We previously reported initial results in 102 multiple myeloma (MM) patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m2 and allogeneic hematopoietic cell transplantation. Here we present long-term clinical outcomes among the 102 initial patients and among 142 additional patients, with a median follow up of 8.3 (range 1.0-18.1) years. Donors included human leukocyte antigen identical siblings (n=179) and HLA-matched unrelated donors (n=65). A total of 209 patients (86%) received tandem autologous-allogeneic upfront, while thirty-five patients (14%) had failed a previous autologous hematopoietic cell transplantation before the planned autologous-allogeneic transplantation. Thirty-one patients received maintenance treatment at a median of 86 days (range, 61-150) after allogeneic transplantation. Five-year rates of overall survival (OS) and progression-free survival (PFS) were 54% and 31%, respectively. Ten-year OS and PFS were 41% and 19%, respectively. Overall non-relapse mortality was 2% at 100 days and 14% at five years. Patients with induction-refractory disease and those with high-risk biological features experienced shorter OS and PFS. A total of 152 patients experienced disease relapse and 117 of those received salvage treatment. Eighty-three of the 117 patients achieved a clinical response, and for those, the median duration of survival after relapse was 7.8 years. Moreover, a subset of patients who became negative for minimal residual disease (MRD) by flow cytometry experienced a significantly lower relapse rate as compared with MRD-positive patients (P=0.03). Our study showed that the graft-versus-myeloma effect after non-myeloablative allografting allowed long-term disease control in standard and high-risk patient subsets. Ultra-high-risk patients did not appear to benefit from tandem autologous/allogeneic hematopoietic cell transplantation because of early disease relapse. Incorporation of newer anti-MM agents into the initial induction treatments before tandem hematopoietic cell transplantation and during maintenance might improve outcomes of ultra-high-risk patients. Clinical trials included in this study are registered at: clinicaltrials.gov identifiers: 00075478, 00005799, 01251575, 00078858, 00105001, 00027820, 00089011, 00003196, 00006251, 00793572, 00054353, 00014235, 00003954.

In the wake of recent advances in scientific research, personalized medicine using deep learning techniques represents a new paradigm. In this work, our goal was to establish deep learning models which distinguish responders from non-responders, and also to predict possible antidepressant treatment outcomes in major depressive disorder (MDD). To uncover relationships between the responsiveness of antidepressant treatment and biomarkers, we developed a deep learning prediction approach resulting from the analysis of genetic and clinical factors such as single nucleotide polymorphisms (SNPs), age, sex, baseline Hamilton Rating Scale for Depression score, depressive episodes, marital status, and suicide attempt status of MDD patients. The cohort consisted of 455 patients who were treated with selective serotonin reuptake inhibitors (treatment-response rate = 61.0%; remission rate = 33.0%). By using the SNP dataset that was original to a genome-wide association study, we selected 10 SNPs (including ABCA13 rs4917029, BNIP3 rs9419139, CACNA1E rs704329, EXOC4 rs6978272, GRIN2B rs7954376, LHFPL3 rs4352778, NELL1 rs2139423, NUAK1 rs2956406, PREX1 rs4810894, and SLIT3 rs139863958) which were associated with antidepressant treatment response. Furthermore, we pinpointed 10 SNPs (including ARNTL rs11022778, CAMK1D rs2724812, GABRB3 rs12904459, GRM8 rs35864549, NAALADL2 rs9878985, NCALD rs483986, PLA2G4A rs12046378, PROK2 rs73103153, RBFOX1 rs17134927, and ZNF536 rs77554113) in relation to remission. Then, we employed multilayer feedforward neural networks (MFNNs) containing 1-3 hidden layers and compared MFNN models with logistic regression models. Our analysis results revealed that the MFNN model with 2 hidden layers (area under the receiver operating characteristic curve (AUC) = 0.8228 ± 0.0571; sensitivity = 0.7546 ± 0.0619; specificity = 0.6922 ± 0.0765) performed maximally among predictive models to infer the complex relationship between antidepressant treatment response and biomarkers. In addition, the MFNN model with 3 hidden layers (AUC = 0.8060 ± 0.0722; sensitivity = 0.7732 ± 0.0583; specificity = 0.6623 ± 0.0853) achieved best among predictive models to predict remission. Our study indicates that the deep MFNN framework may provide a suitable method to establish a tool for distinguishing treatment responders from non-responders prior to antidepressant therapy.

