Biomedical subjects

Tao Shi

Publications and source records attributed to Tao Shi.

15 recordsLinked to original sources

PubMed2026

Unraveling epigenetic and genetic variations in response to cold stress in two lotus ecotypes.

Genetic variations accumulate over long evolutionary timescales, whereas epigenetic modifications can arise rapidly and be inherited across generations. However, the interplay between genetic and epigenetic variations in shaping ecotype-specific phenotypic plasticity remains elusive. Focusing on two lotus ecotypes that evolved under distinct winter temperature regions and display divergent annual growth cycles under cold stress, we generated DNA methylation landscapes across three sequence contexts (CG, CHG, and CHH, where H = A, T, or C) and identified single-cytosine methylation polymorphisms (SMPs) and single-nucleotide polymorphisms (SNPs). Interestingly, only CG methylation patterns mirror population-level genetic variations. Using epigenetic genome-wide association analysis, we identified differentially methylated CG sites that are either cis- or trans-regulated by SNP. Notably, we constructed a multifactorial regulatory network centered on the NnMKK4-NnCYCD5 module, linking cold response with cell cycle regulation. Temperature stress experiments conducted on lotus ecotypes and transgenic Arabidopsis (OE-NnMKK4 and OE-NnCYCD5) confirmed that NnMKK4 acts as a cold receptor and that NnCYCD5 promotes cell cycle progression and growth under cold conditions. Collectively, our findings provide novel insights into the co-evolutionary dynamics of epigenetic and genetic variations that are associated with different growth cycles of lotus ecotypes in response to cold stress.

DNA methylation↗

PubMed2026

Discovery of a potential novel pharmacogenomic biomarker on ANK3 gene for liafensine, a triple reuptake inhibitor for treatment-resistant depression.

Liafensine is a triple reuptake inhibitor targeting transporters for serotonin, norepinephrine, and dopamine for treatment-resistant depression (TRD). It did not exhibit efficacy in non-biomarker-selected TRD patients in two Phase 2b studies. We utilized the blood samples from the patients enrolled in these two studies and extracted genomic DNA to conduct a genome‑wide association study aiming to find a biomarker which can predict liafensine response. A single single-nucleotide polymorphism (SNP), rs12217173, at ANK3 gene was identified as strongly associated with treatment response to liafensine (p = 6.61 × 10-8) in the discovery set (n = 186) and was further confirmed in the replication sample set (n = 47, p = 0.05, combined p = 1.27 × 10-8). In addition, this SNP was not associated with the efficacy of the duloxetine or escitalopram, suggesting it is a liafensine-specific biomarker. This finding was subsequently confirmed in a prospective clinical study. Thus, this study represents a novel approach to translating precision medicine into psychiatric diseases.

Humans↗

PubMed2024

Validating the splicing effect of rare variants in the SLC26A4 gene using minigene assay.

BACKGROUND: The SLC26A4 gene is the second most common cause of hereditary hearing loss in human. The aim of this study was to utilize the minigene assay in order to identify pathogenic variants of SLC26A4 associated with enlarged vestibular aqueduct (EVA) and hearing loss (HL) in two patients. METHODS: The patients were subjected to multiplex PCR amplification and next-generation sequencing of common deafness genes (including GJB2, SLC26A4, and MT-RNR1), then bioinformatics analysis was performed on the sequencing data to identify candidate pathogenic variants. Minigene experiments were conducted to determine the potential impact of the variants on splicing. RESULTS: Genetic testing revealed that the first patient carried compound heterozygous variants c.[1149 + 1G > A]; [919-2 A > G] in the SLC26A4 gene, while the second patient carried compound heterozygous variants c.[2089 + 3 A > T]; [919-2 A > G] in the same gene. Minigene experiments demonstrated that both c.1149 + 1G > A and c.2089 + 3 A > T affected mRNA splicing. According to the ACMG guidelines and the recommendations of the ClinGen Hearing Loss Expert Panel for ACMG variant interpretation, these variants were classified as "likely pathogenic". CONCLUSIONS: This study identified the molecular etiology of hearing loss in two patients with EVA and elucidated the impact of rare variants on splicing, thus contributing to the mutational spectrum of pathogenic variants in the SLC26A4 gene.

Humans↗

PubMed2006

[Simultaneous treatment for benign prostate hyperplasia and its concomitant diseases].

