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Background: Tumor spread through air spaces (STAS) has been recognized as a prognostic factor for several types of lung cancers. However, information regarding its clinical significance in pulmonary lymphoepithelial carcinoma is limited. Therefore, this study investigated effects of STAS on the clinical outcomes for patients with pulmonary lymphoepithelial carcinoma., Methods: This study retrospectively reviewed 56 surgically resected pulmonary lymphoepithelial carcinomas. The study defined STAS as the presence of tumor cells within air spaces in lung parenchyma beyond the tumor edge. Artifacts were excluded. Recurrence-free survival (RFS) was analyzed using the log-rank test and Cox proportional hazards model., Results: In 18 patients (32.1%), STAS was observed and found to be associated with larger tumor size (>3 cm) (p = 0.009), higher pathologic stage (p = 0.026), and tumor necrosis (p = 0.046). Patients with STAS had a significantly lower 5-year RFS rate (p = 0.025). Multivariate analysis showed that STAS was an independent predictor of worse RFS (hazard ratio, 3.395; p = 0.038). Patients with STAS had a significantly increased risk of locoregional recurrence (p = 0.049)., Conclusions: The study findings suggest that STAS is an independent predictor of poor RFS. Based on these findings, a new three-tier grading system based on the patterns of tumor border and STAS was proposed for effective prediction of 5-year RFS in pulmonary lymphoepithelial carcinoma., (© 2024. Society of Surgical Oncology.)

Current genome-wide association studies (GWAS) for kidney function lack ancestral diversity, limiting the applicability to broader populations. The East-Asian population is especially under-represented, despite having the highest global burden of end-stage kidney disease. We conducted a meta-analysis of multiple GWASs (n = 244,952) on estimated glomerular filtration rate and a replication dataset (n = 27,058) from Taiwan and Japan. This study identified 111 lead SNPs in 97 genomic risk loci. Functional enrichment analyses revealed that variants associated with F12 gene and a missense mutation in ABCG2 may contribute to chronic kidney disease (CKD) through influencing inflammation, coagulation, and urate metabolism pathways. In independent cohorts from Taiwan (n = 25,345) and the United Kingdom (n = 260,245), polygenic risk scores (PRSs) for CKD significantly stratified the risk of CKD (p < 0.0001). Further research is required to evaluate the clinical effectiveness of PRS CKD in the early prevention of kidney disease., (© 2024. The Author(s).)

Over the past decade, genome-wide association studies have identified thousands of variants significantly associated with complex traits. For each locus, gene expression levels are needed to further explore its biological functions. To address this, the PrediXcan algorithm leverages large-scale reference data to impute the gene expression level from single nucleotide polymorphisms, and thus the gene-trait associations can be tested to identify the candidate causal genes. However, a challenge arises due to the fact that most reference data are from subjects of European ancestry, and the accuracy and robustness of predicted gene expression in subjects of East Asian (EAS) ancestry remains unclear. Here, we first simulated a variety of scenarios to explore the impact of the level of population diversity on gene expression. Population differentiated variants were estimated by using the allele frequency information from The Genome Aggregation Database. We found that the weights of a variants was the main factor that affected the gene expression predictions, and that ~70% of variants were significantly population differentiated based on proportion tests. To provide insights into this population effect on gene expression levels, we utilized the allele frequency information to develop a gene expression reference panel, Predict Asian-Population (PredictAP), for EAS ancestry. PredictAP can be viewed as an auxiliary tool for PrediXcan when using genotype data from EAS subjects., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: The aim of this study was to evaluate the efficacy of different treatment intensities (TIs) in patients with nasopharyngeal carcinoma (NPC)., Methods: The study assessed newly diagnosed, non-metastatic NPC patients from the Taiwan Cancer Registry between 2010 and 2017. TIs were divided into four groups: TI1 [radiotherapy (RT) alone or induction chemotherapy (IC) followed by RT); TI2 (concurrent chemoradiotherapy (CRT) alone); TI3 (IC followed by CRT or CRT followed by adjuvant chemotherapy (AC)]; and TI4 (IC followed by CRT followed by AC). The primary outcome was cancer-specific survival (CSS)., Results: The study included 9863 patients. For stage I-II NPC patients, there was no significant difference in CSS among the different TI groups. For stage III patients, those receiving TI3 had better CSS (hazard ratio [HR] 0.69) compared with those receiving TI1. No significant differences in CSS were noted among those receiving TI2, TI3, and TI4. For stage IVA-B patients, those receiving TI2 (HR 0.70), TI3 (HR 0.49), and TI4 (HR 0.43) had better CSS compared with those receiving TI1. Compared with stage IVA-B patients receiving TI2, those receiving TI3 (HR 0.70) and TI4 (HR 0.61) had significantly better CSS. No differences in CSS were noted between those receiving TI3 and TI4., Conclusions: For stage I-II NPC patients, RT alone is appropriate. For stage III and IVA-B patients, IC + CRT or CRT + AC may be needed to achieve optimal outcomes. No advantage of IC + CRT + AC over IC + CRT or CRT + AC was observed., (© 2024. Society of Surgical Oncology.)

Disabled people with a high cervical cord injury or quadriplegia face difficulties when controlling a computer. This study presents a digital mouth-controlled mouse-control aid called the bite-press mouth-controlled mouse (BPMCM) to replace the traditional computer mouse. The BPMCM is equipped with a joystick and micro switch, and the disabled person uses neck and head movements to push the joystick and control the cursor position while the three mouse functions (i.e., left-click, right-click, and drag) are activated by bite-pressing for different time intervals. The proposed design eliminates the sip-and-puff technique and the need to recite orders for reduced adaptation time and increased convenience. Furthermore, this design supports plug-and-play and hot plugging in modern mainstream operating systems that can often be directly operated via mouse functions. Experimental results demonstrated that disabled people using a BPMCM were as capable as healthy participants in operating a computer, with both experiments completed within 5 min, and voluntary disabled people immediately adapted to the BPMCM. The proposed design is expected to allow disabled people to operate computers at the same level as healthy participants. The BPMCM also required only half the physical exertion of other mouth-controlled mouse-control aids that require orders to be recited., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Background: Current research on the epigenetic repercussions of exposure to a combination of pollutants is limited. This study aims to discern DNA methylation probes associated with exposure to multiple pollutants, serving as early effect markers, and single-nucleotide polymorphisms (SNPs) as surrogate indicators for population susceptibility. The investigation involved the analysis of urine exposure biomarkers for 11 heavy metals (vanadium, arsenic, mercury, cadmium, chromium, nickel, lead, manganese, copper, strontium, thallium), polycyclic aromatic hydrocarbon (PAHs) (1-hydroxypyrene), genome-wide DNA methylation sequencing, and SNPs array on all study participants. The data were integrated with metabolomics information and analyzed both at a community level based on proximity to home addresses relative to the complex and at an individual level based on exposure biomarker concentrations., Results: On a community level, 67 exposure-related CpG probes were identified, while 70 CpG probes were associated with urine arsenic concentration, 2 with mercury, and 46 with vanadium on an individual level. These probes were annotated to genes implicated in cancers and chronic kidney disease. Weighted quantile sum regression analysis revealed that vanadium, mercury, and 1-hydroxypyrene contributed the most to cg08238319 hypomethylation. cg08238319 is annotated to the aryl hydrocarbon receptor repressor (AHRR) gene, and AHRR hypomethylation was correlated with an elevated risk of lung cancer. AHRR was further linked to deregulations in phenylalanine metabolism, alanine, aspartate, and glutamate metabolism, along with heightened oxidative stress. Additionally, three SNPs (rs11085020, rs199442, and rs10947050) corresponding to exposure-related CpG probes exhibited significant interaction effects with multiple heavy metals and PAHs exposure, and have been implicated in cancer progression and respiratory diseases., Conclusion: Our findings underscore the pivotal role of AHRR methylation in gene-environment interactions and highlight SNPs that could potentially serve as indicators of population susceptibility in regions exposed to multiple heavy metals and PAHs., (© 2024. The Author(s).)