Nowadays diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD). Recent studies have demonstrated that the myosin, heavy chain 9, non-muscle (MYH9) gene is associated with ESRD in African Americans. In this study, we tested the hypothesis that a common single nucleotide polymorphism rs16996677 in the MYH9 gene may contribute to the etiology of DN in type 2 diabetes (T2D) in a Taiwanese population with T2D. There were 180 T2D patients diagnosed with DN and 178 age- and sex-similar T2D without DN controls. Single locus analyses showed no significant main effects of MYH9 rs16996677 on the risk of DN in T2D. The results suggest that the rs16996677 SNP in MYH9 may not contribute to the risk of DN in T2D in Taiwanese T2D patients.

Four serotonin-related genes including guanine nucleotide binding protein beta polypeptide 3 (GNB3), 5-hydroxytryptamine receptor 1A (HTR1A; serotonin receptor 1A), 5-hydroxytryptamine receptor 2A (HTR2A; serotonin receptor 2A), and solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) have been suggested to be candidate genes for influencing antidepressant treatment outcome. The aim of this study was to explore whether interaction among these genes could contribute to the pharmacogenomics of short-term antidepressant response in a Taiwanese population with major depressive disorder (MDD).

Evidence indicates that the pathophysiologic mechanisms associated with insulin resistance may contribute to cognitive aging and Alzheimer's diseases. In this study, we hypothesize that single nucleotide polymorphisms (SNPs) within insulin resistance-associated genes, such as the ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9), glucokinase regulator (GCKR), and peroxisome proliferator activated receptor gamma (PPARG) genes, may be linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. A total of 547 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examinations (MMSE) were administered to all subjects, and MMSE scores were used to measure cognitive functions. Our data showed that four SNPs (rs73832338, rs9985304, rs4317088, and rs9831846) in the ADAMTS9 gene were significantly associated with cognitive aging among the subjects (P = 1.5 x 10-6 ~ 0.0002). This association remained significant after performing Bonferroni correction. Additionally, we found that interactions between the ADAMTS9 rs9985304 and ADAMTS9 rs76346246 SNPs influenced cognitive aging (P < 0.001). However, variants in the GCKR and PPARG genes had no association with cognitive aging in our study. Our study indicates that the ADAMTS9 gene may contribute to susceptibility to cognitive aging independently as well as through SNP-SNP interactions.

It has been suggested that the relationship between cognitive function and functional outcome in schizophrenia is mediated by clinical symptoms, while functional outcome is assessed by the Quality of Life Scale (QLS) and the Global Assessment of Functioning (GAF) Scale. To determine the outcome assessed by QLS and GAF, we established a bagging ensemble framework with a feature selection algorithm resulting from the analysis of factors such as 3 clinical symptom scales and 11 cognitive function scores of 302 patients with schizophrenia in the Taiwanese population. We compared our bagging ensemble framework with other state-of-the-art algorithms such as multilayer feedforward neural networks, support vector machine, linear regression, and random forests. The analysis revealed that the bagging ensemble model with feature selection performed best among predictive models in predicting the QLS functional outcome by using 20-item Scale for the Assessment of Negative Symptoms (SANS20) and 17-item Hamilton Depression Rating Scale (HAMD17). Moreover, to predict the GAF outcome, the bagging ensemble model with feature selection performed best among predictive models by using SANS20 and the Positive and Negative Syndrome Scale-Positive (PANSS-Positive) subscale. The study indicates that there are synergistic effects between negative (SANS20) and depressive (HAMD17) symptoms as well as between negative and positive (PANSS-Positive) symptoms in influencing functional outcome of schizophrenia using the bagging ensemble framework with feature selection.

