Search

Jin-Bor Chen,1,2 Chiung-Chih Chang,2,3 Sin-Hua Moi,4 Lung-Chih Li1,2 1Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and School of Medicine, Kaohsiung, 833, Taiwan, Republic of China; 2College of Medicine, Chang Gung University, Taoyuan, 330, Taiwan, Republic of China; 3Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and School of Medicine, Kaohsiung, 833, Taiwan, Republic of China; 4Center of Cancer Program Development, E-Da Cancer Hospital, I-Shou University, Kaohsiung, 833, Taiwan, Republic of ChinaCorrespondence: Jin-Bor Chen, Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 DaPei Road, Niao Song District, Kaohsiung, 833, Taiwan, Republic of China, Tel +886-7-7317123, ext 8306, Fax +886-7-7322402, Email chenjb1019@gmail.com; jbchen@cgmh.org.twPurpose: This study aimed to compare the plasma levels of nanoparticle-based neurodegenerative biomarkers between hemodialysis (HD) participants with grossly normal cognitive function and healthy controls.Patients and Methods: A cohort of participants undergoing maintenance HD and healthy controls were enrolled for comparison between July and October 2021. The immunomagnetic reduction method was used to measure plasma neurodegenerative biomarkers Aβ1-40, Aβ1-42, tau protein, and neurofilament light chain (NfL). The clinical dementia rating (CDR) was used to evaluate cognitive function. A receiver operating characteristic curve was used to discriminate between HD participants and healthy controls.Results: There were 52 and 18 participants in the HD and healthy control groups, respectively. The mean age of the HD participants was 62 years, and that of the healthy controls was 57 years. The mean HD vintage in the HD cohort was 11.8 years. HD participants demonstrated significantly higher plasma levels of Aβ1-42, tau protein, Aβ1-42 × tau, and NfL and Aβ1-42/Aβ1-40 ratio and significantly lower plasma Aβ1-40 levels than healthy controls. The measured plasma biomarkers could not discriminate between CDR0 and CDR0.5 HD participants. The area under the curve of the study biomarkers to discriminate HD participants from healthy controls ranged from 0.987 (Aβ1-42 × tau) to 0.889 (NfL).Conclusion: The plasma levels of nanoparticle-based neurodegenerative biomarkers were higher in HD participants with grossly normal cognitive function than in healthy controls. These findings imply that neurodegenerative changes appear in HD participants. A profile of plasma neurodegenerative biomarkers could be considered a potential surrogate for evaluating long-term cognitive function in HD participants.Graphical Abstract: Keywords: Aβ proteins, cognitive function, hemodialysis, tau protein

Background: We aimed to develop a preoperative model to predict overall survival (OS) in patients with hepatoma undergoing liver resection (LR)., Methods: Patients who underwent LR for Barcelona Clinic Liver Cancer (BCLC) stage 0, A, or B hepatoma were enrolled. Tumor burden score (TBS) scores were determined using the following equation: TBS (Pinna et al., 2018) 2 = (largest tumor size [in cm])(Pinna et al., 2018) 2 ​+ ​(tumor number) (Pinna et al., 2018) 22. The cutoff values for radiographic TBS were based on our recently published paper: low, <2.6; medium, 2.6-7.9; high, >7.9., Results: Multivariate analysis showed that radiographic TBS (low: referent; medium: HR ​= ​2.89; 95 ​% CI: 1.60-5.21; p ​< ​0.001; high, HR ​= ​7.60; 95 ​% CI: 3.80-15.2; p ​< ​0.001), AFP (<400 ​ng/mL: referent; ≧400 ​ng/mL: HR ​= ​1.67, 95 ​% CI: 1.11-2.52, p ​= ​0.014), and cirrhosis (absence: referent; presence: HR ​= ​1.88, 95 ​% CI: 1.30-2.72, p ​< ​0.001) were associated with OS. A simplified risk score was superior to BCLC system in concordance index (0.688 vs. 0.623)., Conclusions: We have developed a preoperative model that performs better in predicting OS than the BCLC system., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose for all authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives : Although statins are recommended for secondary prevention of acute ischemic stroke, some population-based studies and clinical evidence suggest that they might be used with an increased risk of intracranial hemorrhage. In this nested case-control study, we used Taiwan's nationwide universal health insurance database to investigate the possible association between statin therapy prescribed to acute ischemic stroke patients and their risk of subsequent intracerebral hemorrhage and all-cause mortality in Taiwan. Materials and Methods : All data were retrospectively obtained from Taiwan's National Health Insurance Research Database. Acute ischemic stroke patients were divided into a cohort receiving statin pharmacotherapy and a control cohort not receiving statin pharmacotherapy. A 1:1 matching for age, gender, and index day, and propensity score matching was conducted, producing 39,366 cases and 39,366 controls. The primary outcomes were long-term subsequent intracerebral hemorrhage and all-cause mortality. The competing risk between subsequent intracerebral hemorrhage and all-cause mortality was estimated using the Fine and Gray regression hazards model. Results : Patients receiving statin pharmacotherapy after an acute ischemic stroke had a significantly lower risk of subsequent intracerebral hemorrhage ( p < 0.0001) and lower all-cause mortality rates ( p < 0.0001). Low, moderate, and high dosages of statin were associated with significantly decreased risks for subsequent intracerebral hemorrhage (adjusted sHRs 0.82, 0.74, 0.53) and all-cause mortality (adjusted sHRs 0.75, 0.74, 0.74), respectively. Conclusions : Statin pharmacotherapy was found to safely and effectively reduce the risk of subsequent intracerebral hemorrhage and all-cause mortality in acute ischemic stroke patients in Taiwan.

Background/aim: Following the National Comprehensive Cancer Network guidelines, radiotherapy is administered after breast-conserving surgery (BCS) in patients with more than four positive lymph nodes. Four positive lymph nodes are typically considered an indicator to assess disease spread and patient prognosis. However, the subjective counting of positive axillary lymph nodes underscores the need for biomarkers to improve diagnostic precision and reduce the risk of unnecessary treatments. Loss of E-cadherin expression is associated with cancer metastasis, but its potential as a predictive marker for cancer treatment remains uncertain. This study aimed to investigate the validity of E-cadherin as a reference for adjuvant radiotherapy in breast cancer patients with positive lymph nodes post-mastectomy., Materials and Methods: Immunohistochemistry was performed on 60 clinical tissue specimens to assess these implications., Results: Although no significant result was found in a single E-cadherin subgroup (low, medium, and high subgroups according to the X-tile algorithm), the proposed multivariate model, including the E-cadherin category, breast cancer subtype, and tumor size, yielded satisfactory recurrence risk estimation results for patients undergoing BCS. Patients with a low E-cadherin category, triple-negative breast cancers, and tumor size over 5 cm could have an increased risk of recurrence., Conclusion: Our study proposed a multivariate model that serves as a candidate prognostic factor for recurrence-free survival in patients undergoing BCS and radiotherapy. Utilizing this model for patient stratification in high-risk diseases and as a standard for assessing postoperative intensified therapy can potentially improve patient outcomes., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Mammographic screening has contributed to a significant reduction in breast cancer mortality. Several studies have highlighted the correlation between breast density, as detected through mammography, and a higher likelihood of developing breast cancer. A polygenic risk score (PRS) is a numerical score that is calculated based on an individual's genetic information. This study aims to explore the potential roles of PRS as candidate markers for breast cancer development and investigate the genetic profiles associated with clinical characteristics in Asian females with dense breasts. This is a retrospective cohort study integrated breast cancer screening, population genotyping, and cancer registry database. The PRSs of the study cohort were estimated using genotyping data of 77 single nucleotide polymorphisms based on the PGS000001 Catalog. A subgroup analysis was conducted for females without breast symptoms. Breast cancer patients constituted a higher proportion of individuals in PRS Q4 (37.8% vs. 24.8% in controls). Among dense breast patients with no symptoms, the high PRS group (Q4) consistently showed a significantly elevated breast cancer risk compared to the low PRS group (Q1-Q3) in both univariate (OR = 2.25, 95% CI 1.43-3.50, P < 0.001) and multivariate analyses (OR: 2.23; 95% CI 1.41-3.48, P < 0.001). The study was extended to predict breast cancer risk using common low-penetrance risk variants in a PRS model, which could be integrated into personalized screening strategies for Taiwanese females with dense breasts without prominent symptoms., (© 2024. The Author(s).)