Background and Aims: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries., Methods: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart., Results: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway., Conclusions: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: This study aims to raise awareness of the disparities in survival predictions among races in head and neck cancer (HNC) patients by developing and validating population-based prognostic models specifically tailored for Taiwanese and Asian populations., Methods: A total of 49,137 patients diagnosed with HNCs were included from the Taiwan Cancer Registry (TCR). Six prognostic models, divided into three categories based on surgical status, were developed to predict both overall survival (OS) and cancer-specific survival using the registered demographic and clinicopathological characteristics in the Cox proportional hazards model. The prognostic models underwent internal evaluation through a tenfold cross-validation among the TCR Taiwanese datasets and external validation across three primary racial populations using the Surveillance, Epidemiology, and End Results database. Predictive performance was assessed using discrimination analysis employing Harrell's c-index and calibration analysis with proportion tests., Results: The TCR training and testing datasets demonstrated stable and favorable predictive performance, with all Harrell's c-index values ≥ 0.7 and almost all differences in proportion between the predicted and observed mortality being < 5%. In external validation, Asians exhibited the best performance compared with white and black populations, particularly in predicting OS, with all Harrell's c-index values > 0.7., Conclusions: Survival predictive disparities exist among different racial groups in HNCs. We have developed population-based prognostic models for Asians that can enhance clinical practice and treatment plans., (© 2024. The Author(s).)

Background: Tourniquets (TQ) have been increasingly adopted in pre-hospital settings recently. This study examined the effectiveness and safety of applying TQ in the pre-hospital settings for civilian patients with traumatic vascular injuries to the extremities., Materials and Methods: We systematically searched the Ovid Embase, PubMed, and Cochrane Central Register of Controlled Trials databases from their inception to June 2023. We compared pre-hospital TQ (PH-TQ) use to no PH-TQ, defined as a TQ applied after hospital arrival or no TQ use at all, for civilian vascular extremity trauma patients. The primary outcome was overall mortality rate, and the secondary outcomes were blood product use and hospital stay. We analyzed TQ-related complications as safety outcomes. We tried to include randomized controlled trials (RCTs) and non-randomized studies (including non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies, and case-control studies), if available. Pooled odds ratios (ORs) were calculated and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology., Results: Seven studies involving 4,095 patients were included. In the primary outcome, pre-hospital TQ (PH-TQ) use significantly decrease mortality rate in patients with extremity trauma (odds ratio [OR], 0.48, 95% confidence interval [CI] 0.27-0.86, I 2  = 47%). Moreover, the use of PH-TQ showed the decreasing trend of utilization of blood products, such as packed red blood cells (mean difference [MD]: -2.1 [unit], 95% CI: -5.0 to 0.8, I 2  = 99%) or fresh frozen plasma (MD: -1.0 [unit], 95% CI: -4.0 to 2.0, I 2  = 98%); however, both are not statistically significant. No significant differences were observed in the lengths of hospital and intensive care unit stays. For the safety outcomes, PH-TQ use did not significantly increase risk of amputation (OR: 0.85, 95% CI: 0.43 to 1.68, I 2  = 60%) or compartment syndrome (OR: 0.94, 95% CI: 0.37 to 2.35, I 2  = 0%). The certainty of the evidence was very low across all outcomes., Conclusion: The current data suggest that, in the pre-hospital settings, PH-TQ use for civilian patients with vascular traumatic injury of the extremities decreased mortality and tended to decrease blood transfusions. This did not increase the risk of amputation or compartment syndrome significantly., (© 2024. The Author(s).)

Background: Most sepsis patients could potentially experience advantageous outcomes from targeted medical intervention, such as fluid resuscitation, antibiotic administration, respiratory support, and nursing care, promptly upon arrival at the emergency department (ED). Several scoring systems have been devised to predict hospital outcomes in sepsis patients, including the Sequential Organ Failure Assessment (SOFA) score. In contrast to prior research, our study introduces the novel approach of utilizing the National Early Warning Score 2 (NEWS2) as a means of assessing treatment efficacy and disease progression during an ED stay for sepsis., Objectives: To evaluate the sepsis prognosis and effectiveness of treatment administered during ED admission in reducing overall hospital mortality rates resulting from sepsis, as measured by the NEWS2., Methods: The present investigation was conducted at a medical center from 1997 to 2020. The NEWS2 was calculated for patients with sepsis who were admitted to the ED in a consecutive manner. The computation was based on the initial and final parameters that were obtained during their stay in the ED. The alteration in the NEWS2 from the initial to the final measurements was utilized to evaluate the benefit of ED management to the hospital outcome of sepsis. Univariate and multivariate Cox regression analyses were performed, encompassing all clinically significant variables, to evaluate the adjusted hazard ratio (HR) for total hospital mortality in sepsis patients with reduced severity, measured by NEWS2 score difference, with a 95% confidence interval (adjusted HR with 95% CI). The study employed Kaplan-Meier analysis with a Log-rank test to assess variations in overall hospital mortality rates between two groups: the "improvement (reduced NEWS2)" and "non-improvement (no change or increased NEWS2)" groups., Results: The present investigation recruited a cohort of 11,011 individuals who experienced the first occurrence of sepsis as the primary diagnosis while hospitalized. The mean age of the improvement and non-improvement groups were 69.57 (± 16.19) and 68.82 (± 16.63) years, respectively. The mean SOFA score of the improvement and non-improvement groups were of no remarkable difference, 9.7 (± 3.39) and 9.8 (± 3.38) years, respectively. The total hospital mortality for sepsis was 42.92% (4,727/11,011). Following treatment by the prevailing guidelines at that time, a total of 5,598 out of 11,011 patients (50.88%) demonstrated improvement in the NEWS2, while the remaining 5,403 patients (49.12%) did not. The improvement group had a total hospital mortality rate of 38.51%, while the non-improvement group had a higher rate of 47.58%. The non-improvement group exhibited a lower prevalence of comorbidities such as congestive heart failure, cerebral vascular disease, and renal disease. The non-improvement group exhibited a lower Charlson comorbidity index score [4.73 (± 3.34)] compared to the improvement group [4.82 (± 3.38)] The group that underwent improvement exhibited a comparatively lower incidence of septic shock development in contrast to the non-improvement group (51.13% versus 54.34%, P < 0.001). The improvement group saw a total of 2,150 patients, which represents 38.41% of the overall sample size of 5,598, transition from the higher-risk to the medium-risk category. A total of 2,741 individuals, representing 48.96% of the sample size of 5,598 patients, exhibited a reduction in severity score only without risk category alteration. Out of the 5,403 patients (the non-improvement group) included in the study, 78.57% (4,245) demonstrated no alteration in the NEWS2. Conversely, 21.43% (1,158) of patients exhibited an escalation in severity score. The Cox regression analysis demonstrated that the implementation of interventions aimed at reducing the NEWS2 during a patient's stay in the ED had a significant positive impact on the outcome, as evidenced by the adjusted HRs of 0.889 (95% CI = 0.808, 0.978) and 0.891 (95% CI = 0.810, 0.981), respectively. The results obtained from the Kaplan-Meier analysis indicated that the survival rate of the improvement group was significantly higher than that of the non-improvement group (P < 0.001) in the hospitalization period., Conclusion: The present study demonstrated that 50.88% of sepsis patients obtained improvement in ED, ascertained by means of the NEWS2 scoring system. The practical dynamics of NEWS2 could be utilized to depict such intricacies clearly. The findings also literally supported the importance of ED management in the comprehensive course of sepsis treatment in reducing the total hospital mortality rate., (© 2024. The Author(s).)