OBJECTIVE: To investigate the surgical treatment of benign prostate hyperplasia (BPH) and its concomitant diseases at the same time. METHODS: One hundred and fourteen operations were performed for BPH patients, including transurethral resection/vapor of the prostate (TURP/TUVP), inguinal herniorrhaphy, internal urethrotomy, transurethral resection of bladder tumor (TURBt) or vesical litholapaxy, and the data were reviewed. RESULTS: The procedures were successful in all cases. A follow-up of 3 to 60 months found a good outcome of TURP. There was no recurrence in 30 cases of inguinal hernia and 39 cases of vesical calculus. Of the 25 cases of urethral stricture, 1 had an obvious hypotension during the operation and 4 needed urethral dilatation after operation. Six of the 20 cases of bladder tumor underwent a second TURBt due to the recurring tumor which was far from prostatic urethra. CONCLUSION: Inguinal hernia, urethral stricture, bladder tumor or vesical calculus can be treated simultaneously during TURP.

Aged↗

PubMed2006

[A preliminary study on the effect of prepubertal exposure of male rats to diethylstilbestrol on the apoptosis of spermatogenic cells after sexual maturation and its mechanism].

OBJECTIVE: To preliminarily study the effect of prepubertal exposure of male SD (Sprague-Dawley) rats to diethylstilbestrol (DES) on the apoptosis of spermatogenic cells after sexual maturation and its mechanism. METHODS: Thirty 21-day-old male SD rats were randomly divided into 4 experimental groups, DES 0.01, 0.1, 1.0 and 10.0 microg/(kg x d) and 1 control group. The experimental groups were injected (s.c.) with different doses of DES (dissolved in corn oil) during prepuberty [from postnatal day (PND) 22 to PND 35] and the control group with medium only. The apoptosis and related proteins Bcl-2 and Bax expressions of testicular spermatogenic cells were studied with TUNEL and immunohistochemistry after the rats sexual maturation (at PND 64). RESULTS: Compared with the control group, the apoptosis of testicular spermatogenic cells in the DES 0.01 microg/kg group had no difference, but significantly increased in the DES 0.1, 1.0 and 10.0 microg/kg groups and the apoptosis increased with the increase of DES dose. In the control and DES 0.01 microg/kg groups, Bax protein expressed weakly but Bcl-2 protein strongly in spermatogenic cells. With the increase of DES exposure, Bax protein expression in spermatogenic cells increased but Bcl-2 protein expression decreased. CONCLUSION: Prepubertal exposure of SD rats to inappropriate dose of DES can make the apoptosis of spermatogenic cells increase after sexual maturation. Bax and Bcl-2 proteins participate in the apoptotic course caused by prepubertal DES exposure.

Animals↗

PubMed2005

Global histone modification patterns predict risk of prostate cancer recurrence.

Aberrations in post-translational modifications of histones have been shown to occur in cancer cells but only at individual promoters; they have not been related to clinical outcome. Other than being targeted to promoters, modifications of histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global histone modifications. Here we show that changes in global levels of individual histone modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the histone acetylation and dimethylation of five residues in histones H3 and H4. Grouping of samples with similar patterns of modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.

Acetylation↗

PubMed2005

Tumor classification by tissue microarray profiling: random forest clustering applied to renal cell carcinoma.

We describe a novel strategy (random forest clustering) for tumor profiling based on tissue microarray data. Random forest clustering is attractive for tissue microarray and other immunohistochemistry data since it handles highly skewed tumor marker expressions well and weighs the contribution of each marker according to its relatedness with other tumor markers. This is the first tumor class discovery analysis of renal cell carcinoma patients based on protein expression profiles. The tissue array data contained at least three tumor samples from each of 366 renal cell carcinoma patients. The eight tumor markers explore tumor proliferation, cell cycle abnormalities, cell mobility, and the hypoxia pathway. Since the procedure is unsupervised, no clinicopathological data or traditional classifications are used a priori. To explore whether the tissue microarray data can be used to identify fundamental subtypes of renal cell carcinoma patients, we first carried out random forest clustering of all 366 patients. By analyzing the tumor markers simultaneously, the procedure automatically detected classes that correspond to clear- vs non-clear cell tumors (demonstration of proof-of-principle). The resulting molecular grouping provides better prediction of survival (logrank P=0.000090) than this classical pathological grouping (logrank P=0.023). We then sought to extend the class discovery by searching for finer subclasses of clear cell patients. The procedure automatically discovered: (a) two classes corresponding to low- and high-grade patients (demonstration of proof-of-principle); (b) a subgroup of long-surviving clear cell patients with a distinct molecular profile and (c) two novel tumor subclasses in low-grade clear cell patients that could not be explained by any clinicopathological variables (demonstration of discovery).

Biomarkers, Tumor↗

PubMed2005

p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized renal cell carcinoma.