The present study aimed to elucidate the prognostic mutation signature (PMS) associated with long-term survival in a diffuse large B-cell lymphoma (DLBCL) cohort. All data including derivation and validation cohorts were retrospectively retrieved from The Cancer Genome Atlas (TCGA) database and whole-exome sequencing (WES) data. The Lasso Cox regression analysis was used to construct the PMS based on WES data, and the PMS was determined using the area under the receiver operating curve (AUC). The predictive performance of eligible PMS was analyzed by time-dependent receiver operating curve (ROC) analyses. After the initial evaluation, a PMS composed of 94 PFS-related genes was constructed. Notably, this constructed PMS accurately predicted the 12-, 36-, and 60-month PFS, with AUC values of 0.982, 0.983, and 0.987, respectively. A higher level of PMS was closely linked to a significantly worse PFS, regardless of the molecular subtype. Further evaluation by forest plot revealed incorporation of international prognostic index or tumor mutational burden into PMS increased the prediction capability for PFS. The drug-gene interaction and pathway exploration revealed the PFS-related genes were associated with DNA damage, TP53, apoptosis, and immune cell functions. In conclusion, this study utilizing a high throughput genetic approach demonstrated that the PMS could serve as a prognostic predictor in DLBCL patients. Furthermore, the identification of the key signaling pathways for disease progression also provides information for further investigation to gain more insight into novel drug-resistant mechanisms., (© 2024. The Author(s).)

Next-generation sequencing (NGS) genomic data offer valuable high-throughput genomic information for computational applications in medicine. Using genomic data to identify disease-associated genes to estimate cancer mortality risk remains challenging regarding to computational efficiency and risk integration. For determining mortality-related genes, we propose an information fusion system based on a fuzzy system to fuse the numerous deep-learning-based risk scores, consider the significance of features related to time-varying effects and risk stratifications, and interpret the directional relationship and interaction between outcome and predictors. Fuzzy rules were implemented to integrate the considerations mentioned above by merging all the risk score models to achieve advanced risk estimation. The genomic data of head and neck squamous cell carcinoma (HNSCC) were used to evaluate the performance of the proposed computational approach. The results indicated that the proposed computational approach exhibited optimal ability to identify mortality risk-related genes in HNSCC patients. The results also suggest that HNSCC mortality is associated with cancer inflammatory response, the interleukin-17A signaling pathway, stellate cell activation, and the extracellular-regulated protein kinase five signaling pathway, which might offer new therapeutic targets HNSCC through immunologic or antiangiogenic mechanisms. The proposed information fusion system can promote the determination of high-risk genes related to cancer mortality. This study contributes a valid cancer mortality risk estimate that can identify mortality-related genes.

Background: Benign prostatic hyperplasia (BPH) is common in aging Asian males and is associated with an excess risk of developing prostate cancer (PCa). However, discussions about socially-sensitive experiences such as sexual activity, which can significantly predict PCa risk, may be considered stigmatized in Asian culture. This study aimed to develop a predictive model for PCa risk in Asian males with BPH using non-socially-sensitive information., Methods: A cross-sectional case-control study, with PCa patients as the cases and remaining as the controls, was conducted on a cohort of Taiwanese males with BPH from four medical institutions. Patients who met the inclusion criteria were enrolled, excluding those aged over 86 years or who had received human papillomavirus (HPV) vaccination. Non-socially-sensitive variables such as obesity, occupational exposure, HPV infection, and PCa family history score (FH score) were included in a fully adjusted logistic regression model, and depicted using a nomogram., Results: Among 236 BPH patients, 45.3% had PCa. Obesity, occupational exposure, HPV infection, and family history of PCa were significantly associated with PCa risk. The FH score (OR = 1.89, 95% CI = 1.03-3.47, P = 0.041) had the highest impact, followed by HPV infection (OR = 1.47, 95% CI = 1.03-2.11, P = 0.034), occupational exposure (OR = 1.32, 95% CI = 1.15-1.51, P <0.001), and obesity (OR = 1.22, 95% CI = 1.07-1.41, P = 0.005). The nomogram accurately depicted the predictive risk, and the model demonstrated robust performance compared to individual factors. In addition, the subgroup analysis results showed elderly age group could obtain more favorable predictive performance in our proposed model (AUC = 0.712)., Conclusion: This non-socially-sensitive predictive model for PCa risk in Taiwanese males with BPH integrates multiple factors that could provide acceptable PCa risk-predictive performance, especially for elderly BPH patients over 70 years, aiding clinical decision-making and early cancer detection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Predicting recurrence patterns of hepatocellular carcinoma (HCC) can be helpful in developing surveillance strategies. This study aimed to use the hazard function to investigate recurrence hazard and peak recurrence time transitions in patients with HCC undergoing liver resection (LR). We enrolled 1204 patients with HCC undergoing LR between 2007 and 2018 at our institution. Recurrence hazard, patterns, and peak rates were analyzed. The overall recurrence hazard peaked at 7.2 months (peak hazard rate [pHR]: 0.0197), but varied markedly. In subgroups analysis based on recurrence risk factors, patients with a high radiographic tumor burden score (pHR: 0.0521), alpha-fetoprotein level ≥ 400 ng/ml (pHR: 0.0427), and pT3-4 (pHR: 0.0656) showed a pronounced peak within the first year after LR. Patients with cirrhosis showed a pronounced peak within three years after LR (pHR: 0.0248), whereas those with Barcelona Clinic Liver Cancer stage B (pHR: 0.0609) and poor tumor differentiation (pHR: 0.0451) showed multiple peaks during the 5-year follow-up period. In contrast, patients without these recurrence risk factors had a relatively flat hazard function curve. HCC recurrence hazard, patterns, and peak rates varied substantially depending on different risk factors of HCC recurrence., (© 2023. Italian Society of Surgery (SIC).)

The treatment of head and neck squamous cell carcinomas (HNSCCs) is multimodal, and chemoradiotherapy (CRT) is a critical component. However, the availability of predictive or prognostic markers in patients with HNSCC is limited. Inflammation is a well-documented factor in cancer, and several parameters have been studied, with the neutrophil-to-lymphocyte ratio (NLR) being the most promising. The NLR is the most extensively researched clinical biomarker in various solid tumors, including HNSCC. In our study, we collected clinical and next-generation sequencing (NGS) data with targeted sequencing information from 107 patients with HNSCC who underwent CRT. The difference in the NLR between the good response group and the poor response group was significant, with more patients having a high NLR in the poor response group. We also examined the genetic alterations linked to the NLR and found a total of 41 associated genes across eight common pathways searched from the KEGG database. The overall mutation rate was low, and there was no significant mutation difference between the low- and high-NLR groups. Using a multivariate binomial generalized linear model, we identified three candidate genes ( MAP2K2 , MAP2K4 , and ABL1 ) that showed significant results and were used to create a gene mutation score (GMS). Using the NLR-GMS category, we noticed that the high-NLR-GMS group had significantly shorter relapse-free survival compared to the intermediate- or low-NLR-GMS groups.

Background/aim: The role of postoperative radiotherapy (RT) combined with chemotherapy (CT) for lymph node-positive (LN+) triple-negative breast cancer (TNBC) remains controversial. SUV39H1-mediated epigenetic regulation is associated with cancer cell migration, invasion, metastasis, and treatment resistance. This study aims to identify the role of SUV39H1 in TNBCs., Materials and Methods: Overall, 498 TNBCs with SUV39H1 RNA-seq profiles were retrieved from TCGA-BRCA and analyzed; the X-tile algorithm was used to stratify the population into low, intermediate, and high SUV39H1. Furthermore, we performed an in vitro clonogenic cell survival assay using the MDA-MB-231 cell line to assess the effects of SUV39H1 on cellular responses., Results: The results showed that SUV39H1 was significantly higher in TNBC than normal tissue and luminal subtype breast cancer. Notably, SUV39H1 is significantly expressed in the basal-like 1 (BL1) and immunomodulatory (IM) subgroups, compared to other subtypes. Compared to patients with a low or medium expression of SUV39H1, omitting RT only worsens disease-free survival (DFS) in those with high SUV39H1 expression. The experimental results showed SUV39H1 was suppressed by si-SUV39H1, and SUV39H1 knockdown in MDA-MB-231-IV2-1 cells enhanced the cellular toxicity of doxorubicin and paclitaxel., Conclusion: Targeting SUV39H1 may provide a potential guiding indication of omitting RT to avoid over-treatment and chemosensitivity for TNBC., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The problem of antibiotic-resistant strains has become a global public issue; antibiotic resistance not only limits the choice of treatments but also increases morbidity, mortality and treatment costs. The multi-drug resistant Acinetobacter baumannii is occurring simultaneously in hospitals and has become a major public health issue worldwide. Although many medical units have begun to control the use of antibiotics and paid attention to the issue of drug resistance, understanding the transmission pathways of clinical drug-resistant bacteria and drug-resistant mechanisms can be effective in real-time control and prevent the outbreak of antibiotic-resistant pathogens. In this study, a total of 154 isolates of Acinetobacter baumannii obtained from Chia-Yi Christian Hospital in Taiwan were collected for specific resistance genotyping analysis. Ten genes related to drug resistance, including bla OXA-51-like, bla OXA-23-like, bla OXA-58-like, bla OXA-24-like, bla OXA-143-like, tnp A, IS Aba 1, bla PER-1, bla NDM and bla ADC, and the repetitive element (ERIC2) were selected for genotyping analysis. The results revealed that 135 A. baumannii isolates (87.6%) carried the bla OXA-51-like gene, 4.5% of the isolates harbored the bla OXA-23-like gene, and 3.2% of the isolates carried the bla OXA-58-like gene. However, neither the bla OXA-24-like nor bla OXA-143-like genes were detected in the isolates. Analysis of ESBL-producing strains revealed that bla NDM was not found in the test strains, but 38.3% of the test isolates carried bla PER-1. In addition, bla ADC, tnp A and IS Aba 1genes were found in 64.9%, 74% and 93% of the isolates, respectively. Among the carbapenem-resistant strains of A. baumannii , 68% of the isolates presenting a higher antibiotic resistance carried both tnp A and IS Aba 1 genes. Analysis of the relationship between their phenotypes (antibiotic resistant and biofilm formation) and genotypes (antibiotic-resistant genes and biofilm-related genes) studied indicated that the bap , omp A, IS Aba 1and bla OXA-51 genes influenced biofilm formation and antibiotic resistance patterns based on the statistical results of a hierarchical clustering dendrogram. The analysis of the antibiotic-resistant mechanism provides valuable information for the screening, identification, diagnosis, treatment and control of clinical antibiotic-resistant pathogens, and is an important reference pointer to prevent strains from producing resistance.