Large-scale cancer drug sensitivity data have become available for a collection of cancer cell lines, but only limited drug response data from patients are available. Bridging the gap in pharmacogenomics knowledge between in vitro and in vivo datasets remains challenging. In this study, we trained a deep learning model, Scaden-CA, for deconvoluting tumor data into proportions of cancer-type-specific cell lines. Then, we developed a drug response prediction method using the deconvoluted proportions and the drug sensitivity data from cell lines. The Scaden-CA model showed excellent performance in terms of concordance correlation coefficients (>0.9 for model testing) and the correctly deconvoluted rate (>70% across most cancers) for model validation using Cancer Cell Line Encyclopedia (CCLE) bulk RNA data. We applied the model to tumors in The Cancer Genome Atlas (TCGA) dataset and examined associations between predicted cell viability and mutation status or gene expression levels to understand underlying mechanisms of potential value for drug repurposing., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Purpose: The purpose of this study is to find essential risk factors associated with liver function (LF) deteriorations within fluctuating long-term LF and their time-varying effects in patients with hepatocellular carcinoma (HCC) receiving hepatic radiotherapy and to identify high-risk groups for adverse LF deteriorations and their changes over time in facilitating the prevention of hepatic decompensation and the improvement of survival., Materials and Methods: A total of 133 HCC patients treated by hepatic radiotherapy were enrolled. A study design was conducted to convert posttreatment long-term LF with fluctuating levels over time to recurrent LF events using defined upgrades in a grading scale. The hazard ratios (HR) of pretreatment biochemical, demographic, clinical, and dosimetric factors in developing posttreatment LF events were estimated using the Cox model. Methodologies of the counting process approach, robust variance estimation, goodness-of-fit testing based on the Schoenfeld residuals, and time-dependent covariates in survival analysis were employed to handle the correlation within subjects and evaluate the time-varying effects during long-term follow-up., Results: Baseline LF score before radiotherapy and gender were significant factors. Initial HR in developing LF events was 1.17 (95% CI 1.11-1.23; P < 0.001) for each increase of baseline LF score and kept almost constant over time (HR, 1.00; 95% CI 1.00-1.01; P = 0.065). However, no difference was observed regarding initial hazards for gender (HR, 1.00; 95% CI 0.64-1.56; P = 0.994), but the hazard for women got higher monthly over time compared with men (HR, 1.04; 95% CI 1.01-1.07; P = 0.006)., Conclusions: High-risk groups for adverse LF deteriorations after hepatic radiotherapy may change over time. Patients with poor baseline LF are vulnerable from the beginning. Women require prevention strategies and careful monitoring for deteriorations at a later stage., (© 2024. The Author(s).)

Periodic mammography and/or sonography examinations are conducted across numerous hospitals nationalwidely, especially for antedees with a positive mammography screening. Despite the regular practice, clinical efficacy of hospital-based breast cancer surveillance remains unclear. Specifically, the impact of surveillance interval upon survival and prognostic surrogates stratified by menopausal status, as well as malignant transition rate should be deciphered. We retrieved cancer registry to ascertain 841 breast cancers with surveillance history through administration data. Healthy controls underwent breast surveillance and were concurrently free of cancer. More benign diseases rather than cancers were identified from premenopausal women (age ≤50 years) with sonography alone within one year, as well as older women (age >50) with both mammography and sonography one to two years before a cancer or benign diagnosis. Among breast cancers, mammography alone during the antecedent one to two years had a protective effect for diagnosing carcinoma in situ rather than invasive cancer (age-adjusted odds ratio: 0.048, P = 0.016). Three-state time homogeneous Markov model showed that hospital-based breast surveillance within 2 years of disease onset reduced the malignant transition rate by 65.16% (59.79-76.74%). The clinical efficacy of breast cancer surveillance was evidenced., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Purpose: Breast cancer is a molecularly heterogeneous disease, and multiple genetic variants contribute to its development and prognosis. Most of previous genome-wide association studies (GWASs) and polygenic risk scores (PRSs) analyses focused on studying breast cancers of Caucasian populations, which may not be applicable to other population. Therefore, we conducted the largest breast cancer cohort of Taiwanese population to fill in the knowledge gap., Methods: A total of 152,534 Participants recruited by China Medical University Hospital between 2003 and 2019 were filtered by several patient selection criteria and GWAS quality control steps, resulting in the inclusion of 2496 cases and 9984 controls for this study. We then conducted GWAS for all breast cancers and PRS analyses for all breast cancers and the four breast cancer subtypes, including luminal A, luminal B, basal-like, and HER2-enriched., Results: The GWAS analyses identified 113 SNPs, 50 of which were novel. The PRS models for all breast cancers and the luminal A subtype showed positively correlated trends between the PRS and the risk of developing breast cancer. The odds ratios (95% confidence intervals) for the groups with the highest PRS in all breast cancers and the luminal A subtype were 5.33 (3.79-7.66) and 3.55 (2.13-6.14), respectively., Conclusion: In summary, we explored the association of genetic variants with breast cancer in the largest Taiwanese cohort and developed two PRS models that can predict the risk of developing any breast cancer and the luminal A subtype in Taiwanese women., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

With new advances in next generation sequencing (NGS) technology at reduced costs, research on bacterial genomes in the environment has become affordable. Compared to traditional methods, NGS provides high-throughput sequencing reads and the ability to identify many species in the microbiome that were previously unknown. Numerous bioinformatics tools and algorithms have been developed to conduct such analyses. However, in order to obtain biologically meaningful results, the researcher must select the proper tools and combine them to construct an efficient pipeline. This complex procedure may include tens of tools, each of which require correct parameter settings. Furthermore, an NGS data analysis involves multiple series of command-line tools and requires extensive computational resources, which imposes a high barrier for biologists and clinicians to conduct NGS analysis and even interpret their own data. Therefore, we established a public gut microbiome database, which we call Twnbiome, created using healthy subjects from Taiwan, with the goal of enabling microbiota research for the Taiwanese population. Twnbiome provides users with a baseline gut microbiome panel from a healthy Taiwanese cohort, which can be utilized as a reference for conducting case-control studies for a variety of diseases. It is an interactive, informative, and user-friendly database. Twnbiome additionally offers an analysis pipeline, where users can upload their data and download analyzed results. Twnbiome offers an online database which non-bioinformatics users such as clinicians and doctors can not only utilize to access a control set of data, but also analyze raw data with a few easy clicks. All results are customizable with ready-made plots and easily downloadable tables. Database URL: http://twnbiome.cgm.ntu.edu.tw/ ., (© 2023. The Author(s).)

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Polygenic risk score (PRS) is a quantity that aggregates the effects of variants across the genome and estimates an individual's genetic predisposition for a given trait. PRS analysis typically contains two input data sets: base data for effect size estimation and target data for individual-level prediction. Given the availability of large-scale base data, it becomes more common that the ancestral background of base and target data do not perfectly match. In this paper, we treat the GWAS summary information obtained in the base data as knowledge learned from a pre-trained model, and adopt a transfer learning framework to effectively leverage the knowledge learned from the base data that may or may not have similar ancestral background as the target samples to build prediction models for target individuals. Our proposed transfer learning framework consists of two main steps: (1) conducting false negative control (FNC) marginal screening to extract useful knowledge from the base data; and (2) performing joint model training to integrate the knowledge extracted from base data with the target training data for accurate trans-data prediction. This new approach can significantly enhance the computational and statistical efficiency of joint-model training, alleviate over-fitting, and facilitate more accurate trans-data prediction when heterogeneity level between target and base data sets is small or high., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jeng 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.)

