INR between CYP4F2 variant patients and those with a wild-type allele. Assessing CYP2C9 and VKORC1 genetic polymorphisms before initiating warfarin treatment in real-world practice is essential for potentially vulnerable patients and is likely to optimize therapeutic dosing.

Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers.

The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-γ (IFN-γ) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN-γ before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p < 0.001). Furthermore, in the pN+ population, patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year DFS and OS. PD-L1 and IFN-γ upregulation increased in tumor tissues after neoCRT, and patients with high PD-L1 and high IFN-γ exhibit improved 5-year DFS and OS (p = 0.04 and p = 0.001, respectively). To the best of our knowledge, this study is the first to demonstrate that PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFN-γ were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity.

Clinical significance of programmed death 1 ligand-1 (CD274/PD-L1) and intra-tumoral CD8+ T-cell infiltration in stage II-III colorectal cancer.

Programmed cell death-1 (PDCD1/PD-1) and its ligand programmed cell death 1 ligand 1 (CD274/PD-L1) have been reported to suppress anti-tumor T cell-mediated immune responses. However, the clinical significance of CD274 in colorectal cancer were still elusive. We aim to clarify the relationships between CD8+ intratumor-infiltrating lymphocytes (TILs) and CD274 as well as their prognostic values in stage II-III colon carcinoma. Tumor differentiation, perineural invasion (PNI), pN stage and DNA mismatch repair (MMR)-deficient were clearly correlated with CD8+ TILs counts within the tumor microenvironment (p < 0.0001). Furthermore, tumor differentiation and PNI were suggestively correlated with tumor CD274 expression (p = 0.02 and p = 0.0195). Tumor CD274 level was significantly correlated with higher CD8+ TILs (p < 0.0001) but was not associated with MMR-deficient status (p = 0.14). High tumor CD274 expression [hazard ratio (HR) = 2.16, 95% CI = 1.63-2.86, p < 0.0001] and CD8+ TILs [HR = 1.51, 95% CI = 1.19-1.91, p = 0.0007] were associated with improved disease-free survival and overall survival. Additionally, the subgroup of patients who had a high CD8+ TILs/tumor CD274 have better survival outcomes compared with other subgroups (71% vs 53%; p < 0.0001). Therefore, the CD8+ TILs counts and tumor CD274 may be prognostic factors to predict survival and therapeutic responses in stage II-III colon carcinoma patients.

HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer.

Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1Ser616 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1Ser616 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.

Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy.

Rectal cancer, which comprises 30% of all colorectal cancer cases, is one of the most common forms of cancer in the world. Patients with locally advanced rectal cancer (LARC) are often treated with neoadjuvant chemoradiotherapy (neoCRT) followed by surgery. However, after neoCRT treatment, approximately one-third of the patients progress to local recurrence or distant metastasis. In these studies, we found that patients with tumors that exhibited cytosolic HMGB1(Cyto-HMGB1) translocation and/or the presence of PD-1+ tumor-infiltrating lymphocytes (TILs) before treatment had a better clinical outcome. The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+ tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging. In conclusion, our results provide evidence that cyto-HMGB1 and/or PD-1+TIL are not only predictive biomarkers before treatment, but they can also potentially designate patients for personalized oncological management including immunotherapy.

Association between the metabolome and low bone mineral density in Taiwanese women determined by (1)H NMR spectroscopy.

Osteoporosis is related to the alteration of specific circulating metabolites. However, previous studies on only a few metabolites inadequately explain the pathogenesis of this complex syndrome. To date, no study has related the metabolome to bone mineral density (BMD), which would provide an overview of metabolism status and may be useful in clinical practice. This cross-sectional study involved 601 healthy Taiwanese women aged 40 to 55 years recruited from MJ Health Management Institution between 2009 and 2010. Participants were classified according to high (2nd tertile plus 3rd tertile) and low (1st tertile) BMD groups. The plasma metabolome was evaluated by proton nuclear magnetic resonance spectroscopy ((1) H NMR). Principal components analysis (PCA), partial least-squares discriminant analysis (PLS-DA), and logistic regression analysis were used to assess the association between the metabolome and BMD. The high and low BMD groups could be differentiated by PLS-DA but not PCA in postmenopausal women (Q(2) = 0.05, ppermutation = 0.04). Among postmenopausal women, elevated glutamine was significantly associated with low BMD (adjusted odds ratio [AOR] = 5.10); meanwhile, elevated lactate (AOR = 0.55), acetone (AOR = 0.51), lipids (AOR = 0.04), and very low-density lipoprotein (AOR = 0.49) protected against low BMD. To the best of our knowledge, this study is the first to identify a group of metabolites for characterizing low BMD in postmenopausal women using a (1) H NMR-based metabolomic approach. The metabolic profile may be useful for predicting the risk of osteoporosis in postmenopausal women at an early age.

Low-dose LBH589 increases the sensitivity of cisplatin to cisplatin-resistant ovarian cancer cells.

OBJECTIVE: There is a need to develop alternative therapeutic strategies to overcome cisplatin-associated resistance in patients with ovarian cancer. Histone deacetylation (HDAC) associated with inactivation of genes has been implicated in the epigenetic silencing of tumor suppressor genes affecting critical biological activities in cancer cells and may be an important factor in acquired cisplatin-associated resistance. In this report, we tested a combination of cisplatin and LBH589 (histone deacetylation inhibitor) in cisplatin-resistant ovarian cancer cells to explore the reversal effect of cisplatin resistance and changes of gene expression. MATERIALS AND METHODS: To detect the synergistic effects of antiproliferation between cisplatin and LBH589 in ovarian cancer cells, we performed a cell viability assay and a clonogenic assay. To investigate the differences of gene expression between cells treated by cisplatin alone and cotreated with cisplatin and LBH589, a microarray mRNA analysis was performed. RESULTS: In the presence of low-dose LBH589, the inhibition concentration value of cisplatin for A2780-cp70 cells was much lower than with cisplatin treatment alone. Gene expression profiles identified that a total of 354 genes had been significantly upregulated and a total of 63 genes been downregulated with LBH589 cotreatment. CONCLUSION: We hypothesized that combination of cisplatin and LBH589 can override cisplatin-associated resistance in ovarian cancer cells. These results provide initial evidence for testing this combination in clinical use.