Background: Current healthcare trends emphasize the use of shared decision-making (SDM) for renal replacement treatment (RRT) in patients with chronic kidney disease (CKD). This is crucial to understand the relationship between SDM and illness perception of CKD patients. Few studies have focused on SDM and illness perception status of CKD patients and the impact of illness perception on RRT after SDM., Methods: In this cross-sectional study, we used a questionnaire with purposive sampling from March 2019 to February 2020 at the nephrology outpatient department of a medical center in southern Taiwan. The nephrology medical team in this study used the SHARE five-step model of SDM to communicate with the patients about RRT and Brief Illness Perception Questionnaire (BIPQ) was applied to evaluate illness perception of these patients at the beginning of SDM. According to the SDM decision time, the study participants were classified general and delayed SDM groups. The distribution between SDM groups was estimated using independent two sample t-test, chi-squared test or Fisher's exact test. The correlation between illness perception and SDM decision time were illustrated and evaluated using Spearman's correlation test. A p-value less than 0.05 is statistically significant., Results: A total of 75 patients were enrolled in this study. The average time to make a dialysis decision after initiating SDM was 166.2 ± 178.1 days. 51 patients were classified as general group, and 24 patients were classified as delayed group. The median SDM decision time of delayed group were significantly longer than general group (56 vs. 361 days, P < 0.001). Our findings revealed that delayed group was significantly characterized with not created early surgical assess (delayed vs. general: 66.7% vs. 27.5%, p = 0.001) compared to general group. The average BIPQ score was 54.0 ± 8.1 in our study. We classified the patients into high and low illness perception group according to the median score of BIPQ. The total score of BIPQ in overall participants might increase by the SDM decision time (rho = 0.83, p = 0.830) and the linear regression line also showed consistent trends between BIPQ and SDM decision time in correspond cohorts. However, no statistically significant findings were found., Conclusions: The patients with advanced chronic kidney disease took an average of five and a half months to make a RRT decision after undergoing SDM. Although there is no statistical significance, the trend of illness perception seems correlated with decision-making time. The stronger the illness perception, the longer the decision-making time. Furthermore, shorter decision times may be associated with earlier establishment of surgical access. We need more research exploring the relationship between illness perception and SDM for RRT in CKD patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Aim: The updated Barcelona Clinic Liver Cancer guidelines recommend liver resection (LR) for patients with single hepatocellular carcinoma (HCC) of any size. This study developed a preoperative model for predicting early recurrence in patients undergoing LR for single HCC., Materials and Methods: We identified 773 patients undergoing LR for single HCC between 2011 and 2017 from the cancer registry database of our institution. Multivariate Cox regression analyses were performed to construct a preoperative model for predicting early recurrence, i.e., recurrence within 2 years of LR., Results: Early recurrence was identified in 219 patients (28.3%). The final model of early recurrence included four predictive factors-alpha-fetoprotein level of ≥20 ng/mL, tumor size of >30 mm, Model for End-Stage Liver Disease score of >8, and cirrhosis. Preoperative application of this model provided three risk strata for recurrence-free survival (RFS): low risk, with 2-year RFS of 79.8% (95% confidence interval [CI]: 75.7-84.2%); intermediate risk, with 2-year RFS of 66.6% (95% CI: 61.1-72.6%); and high risk, with 2-year RFS of 51.1% (95% CI: 43.0-60.8%)., Conclusion: We developed a preoperative model for predicting early recurrence after LR for single HCC. This model provides useful information for clinical decision-making., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose for all authors., (Copyright © 2023 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Personalized genetic profiling has focused on improving treatment efficacy and predicting risk stratification by identifying mutated genes and selecting targeted agents according to genetic testing. Therefore, we evaluated the role of genetic profiling and tumor mutation burden (TMB) using next-generation sequencing in patients with head and neck squamous cell carcinoma (HNSC). The relapse mutation signature (RMS) and chromatin remodeling mutation signature (CRMS) were explored to predict the risk of relapse in patients with HNSC treated with concurrent chemoradiotherapy (CCRT) with platinum-based chemotherapy. Patients in the high RMS and CRMS groups showed significantly shorter relapse-free survival than those in the low RMS and CRMS groups, respectively (p < 0.001 and p = 0.006). Multivariate Cox regression analysis showed that extranodal extension, CCRT response, and three somatic mutation profiles (TMB, RMS, and CRMS) were independent risk predictors for HNSC relapse. The predictive nomogram showed satisfactory performance in predicting relapse-free survival in patients with HNSC treated with CCRT., (© 2023. The Author(s).)

2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-9,11-dihydro-trifluoroethyl amide (CDDO-dhTFEA) has antioxidant and anti-inflammatory activities; however, whether CDDO-dhTFEA has anticancer effects is unclear. The objective of this research was to investigate the possibility of CDDO-dhTFEA as a potential cancer-fighting treatment in glioblastoma cells. Our experiments were performed on U87MG and GBM8401 cells, and we found that CDDO-dhTFEA was effective in reducing cell proliferation in both cell lines, in a manner that was dependent on both time and concentration. Additionally, we observed that CDDO-dhTFEA had a significant impact on the regulation of cell proliferation, which was evident in the increase in DNA synthesis that was observed in both cell types. CDDO-dhTFEA induced G2/M cell cycle arrest and mitotic delay, which may be associated with the inhibition of proliferation. Treatment with CDDO-dhTFEA led to cell cycle G2/M arrest and inhibited proliferation of U87MG and GBM8401 cells by regulating G2/M cell cycle proteins and gene expression in GBM cells in vitro.

The treatment provided for breast cancer depends on the expression of hormone receptors, human epidermal growth factor receptor-2 (HER2), and cancer staging. Surgical intervention, along with chemotherapy or radiation therapy, is the mainstay of treatment. Currently, precision medicine has led to personalized treatment using reliable biomarkers for the heterogeneity of breast cancer. Recent studies have shown that epigenetic modifications contribute to tumorigenesis through alterations in the expression of tumor suppressor genes. Our aim was to investigate the role of epigenetic modifications in genes involved in breast cancer. A total of 486 patients from The Cancer Genome Atlas Pan-cancer BRCA project were enrolled in our study. Hierarchical agglomerative clustering analysis further divided the 31 candidate genes into 2 clusters according to the optimal number. Kaplan-Meier plots showed worse progression-free survival (PFS) in the high-risk group of gene cluster 1 (GC1). In addition, the high-risk group showed worse PFS in GC1 with lymph node invasion, which also presented a trend of better PFS when chemotherapy was combined with radiotherapy than when chemotherapy was administered alone. In conclusion, we developed a novel panel using hierarchical clustering that high-risk groups of GC1 may be promising predictive biomarkers in the clinical treatment of patients with breast cancer.

Head and neck cancers (HNCs) are among the ten leading malignancies worldwide. Despite significant progress in all therapeutic modalities, predictive biomarkers, and targeted therapies for HNCs are limited and the survival rate is unsatisfactory. The importance of telomere maintenance via telomerase reactivation in carcinogenesis has been demonstrated in recent decades. Several mechanisms could activate telomerase reverse transcriptase (TERT), the most common of which is promoter alternation. Two major hotspot TERT promoter mutations (C228T and C250T) have been reported in different malignancies such as melanoma, genitourinary cancers, CNS tumors, hepatocellular carcinoma, thyroid cancers, sarcomas, and HNCs. The frequencies of TERT promoter mutations vary widely across tumors and is quite high in HNCs (11.9-64.7%). These mutations have been reported to be more enriched in oral cavity SCCs and HPV-negative tumors. The association between TERT promoter mutations and poor survival has also been demonstrated. Till now, several therapeutic strategies targeting telomerase have been developed although only a few drugs have been used in clinical trials. Here, we briefly review and summarize our current understanding and evidence of TERT promoter mutations in HNC patients.