PURPOSE: We determined which clinical and molecular variables can predict cancer recurrence in patients following surgical management for localized renal cell carcinoma (RCC). MATERIALS AND METHODS: From a custom kidney cancer tissue microarray containing tumors specimens from 350 patients 193 undergoing nephrectomy for localized RCC at our institution between 1989 and 2000 were identified. The array was then analyzed by immunohistochemistry for certain molecular markers, namely CA9, CA12, Ki67, gelsolin, p53, EpCAM, pTEN and vimentin. The medical records of these patients were then reviewed for age, sex, TNM stage, tumor size, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status, recurrence status and, when applicable, time to recurrence. Cox regression analyses were done to determine clinical and molecular predictors of time to tumor recurrence. RESULTS: Of the patients 15% demonstrated evidence of tumor recurrence following nephrectomy (29 of 193). Univariate Cox regression demonstrated that tumor size, T stage, grade, ECOG performance status, Ki67, EpCAM and p53 were significantly associated with recurrence (p <0.05). A multivariate Cox regression model showed that T stage (p = 0.018), ECOG (p = 0.004) and p53 (p = 0.003) were the 3 most significant predictors. p53 expression correlated significantly with nuclear grade (Pearson correlation 0.22, p = 0.023) but not with any other clinical factors. Patients with localized tumors demonstrating mean p53 staining values above and below 20% of cells had recurrence rates of 37.7% and 14.4%, respectively (RR = 3.28, p = 0.018). CONCLUSIONS: p53 is a significant molecular predictor of tumor recurrence, as identified in patients undergoing treatment for localized RCC.

Adult↗

PubMed2005

Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma.

PURPOSE: Approximately 30% of renal cell carcinomas (RCCs) present as metastatic disease. Molecular markers have the potential to characterize accurately the biological behavior of tumors and they may be useful for determining prognosis. MATERIALS AND METHODS: A custom tissue array was constructed using clear cell RCC from 150 patients with metastatic RCC who underwent nephrectomy prior to immunotherapy. The tissue array was stained for 8 molecular markers, namely Ki67, p53, gelsolin, carbonic anhydrase (CA)9, CA12, PTEN (phosphatase and tensin homologue deleted on chromosome 10), epithelial cell adhesion molecule and vimentin. Marker status and established clinical predictors of prognosis were considered when developing a prognostic model for disease specific survival. RESULTS: On univariate Cox regression analysis certain markers were statistically significant predictors of survival, namely CA9 (p <0.00001), p53 (p = 0.0072), gelsolin (p = 0.030), Ki67 (p = 0.036) and CA12 (p = 0.043). On multivariate Cox regression analysis that included all markers and clinical variables CA9 (p = 0.00002), PTEN (p <0.0001), vimentin (p = 0.0032), p53 (p = 0.028), T category (p = 0.0025) and performance status (p = 0.0013) were significant independent predictors of disease specific survival and they were used to construct a combined molecular and clinical prognostic model. The bias corrected concordance index (C-index) of this combined prognostic model was C = 0.68, which was significantly higher (p = 0.0033) than that of a multivariate clinical predictor model (C = 0.62) based on the UCLA Integrated Staging System (T category, histological grade and performance status). CONCLUSIONS: In patients with clear cell RCC a prognostic model for survival that includes molecular and clinical predictors is significantly more accurate than a standard clinical model using the combination of stage, histological grade and performance status.

Adult↗

PubMed2005

Expression of transcription factor Yin Yang 1 in prostate cancer.

The transcription repressor Yin Yang 1 (YY1) is expressed in several human cancer cell lines and its expression correlates with resistance to immune-mediated apoptosis. This study used tissue microarrays to investigate the expression and localization of YY1 in 1364 representative tissue samples from 246 hormone naive prostate cancer patients who underwent radical prostatectomy. Staining intensity and frequency measures for both YY1 nuclear and cytoplasmic expression were higher in neoplastic tissues and in PIN samples compared to matched benign cells (p < 0.0001 for all comparisons). Expression of YY1 is predominantly elevated in early malignancy (PIN), as well as in tumors of intermediate to high morphologic grade (Gleason's grade 3-5). Using multivariate Cox proportional hazards analysis, we observed that low nuclear YY1 staining is an independent predictor of a shorter time to recurrence (p = 0.012). Based on these results, we hypothesize that YY1 may play a role in prostate cancer development; however, decreased YY1 may give metastatic cells a survival advantage. These results may also implicate YY1 as a useful diagnostic and prognostic marker.

Aged↗

PubMed2004

Using protein expressions to predict survival in clear cell renal carcinoma.

