Polygenic risk score predicting susceptibility and outcome of benign prostatic hyperplasia in the Han Chinese.

BACKGROUND: Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. METHODS: A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. RESULTS: Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274-1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. CONCLUSIONS: In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.

The Expression of TP63 as a Biomarker of Early Recurrence in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy.

Esophageal cancer ranks among the ten most common cancers worldwide. Despite the adoption of neoadjuvant concurrent chemoradiotherapy (nCCRT) followed by surgery as the standard treatment approach in recent years, the local recurrence rate remains high. In this study, we employed RNA-seq to investigate distinctive gene expression profiles in esophageal squamous cell carcinoma (ESCC) with or without recurrence following a standard treatment course. Our findings indicate that recurrent ESCC exhibits heightened keratinizing and epidermis development activity compared to non-recurrent ESCC. We identified TP63 as a potential candidate for distinguishing clinical outcomes. Furthermore, immunohistochemistry confirmed the trend of TP63 overexpression in ESCC recurrence. Patients with elevated TP63 expression had poorer overall survival and lower 3-year recurrence-free survival. This study underscores the potential of TP63 as a biomarker for detecting cancer recurrence and suggests its role in guiding future treatment options.

Predicting drug response through tumor deconvolution by cancer cell lines.

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.

Polygenic Risk Score Predicts Earlier-Onset Adult Systemic Lupus Erythematosus and First-Year Renal Diseases in a Taiwanese Cohort.

OBJECTIVES: This study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population. METHODS: Patients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE. RESULTS: In the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p<0.01), higher Systemic Lupus Erythematosus Disease Activity Index scores (3.00 vs 2.37, p=0.04), elevated risks of renal involvement within the first year of SLE diagnosis, including WHO class III-IV lupus nephritis (OR 2.36, 95% CI 1.47 to 3.80, p<0.01), estimated glomerular filtration rate <60 mL/min/1.73m2 (OR 1.49, 95% CI 1.18 to 1.89, p<0.01) and urine protein-to-creatinine ratio >150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p<0.01), along with increased seropositivity risks, compared with those in the lowest quartile. Furthermore, among patients with SLE with onset before 50 years, the highest PRS quartile was significantly associated with more serious renal diseases within the first year of SLE diagnosis. CONCLUSIONS: PRS of SLE is associated with earlier onset, renal involvement within the first year of SLE diagnosis and seropositivity in Taiwanese patients. Integrating PRS with clinical decision-making may enhance lupus nephritis screening and early treatment to improve renal outcomes in patients with SLE.

Polygenic risk score-based prediction of breast cancer risk in Taiwanese women with dense breast using a retrospective cohort study.

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.

Genetic mutation patterns among glioblastoma patients in the Taiwanese population - insights from a single institution retrospective study.

This study utilized Next-Generation Sequencing (NGS) to explore genetic determinants of survival duration in Glioblastoma Multiforme (GBM) patients. We categorized 30 primary GBM patients into two groups based on their survival periods: extended survival (over two years, N = 17) and abbreviated survival (under two years, N = 13). For identifying pathogenic or likely pathogenic variants, we leveraged the ClinVar database. The cohort, aged 23 to 66 (median: 53), included 17 patients in Group A (survival >2 years, 10 males, 7 females), and 13 patients in Group B (survival <2 years, 8 males, 5 females), with a 60% to 40% male-to-female ratio. Identified mutations included CHEK2 (c.1477 G > A, p.E493K), IDH1 (c.395 G > A, p.R132H), and TP53 mutations. Non-coding regions exhibited variants in the TERT promoter (c.-146C > T, c.-124C > T) and TP53 RNA splicing site (c.376-2 A > C, c.376-2 A > G). While Group A had more mutations, statistical significance wasn't reached, likely due to sample size. Notably, TP53, and ATR displayed a trend toward significance. Surprisingly, TP53 mutations were more prevalent in Group A, contradicting Western findings on poorer GBM prognosis. In Taiwanese GBM patients, bevacizumab usage is linked to improved survival rates, affirming its safety and effectiveness. EGFR mutations are infrequent, suggesting potential distinctions in carcinogenic pathways. Further research on EGFR mutations and amplifications is essential for refining therapeutic approaches. TP53 mutations are associated with enhanced survival, but their functional implications necessitate detailed exploration. This study pioneers genetic analysis in Taiwanese GBM patients using NGS, advancing our understanding of their genetic landscape.