In recent years, translational research and pharmacological targeting of epigenetic modifications have become the focus of personalized therapy for patients with pancreatic cancer. Preclinical and clinical trials targeting post-translational modifications have been evaluated as monotherapy or in combination with standard chemotherapy. In this study, we selected 43 genes from seven families of chromatin-modifying enzymes and investigated the influences of epigenetic modifications and their interactions on pancreatic ductal adenocarcinoma (PDAC) using hierarchical clustering analysis. Our analysis also evaluated their effects on treatment modalities and regimens of chemotherapy for PDAC. RNA-seq data for a total of 177 patients with pancreatic cancer, obtained from The Cancer Genome Atlas database, were analyzed. Our results suggested that high-risk patients of survival significant chromatin remodeling-associated gene cluster (gene cluster 2), composed of histone methyltransferases, histone acetyltransferases, histone deacetylases, histone demethylases, and 10-11 translocation family, demonstrated inferior progression-free survival and overall survival in patients with PDAC, especially in men. Our novel biomarker, survival significant chromatin remodeling-associated gene cluster, showed superior prediction performance compared with the conventional TNM system. Overall, these findings suggest that epigenetic modifications and interactions play an important role in the prognosis and therapeutic response of patients with PDAC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Endocrine therapy (ET) of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs) has been used as the gold standard treatment for hormone-receptor-positive (HR+) breast cancer. Despite its clinical benefits, approximately 30% of patients develop ET resistance, which remains a major clinical challenge in patients with HR+ breast cancer. The mechanisms of ET resistance mainly focus on mutations in the ER and related pathways; however, other targets still exist from ligand-independent ER reactivation. Moreover, mutations in the ER that confer resistance to SERMs or AIs seldom appear in SERDs. To date, little research has been conducted to identify a critical target that appears in both SERMs/SERDs and AIs. In this study, we conducted comprehensive transcriptomic and proteomic analyses from two cohorts of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) to identify the critical targets for both SERMs/SERDs and AIs of ET resistance. From a treatment response cohort with treatment response for the initial ET regimen and an endocrine therapy cohort with survival outcomes, we identified candidate gene sets that appeared in both SERMs/SERDs and AIs of ET resistance. The candidate gene sets successfully differentiated progress/resistant groups (PD) from complete response groups (CR) and were significantly correlated with survival outcomes in both cohorts. In summary, this study provides valuable clinical implications for the critical roles played by candidate gene sets in the diagnosis, mechanism, and therapeutic strategy for both SERMs/SERDs and AIs of ET resistance for the future., Competing Interests: The authors declare no conflict of interest. The funders had no role in the study design; collection, analyses, or interpretation of data; writing of the manuscript, or decision to publish the results.

Introduction: Mortality is a major primary endpoint for long-term hemodialysis (HD) patients. The clinical status of HD patients generally relies on longitudinal clinical observations such as monthly laboratory examinations and physical examinations., Methods: A total of 829 HD patients who met the inclusion criteria were analyzed. All patients were tracked from January 2009 to December 2013. Taken together, this study performed full-adjusted-Cox proportional hazards (CoxPH), stepwise-CoxPH, random survival forest (RSF)-CoxPH, and whale optimization algorithm (WOA)-CoxPH model for the all-cause mortality risk assessment in HD patients. The model performance between proposed selections of CoxPH models were evaluated using concordance index., Results: The WOA-CoxPH model obtained the highest concordance index compared with RSF-CoxPH and typical selection CoxPH model. The eight significant parameters obtained from the WOA-CoxPH model, including age, diabetes mellitus (DM), hemoglobin (Hb), albumin, creatinine (Cr), potassium (K), Kt/V, and cardiothoracic ratio, have also showed significant survival difference between low- and high-risk characteristics in single-factor analysis. By integrating the risk characteristics of each single factor, patients who obtained seven or more risk characteristics of eight selected parameters were dichotomized as high-risk subgroup, and remaining is considered as low-risk subgroup. The integrated low- and high-risk subgroup showed greater discrepancy compared with each single risk factor selected by WOA-CoxPH model., Conclusion: The study findings revealed WOA-CoxPH model could provide better risk assessment performance compared with RSF-CoxPH and typical selection CoxPH model in the HD patients. In summary, patients who had seven or more risk characteristics of eight selected parameters were at potentially increased risk of all-cause mortality in HD population., Competing Interests: Competing interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: Endoscopic submucosal dissection (ESD) has become the standard treatment for superficial esophageal squamous cell neoplasia (SESCN); however, local recurrence still occurs occasionally even in patients who meet the current curative criteria. Esophageal ducts of the submucosal gland may serve as a pathway for the spread of SESCN to a deeper layer. However, the clinical impact of ductal involvement (DI) in patients undergoing ESD has yet to be investigated., Methods: We consecutively enrolled patients with SESCN who were treated with ESD. The resected specimens were meticulously reviewed in multiple section slices for the presence and resected margins of DI, and their correlations with clinical factors were evaluated., Results: A total of 210 lesions were analyzed, of which 78 (37.1%) presented with DI. The presence of submucosal invasion, lymphovascular invasion (LVI), and DI were indicators of worse prognosis (P < .05). Deep extended DIs were misdiagnosed as deep submucosal invasive cancer in 4 cases (2%). Of the 185 patients who met the criteria for curative ESD (ie, R0 resection and no deep submucosal invasion or LVI), 11 (5.9%) developed local recurrence/metastasis during a mean follow-up of 55.2 months (range, 6 to 140) months. Compared with patients with without DI, patients with DI had worse recurrence-free survival (P = .008, log-rank test) and a higher local risk of recurrence (12.7% vs 2.5%) after curative ESD (hazard ratio, 4.20; P = .038)., Conclusions: A precise histological assessment of DI in SESCN is crucial after ESD, given that DI is common and associated with worse outcome. Whether total removal of esophageal glands/ducts can improve outcome requires future study., (Copyright © 2021. Published by Elsevier Inc.)

Identifying and characterizing the interaction between risk factors for multiple outcomes (multi-outcome interaction) has been one of the greatest challenges faced by complex multifactorial diseases. However, the existing approaches have several limitations in identifying the multi-outcome interaction. To address this issue, we proposed a multi-outcome interaction identification approach called MOAI. MOAI was motivated by the limitations of estimating the interaction simultaneously occurring in multi-outcomes and by the success of Pareto set filter operator for identifying multi-outcome interaction. MOAI permits the identification for the interaction of multiple outcomes and is applicable in population-based study designs. Our experimental results exhibited that the existing approaches are not effectively used to identify the multi-outcome interaction, whereas MOAI obviously exhibited superior performance in identifying multi-outcome interaction. We applied MOAI to identify the interaction between risk factors for colorectal cancer (CRC) in both metastases and mortality prognostic outcomes. An interaction between vaspin and carcinoembryonic antigen (CEA) was found, and the interaction indicated that patients with CRC characterized by higher vaspin (≥30%) and CEA (≥5) levels could simultaneously increase both metastases and mortality risk. The immunostaining evidence revealed that determined multi-outcome interaction could effectively identify the difference between non-metastases/survived and metastases/deceased patients, which offers multi-prognostic outcome risk estimation for CRC. To our knowledge, this is the first report of a multi-outcome interaction associated with a complex multifactorial disease. MOAI is freely available at https://sites.google.com/view/moaitool/home., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The atezolizumab (Tecentriq), a humanized antibody against human programmed death ligand 1 (PD-L1), combined with nab-paclitaxel was granted with accelerated approval to treat unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) due to the encouraging positive results of the phase 3 IMpassion130 trial using PD-L1 biomarker from immune cells to stratify patients. However, the post-market study IMpassion131 did not support the original observation, resulting in the voluntary withdrawal of atezolizumab from the indication in breast cancer by Genentech in 2021. Emerging evidence has revealed a high frequency of false negative result using the standard immunohistochemical (IHC) staining due to heavy glycosylation of PD-L1. The removal of glycosylation prevents from the false negative staining, enabling more accurate assessment of PD-L1 levels and improving prediction for response to immune checkpoint therapy. In the present study, the natural and de-glycosylated PD-L1 expression in tumor and immune cells from nine TNBC patients were analyzed by using clone 28-8 monoclonal antibody to correlate with treatment outcome. Our results demonstrate that: (1) Removal of the glycosylation indeed enhances the detection of PD-L1 by IHC staining, (2) The PD-L1 levels on tumor cell surface after removal of the glycosylation correlates well with clinical responses for atezolizumab treatment; (3) The criteria used in the IMpassion130 and IMpassion131 trials which scored the natural PD-L1 in the immune cells failed to correlate with the clinical response. Taken together, tumor cell surface staining of PD-L1 with de-glycosylation has a significant correlation with the clinical response for atezolizumab treatment, suggesting that treatment of atezolizumab may be worthy of further consideration with de-glycosylation procedure as a patient stratification strategy. A larger cohort to validate this important issue is warranted to ensure right patient population who could benefit from the existing FDA-approved drugs., Competing Interests: Mien-Chie Hung holds a patent on the methodology for de-glycosylation staining., (AJCR Copyright © 2022.)