Background: Radiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ (DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS., Methods/design: This is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring < 2.5 cm with margins ≥ 3 mm, and estrogen receptor-positive status) of DCIS who underwent BCS will be randomized at a 1:1 ratio to either receive tamoxifen (5 mg/day) for 5 years or undergo RT with conventional fractions (50 Gy in 25 fractions) or hypofractionations (40.05 Gy in 15 fractions). Randomization will be stratified by the Taiwan Breast Cancer Consortium. As approximately 5% of patients cannot tolerate the side effects of low-dose tamoxifen and will receive RT, we estimate that 405 patients will be randomized to a low-dose tamoxifen arm and 405 patients to the RT arm, according to a non-inferiority margin within 5% of IBTR difference and 90% β-power noticing non-inferiority. The primary endpoints are breast tumor recurrence, including ipsilateral, regional, contralateral, and distant recurrence of breast DCIS or invasive cancer. The secondary endpoints are overall survival and adverse effects of RT and tamoxifen. Translational studies will also be conducted for this trial., Discussion: This is the first non-inferiority trial on breast DCIS. This study will provide an important recommendation for clinical physicians on whether to use low-dose adjuvant tamoxifen for patients with low-risk breast DCIS who do not want to receive adjuvant RT., Trial Registration: ClinicalTrials.gov, ID: NCT04046159, Registered on April 30, 2019., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background/purpose: No studies have compared between uniportal and multiportal nonintubated thoracoscopic anatomical resection for non-small cell lung cancer (NSCLC). We aimed to compare short- and long-term postoperative outcomes concerning these two methods., Methods: Our retrospective dataset comprised patients with NSCLC who underwent uniportal or multiportal nonintubated thoracoscopic anatomical resection between January 2011 and December 2019. The primary outcome was recurrence-free survival. Propensity scores were matched according to age, sex, body mass index, pulmonary function, tumor size, cancer stage, and surgical method., Results: In total, 1130 such patients underwent nonintubated video-assisted thoracoscopic surgery (VATS), and 490 consecutive patients with stage I-III NSCLC underwent nonintubated anatomical resection, including lobectomy and segmentectomy (uniportal, n = 158 [32.3%]; multiportal, n = 331 [67.7%]). The uniportal group had fewer dissected lymph nodes and lymph node stations. In paired group analysis, the uniportal group had shorter operation durations (99.8 vs. 138.2 min; P < 0.001), lower intensive care unit (ICU) admission rates and ICU admission intervals (7.0% vs. 27.8%; P < 0.001), and shorter postoperative hospital stays (4.1 days vs. 5.2 days; P < 0.001). The most common postoperative complication was prolonged air leaks. No surgical mortality was observed. The multiportal group had higher complication rates for grades ≥ II NSCLC; however, this difference was not significant (4.4% vs. 1.3%, respectively; P = 0.09)., Conclusion: Nonintubated uniportal VATS for anatomical resection had better results for some perioperative outcomes than multiportal VATS. Oncological outcomes such as recurrence-free and overall survival remained uncompromised, despite fewer dissected lymph nodes., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Context: Extremely early age at menarche, also called precocious puberty, has been associated with various cardiometabolic traits, but their shared heritability remains unclear., Objectives: This work aimed to identify new shared genetic variants and their pathways for age at menarche and cardiometabolic traits and to investigate the influence of central precocious puberty on childhood cardiometabolic traits., Methods: Using the conjunction false discovery rate method, this study analyzed genome-wide association study data from the menarche-cardiometabolic traits among 59 655 females of Taiwanese ancestry and systemically investigated pleiotropy between age at menarche and cardiometabolic traits. To support the novel hypertension link, we used the Taiwan Puberty Longitudinal Study (TPLS) to investigate the influence of precocious puberty on childhood cardiometabolic traits., Results: We discovered 27 novel loci, with an overlap between age at menarche and cardiometabolic traits, including body fat and blood pressure. Among the novel genes discovered, SEC16B, CSK, CYP1A1, FTO, and USB1 are within a protein interaction network with known cardiometabolic genes, including traits for obesity and hypertension. These loci were confirmed through demonstration of significant changes in the methylation or expression levels of neighboring genes. Moreover, the TPLS provided evidence regarding a 2-fold higher risk of early-onset hypertension that occurred in girls with central precocious puberty., Conclusion: Our study highlights the usefulness of cross-trait analyses for identifying shared etiology between age at menarche and cardiometabolic traits, especially early-onset hypertension. The menarche-related loci may contribute to early-onset hypertension through endocrinological pathways., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Genotype imputation is a commonly used technique that infers un-typed variants into a study's genotype data, allowing better identification of causal variants in disease studies. However, due to overrepresentation of Caucasian studies, there's a lack of understanding of genetic basis of health-outcomes in other ethnic populations. Therefore, facilitating imputation of missing key-predictor-variants that can potentially improve a risk health-outcome prediction model, specifically for Asian ancestry, is of utmost relevance., Methods: We aimed to construct an imputation and analysis web-platform, that primarily facilitates, but is not limited to genotype imputation on East-Asians. The goal is to provide a collaborative imputation platform for researchers in the public domain towards rapidly and efficiently conducting accurate genotype imputation., Results: We present an online genotype imputation platform, Multi-ethnic Imputation System (MI-System) (https://misystem.cgm.ntu.edu.tw/), that offers users 3 established pipelines, SHAPEIT2-IMPUTE2, SHAPEIT4-IMPUTE5, and Beagle5.1 for conducting imputation analyses. In addition to 1000 Genomes and Hapmap3, a new customized Taiwan Biobank (TWB) reference panel, specifically created for Taiwanese-Chinese ancestry is provided. MI-System further offers functions to create customized reference panels to be used for imputation, conduct quality control, split whole genome data into chromosomes, and convert genome builds., Conclusion: Users can upload their genotype data and perform imputation with minimum effort and resources. The utility functions further can be utilized to preprocess user uploaded data with easy clicks. MI-System potentially contributes to Asian-population genetics research, while eliminating the requirement for high performing computational resources and bioinformatics expertise. It will enable an increased pace of research and provide a knowledge-base for genetic carriers of complex diseases, therefore greatly enhancing patient-driven research., Statement of Significance: Multi-ethnic Imputation System (MI-System), primarily facilitates, but is not limited to, imputation on East-Asians, through 3 established prephasing-imputation pipelines, SHAPEIT2-IMPUTE2, SHAPEIT4-IMPUTE5, and Beagle5.1, where users can upload their genotype data and perform imputation and other utility functions with minimum effort and resources. A new customized Taiwan Biobank (TWB) reference panel, specifically created for Taiwanese-Chinese ancestry is provided. Utility functions include (a) create customized reference panels, (b) conduct quality control, (c) split whole genome data into chromosomes, and (d) convert genome builds. Users can also combine 2 reference panels using the system and use combined panels as reference to conduct imputation using MI-System., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rescuing patients with out-of-hospital cardiac arrest (OHCA), especially those with end-stage kidney disease (ESKD), is challenging. This study hypothesizes that OHCA patients with ESKD undergoing maintenance hemodialysis have (1) higher rates of return of spontaneous circulation (ROSC) during cardio-pulmonary resuscitation (CPR) and (2) lower rates of hyperkalemia and less severe acidosis than those without ESKD. OHCA patients who received CPR between 2011 and 2020 were dichotomized into ESKD and non-ESKD groups. The association of ESKD with "any" and "sustained" ROSC were examined using logistic regression analysis. Furthermore, the effect of ESKD on hospital outcomes for OHCA patients who survived to admission was evaluated using Kaplan-Meier analysis. ESKD patients without "any" ROSC displayed lower potassium and higher pH levels than non-ESKD patients. ESKD was positively associated with "any" ROSC (adjusted-OR: 4.82, 95% CI 2.70-5.16, P < 0.01) and "sustained" ROSC (adjusted-OR: 9.45, 95% CI 3.83-24.13, P < 0.01). Kaplan-Meier analysis demonstrated ESKD patients had a non-inferior hospital survival than non-ESKD patients. OHCA patients with ESKD had lower serum potassium level and less severe acidosis compared to the general population in Taiwan; therefore, should not be treated under the stereotypical assumption that hyperkalemia and acidosis always occur., (© 2023. The Author(s).)