Machine learning approaches to identify systemic lupus erythematosus in anti-nuclear antibody-positive patients using genomic data and electronic health records.

BACKGROUND: Although the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE) has required at least a positive anti-nuclear antibody (ANA) titer (≥ 1:80), it remains challenging for clinicians to identify patients with SLE. This study aimed to develop a machine learning (ML) approach to assist in the detection of SLE patients using genomic data and electronic health records. METHODS: Participants with a positive ANA (≥ 1:80) were enrolled from the Taiwan Precision Medicine Initiative cohort. The Taiwan Biobank version 2 array was used to detect single nucleotide polymorphism (SNP) data. Six ML models, Logistic Regression, Random Forest (RF), Support Vector Machine, Light Gradient Boosting Machine, Gradient Tree Boosting, and Extreme Gradient Boosting (XGB), were used to identify SLE patients. The importance of the clinical and genetic features was determined by Shapley Additive Explanation (SHAP) values. A logistic regression model was applied to identify genetic variations associated with SLE in the subset of patients with an ANA equal to or exceeding 1:640. RESULTS: A total of 946 SLE and 1,892 non-SLE controls were included in this analysis. Among the six ML models, RF and XGB demonstrated superior performance in the differentiation of SLE from non-SLE. The leading features in the SHAP diagram were anti-double strand DNA antibodies, ANA titers, AC4 ANA pattern, polygenic risk scores, complement levels, and SNPs. Additionally, in the subgroup with a high ANA titer (≥ 1:640), six SNPs positively associated with SLE and five SNPs negatively correlated with SLE were discovered. CONCLUSIONS: ML approaches offer the potential to assist in diagnosing SLE and uncovering novel SNPs in a group of patients with autoimmunity.

Prevalence and prognosis of genetically proven familial hypercholesterolemia in subjects with coronary artery disease and reduced ejection fraction.

Few studies have genetically screened variants related to familial hypercholesterolemia (FH) and investigated their survival impact in patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (EF). Patients with CAD and reduced EF (< 40%) were enrolled. Their genomic DNAs were sequenced for FH-related genes. All-cause and cardiovascular mortality data served as the major outcome. A total of 256 subjects were analyzed and 12 subjects (4.7%) carried FH-related genetic variants. After a median follow-up period of 44 months, 119 of the study subjects died. Cox survival analysis showed that carrying the FH genetic variant did not have a significant impact on the survival of CAD with reduced EF. However, higher estimated glomerular filtration rate (eGFR), better EF and beta blocker use were protective for a lower all-cause mortality. Further larger studies are needed to evaluate the impact of carrying the FH-related genetic variant on survival of CAD with reduced EF.

Clinical Features and Outcomes of Primary Breast Diffuse Large B-Cell Lymphoma: A Matched-Pair Study.

Background: The influence of the breast as the primary site on the outcome of diffuse large B-cell lymphoma (DLBCL) and further changes in therapeutic strategies remain unclear. We aimed to compare the outcomes between primary breast and non-breast DLBCL and analyze the genetic profiles of some of the study cohorts using next-generation sequencing. Methods: This matched-pair study reviewed the medical records of 19 patients with stage I and II primary breast DLBCL diagnosed between January 2005 and December 2021 on the basis of the Wiseman and Liao criteria, and we used 1:4 propensity score matching to identify patients with non-breast DLBCL as the control group. The overall response rate, progression-free survival (PFS), and overall survival (OS) were the outcome measures. Results: Patients with primary breast and non-breast DLBCL had a 5-year PFS of 72.6% and 86.9%, respectively (P = .206). These 2 groups also had comparable 5-year OS (86.9% vs 87.8%; P = .772). The breast as the primary site was not associated with inferior PFS (hazard ratio [HR]: 2.14; 95% CI: 0.66-6.96; P = .206) and OS (HR: 1.26; 95% CI: 0.27-5.93; P = .772). Conclusion: Patients with primary breast DLBCL and those with non-breast DLBCL had comparable PFS and OS under rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens. Further investigations of the mutation profile, its clinical impact, potential central nervous system relapse, and prognosis of primary breast DLBCL are required.