Purpose: This study aimed to investigate the association between clinical factors and temporary changes in functional performance in patients undergoing hemodialysis., Methods: This was a retrospective, longitudinal observational study conducted from 2015 to 2017. Eight-two patients undergoing hemodialysis in the outpatient clinic were enrolled. Functional performance was measured using the Karnofsky Performance Status (KPS) scale. Collected data for analysis included demographics, laboratory parameters, and KPS scale scores. All participants were grouped into a high KPS cluster and a low KPS cluster based on dynamic changes in KPS scales from 2015 to 2017., Results: Participants in the high KPS cluster demonstrated an approximate trend, and those in the low KPS cluster demonstrated a low pattern. By stepwise selection model analysis, age (OR 1.12, 95% CI 1.03-1.23, p  = 0.011), serum BUN (OR 1.08, 95% CI 1.02-1.16, p  = 0.015), calcium levels (OR 3.24, 95% CI 1.2-8.73, p  = 0.02), and beta-2-microglobulin (OR > 1.0, CI >1.00-<1.01, p  = 0.031) showed risk for the low KPS cluster. Male sex (OR 0.20, 95% CI 0.04-0.96, p  = 0.045) and albumin level (OR 0.02, 95% CI 0-0.4, p  = 0.009) showed a low risk for the low KPS cluster., Conclusions: A different trajectory pattern was observed between the high and low KPS clusters in a 3-year period. Risk factors for the low KPS cluster were age, serum BUN, calcium, and beta-2-microglobulin levels. Male sex and serum albumin levels reduced the risk for the low KPS cluster.

Introduction: Invasive ductal carcinoma (IDC) of the breast is a heterogeneous disease characterized by multiple subtypes. IDC survival is highly impacted by tumor burden, molecular subtypes, and gene profiles. Gene mutation is a type of genomic instability regarded as having a considerable effect on IDC prognosis. Using integrated survival analysis, this study identified candidate genes and a high-risk group of patients with early-stage IDC to provide further understanding of the genetic characteristics associated with poor survival., Methods: The gene mutation profiles, baseline demographics, clinicopathologic variables, and treatment characteristics of the early-stage IDC subpopulation were downloaded from an open access data platform. These data were analyzed for a total of 444 patients. In total, 40 genes commonly involved in IDC were listed, and the genes exhibiting significant differences (as estimated using the log-rank test) were selected as the candidate genes., Results: The patients were divided into control, low-risk, and high-risk groups according to their gene mutation profiles. The 5-year overall survival rates of low-risk, control, and high-risk patients were 97.4%, 96.1%, and 73.0%, respectively. The high-risk group had a significantly higher risk of poor overall -survival (adjusted hazard ratio = 6.57, 95% confidence interval = 1.51-28.7, p = 0.012) than that of the control group, and the low-risk group did not have a significant survival difference compared with control group., Conclusions: This study proposed an integrative approach for the identification of candidate genes for risk assessment of overall survival in these patients through typical survival analysis methods. The 14 candidate genes selected are particularly involved in cell-cycle processes, deoxyribonucleic acid repair, and drug resistance; their mutations were found to be generally associated with disease progression or therapeutic resistance, which is commonly associated with poor overall survival outcomes in IDC., (© 2021 The Author(s. Published by S. Karger AG, Basel.)

In Western countries, breast cancer tends to occur in older postmenopausal women. However, in Asian countries, the proportion of younger premenopausal breast cancer patients is increasing. Increasing evidence suggests that the gut microbiota plays a critical role in breast cancer. However, studies on the gut microbiota in the context of breast cancer have mainly focused on postmenopausal breast cancer. Little is known about the gut microbiota in the context of premenopausal breast cancer. This study aimed to comprehensively explore the gut microbial profiles, diagnostic value, and functional pathways in premenopausal breast cancer patients. Here, we analyzed 267 breast cancer patients with different menopausal statuses and age-matched female controls. The α-diversity was significantly reduced in premenopausal breast cancer patients, and the β-diversity differed significantly between breast cancer patients and controls. By performing multiple analyses and classification, 14 microbial markers were identified in the different menopausal statuses of breast cancer. Bacteroides fragilis was specifically found in young women of premenopausal statuses and Klebsiella pneumoniae in older women of postmenopausal statuses. In addition, menopausal-specific microbial markers could exhibit excellent discriminatory ability in distinguishing breast cancer patients from controls. Finally, the functional pathways differed between breast cancer patients and controls. Our findings provide the first evidence that the gut microbiota in premenopausal breast cancer patients differs from that in postmenopausal breast cancer patients and shed light on menopausal-specific microbial markers for diagnosis and investigation, ultimately providing a noninvasive approach for breast cancer detection and a novel strategy for preventing premenopausal breast cancer., (© 2021. The Author(s).)

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma, and the disease course is often aggressive with poor prognosis outcomes. PCNSL undergoes germinal center reactions and impairs B-cell maturation. However, angiogenesis is also involved in the tumorigenesis and progression of PCNSL. This study investigated the effects of the tumor microenvironment and angiogenesis-associated genomic alterations on the outcomes of PCNSL. The analysis also evaluated the influence of treatment modality and timing on PCNSL survival using partial least squares variance-based path modeling (PLS-PM). PLS-PM can be used to evaluate the complex relationship between prognostic variables and disease outcomes with a small sample of measurements and structural models. A total of 19 immunocompetent PCNSL samples were analyzed by exome sequencing. Our results suggest that the timing of radiotherapy and mutations of ROBO1 and KAT2B are potential indicators of PCNSL outcomes and may be affected by baseline characteristics such as age and sex. Our results also showed that patients with no mutations of ROBO1 and KAT2B, SubRT subgroup showed favorable survival outcomes compared with no SubRT subgroup in short-term follow-up. All SubRT patients have received high-dose methotrexate induction chemotherapy in the initial treatment. Therefore, initial induction chemotherapy combined with subsequent radiotherapy might improve survival outcomes in PCNSL patients who have no ROBO1 and KAT2B somatic mutations in short-term follow-up. The overall findings suggest that the tumor microenvironment and angiogenesis-associated genomic alterations and treatment modalities are potential indicators of overall survival and may be affected by the baseline characteristics of PCNSL patients., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Hui-Ching Wang et al.)

This study aimed to investigate whether the progression risk score (PRS) developed from cytoplasmic immunohistochemistry (IHC) biomarkers is available and applicable for assessing risk and prognosis in oral cancer patients. Participants in this retrospective case-control study were diagnosed between 2012 and 2014 and subsequently underwent surgical intervention. The specimens from surgery were stained by IHC for 16 cytoplasmic target markers. We evaluated the results of IHC staining, clinical and pathological features, progression-free survival (PFS), and overall survival (OS) of 102 oral cancer patients using a novel estimation approach with unsupervised hierarchical clustering analysis. Patients were stratified into high-risk (52) and low-risk (50) groups, according to their PRS; a metric consisting of cytoplasmic PLK1, PhosphoMet, SGK2, and SHC1 expression. Moreover, PRS could be extended for use in the Cox proportional hazard regression model to estimate survival outcomes with associated clinical parameters. Our study findings revealed that the high-risk patients had a significantly increased risk in cancer progression compared with low-risk patients (hazard ratio (HR) = 2.20, 95% confidence interval (CI) = 1.10-2.42, p = 0.026). After considering the influences of demographics, risk behaviors, and tumor characteristics, risk estimation with PRS provided distinct PFS groups for patients with oral cancer ( p = 0.017, p = 0.019, and p = 0.020). Our findings support that PRS could serve as an ideal biomarker for clinical use in risk stratification and progression assessment in oral cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and exhibits an overall poor outcome. Due to the lack of targeted therapy, conventional systemic chemotherapy has been the main strategy for the treatment of TNBC. Further evidence has shown that combining radiation with chemotherapy is also a suitable treatment based on DNA repair deficiencies in patients with TNBC. However, the preferred treatment for metastatic TNBC remains unclear. Therefore, identification of biomarkers is an unmet need in personalized therapy for TNBC. RNF8 (ring finger protein 8) is a ubiquitin ligase implicated in TNBC metastasis; however, its role in TNBC pathogenesis is unclear. The purpose of the present study was to investigate the roles of the RNF8-CDH1(Cadherin 1) axis in node-positive TNBC patients. We found that the RNF8 high / CDH1 low index was significantly higher in patients with TNBC than in patients without TNBC. Furthermore, patients with an RNF8 high / CDH1 low index displayed poorer outcomes than those with an RNF8 low -medium / CDH1 medium -high index. Notably, as compared to patients with an RNF8 low -medium / CDH1 medium -high index, those with an RNF8 high / CDH1 low index had a poorer survival rate with chemotherapy treatment alone. The combination of radiation and chemotherapy resulted in a better survival rate than chemotherapy alone in patients with an RNF8 high / CDH1 low index. Taken together, the RNF8 high / CDH1 low index not only functions as a prognostic and therapeutic marker but may also act as a target in the development of anti-cancer agents for patients with TNBC.