The dopamine receptor-related loci have been suggested to be associated with cognitive functions and neurodegenerative diseases. It is unknown whether genetic variants such as single nucleotide polymorphisms (SNPs) in the dopamine receptor-related loci could contribute to cognitive aging independently as well as by virtue of complicated interplays in the elder population. To assess whether SNPs in the dopamine receptor-related loci are associated with cognitive aging in the elder population, we evaluated SNPs in the DRD1, NCAM1-TTC12-ANKK1-DRD2, DRD3-LOC107986115-ZNF80-TIGIT-MIR568-ZBTB20, DRD4, and DRD5-SLC2A9 loci from 25,195 older Taiwanese individuals from the Taiwan Biobank. Mini-Mental State Examination (MMSE) was scrutinized for all participants, where MMSE scores were employed to evaluate cognitive functions. From our analysis, we identified three novel genes for cognitive aging that have not previously been reported: ZBTB20 on chromosome 3 and NCAM1 and TTC12 on chromosome 11. NCAM1 and ZBTB20 are strong candidates for having a role in cognitive aging with mutations in ZBTB20 resulting in intellectual disability, and NCAM1 previously found to be associated with associative memory in humans. Additionally, we found the effects of interplays between physical activity and these three novel genes. Our study suggests that genetic variants in the dopamine receptor-related loci may influence cognitive aging individually and by means of gene-physical activity interactions.

To ascertain the consequences of severe leukopenia and the tempo of recovery, we studied the immunity of 56 adult patients treated for multiple sclerosis or systemic sclerosis with autologous CD34 cell transplantation using extremely lymphoablative conditioning. NK cell, monocyte, and neutrophil counts recovered to normal by 1 month; dendritic cell and B cell counts by 6 months; and T cell counts by 2 years posttransplant, although CD4 T cell counts remained borderline low. Initial peripheral expansion was robust for CD8 T cells but only moderate for CD4 T cells. Subsequent thymopoiesis was slow, especially in older patients. Importantly, levels of antibodies, including autoantibodies, did not drop substantially. Infections were frequent during the first 6 months, when all immune cells were deficient, and surprisingly rare (0.21 per patient year) at 7-24 months posttransplant, when only T cells (particularly CD4 T cells) were deficient. In conclusion, peripheral expansion of CD8 but not CD4 T cells is highly efficient. Prolonged CD4 lymphopenia is associated with relatively few infections, possibly due to antibodies produced by persisting pretransplant plasma cells.

Mouse polyomavirus (MuPyV) causes a smoldering persistent infection in immunocompetent mice. To lower MuPyV infection in acutely and persistently infected mice, and study the impact of a temporal reduction in viral loads on the memory CD8 T cell response, we created a recombinant MuPyV in which a loxP sequence was inserted into the A2 strain genome upstream of the early promoter and another loxP sequence was inserted in cis into the intron shared by all three T antigens. Using mice transgenic for tamoxifen-inducible Cre recombinase, we demonstrated that reduction in MuPyV load during persistent infection was associated with differentiation of virus-specific CD8 T cells having a superior recall response. Evidence presented here supports the concept that reduction in viral load during persistent infection can promote differentiation of protective virus-specific memory CD8 T cells in patients at risk for diseases caused by human polyomaviruses.

Stent-assisted coil embolization using the new generation Neuroform Atlas Stent System has shown promising safety and efficacy. The primary study results of the anterior circulation aneurysm cohort of the treatment of wide-neck, saccular, intracranial, aneurysms with the Neuroform Atlas Stent System (ATLAS trial [Safety and Effectiveness of the Treatment of Wide Neck, Saccular Intracranial Aneurysms With the Neuroform Atlas Stent System]) are presented.

Single-cell RNA sequencing (scRNA-seq) is an emerging technology that can assess the function of an individual cell and cell-to-cell variability at the single cell level in an unbiased manner. Dimensionality reduction is an essential first step in downstream analysis of the scRNA-seq data. However, the scRNA-seq data are challenging for traditional methods due to their high dimensional measurements as well as an abundance of dropout events (that is, zero expression measurements).