Risk Prediction of Chronic Rhinosinusitis with or without Nasal Polyps in Taiwanese Population Using Polygenic Risk Score for Nasal Polyps.

The association between single nucleotide polymorphisms and chronic rhinosinusitis (CRS) has been determined. However, it was not known whether the polygenic risk score (PRS) for nasal polyps (NP) could predict CRS with NP (CRSwNP) or without NP (CRSsNP). The aim of this study was to investigate the association between PRSs for NP and the risk of CRS with or without NP. Data from 535 individuals with CRS and 5350 control subjects in the Taiwan Precision Medicine Initiative project were collected. Four PRSs for NP, including PGS000933, PGS000934, PGS001848, and PGS002060 from UK Biobank, were tested in these participants. They were divided into four groups according to quartiles of PRSs. The logistic regression model was performed to evaluate CRSwNP and CRSsNP risk according to PRSs for NP. The PGS002060 had the highest area under the curve at 0.534 for CRSsNP prediction and at 0.588 for CRSwNP prediction. Compared to subjects in the lowest PRS category, the PGS002060 significantly increased the odds for CRSsNP by 1.48 at the highest quintile (p = 0.003) and by 2.32 at the highest quintile for CRSwNP (p = 0.002). In addition, the odds for CRSwNP increased by 3.01 times in female CRSwNP patients (p = 0.009) at the highest quintile compared with those in the lowest PRS category. The PRSs for NP developed from European populations could be applied to the Taiwanese population to predict CRS risk, especially for female CRSwNP.

CYP2C19 genotypes and osteoporotic fractures in long-term users of proton pump inhibitors: A hospital-based study.

Proton pump inhibitors (PPIs) are commonly prescribed medications. The existing data suggest that individuals at a high risk of fractures have been exposed to high doses of PPIs for prolonged durations. CYP2C19 plays a pivotal role in metabolism of PPIs and thereby influences their pharmacokinetic profile. Hence, we hypothesize that CYP2C19 genotypes may be associated with fragility fracture among PPIs users due to PPI exposure. This study aimed to investigate the association between CYP2C19 genotypes, bone mineral density (BMD), and osteoporotic fracture in a hospital-based population. This retrospective cohort study enrolled patients who were prescribed long-term PPIs at Taichung Veterans General Hospital using data extracted from the Taiwan Precision Medicine Initiative between January 2010 and April 2021. Associations between CYP2C19 phenotypes, comorbidities, and fractures in PPI users were analyzed. We enrolled 1518 long-term PPI users; 571 (38%), 727 (48%), and 220 (14%) CYP2C19 normal metabolizers (NMs), intermediate metabolizers (IMs), and poor metabolizers (PMs), respectively. Among them, 49 (3.2%) patients developed fractures within the 1-year follow-up period; 20 (3.5%) fractures in NMs, 24 (3.3%) in IMs, and 5 (2.3%) in PMs, respectively. No significant difference was observed among CYP2C19 genotypes and fracture. Additionally, BMD measurements during the 1-year follow-up period were made available among 75 participants. No significant difference in BMD between CYP2C19 PMs and non-PMs was found. This real-world, hospital-based study concludes that CYP2C19 PMs/IMs are not associated with an increased risk for fractures or reduced BMD in individuals on long-term PPI therapy.

GJB2 p.V37I Mutation Associated With Moderate Nonsyndromic Hearing Loss in an Adult Taiwanese Population.