The aim of this single-center case-control study is to investigate the feasibility and accuracy of oral cancer protein risk stratification (OCPRS) to analyze the risk of cancer progression. All patients diagnosed with oral cancer in Taiwan, between 2012 and 2014, and who underwent surgical intervention were selected for the study. The tissue was further processed for immunohistochemistry (IHC) for 21 target proteins. Analyses were performed using the results of IHC staining, clinicopathological characteristics, and survival outcomes. Novel stratifications with a hierarchical clustering approach and combinations were applied using the Cox proportional hazard regression model. Of the 163 participants recruited, 102 patients were analyzed, and OCPRS successfully identified patients with different progression-free survival (PFS) profiles in high-risk (53 subjects) versus low-risk (49 subjects) groups ( p = 0.012). OCPRS was composed of cytoplasmic PLK1, phosphoMet, and SGK2 IHC staining. After controlling for the influence of clinicopathological features, high-risk patients were 2.33 times more likely to experience cancer progression than low-risk patients ( p = 0.020). In the multivariate model, patients with extranodal extension (HR = 2.66, p = 0.045) demonstrated a significantly increased risk for disease progression. Risk stratification with OCPRS provided distinct PFS groups for patients with oral cancer after surgical intervention. OCPRS appears suitable for routine clinical use for progression and prognosis estimation.

Current strategies targeting serum cholesterol bring limited benefits to mortality and macrovascular events prevention among hemodialysis patients. Direct measurements and analysis on circulating markers of cholesterol homeostasis could be promising solutions to this bottleneck. We prospectively enrolled 90 maintenance hemodialysis patients and 9 healthy controls in 2019 for 1 year. We measured circulating desmosterol and lathosterol as markers for cholesterol synthesis and campesterol and sitosterol for cholesterol absorption. At baseline, hemodialysis patients showed higher levels of campesterol ( p = 0.023) compared to healthy controls. During follow-up, we identified 14 (15.4%) patients who experienced macrovascular events. Comparisons of cholesterol homeostasis markers between cohorts with and without macrovascular events showed no significant differences in markers of cholesterol synthesis or absorption. Using logistic regression analysis, the odds ratio was not statistically significant for the prediction of macrovascular events after full-adjusting for age, sex, diabetes, serum albumin, cholesterol, and triglyceride. We concluded that hemodialysis patients demonstrated higher level of cholesterols absorption, indicated by circulating campesterol compared to healthy subjects. Markers for cholesterol homeostasis were not significantly associated with macrovascular events during a 1-year follow-up. Our results shed light on the novel therapeutic target of modulating cholesterol absorption in HD patients.

Most patients with oral squamous cell cancer (OSCC) have a locally advanced stage at diagnosis. The treatment strategies are diverse, including surgery, radiotherapy and chemotherapy. Despite multimodality treatment, the response rate is unsatisfactory. DNA repair and genetic instability are highly associated with carcinogenesis and treatment outcomes in oral squamous cell cancer, affecting cell growth and proliferation. Therefore, focusing on DNA repair and genetic instability interactions could be a potential target for improving the outcomes of OSCC patients. DNA polymerase-β (POLB) is an important enzyme in base excision repair and contributes to gene instability, leading to tumorigenesis and cancer metastasis. The aim of our study was to confirm POLB regulates the growth of OSCC cells through modulation of cell cycle and chromosomal instability. We analyzed a tissue array from 133 OSCC patients and discovered that low POLB expression was associated with advanced tumor stage and poor overall survival. In multivariate Cox proportional hazards regression analysis, low POLB expression and advanced lymph node status were significantly associated with poor survival. By performing in vitro studies on model cell lines, we demonstrated that POLB silencing regulated cell cycles, exacerbated mitotic abnormalities and enhanced cell proliferation. After POLB depletion, OSCC cells showed chromosomal instability and aneuploidy. Thus, POLB is an important maintainer of karyotypic stability in OSCC cells., Competing Interests: The authors report no conflict of interest.

Introduction: Kidney renal clear cell carcinoma (KIRCC) is a highly heterogeneous and lethal cancer that can arise in patients with renal disease. DeepSurv combines a deep feed-forward neural network with a Cox proportional hazards function and could provide optimized survival results compared with convenient survival analysis., Methods: This study used an improved DeepSurv algorithm to identify the candidate genes to be targeted for treatment on the basis of the overall mortality status of KIRCC subjects. All the somatic mutation missense variants of KIRCC subjects were abstracted from TCGA-KIRC database., Results: The improved DeepSurv model (95.1%) achieved greater balanced accuracy compared with the DeepSurv model (75%), and identified 610 high-risk variants associated with overall mortality. The results of gene differential expression analysis also indicated nine KIRCC mortality-risk-related pathways, namely the tRNA charging pathway, the D-myo-inositol-5-phosphate metabolism pathway, the DNA double-strand break repair by nonhomologous end-joining pathway, the superpathway of inositol phosphate compounds, the 3-phosphoinositide degradation pathway, the production of nitric oxide and reactive oxygen species in macrophages pathway, the synaptic long-term depression pathway, the sperm motility pathway, and the role of JAK2 in hormone-like cytokine signaling pathway. The biological findings in this study indicate the KIRCC mortality-risk-related pathways were more likely to be associated with cancer cell growth, cancer cell differentiation, and immune response inhibition., Conclusion: The results proved that the improved DeepSurv model effectively classified mortality-related high-risk variants and identified the candidate genes. In the context of KIRCC overall mortality, the proposed model effectively recognized mortality-related high-risk variants for KIRCC., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Altered high-density lipoprotein cholesterol (HDL-C) subclass distribution in hemodialysis (HD) patients is well documented. Aim of this study is to investigate the relationship between HDL-C subclass distribution and macrovascular events in patients undergoing HD. A total of 164 prevalent HD patients and 71 healthy individuals in one hospital-facilitated clinic were enrolled from May 2019 to July 2019 and individual HD patients was follow-up for one year. Macrovascular events (cerebral stroke, coronary heart disease) were recorded in the study period. The HDL-2b, HDL-3 proportions and biochemical parameters were measured. Pearson correlation test and logistic regression analysis were used to examine correlation and odds ratio (OR). 144 HD patients completed one-year follow-up. Cohort with macrovascular events revealed significantly lower HDL-2b and higher HDL-3 subclass proportions compared to those without events. By multivariable adjustment, HDL-3 subclass proportion revealed significantly increase risk for these events (OR 1.17, 95% CI 1.02-1.41, P = 0.044). HDL-2b subclass was significantly higher and HDL-3 subclass was significantly lower in the HD cohort under the hs-CRP level of < 3 mg/L compared to higher hs-CRP level. In conclusion, HDL-2b and HDL-3 subclasses distributions were associated with macrovascular events in HD patients. Proinflammatory status influences the distribution of HDL-2b and HDL-3 subclasses in HD patients.

Hypersialylation caused by the overexpression of sialyltransferases (STs) is a common feature in cancer that is associated with several characteristics of tumorigenesis. Thus, identifying cancer-associated STs is critical for cancer therapy. However, ST screening has been frequently conducted in cell line models. In this study, we conducted a comprehensive analysis of STs in the clinical database and identified the STs related with the survival of breast cancer patients. RNA sequencing (RNA-Seq) data of 496 patients were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA). Of the eight mapped STs, ST3GAL5 , and ST8SIA1 met the acceptable area under the curve (AUC) criteria for overall survival (OS). Using Kaplan-Meier methods, we determined that high expression of ST8SIA1 was associated with poor 10-year OS in all patients, triple-negative breast cancer (TNBC), and non-TNBC patients, and poor disease-free survival (DFS) rates particularly in TNBC. ST8SIA1 also had superior AUC values in terms of OS/DFS. High ST8SIA1 levels showed a higher risk for poor OS in different groups of patients and a higher risk for poor DFS particularly in TNBC. In summary, we conducted a comprehensive analysis of STs from the clinical database and identified ST8SIA1 as a crucial survival-related ST, which might be a potential therapeutic target for breast cancer and TNBC patients.