It is well established that brain-derived neurotrophic factor (BDNF) signaling pathway plays a key role in the pathophysiology of major depressive disorder (MDD) and in therapeutic mechanisms of antidepressants. We aim to identify genetic vairiants related to MDD susceptibility and antidepressant therapeutic response by using gene-based association analysis with genes related to the neurotrophic pathway. The present study investigated the role of genetic variants in the 10 neurotrophic-related genes (BDNF, NGFR, NTRK2, MTOR, VEGFA, S100A10, SERPINE1, ARHGAP33, GSK3B, CREB1) in MDD susceptibility through a case-control (455 MDD patients and 2,998 healthy controls) study and in antidepressant efficacy (n = 455). Measures of antidepressant therapeutic efficacy were evaluated using the 21-item Hamilton Rating Scale for Depression. Our single-marker and gene-based analyses with ten genes related to the neurotrophic pathway identified 6 polymorphisms that reached a significant level (p-value < 5.0 × 10-3) in both meta- and mega-analyses in antidepressant therapeutic response. One polymorphism was mapped to BDNF and 5 other polymorphisms were mapped to VEGFA. For case-control association study, we found that all of these reported polymorphisms and genes did not reach a suggestive level. The present study supported a role of BDNF and VEGFA variants in MDD therapeutic response.

Increased risk of developing metabolic syndrome (MetS) has been associated with the circadian clock genes. In this study, we assessed whether 29 circadian clock-related genes (including ADCYAP1, ARNTL, ARNTL2, BHLHE40, CLOCK, CRY1, CRY2, CSNK1D, CSNK1E, GSK3B, HCRTR2, KLF10, NFIL3, NPAS2, NR1D1, NR1D2, PER1, PER2, PER3, REV1, RORA, RORB, RORC, SENP3, SERPINE1, TIMELESS, TIPIN, VIP, and VIPR2) are associated with MetS and its individual components independently and/or through complex interactions in a Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing MetS and its individual components. A total of 3,000 Taiwanese subjects from the Taiwan Biobank were assessed in this study. Metabolic traits such as waist circumference, triglyceride, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and fasting glucose were measured. Our data showed a nominal association of MetS with several single nucleotide polymorphisms (SNPs) in five key circadian clock genes including ARNTL, GSK3B, PER3, RORA, and RORB; but none of these SNPs persisted significantly after performing Bonferroni correction. Moreover, we identified the effect of GSK3B rs2199503 on high fasting glucose (P = 0.0002). Additionally, we found interactions among the ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, RORA rs8034880, and RORB rs972902 SNPs influenced MetS (P < 0.001 ~ P = 0.002). Finally, we investigated the influence of interactions between ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, and RORB rs972902 with environmental factors such as alcohol consumption, smoking status, and physical activity on MetS and its individual components (P < 0.001 ~ P = 0.002). Our study indicates that circadian clock genes such as ARNTL, GSK3B, PER3, RORA, and RORB genes may contribute to the risk of MetS independently as well as through gene-gene and gene-environment interactions.

Gamma-aminobutyric acid type A (GABAA) receptors mainly mediate the effects of gamma-aminobutyric acid, which is the primary inhibitory neurotransmitter in the central nervous system. Abundant evidence suggests that GABAA receptors play a key role in sleep-regulating processes. No genetic association study has explored the relationships between GABAA receptor genes and sleep duration, sleep quality, and sleep timing in humans.

One particularly interesting single nucleotide polymorphism (SNP), rs6235 (encoding an S690T substitution), in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene has been widely associated with obesity in several European cohorts. The present study was intended to investigate the association between the PCSK1 rs6235 SNP and the prevalence of overweight or obesity, or obesity-related metabolic traits in a Taiwanese population. A total of 964 Taiwanese subjects with general health examinations were analyzed. Our data revealed no association of PCSK1 rs6235 with the risk of obesity or overweight in the complete subjects. However, the PCSK1 rs6235 SNP exhibited a significant association with overweight among the male subjects (P=0.03), but not among the female subjects. Furthermore, the carriers of GG variant had a significantly higher waist circumference than those with the CC variant (82.5 ± 11.5 vs. 81.2 ± 10.2 cm; P=0.01) and those with the CG variant (82.5 ± 11.5 vs. 81.4 ± 10.4 cm; P=0.021). In addition, the carriers of GG variant had a higher diastolic blood pressure than those with the CC variant (81.9 ± 14.2 vs. 80.3 ± 12.9 mm Hg; P=0.023). Our study indicates that the PCSK1 rs6235 SNP may contribute to the risk of overweight in men and predict obesity-related metabolic traits such as waist circumference and diastolic blood pressure in Taiwanese subjects.