Aims: Cardiovascular diseases (CVDs) are the leading cause of deaths globally. Mortality and incidence of CVDs are significantly higher in people with mood disorders. About 81.1% of CVD patients were reported with comorbidities in 2019, where the second most common comorbidity was due to major depressive disorder (MDD). This study, therefore, aimed to evaluate the genetic correlation between CVDs and mood disorders by using data from the UK Biobank towards understanding the influence of genetic factors on the comorbidity due to CVDs and mood disorders., Methods: The UK Biobank database provides genetic and health information from half a million adults, aged 40-69 years, recruited between 2006 and 2010. A total of 117,925 participants and 6,128,294 variants were included for analysis after applying exclusion criteria and quality control steps. This study focused on two CVD phenotypes, two mood disorders and 12 cardiometabolic-related traits to conduct association studies., Results: The results indicated a significant positive genetic correlation between CVDs and overall mood disorders and MDD specifically, showing substantial genetic overlap. Genetic correlation between CVDs and bipolar disorder was not significant. Furthermore, significant genetic correlation between mood disorders and cardiometabolic traits was also reported., Conclusions: The results of this study can be used to understand that CVDs and mood disorders share a great deal of genetic liability in individuals of European ancestry.

Background: Breast cancer is a prevalent disease in women, with high prevalence worldwide. The hypoxic microenvironment of solid tumors develops during the progress of carcinogenesis and leads to greater malignancy and treatment resistance. Recently, accumulating evidence indicates that non-coding RNAs, such as circular RNAs (circRNAs), play a pivotal role in altering cellular functions. However, the underlying mechanisms of circRNAs in breast cancer are still unclear. Therefore, the purpose of this study was to investigate the role of a tumor-suppressive circRNA, circAAGAB, in breast cancer by assuming down-regulation of circAAGAB under hypoxia and the properties of a tumor suppressor., Methods: Firstly, circAAGAB was identified from expression profiling by next generation sequencing. Next, the stability of circAAGAB increased by interacting with the RNA binding protein FUS. Moreover, cellular and nuclear fractionation showed that most circAAGAB resided in the cytoplasm and that it up-regulated KIAA1522, NKX3-1, and JADE3 by sponging miR-378 h. Lastly, the functions of circAAGAB were explored by identifying its down-stream genes using Affymetrix microarrays and validated by in vitro assays., Results: The results showed that circAAGAB reduced cell colony formation, cell migration, and signaling through p38 MAPK pathway, as well as increased radiosensitivity., Conclusion: These findings suggest that the oxygen-responsive circAAGAB acts as a tumor suppressor in breast cancer, and may contribute to the development of a more specific therapeutic regimen for breast cancer., (© 2023. The Author(s).)

Background: The initial diagnosis of ductal carcinoma in situ (DCIS) can be upstaged to invasive cancer after definitive surgery. This study aimed to identify risk factors for DCIS upstaging using routine breast ultrasonography and mammography (MG) and to propose a prediction model., Methods: In this single-center retrospective study, patients initially diagnosed with DCIS (January 2016-December 2017) were enrolled (final sample size = 272 lesions). Diagnostic modalities included ultrasound-guided core needle biopsy (US-CNB), MG-guided vacuum-assisted breast biopsy, and wire-localized surgical biopsy. Breast ultrasonography was routinely performed for all patients. US-CNB was prioritized for lesions visible on ultrasound. Lesions initially diagnosed as DCIS on biopsy with a final diagnosis of invasive cancer at definitive surgery were defined as "upstaged.", Results: The postoperative upstaging rates were 70.5%, 9.7%, and 4.8% in the US-CNB, MG-guided vacuum-assisted breast biopsy, and wire-localized surgical biopsy groups, respectively. US-CNB, ultrasonographic lesion size, and high-grade DCIS were independent predictive factors for postoperative upstaging, which were used to construct a logistic regression model. Receiver operating characteristic analysis showed good internal validation (area under the curve = 0.88)., Conclusions: Supplemental screening breast ultrasonography possibly contributes to lesion stratification. The low upstaging rate for ultrasound-invisible DCIS diagnosed by MG-guided procedures suggests that it is unnecessary to perform sentinel lymph node biopsy for lesions invisible on ultrasound. Case-by-case evaluation of DCIS detected by US-CNB can help surgeons determine if repeating biopsy with vacuum-assisted breast biopsy is necessary or if sentinel lymph node biopsy should accompany breast-preserving surgery., Trial Registration: This single-center retrospective cohort study was conducted with the approval of the institutional review board of our hospital (approval number 201610005RIND). As this was a retrospective review of clinical data, it was not registered prospectively., (© 2023. The Author(s).)

Background: Left ventricular mass is a highly heritable disease. Previous studies have suggested common genetic variants to be associated with left ventricular mass; however, the roles of rare variants are still unknown. We performed targeted next-generation sequencing using the TruSight Cardio panel, which provides comprehensive coverage of 175 genes with known associations to 17 inherited cardiac conditions. Methods: We conducted next-generation sequencing using the Illumina TruSight Cardiomyopathy Target Genes platform using the 5% and 95% extreme values of left ventricular mass from community-based participants. After removing poor-quality next-generation sequencing subjects, including call rate <98% and Mendelian errors, 144 participants were used for the analysis. We performed downstream analysis, including quality control, alignment, coverage length, and annotation; after setting filtering criteria for depths more than 60, we found a total of 144 samples and 165 target genes for further analysis. Results: Of the 12,287 autosomal variants, most had minor allele frequencies of <1% (rare frequency), and variants had minor allele frequencies ranging from 1% to 5%. In the multi-allele variant analyses, 16 loci in 15 genes were significant using the false discovery rate of less than .1. In addition, gene-based analyses using continuous and binary outcomes showed that three genes ( CASQ2 , COL5A1 , and FXN ) remained to be associated with left ventricular mass status. One single-nucleotide polymorphism (rs7538337) was enriched for the CASQ2 gene expressed in aorta artery ( p = 4.6 × 10-18), as was another single-nucleotide polymorphism (rs11103536) for the COL5A1 gene expressed in aorta artery ( p = 2.0 × 10-9). Among the novel genes discovered, CASQ2 , COL5A1 , and FXN are within a protein-protein interaction network with known cardiovascular genes. Conclusion: We clearly demonstrated candidate genes to be associated with left ventricular mass. Further studies to characterize the target genes and variants for their functional mechanisms are warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fan, Lin, Lu, Chen, Hsu, Yu, Su, Lin, Chen and Chien.)

Background: Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare with low-grade malignancy and unclarified clinicopathological features. This study aimed to examine their characteristics and re-evaluate current treatments., Methods: Databases from three sources were screened for patients with SPNs. We compared the perioperative variables, clinical data, overall survival (OS), and prognostic factors for recurrence among the three corresponding cohorts., Results: We identified 286 patients diagnosed with SPNs between 1988 and 2020. Patients were mostly women (81%; median age: 38 years), and peak incidence was observed in women of 20-29 years of age. SPNs had a peak incidence in Asian men at 50-59 years of age (p = 0.002) and a delayed peak incidence in Asian women at 30-39 years of age (p < 0.001). Treatment strategies differed significantly across the institutions and included variations in the number of harvested lymph nodes and rates of vascular resection. Lymph node positivity was the only predictor of postoperative recurrence (odds ratio, 2.2; 95% confidence interval, 1.38-2.99; p = 0.007). Higher rates of lymphovascular invasion (p = 0.02), perineural invasion (p < 0.001), and R1 margin involvement (p < 0.001), as seen in one institution, did not result in poorer long-term survival in terms of the overall (p = 0.43), SPN-specific (p = 0.69), and recurrence-free survivals (p = 0.067)., Conclusions: In contrast to previous findings that SPNs are prevalent in young women, a racial predilection for middle-aged Asian men and a delayed female peak incidence were noted. Parenchyma-preserving pancreatectomy may be an acceptable treatment. Non-radical surgery may be appropriate in patients with multiple comorbidities., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

End-stage renal disease (ESRD) patients on long-term hemodialysis (HD) have an elevated risk of sudden cardiac death. This study hypothesizes, for the first time, that these patients have a higher odds of return of spontaneous circulation (ROSC) and subsequent better hospital-outcomes, post out-of-hospital cardiac arrest (OHCA), as opposed to non-ESRD patients. A national database from Taiwan was utilized, in which 101,876 ESRD patients undergoing HD and propensity score-matched non-ESRD patients were used to conduct two analyses: (i) Cox-proportional-hazards-regression for OHCA incidence and (ii) logistic-regression analysis of attaining ROSC after OHCA, both for ESRD patients in comparison to non-ESRD patients. Kaplan-Meier analyses were conducted to determine the difference of survival rates after ROSC between the two cohorts. ESRD patients were found to be at a higher risk of OHCA (adjusted-HR = 2.11, 95% CI: (1.89−2.36), p < 0.001); however, they were at higher odds of attaining ROSC (adjusted-OR = 2.47, 95% CI: 1.90−3.21, p < 0.001), as opposed to non-ESRDs. Further, Kaplan-Meier analysis demonstrated ESRD patients with a better 30-day hospital survival rate than non-ESRD patients. Although ESRD patients had a higher risk of OHCA, they demonstrated higher possibility of ROSC and a better short-term hospital outcome than non-ESRDs. Chronic toxin tolerance and the training of vascular-compliance during regular HD may be possible explanations for better outcomes in ESRD patients.