Background: To describe the associated factors for non-medical reasons for dropout in peritoneal dialysis (PD) patients., Methods: A retrospective cohort study was performed using registry data of adult patients commencing PD as their initial renal replacement therapy in one hospital-facilitated PD center in Taiwan between 2014 and 2018. The collected data included socio-demographics and relevant medical and PD-related parameters. Kaplan-Meier analysis was used to determine the impact of non-medical reasons and medical reasons on PD dropout., Results: The analysis included 224 PD patients, of whom 37 dropped out for non-medical reasons and 187 for medical reasons during the study period. There was significant difference between the two cohorts in age (62.3 years vs. 56.1 years, P = 0.010) and PD vintage (median 3.4 years vs. 4.8 years, P = 0.001). Diabetes was more predominant in the cohort for non-medical reasons than in the one for medical reasons (54.1% vs. 27.3% respectively, P = 0.001). In non-medical reason cohort, two leading reasons given for dropping out were lacking of caregivers (n = 12) and losing confidence (n = 10), whereas PD-related peritonitis (n = 101) was the main medical reason for PD dropout. Using Kaplan-Meier curve analysis, patients in the non-medical reason cohort demonstrated higher cumulative dropout rate compared to patients in the medical reason cohort during a 10-year period (P < 0.001)., Conclusions: The main characteristics of PD dropout patients for non-medical reasons are age, diabetes, patients' perception and caregiver support.

Cognitive impairment (CI) is not uncommon in dialysis patients. Various factors have been implicated. This study aims to examine mutual interaction of various clinical factors for CI in patients receiving hemodialysis. A total of 48 hemodialysis patients in outpatient clinic were recruited from 2015 to 2017. Demographics, circulating uremic toxin concentrations, miRNA concentrations, and nerve injury protein concentrations were collected. Clinical dementia rating (CDR) scores were used to stratify the functional scores of the patients. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic test performance for predicting dichotomous results, and cumulative ROC analysis was used to examine the combined contribution of clinical factors. CDR scale 0 included 15 patients (mean age, 59.1 years); CDR > 0.5 included 33 patients (mean age, 64.0 years). On cumulative ROC analysis, the major predictors of mild CI were hemoglobin, age, sex, homocysteine, neuron-specific enolase (NSE), and miR-486. The cumulative area under the curve (AUC) on combining hemoglobin, age, and miR-486 was the highest (0.897, 95% confidence interval 0.806-0.988). Two dichotomized variables reached 81.82% sensitivity and 86.67% specificity, with the likelihood ratio for positive and negative results being 6.14 and 0.21, respectively. In conclusion, hemoglobin, age, and miR-486 display high-degree combined effects on mild CI in patients receiving hemodialysis.

Colorectal cancer is a highly heterogeneous malignancy in the Asian population, and it is considered an important prognostic factor for baseline characteristics, tumor burden, and tumor markers. This study investigated the effect of baseline characteristics and tumor burden on tumor marker expression and progressive disease in colorectal cancer by using partial least squares variance-based path modeling (PLS-PM). PLS-PM can be used to evaluate the complex relationship between prognostic variables and progressive disease status with a small sample of measurements and structural models. A total of 89 tissue samples of colorectal cancer were analyzed. Our results suggested that the expression of visceral adipose tissue-derived serpin (vaspin) is a potential indicator of colorectal cancer progression and may be affected by baseline characteristics such as age, sex, body mass index, and diabetes mellitus. Moreover, according to the characteristics of tumor burden, the expression of vaspin was generally higher in each progressive disease patient. The overall findings suggest that vaspin is a potential indicator of the progressive disease and may be affected by the baseline characteristics of patients.

Background and Aims: In Taiwan, approximately 90% of patients with end-stage renal disease receive maintenance hemodialysis. Although studies have reported the survival predictability of multiclinical factors, the higher-order interactions among these factors have rarely been discussed. Conventional statistical approaches such as regression analysis are inadequate for detecting higher-order interactions. Therefore, this study integrated receiver operating characteristic, logistic regression, and balancing functions for adjusting the ratio in risk classes and classification errors for imbalanced cases and controls using multifactor-dimensionality reduction (MDR-ER) analyses to examine the impact of interaction effects between multiclinical factors on overall mortality in patients on maintenance hemodialysis., Meterials and Methods: In total, 781 patients who received outpatient hemodialysis dialysis three times per week before 1 January 2009 were included; their baseline clinical factor and mortality outcome data were retrospectively collected using an approved data protocol (201800595B0)., Results: Consistent with conventional statistical approaches, the higher-order interaction model could indicate the impact of potential risk combination unique to patients on maintenance hemodialysis on the survival outcome, as described previously. Moreover, the MDR-based higher-order interaction model facilitated higher-order interaction effect detection among multiclinical factors and could determine more detailed mortality risk characteristics combinations., Conclusion: Therefore, higher-order clinical risk interaction analysis is a reasonable strategy for detecting non-traditional risk factor interaction effects on survival outcome unique to patients on maintenance hemodialysis and thus clinically achieving whole-scale patient care., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: In this study, we investigated the association of time-varying serum albumin levels with mortality over a 5-year period in one cohort of patients undergoing long-term peritoneal dialysis (PD) therapy., Methods: The participants in this study enrolled 302 patients who underwent long-term PD at a single PD center in Taiwan. We reviewed medical records from 2011 to 2015 retrospectively. Time-averaged albumin level and serum albumin reach rate (defined as the percentage of serum albumin measurements that reached ≥3.5 g/dL) were applied as the predictor variables in the first 2 years (2011-2012). All-cause mortality was used as the outcome variable in the subsequent 3 years (2013-2015). Hazard function of all-cause mortality in the study participants was examined by using Cox proportional hazard regression models ., Results: Patients with different albumin reach rates (75-< 100%, 50-< 75%, 1-< 50%) did not exhibit a significantly increased risk for all-cause mortality. Patients with a 0% albumin reach rate exhibited a significantly increased risk for all-cause mortality (hazard ratio [HR] 7.59, 95% confidence interval [CI], 2.38-24.21) by fully adjusted analysis. Patients with time-averaged albumin levels of < 3.5 g/dL (HR 15.49, 95% CI 1.74-137.72) exhibited a higher risk for all-cause mortality than those with serum albumin levels ≥4.0 g/dL., Conclusions: This study demonstrated that higher serum albumin reach rates and higher time-averaged serum albumin levels are associated with a lower mortality rate over a 5-year period among patients undergoing long-term PD.

Strains of Acinetobacter baumannii are commensal and opportunistic pathogens that have emerged as problematic hospital pathogens due to its biofilm formation ability and multiple antibiotic resistances. The biofilm-associated pathogens usually exhibit dramatically decreased susceptibility to antibiotics. This study was aimed to investigate the correlation of biofilm-forming ability, antibiotic resistance and biofilm-related genes of 154 A. baumannii isolates which were collected from a teaching hospital in Taiwan. Biofilm-forming ability of the isolates was evaluated by crystal violet staining and observed by scanning electron microscopy. Antibiotic susceptibility was determined by disc diffusion method and minimum inhibitory concentration; the biofilm-related genes were screened by polymerase chain reaction. Results showed that among the 154 tested isolates, 15.6% of the clinical isolates were weak biofilm producers, while 32.5% and 45.4% of them possessed moderate and strong biofilm formation ability, respectively. The experimental results revealed that the multiple drug resistant isolates usually provided a higher biofilm formation. The prevalence of biofilm related genes including bap , bla PER-1 , csu E and omp A among the isolated strains was 79.2%, 38.3%, 91.6%, and 68.8%, respectively. The results indicated that the antibiotic resistance, the formation of biofilm and the related genes were significantly correlated. The results of this study can effectively help to understand the antibiotic resistant mechanism and provides the valuable information to the screening, identification, diagnosis, treatment and control of clinical antibiotic-resistant pathogens.

Breast cancer is the most common cancer among women and is considered a major public health concern worldwide. Biogeography-based optimization (BBO) is a novel metaheuristic algorithm. This study analyzed the relationship between the clinicopathologic variables of breast cancer using Cox proportional hazard (PH) regression on the basis of the BBO algorithm. The dataset is prospectively maintained by the Division of Breast Surgery at Kaohsiung Medical University Hospital. A total of 1896 patients with breast cancer were included and tracked from 2005 to 2017. Fifteen general breast cancer clinicopathologic variables were collected. We used the BBO algorithm to select the clinicopathologic variables that could potentially contribute to predicting breast cancer prognosis. Subsequently, Cox PH regression analysis was used to demonstrate the association between overall survival and the selected clinicopathologic variables. C-statistics were used to test predictive accuracy and the concordance of various survival models. The BBO-selected clinicopathologic variables model obtained the highest C-statistic value (80%) for predicting the overall survival of patients with breast cancer. The selected clinicopathologic variables included tumor size (hazard ratio [HR] 2.372, p = 0.006), lymph node metastasis (HR 1.301, p = 0.038), lymphovascular invasion (HR 1.606, p = 0.096), perineural invasion (HR 1.546, p = 0.168), dermal invasion (HR 1.548, p = 0.028), total mastectomy (HR 1.633, p = 0.092), without hormone therapy (HR 2.178, p = 0.003), and without chemotherapy (HR 1.234, p = 0.491). This number was the minimum number of discriminators required for optimal discrimination in the breast cancer overall survival model with acceptable prediction ability. Therefore, on the basis of the clinicopathologic variables, the survival prediction model in this study could contribute to breast cancer follow-up and management.