BACKGROUND: Gap junction protein beta 2 ( GJB2 ) p.V37I mutations are the most important hereditary cause of sensorineural hearing loss (SNHL) in Taiwan. Hearing outcomes are associated with hearing levels at baseline and the duration of follow-up. However, the audiological features of GJB2 p.V37I mutations in the adult population are unknown. The objectives of the present study were to investigate the audiological features, progression rate, and allele frequency of GJB2 p.V37I mutations among an adult Taiwanese population. METHODS: Subjects of this case-control study were chosen from 13,580 participants of the Taiwan Precision Medicine Initiative. The genetic variations of GJB2 p.V37I were determined by polymerase chain reaction. We analyzed existing pure-tone threshold data from 38 individuals who were homozygous or compound heterozygotes for GJB2 p.V37I, 129 who were heterozygotes, and 602 individuals who were wild-type. Phenome-wide association studies (PheWAS) analysis was also performed to identify phenotypes associated with GJB2 p.V37I. RESULTS: The minor allele frequency of GJB2 p.V37I was 0.92% in our study population. The mean hearing level of participants with a p.V37I mutation indicated moderate to severe hearing loss with 38.2% ± 22.3% binaural hearing impairment. GJB2 p.V37I was associated with an increased risk of hearing disability (odds ratio: 21.46, 95% confidence interval: 8.62 to 53.44, p < 0.001) in an autosomal recessive pattern. In addition, PheWAS discovered a significant association between GJB2 p.V37I and fracture of the humerus. GJB2 p.V37I is a pathogenic and prevalent variant of SNHL among the adult population. CONCLUSIONS: The present study recommends patients with known GJB2 p.V37I mutations receive regular audiometric evaluation and genetic counseling. Early assistive listening device intervention is suggested to improve the quality of hearing.

Multi-ethnic Imputation System (MI-System): A genotype imputation server for high-dimensional data.

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.

The Prevalence and Features of Medications With Actionable Pharmacogenomic Biomarkers Prescribed to Kidney Transplant Recipients.

BACKGROUND: Genetic variants are associated with pharmacokinetic and pharmacodynamic changes, leading to variability in drug effects and safety profiles in the clinical response. The role of genetic variants in kidney transplant recipients (KTRs) has not been extensively studied. Here, we explored the potential of incorporating pharmacogenomic (PGx) gene biomarkers into prescription practices for KTRs. METHODS: This study analyzed 490 KTRs participating in the Taiwan Precision Medicine Initiative program and used medications with actionable PGx biomarkers. The analysis included prescriptions issued between January 2000 and December 2021 with 206 CPIC-recommended level A or B gene-drug pairs, encompassing 363 single or combination drug products. RESULTS: All KTRs had the potential to receive at least one prescription that could be adjusted based on their genetic profiles after the day of surgery. The top 5 medications prescribed within the first 3 months after transplantation were mycophenolic acid, tacrolimus, pantoprazole, labetalol, and tramadol. These findings highlight the significant potential of PGx-guided prescriptions for KTRs. Additionally, some drug-gene pairs, such as tramadol/CYP2D6, pantoprazole/CYP2C19, and atorvastatin/SLCO1B1, were considered high-quality evidence by the Clinical Pharmacogenetics Implementation Consortium and were included in the Food and Drug Administration's drug labels, indicating that they have the potential for clinical application. CONCLUSIONS: Overall, this study demonstrated the potential of incorporating PGx gene biomarkers into prescribing practices for KTRs, which could improve personalized pharmacotherapy for these patients.

Genome-wide association study and identification of systemic comorbidities in development of age-related macular degeneration in a hospital-based cohort of Han Chinese.