Background: Availability of next generation sequencing data, allows low-frequency and rare variants to be studied through strategies other than the commonly used genome-wide association studies (GWAS). Rare variants are important keys towards explaining the heritability for complex diseases that remains to be explained by common variants due to their low effect sizes. However, analysis strategies struggle to keep up with the huge amount of data at disposal therefore creating a bottleneck. This study describes CLIN&#95;SKAT, an R package, that provides users with an easily implemented analysis pipeline with the goal of (i) extracting clinically relevant variants (both rare and common), followed by (ii) gene-based association analysis by grouping the selected variants., Results: CLIN&#95;SKAT offers four simple functions that can be used to obtain clinically relevant variants, map them to genes or gene sets, calculate weights from global healthy populations and conduct weighted case-control analysis. CLIN&#95;SKAT introduces improvements by adding certain pre-analysis steps and customizable features to make the SKAT results clinically more meaningful. Moreover, it offers several plot functions that can be availed towards obtaining visualizations for interpretation of the analyses results. CLIN&#95;SKAT is available on Windows/Linux/MacOS and is operative for R version 4.0.4 or later. It can be freely downloaded from https://github.com/ShihChingYu/CLIN&#95;SKAT , installed through devtools::install&#95;github("ShihChingYu/CLIN&#95;SKAT", force=T) and executed by loading the package into R using library(CLIN&#95;SKAT). All outputs (tabular and graphical) can be downloaded in simple, publishable formats., Conclusions: Statistical association analysis is often underpowered due to low sample sizes and high numbers of variants to be tested, limiting detection of causal ones. Therefore, retaining a subset of variants that are biologically meaningful seems to be a more effective strategy for identifying explainable associations while reducing the degrees of freedom. CLIN&#95;SKAT offers users a one-stop R package that identifies disease risk variants with improved power via a series of tailor-made procedures that allows dimension reduction, by retaining functionally relevant variants, and incorporating ethnicity based priors. Furthermore, it also eliminates the requirement for high computational resources and bioinformatics expertise., (© 2022. The Author(s).)

Background/purpose: Previously we had identified concurrent genes, which highlighted the interplay between copy number variation (CNV) and differential gene expression (GE) for Han Chinese breast cancers. The merit of the approach is to discovery biomarkers not identifiable by conventional GE only data, for which phenotype-correlation or gene variability is the criteria of gene selection., Materials and Methods: Thirty-one comparative genomic hybridization (CGH) and 83 GE microarrays were performed, with 29 breast cancers assayed from both platforms. Potential targets were revealed by Genomic Identification of Significant Targets in Cancer (GISTIC) from CGH arrays. Concurrent genes and genes with significant GISTIC scores were used to derive the extended concurrent genes signature, which was consensus from leading edge analysis across all studies and a supervised partial least square (PLS) regression predictive model of disease-free survival was constructed., Results: There were 1584 concurrent genes from 29 samples with both CGH and GE microarrays. Enriched concurrent genes sets for disease-free survival were identified independently from 83 GE arrays and another one with Han Chinese origin as well as three studies of Western origin. For five studies with disease-free survival follow up, prognostic discrepancy was observed between predicted high-risk and low-risk group patients., Conclusion: We concluded that through parallel analyses of CGH and GE microarrays, the proposed extended concurrent gene expression signature can identify biomarkers with prognostic values., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Mood disorders are an important public health issue and recent advances in genomic studies have indicated that molecules involved in neurodevelopment are causally related to mood disorders. BLM-s (BCL-2-like molecule, small transcript isoform), a BH3-only proapoptotic BCL-2 family member, mediates apoptosis of postmitotic immature neurons during embryonic cortical development, but its role in the adult brain is unknown. To better understand the physiological role of Blm-s gene in vivo, we generated a Blm-s-knockout (Blm-s -/- ) mouse. The Blm-s -/- mice breed normally and exhibit grossly normal development. However, global depletion of Blm-s is highly associated with depression- and anxiety-related behaviors in adult mutant mice with intact learning and memory capacity. Functional magnetic resonance imaging of adult Blm-s -/- mice reveals reduced connectivity mainly in the ventral dentate gyrus (vDG) of the hippocampus with no alteration in the dorsal DG connectivity and in total hippocampal volume. At the cellular level, BLM-s is expressed in DG granule cells (GCs), and Blm-s -/- mice show reduced dendritic complexity and decreased spine density in mature GCs. Electrophysiology study uncovers that mature vGCs in adult Blm-s -/- DG are intrinsically more excitable. Interestingly, certain genetic variants of the human Blm homologue gene (VPS50) are significantly associated with depression traits from publicly resourced UK Biobank data. Taken together, BLM-s is required for the hippocampal mood control function. Loss of BLM-s causes abnormality in the electrophysiology and morphology of GCs and a disrupted vDG neural network, which could underlie Blm-s-null-associated anxiety and depression., (© 2022. The Author(s).)

Hypoxia is a classic feature of the tumor microenvironment that has profound effects on cancer progression and is tightly associated with poor prognosis. Long noncoding RNAs (lncRNAs), a component of the noncoding genome, have been increasingly investigated due to their diverse roles in tumorigenesis. Previously, a hypoxia-induced lncRNA, NDRG1-OT1, was identified in MCF-7 breast cancer cells using next-generation sequencing. However, the regulatory mechanisms of NDRG1-OT1 remain elusive. Therefore, the purpose of this study was to investigate the regulatory mechanisms and functional roles of NDRG1-OT1 in breast cancer cells. Expression profiling of NDRG1-OT1 revealed that it was upregulated under hypoxia in different breast cancer cells. Overexpression and knockdown of HIF-1α up- and downregulated NDRG1-OT1, respectively. Luciferase reporter assays and chromatin immunoprecipitation assays validated that HIF-1α transcriptionally activated NDRG1-OT1 by binding to its promoter (-1773 to -1769 and -647 to -643 bp). Next, to investigate whether NDRG1-OT1 could function as a miRNA sponge, results of in silico analysis, expression profiling of predicted miRNAs, and RNA immunoprecipitation assays indicated that NDRG1-OT1 could act as a miRNA sponge of miR-875-3p. In vitro and in vivo functional assays showed that NDRG1-OT1 could promote tumor growth and migration. Lastly, a small peptide (66 a.a.) translated from NDRG1-OT1 was identified. In summary, our findings revealed novel regulatory mechanisms of NDRG1-OT1 by HIF-1α and upon miR-875-3p. Also, NDRG1-OT1 promoted the malignancy of breast cancer cells and encoded a small peptide., (© 2022. The Author(s).)