Retinoic acid (RA) has been believed to be an anticancer drug for a long history. However, the molecular mechanisms of RA actions on cancer cells remain diverse. In this study, the dose-dependent inhibition of RA on DU145 cell proliferation was identified. Interestingly, RA treatment triggered p35 cleavage (p25 formation) and Cdk5 overactivation, and all could be blocked by Calpain inhibitor, Calpeptin (CP). Subsequently, RA-triggered DU145 apoptosis detected by sub-G1 phase accumulation and Annexin V staining could also be blocked by CP treatment. Furthermore, RA-triggered caspase 3 activation and following Cdk5 over-activation were destroyed by treatments of both CP and Cdk5 knockdown. In conclusion, we report a new mechanism in which RA could cause apoptosis of androgen-independent prostate cancer cells through p35 cleavage and Cdk5 over-activation. This finding may contribute to constructing a clearer image of RA function and bring RA as a valuable chemoprevention agent for prostate cancer patients.

Multidisciplinary care (MDC) programs have been proposed as a way to alleviate the cost and morbidity associated with chronic kidney disease (CKD) in the US.

Evidence indicates that the age-related neuropathological mechanisms associated with DNA repair genes may contribute to cognitive aging and Alzheimer's disease. In this study, we hypothesize that single nucleotide polymorphisms (SNPs) within 155 DNA repair genes may be linked to cognitive aging independently and/or through complex interactions in an older Taiwanese population. A total of 3,730 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) was administered to all subjects, and MMSE scores were used to measure cognitive functions. Our data showed that out of 1,652 SNPs, the rs1776181 (P = 1.47 × 10-5), rs1776177 (P = 8.42 × 10-7), rs1635510 (P = 7.97 × 10-6), and rs2526698 (P = 7.06 × 10-6) SNPs in the EXO1 gene were associated with cognitive aging. The association with these SNP remained significant after performing Bonferroni correction. Additionally, we found that interactions between the EXO1 and RAD51C genes influenced cognitive aging (P = 0.002). Finally, we pinpointed the influence of interactions between EXO1 and physical activity (P < 0.001) as well as between DCLRE1C and physical activity (P < 0.001). Our study indicated that DNA repair genes may contribute to susceptibility in cognitive aging independently as well as through gene-gene and gene-physical interactions.

Evidence suggests that the neuro-inflammation mechanisms associated with interleukin-12 (IL-12) may be linked to Alzheimer's diseases and cognitive aging. In this study, we speculate that single nucleotide polymorphisms (SNPs) in IL-12-associated genes, such as IL12A, IL12B, IL12RB1, and IL12RB2 genes, could be associated with cognitive aging individually and/or via complicated interactions in the elder Taiwanese population. There were totally 3,730 Taiwanese individuals with age ≥60 years from the Taiwan Biobank. Mini-Mental State Examination (MMSE) was analyzed for all participants. We employed MMSE scores to assess cognitive functions. Our analysis revealed that the IL12A gene (including rs116910715, rs78902931, and rs78569420), the IL12B gene (including rs730691), and the IL12RB2 gene (including rs3790558, rs4655538, rs75699623, and rs1874396) were associated with cognitive aging. Among these SNPs, the association with the IL12RB2 rs3790558 SNP remained significant after performing Bonferroni correction (P = 6.87 × 10-4). Additionally, we found that interactions between the IL12A and IL12RB2 genes influenced cognitive aging (P = 0.022). Finally, we pinpointed the effects of interactions between IL12A, IL12B, and IL12RB2 with physical activity (P < 0.001, = 0.002, and < 0.001, respectively). Our study suggests that the IL-12-associated genes may contribute to susceptibility to cognitive aging independently as well as through gene-gene and gene-physical activity interactions.

Standard treatment for locally advanced anal squamous cell carcinoma (SCC) consists of concurrent chemoradiation. We evaluated whether racial differences exist in the receipt of standard treatment and its association with survival.