Purpose: We examined the association between catheter use for maintenance hemodialysis (HD) and mortality/hospitalization in a cohort of patients with prevalent HD., Methods: In this study, 70 HD patients with tunneled cuffed central venous catheters (TCVCs) from a Taiwanese HD center during 2014-2016 were enrolled and compared with 70 matched HD patients with native arteriovenous fistulae (AVF). The compared variables included demographic parameters and laboratory and dialysis-related indices. Cox regression analysis was used to assess the risk of mortality/hospitalization within a year., Results: Low baseline serum albumin levels were found in patients with TCVCs (3.64 g/dL vs 3.79 g/dL, p = 0.030). The mortality rates of patients with AVF and TCVCs were 14 per 1000 patients and 171 per 1000 patients, respectively. Infection was the leading cause of mortality/hospitalization in patients with TCVCs. Using multivariate analyses, the risk of death was found to be significantly higher in patients with TCVCs than in those with AVF (Hazard ratio [HR] 12.15, 95% CI 1.16-127.17; p = 0.037). Patients with TCVC also had a higher hospitalization rate (HR 1.33, 95% CI 0.71-2.49; p = 0.369) (not statistically significant)., Conclusion: Catheter use for maintenance HD was associated with increased all-cause mortality., (Copyright © 2018. Published by Elsevier B.V.)

Aim: PEGylated liposomal doxorubicin (PLD) has comparable efficacy and differing toxicity from conventional anthracyclines used to treat advanced breast cancer. This study compared disease-free survival and toxicity between PLD-based and conventional anthracycline-based regimens as adjuvant treatments for early-stage breast cancer., Methods: We analyzed disease-free survival (DFS) rates, and adverse events in 102 women with early-stage (I-IIIa) breast cancer who received adjuvant PLD-based chemotherapy from 2002 to 2008. Each patient was matched for age, stage at diagnosis, HER-2 expression and hormone therapy use to a patient treated with an epirubicin-based regimen. Fisher's exact and Pearson's chi-square tests were used for categorical data analysis. Kaplan-Meier analysis and Cox regression models were used to analyze DFS., Results: DFS at 5 years was 81.3% for PLD-based regimen and 82.3% for epirubicin-based regimen. This difference was not significant (p = 0.939). Stage IIIa disease was associated with a shorter DFS in univariate analysis (p = 0.048). In multivariate analysis that controlled for adjuvant treatment, age at diagnosis, stage, HER-2 expression, type of surgery and hormone and radiation therapy, stage IIIa disease (P = 0.023) and lack of hormone therapy (P = 0.024) were each independently associated with shorter DFS. Adverse events were evaluated, and with the exception of hand-foot syndrome, more grade 3 and 4 toxicities occurred in patients who received epirubicin-based regimens than in those given PLD-based regimens., Conclusion: For patients with early-stage breast cancer who received PLD-based adjuvant chemotherapy, 5-year DFS was comparable and toxicity was acceptable, yet different from those of patients who received epirubicin-based regimens., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: This study aimed to evaluate the longitudinal changes in cardiac structure and function in incident-automated peritoneal dialysis (APD) patients., Methods: We conducted a 2-year prospective, randomized, open-label, parallel-group study to compare the efficacy of icodextrin solution versus glucose-based solution. Echocardiography was performed at baseline, 1 and 2 years. Echocardiographic parameters over 2 years were evaluated for each group, using the Friedman test. Generalized linear regression analysis was used to test the associations between baseline clinical variables and echocardiographic changes, and a multivariate model was used to analyze cardiac function between the two groups., Results: A total of 43 APD patients were enrolled in the beginning of this study. Twenty patients in the icodextrin group (ICO) and 18 patients in the glucose group (GLU) completed the study. In left ventricular (LV) systolic function measurements, ejection fraction (EF) increased significantly in the GLU group. Measurements of LV diastolic function and septal early mitral annulus velocity (EMV) increased significantly from baseline to 24-months in the ICO group (5.43-5.51 ms). The GLU group showed a significant decrease in peak early diastolic velocity (EDV) (70.67-68.25 cm/s), but a significant increase in septal EMV (5.94-7.57 ms) from baseline to 24-months. No significant association was found between the baseline clinical variables and echocardiographic changes within 24 months in the generalized linear regression analysis. Multivariate models were used to investigate changes in the four primary endpoints, namely, myocardial performance index (MPI), left ventricular ejection fraction (LVEF), deceleration time (DT), and E/e' ratio. These primary endpoints show no significant association with the baseline values in both the ICO and GLU groups., Conclusion: The present study demonstrates that long-dwell icodextrin solution can maintain reasonable cardiac structure and function in incident-APD patients., Trial Registration: ISRCTN14931270 (retrospectively registered on 23/03/2018).

Background: Visfatin has been reported to be associated with breast cancer progression, but the interaction between the visfatin and clinicopathologic factors in breast cancer progression status requires further investigation. To address this problem, it is better to simultaneously consider multiple factors in sensitivity and specificity assays., Methods: In this study, a dataset for 105 breast cancer patients (84 disease-free and 21 progressing) were chosen. Individual and cumulative receiver operating characteristics (ROC) were used to analyze the impact of each factor along with interaction effects., Results: In individual ROC analysis, only 3 of 13 factors showed better performance for area under curve (AUC), i.e., AUC > 7 for hormone therapy (HT), tissue visfatin, and lymph node (LN) metastasis. Under our proposed scoring system, the cumulative ROC analysis provides higher AUC performance (0.746-0.886) than individual ROC analysis in predicting breast cancer progression. Considering the interaction between these factors, a minimum of six factors, including HT, tissue visfatin, LN metastasis, tumor stage, age, and tumor size, were identified as being highly interactive and associated with breast cancer progression, providing potential and optimal discriminators for predicting breast cancer progression., Conclusion: Taken together, the cumulative ROC analysis provides better prediction for breast cancer progression than individual ROC analysis.

Background/aims: We investigated factors associated with functional performance in hemodialysis (HD) patients as well as their relationships with mortality., Methods: We enrolled 790 HD patients who were followed up from 2009 to 2013. Functional performance was evaluated by Karnofsky Performance Status Scale (KPSS) scores. We examined the associations of clinical variables and all-cause mortality with KPSS scores., Results: Of the participants, 460 had high KPSS scores (range 90-100) and 330 had low KPSS scores (below 80). On multivariate analysis, age and weekly HD sessions were associated with significantly increased odds of a lower KPSS score (age: OR 1.05, 95% CI 1.04-1.07, p < 0.001; weekly HD: OR 2.10, 95% CI 1.37-3.21, p = 0.001). A low KPSS score was a significant predictor of increased all-cause mortality (hazard ratio 1.49; 95% CI 1.02-2.16, p = 0.037), as determined using Cox regression analysis., Conclusion: Functional performance was associated with clinical variables and all-cause mortality in HD patients., (© 2018 S. Karger AG, Basel.)

Objectives: To survey by measuring patient's functional status which is crucial when end-stage renal disease patients begin a dialysis program. The influence of the disease on patients can be examined by the measurement of Karnofsky Performance Status (KPS) scores, together with a quality of life survey, and clinical variables., Methods: The details for the dataset in the study were collected from patients receiving regular hemodialysis (HD) in one hospital, which were available retrospectively for 1166 patients during the 5-year study period. KPS scores were applied for quantifying functional status. To identify risk factors for functional status, clinical factors including demographics, laboratory data, and HD vintage were selected. This study applied a classification and regression tree approach (CART) and logistic regression to determine risk factors on functional impairment among HD patients., Results: Ten risk factors were identified by CART and regression model (age, primary kidney disease subclass, treatment years, hemoglobin, albumin, creatinine, phosphorus, intact parathyroid hormone, ferritin, and cardiothoracic ratio). The results of logistic regression with selected interaction models showed older age or higher hematocrit, blood urea nitrogen, and glucose levels could significantly increase the log-odds of obtaining low KPS scores at in-person visits., Conclusions: In interaction results, the combination of older age with higher albumin level and higher creatinine level with longer HD treatment years could significantly decrease the log-odds of a low KPS score assessment during in-person visits. Age, hemoglobin, albumin, urea, creatinine levels, primary kidney disease subclass, and HD duration are the major determinants for functional status in HD patients.