Background: Age-related macular degeneration (AMD) is the main cause of severe vision loss in elderly populations of the developed world with limited therapeutic medications available. It is a multifactorial disease with a strong genetic susceptibility which exhibits the differential genetic landscapes among different ethnic groups. Methods: To investigate the Han Chinese-specific genetic variants for AMD development and progression, we have presented a genome-wide association study (GWAS) on 339 AMD cases and 3,390 controls of a Han Chinese population recruited from the Taiwan Precision Medicine Initiative (TPMI). Results: In this study, we have identified several single nucleotide polymorphisms (SNPs) significantly associated with AMD, including rs10490924, rs3750848, and rs3750846 in the ARMS2 gene, and rs3793917, rs11200638, and rs2284665 in the HTRA1 gene, in which rs10490924 was highly linked to the other variants based upon linkage disequilibrium analysis. Moreover, certain systemic comorbidities, including chronic respiratory diseases and cerebrovascular diseases, were also confirmed to be independently associated with AMD. Stratified analysis revealed that both non-exudative and exudative AMD were significantly correlated with these risk factors. We also found that homozygous alternate alleles of rs10490924 could lead to an increased risk of AMD incidence compared to homozygous references or heterozygous alleles in the cohorts of chronic respiratory disease, cerebrovascular disease, hypertension, and hyperlipidemia. Ultimately, we established the SNP models for AMD risk prediction and found that rs10490924 combined with the other AMD-associated SNPs identified from GWAS improved the prediction model performance. Conclusion: These results suggest that genetic variants combined with the comorbidities could effectively identify any potential individuals at a high risk of AMD, thus allowing for both early prevention and treatment.

Whole transcriptome analysis to explore the impaired immunological features in critically ill elderly patients with sepsis.

BACKGROUND: Sepsis is a frequent complication in critically ill patients, is highly heterogeneous and is associated with high morbidity and mortality rates, especially in the elderly population. Utilizing RNA sequencing (RNA-Seq) to analyze biological pathways is widely used in clinical and molecular genetic studies, but studies in elderly patients with sepsis are still lacking. Hence, we investigated the mortality-relevant biological features and transcriptomic features in elderly patients who were admitted to the intensive care unit (ICU) for sepsis. METHODS: We enrolled 37 elderly patients with sepsis from the ICU at Taichung Veterans General Hospital. On day-1 and day-8, clinical and laboratory data, as well as blood samples, were collected for RNA-Seq analysis. We identified the dynamic transcriptome and enriched pathways of differentially expressed genes between day-8 and day-1 through DVID enrichment analysis and Gene Set Enrichment Analysis. Then, the diversity of the T cell repertoire was analyzed with MiXCR. RESULTS: Overall, 37 patients had sepsis, and responders and non-responders were grouped through principal component analysis. Significantly higher SOFA scores at day-7, longer ventilator days, ICU lengths of stay and hospital mortality were found in the non-responder group, than in the responder group. On day-8 in elderly ICU patients with sepsis, genes related to innate immunity and inflammation, such as ZDHCC19, ALOX15, FCER1A, HDC, PRSS33, and PCSK9, were upregulated. The differentially expressed genes (DEGs) were enriched in the regulation of transcription, adaptive immune response, immunoglobulin production, negative regulation of transcription, and immune response. Moreover, there was a higher diversity of T-cell receptors on day-8 in the responder group, than on day-1, indicating that they had better regulated recovery from sepsis compared with the non-response patients. CONCLUSION: Sepsis mortality and incidence were both high in elderly individuals. We identified mortality-relevant biological features and transcriptomic features with functional pathway and MiXCR analyses based on RNA-Seq data; and found that the responder group had upregulated innate immunity and increased T cell diversity; compared with the non-responder group. RNA-Seq may be able to offer additional complementary information for the accurate and early prediction of treatment outcome.

Chemoresistance in acute myeloid leukemia: An alternative single-cell RNA sequencing approach.