Competitive endogenous RNA (ceRNA) represents a novel mechanism of gene regulation that controls several biological and pathological processes. Recently, an increasing number of in silico methods have been developed to accelerate the identification of such regulatory events. However, there is still a need for a tool supporting the hypothesis that ceRNA regulatory events only occur at specific miRNA expression levels. To this end, we present an R package, ceRNAR, which allows identification and analysis of ceRNA-miRNA triplets via integration of miRNA and RNA expression data. The ceRNAR package integrates three main steps: (i) identification of ceRNA pairs based on a rank-based correlation between pairs that considers the impact of miRNA and a running sum correlation statistic, (ii) sample clustering based on gene-gene correlation by circular binary segmentation, and (iii) peak merging to identify the most relevant sample patterns. In addition, ceRNAR also provides downstream analyses of identified ceRNA-miRNA triplets, including network analysis, functional annotation, survival analysis, external validation, and integration of different tools. The performance of our proposed approach was validated through simulation studies of different scenarios. Compared with several published tools, ceRNAR was able to identify true ceRNA triplets with high sensitivity, low false-positive rates, and acceptable running time. In real data applications, the ceRNAs common to two lung cancer datasets were identified in both datasets. The bridging miRNA for one of these, the ceRNA for MAP4K3, was identified by ceRNAR as hsa-let-7c-5p. Since similar cancer subtypes do share some biological patterns, these results demonstrated that our proposed algorithm was able to identify potential ceRNA targets in real patients. In summary, ceRNAR offers a novel algorithm and a comprehensive pipeline to identify and analyze ceRNA regulation. The package is implemented in R and is available on GitHub (https://github.com/ywhsiao/ceRNAR)., Competing Interests: The authors have declared that no competing interests exist.

Background: In studies of stage IV epidermal growth factor receptor (EGFR)-mutant nonsmall-cell lung cancer (NSCLC), <10% of patients underwent surgery; thus, the effect of surgery in these patients remains unclear. We investigated whether primary lung tumor resection could improve the survival of patients with stage IV EGFR-mutant NSCLC without progression after first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment., Methods: This retrospective case-control study included patients treated with first-line EGFR-TKIs without progression on follow-up imaging. Patients in the surgery group (n = 56) underwent primary tumor resection, followed by TKI maintenance therapy. Patients in the control group (n = 224; matched for age, metastatic status, and Eastern Cooperative Oncology Group performance status) received only TKI maintenance therapy. Local ablative therapy for distant metastasis was allowed in both groups. The primary endpoint was progression-free survival. The secondary endpoints were overall survival, failure patterns, and complications/adverse events., Results: The median time from TKI treatment to surgery was 5.1 months. For the surgery and control groups, the median follow-up periods were 34.0 and 38.5 months, respectively, with a median (95% confidence interval) progression-free survival of 29.6 (18.9-40.3) and 13.0 (11.8-14.2) months, respectively (P < 0.001). Progression occurred in 29/56 (51.8%) and 207/224 (92.4%) patients, respectively. The median overall survival in the surgery group was not reached. The rate of surgical complications of grade ≥2 was 12.5%; complications were treated conservatively., Conclusions: Primary tumor resection is feasible for patients with EGFR-mutant nonprogressed NSCLC during first-line EGFR-TKI treatment and may improve survival better than maintenance EGFR-TKI therapy alone., (© 2022. Society of Surgical Oncology.)

Airborne fungal spores are important aeroallergens that are remarkably diverse in terms of taxonomic richness. Indoor fungal richness is dominated by outdoor fungi and is geographically patterned, but the influence of natural landscape is unclear. We aimed to elucidate the relationship between indoor fungal spore richness and natural landscape by examining the amount of surrounding forest cover. Passive sampling of airborne fungal spores was conducted in 24 schools in Taiwan during hot and cool seasons, and amplicon sequencing was used to study fungal spore (genus) richness targeting the internal transcribed spacer 2 (ITS2) region. In total, 693 fungal genera were identified, 12 of which were ubiquitous. Despite overall similarity of fungal spore richness between seasons, Basidiomycota and Ascomycota richness increased during the hot and cool seasons, respectively. Fungal spore richness in schools had a strong positive correlation with the amount of surrounding forest cover during the cool season, but not during the hot season. Fungal assemblages in schools were more similar during the hot season due to the increased ubiquity of Agaricomycetes genera. These observations indicate dispersal limitation at the kilometer scale during the cool season and increased long-distance dispersal during the hot season. Several allergenic fungi were commonly identified in schools, including some previously overlooked by conventional methods, which may be targeted as sensitizing agents in future investigations into atopic conditions. More generally, the relative importance of fungal spore richness in the development, chronicity, and severity of atopic conditions in children requires investigation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Despite the brain's high demand for energy, research on its epigenetics focuses on nuclear methylation, and much of the mitochondrial DNA methylation remains seldom investigated. With a focus on the nucleus accumbens (NAcc) and the prefrontal cortex (PFC), we aimed to identify the mitochondrial methylation signatures for (1) distinguishing the two brain areas, (2) correlating with aging, and (3) reflecting the influence of illicit drugs on the brain., Result: We collected the brain tissue in the NAcc and the PFC from the deceased individuals without (n = 39) and with (n = 14) drug use and used whole-genome bisulfite sequencing to cover cytosine sites in the mitochondrial genome. We first detected differential methylations between the NAcc and the PFC in the nonusers group (P = 3.89 × 10 -9 ). These function-related methylation differences diminished in the drug use group due to the selective alteration in the NAcc. Then, we found the correlation between the methylation levels and the chronological ages in the nonusers group (R 2  = 0.34 in the NAcc and 0.37 in the PFC). The epigenetic clocks in illicit drug users, especially in the ketamine users, were accelerated in both brain regions by comparison with the nonusers. Finally, we summarized the effect of the illicit drugs on the methylation, which could significantly differentiate the drug users from the nonusers (AUC = 0.88 in the NAcc, AUC = 0.94 in the PFC)., Conclusion: The mitochondrial methylations were different between different brain areas, generally accumulated with aging, and sensitive to the effects of illicit drugs. We believed this is the first report to elucidate comprehensively the importance of mitochondrial DNA methylation in human brain., (© 2022. The Author(s).)

Introduction: In most developed countries, lung cancer is associated with the highest mortality rate among all cancers. The number of elderly patients with lung cancer is increasing, reflecting the global increase in aging population. Patients with impaired lung or cardiac function are at a high risk during intubated general anesthesia, which may preclude them from surgical lung cancer treatment. We evaluated the safety and survival of non-intubated video-assisted thoracoscopic surgery (VATS) versus those of intubated thoracoscopic surgery for surgical resection for lung cancer in older patients., Methods: Patients aged ≥75 years who underwent non-intubated and intubated VATS resection with pathologically confirmed non-small cell lung cancer, using a combination of thoracic epidural anesthesia or intercostal nerve block and intra-thoracic vagal block with target-controlled sedation, from January 2011 to December 2019 were included. Ultimately, 79 non-intubated patients were matched to 158 patients based on age, sex, body mass index, family history, comorbidity index, pulmonary function (forced expiratory volume in one second/ forced vital capacity [%]), and disease stage. The endpoints were overall survival and recurrence progression survival., Results: All patients had malignant lung lesions. Data regarding conversion data and the postoperative result were collected. Both groups had comparable preoperative demographic and cancer staging profiles. The anesthetic duration in the non-intubated group was shorter than that in the intubated group, which showed a significantly higher mean number of lymph nodes harvested (intubated vs non-intubated, 8.3 vs. 6.4) and lymph stations dissected (3.0 vs. 2.6). Intensive care unit (ICU) admission rate and postoperative ICU stay were significantly longer in the intubated group. The complication rate was higher and hospital stay were longer in the intubated group, but these differences were not significant (12% vs. 7.6%; p  = .07, respectively)., Conclusions: In the elderly, non-intubated thoracoscopic surgery provides similar survival results as the intubated approach, although fewer lymph nodes are harvested. Non-intubated surgery may serve as an alternative to intubated general anesthesia in managing lung cancer in carefully selected elderly patients with a high risk of impaired pulmonary and cardiac function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Chuang, Lu, Hung, Liao, Tsai, Lin, Chen, Hsu and Chen.)

Rationale and Objective: Gut microbiota have been targeted by alternative therapies for non-communicable diseases. We examined the gut microbiota of a healthy Taiwanese population, identified various bacterial drivers in different demographics, and compared them with dialysis patients to associate kidney disease progression with changes in gut microbiota., Study Design: This was a cross-sectional cohort study., Settings and Participants: Fecal samples were obtained from 119 healthy Taiwanese volunteers, and 16S rRNA sequencing was done on the V3-V4 regions to identify the bacterial enterotypes. Twenty-six samples from the above cohort were compared with fecal samples from 22 peritoneal dialysis and 16 hemodialysis patients to identify species-level bacterial biomarkers in the dysbiotic gut of chronic kidney disease (CKD) patients., Results: Specific bacterial species were identified pertaining to different demographics such as gender, age, BMI, physical activity, and sleeping habits. Dialysis patients had a significant difference in gut microbiome composition compared to healthy controls. The most abundant genus identified in CKD patients was Bacteroides , and at the species level hemodialysis patients showed significant abundance in B. ovatus , B. caccae, B. uniformis , and peritoneal dialysis patients showed higher abundance in Blautia producta (p ≤ 0.05) than the control group. Pathways pertaining to the production of uremic toxins were enriched in CKD patients. The abundance of the bacterial species depended on the type of dialysis treatment., Conclusion: This study characterizes the healthy gut microbiome of a Taiwanese population in terms of various demographics. In a case-control examination, the results showed the alteration in gut microbiota in CKD patients corresponding to different dialysis treatments. Also, this study identified the bacterial species abundant in CKD patients and their possible role in complicating the patients' condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shivani, Kao, Chattopadhyay, Chen, Lai, Lin, Lu, Huang, Tsai, Teng, Wu, Hsieh, Wang and Chuang.)

Inflammatory leiomyosarcoma is a rare myogenic tumor with striking inflammatory infiltrates and a specific genomic pattern of near-haploidization despite exception(s). Recent studies demonstrated that inflammatory leiomyosarcoma shares substantially overlapping features with histiocyte-rich rhabdomyoblastic tumor, including expression of rhabdomyoblastic markers such as myogenin, MyoD1, and PAX7 and a high prevalence of genomic near-haploidization, suggesting that they represent a unifying entity, for which the term inflammatory rhabdomyoblastic tumor was coined. In this study, we identified 4 pulmonary tumors histologically typical of inflammatory leiomyosarcomas, all in men (aged 26 to 49), presented as slow-growing well-defined nodules ranging from 1.4 to 3.5 cm, and following uneventful postoperative courses. All tumors were positive for desmin immunostaining, while only 1 and 2 were focally positive for smooth muscle actin and smooth muscle myosin heavy chain, respectively. They showed no expression of myogenin, MyoD1, or PAX7 by immunohistochemistry or RNA sequencing. Copy number analyses by whole-exome sequencing (N=1), OncoScan single-nucleotide polymorphism array (2), and fluorescence in situ hybridization (1) revealed/suggested diploid genomes. Together with a previously reported case, all these pulmonary "inflammatory leiomyosarcomas" seemed clinically, pathologically, and genomically alike. Despite a superficial resemblance to conventional inflammatory leiomyosarcoma in somatic soft tissues (now preferably termed inflammatory rhabdomyoblastic tumor), they differ in the lack of convincing rhabdomyoblastic differentiation and genomic near-haploidization. Therefore, we propose that these pulmonary tumors probably represent a distinct entity, for which the exact line of differentiation, and perhaps the most suitable terminology to better reflect its nature, remains to be determined. The term inflammatory rhabdomyoblastic tumor seems inappropriate for this group of tumors., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by the research fund from the Ministry of Science and Technology, Taiwan (MOST 106-2320-B-002-028-MY3) and National Taiwan University Hospital (NTUH 108-S4295) to J.-C.L. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Pancreatic cancer is one of the most malignant cancers with poor survival. The latest edition of the American Joint Committee on Cancer (AJCC) staging system classifies the majority of operable pancreatic cancer patients as stage-III, while dramatic heterogeneity is observed among these patients. Therefore, subgrouping is required to accurately predict their prognosis and define a treatment plan. This study conducts a cohort study to provide a more precise classification system for stage-III pancreatic cancer patients by utilizing clinical variables., Methods: We analyzed survival using log-rank tests, univariate Cox-regression models, and Kaplan-Meier survival curves for stage-III pancreatic ductal adenocarcinoma (PDAC) patients from the Taiwan Cancer Registry (TCR). Patients were further divided into subgroups using classification and regression tree (CART) algorithm. All results were validated using the SEER database., Results: Among stage-III PDAC patients, lymph node and tumor grade showed significant association with survival. Patients with N2 stage had higher mortality risks (hazard ratio [HR] = 2.30, 95% confidence interval [CI] 1.71-3.08, p < 0.0001) than N0 patients. Patients with grade 3 also had higher risk of mortality (HR = 3.80, 95% CI 2.25-6.39, p < 0.0001) than grade 1 patients. The CART algorithm stratified stage-III patients into four subgroups with significantly different survival rates. The median survival of the four subgroups was 23.5, 18.4, 14.5, and 9.0 months, respectively (p < 0.0001). Similar results were observed with SEER data., Conclusions: Lymph node involvement and tumor grade are predictive factors for survival in stage-III PDAC patients. This new precise classification system can be used to guide treatment planning in advanced-stage pancreatic cancer., (© 2021. The Author(s).)

Purpose: Colon cancer is the third most incident and life-threatening cancer in Taiwan. A comprehensive survival prediction system would greatly benefit clinical practice in this area. This study was designed to develop an accurate prognostic model for colon cancer patients by using clinicopathological variables obtained from the Taiwan Cancer Registry database., Methods: We analyzed 20,218 colon cancer patients from the Taiwan Cancer Registry database, who were diagnosed between 2007 and 2015, were followed up until December 31, 2017, and had undergone curative surgery. We proposed two prognostic models, with different combinations of predictors. The first model used only traditional clinical features. The second model included several colon cancer site-specific factors (circumferential resection margin, perineural invasion, obstruction, and perforation), in addition to the traditional features. Both prediction models were developed by using a Cox proportional hazards model. Furthermore, we investigated whether race is a significant predictor of survival in colon cancer patients by using Model 1 on the Surveillance, Epidemiology, and End Results (SEER) cancer registry dataset., Results: The proposed models displayed a robust prediction performance (all Harrell's c-index >0.8). For both the calibration and validation steps, the differences between the predicted and observed mortality were mostly less than 5%., Conclusions: The prediction model (Model 1) is an effective predictor of survival regardless of the ethnic background of patients and can potentially help to provide better prediction of colon cancer-specific survival outcomes, thus allowing physicians to improve treatment plans., (© 2021. Society of Surgical Oncology.)

Semaphorin 5A (SEMA5A), which was originally identified as an axon guidance molecule in the nervous system, has been subsequently identified as a prognostic biomarker for lung cancer in nonsmoking women. SEMA5A acts as a tumor suppressor by inhibiting the proliferation and migration of lung cancer cells. However, the regulatory mechanism of SEMA5A is not clear. Therefore, the purpose of the present study was to explore the roles of different domains of SEMA5A in its tumor‑suppressive effects in lung adenocarcinoma cell lines. First, it was revealed that overexpression of full length SEMA5A or its extracellular domain significantly inhibited the proliferation and migration of both A549 and H1299 cells using MTT, colony formation and gap closure assays. Next, microarray analyses were performed to identify genes regulated by different domains of SEMA5A. Among the differentially expressed genes, the most significant function of these genes that were enriched was the 'Interferon Signaling' pathway according to Ingenuity Pathway Analysis. The activation of the 'Interferon Signaling' pathway was validated by reverse transcription‑quantitative PCR and western blotting. In summary, the present study demonstrated that the extracellular domain of SEMA5A could upregulate genes in interferon signaling pathways, resulting in suppressive effects in lung adenocarcinoma cells.