Our previous study demonstrated that myc, mitochondrial oxidative phosphorylation, mTOR, and stemness are independently responsible for chemoresistance in acute myeloid leukemia (AML) cells. This study aimed to identify potential mechanisms of chemoresistance of the "7 + 3" induction in AML by using a single-cell RNA sequencing (scRNA-seq) approach. In the present study, 13 untreated patients with de novo AML were enrolled and stratified into two groups: complete remission (CR; n = 8) and non-CR (n = 5). Single-cell RNA sequencing was used to analyze genetic profiles of 28,950 AML cells from these patients; results were validated using a previously published bulk RNA-seq dataset. Our study results showed chemoresistant AML cells had premature accumulation during early hematopoiesis. Hematopoietic stem cell-like cells from the non-CR group expressed more leukemic stem cell markers (CD9, CD82, IL3RA, and IL1RAP) than those from the CR group. Chemoresistant progenitor cells had impaired myeloid differentiation owing to early arrest of hematopoiesis. Notably, AML cells analyzed by scRNA-seq and bulk RNA-seq harbored a comparable myeloid lineage cell fraction, which internally validated our results. Using the TCGA database, our analysis demonstrated that patients with AML with higher expression of chemoresistant genetic markers (IL3RA and IL1RAP) had a worse overall survival (p < 0.01 for IL3RA; p < 0.05 for IL1RAP). In conclusion, AML cells responsive and resistant to the "7 + 3" induction were derived from a diverse cancerous hematopoietic stem cell population, as indicated by the specific genetic biomarkers obtained using scRNA-seq approach. Furthermore, arrest of hematopoiesis was shown to occur earlier in chemoresistant AML cells, furthering the current understanding of chemoresistance in AML.

Perinatal lethal Gaucher disease due to compound heterozygosity of the splicing mutations in GBA gene.

OBJECTIVE: In order to figure out the cause for two consecutive fetuses with nonimmune hydrops fetalis (NIHF) in a Taiwanese couple, whole-Exome Sequencing and Sanger Sequencing were applied for the family. CASE REPORT: The two fetuses developed NIHF at gestation age of 19 and 21 weeks, respectively. The clinical features included ascites and pleural effusion, flattened nasofrontal angle, skin edema, clenched hands, ambiguous genitalia, hepatosplenomegaly and fetal thrombocytopenia. Magnetic resonance imaging of the brain showed cerebellar hypoplasia and delayed cortical maturation. The GBA deleterious variants c.1505+5G > C and c.308-1G > A were both detected in the two fetuses. CONCLUSION: The report provided the precious experience of the clinical presentation of perinatal lethal Gaucher disease (PLGD) and advice on reproductive medicine for the next pregnancy in a couple. The novel genetic mutations identified in the study also contribute to the known spectrum of PLGD-related mutations.

Impacts of ADH1B rs1229984 and ALDH2 rs671 polymorphisms on risks of alcohol-related disorder and cancer.

BACKGROUND: ADH1B rs1229984 and ALDH2 rs671 are the specifically prevalent functional variants in the East Asians. These variants, which result in a dramatic change in enzyme activity, are highly associated with alcohol-related disorders and cancer. Previous studies focusing on the additive and synergic effects of the variants are few and inconsistent. The aim of the research was to evaluate the associations of ADH1B rs1229984 and ALDH2 rs671 with the risks of alcohol-related disorder and cancer. METHODS: This cohort study enrolled 42,665 participants from the Taiwan Precision Medicine Initiative database, including 19,522 and 20,534, ADH1B and ALDH2 carriers, respectively. The associations between the two variants and cancer risk were analyzed by univariable and multivariable logistic regression. RESULTS: Compared with the noncarriers, the ADH1B rs1229984 variant had a stronger effect on alcohol-related disorders and was related to an increased risk of alcohol-related cancers. The CC genotype of ADH1B rs1229984 was significantly associated with cancer of the larynx, pharynx, and nasal cavities [odds ratio (OR) = 1.56, p = 0.0009], cancer of the pancreas (OR = 1.66, p = 0.018), and cancer of the esophagus (OR = 4.10, p < 0.001). Participants who carried the rs1229984 TC/CC and rs671 GG genotypes were at higher risk of esophageal cancer (OR = 3.02, p < 0.001). The risk of esophageal cancer was increased by 381% (OR = 4.81, p < 0.001) in those carrying the rs1229984 TC/CC and rs671 GA/AA genotypes. CONCLUSION: rs1229984 and rs671 are common and functionally important genetic variants in the Taiwanese population. Our findings provide strong evidence of additive and synergic risks of ADH1B and ALDH2 variants for alcohol-related disorders and cancer. The results suggested that are reduction in alcohol consumption should be advised as a preventive measure for high-risk patients carrying ADH1B rs1229984 C or the ALDH2 rs671 A allele.