PURPOSE: An accurate system for predicting survival for patients with solid tumors will allow for better patient selection for both established and novel therapies. We propose a staging system for clear cell variants of renal cell carcinoma (RCC) that includes molecular predictors and standard clinical predictors such as tumor-node-metastasis (TNM) stage, histological grade, and performance status (PS). EXPERIMENTAL DESIGN: A custom tissue array was constructed using clear cell RCC from 318 patients, representing all stages of localized and metastatic RCC, and immunohistochemically stained for molecular markers Ki67, p53, gelsolin, CA9, CA12, PTEN, EpCAM, and vimentin. We present a strategy for evaluating individual candidate markers for prognostic information and integrating informative markers into a multivariate prognostic system. RESULTS: The overall median follow-up and the median follow-up for surviving patients were 28 and 55 months, respectively. A prognostic model based primarily on molecular markers included metastasis status, p53, CA9, gelsolin, and vimentin as predictors and had high discriminatory power: its statistically validated concordance index (C-index) was found to be 0.75. A prognostic model based on a combination of clinical and molecular predictors included metastasis status, T stage, Eastern Cooperative Oncology Group PS, p53, CA9, and vimentin as predictors and had a C-index of 0.79, which was significantly higher (P < 0.05) than that of prognostic models based on grade alone (C = 0.65), TNM stage alone (C = 0.73), or the University of California Los Angeles integrated staging system (C = 0.76). CONCLUSIONS: Protein expressions obtained using widely available technology can complement standard clinical predictors such as TNM stage, histological grade, and PS.

Adenocarcinoma, Clear Cell↗

PubMed2003

Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation.

The classic view of brain sexual differentiation and behavior is that gonadal steroid hormones act directly to promote sex differences in neural and behavioral development. In particular, the actions of testosterone and its metabolites induce a masculine pattern of brain development, while inhibiting feminine neural and behavioral patterns of differentiation. However, recent evidence indicates that gonadal hormones may not solely be responsible for sex differences in brain development and behavior between males and females. Here we examine an alternative hypothesis that genes, by directly inducing sexually dimorphic patterns of neural development, can influence the sexual differences between male and female brains. Using microarrays and RT-PCR, we have detected over 50 candidate genes for differential sex expression, and confirmed at least seven murine genes which show differential expression between the developing brains of male and female mice at stage 10.5 days post coitum (dpc), before any gonadal hormone influence. The identification of genes differentially expressed between male and female brains prior to gonadal formation suggests that genetic factors may have roles in influencing brain sexual differentiation.

Animals↗

PubMed2003

Gene expression profiling identifies molecular subtypes of gliomas.

Identification of distinct molecular subtypes is a critical challenge for cancer biology. In this study, we used Affymetrix high-density oligonucleotide arrays to identify the global gene expression signatures associated with gliomas of different types and grades. Here, we show that the global transcriptional profiles of gliomas of different types and grades are distinct from each other and from the normal brain. To determine whether our data could be used to uncover molecular subtypes without prior knowledge of pathologic type and grade, we performed K-means clustering analysis and found evidence for three clusters with the aid of multidimensional scaling plots. These clusters corresponded to glioblastomas, lower grade astrocytomas and oligodendrogliomas (P<0.00001). A predictor constructed from the 170 genes that are most differentially expressed between the subsets correctly identified the type and grade of all samples, indicating that a relatively small number of genes can be used to distinguish between these molecular subtypes. These results further define molecular subsets of gliomas which may potentially be used for patient stratification, and suggest potential targets for treatment.

Astrocytoma↗

PubMed2003

Identification of molecular subtypes of glioblastoma by gene expression profiling.

Epidermal growth factor receptor (EGFR) overexpression occurs in nearly 50% of cases of glioblastoma (GBM), but its clinical and biological implications are not well understood. We have used Affymetrix high-density oligonucleotide arrays to demonstrate that EGFR-overexpressing GBMs (EGFR+) have a distinct global gene transcriptional profile. We show that the expression of 90 genes can distinguish EGFR+ from EGFR nonexpressing (EGFR-) GBMs, including a number of genes known to act as growth/survival factors for GBMs. We have also uncovered two additional novel molecular subtypes of GBMs, one of which is characterized by coordinate upregulation of contiguous genes on chromosome 12q13-15 and expression of both astrocytic and oligodendroglial genes. These results define distinct molecular subtypes of GBMs that may be important in disease stratification, and in the discovery and assessment of GBM treatment strategies.

Astrocytes↗

PubMed2003

Analysis of the Na,K-ATPase alpha- and beta-subunit expression profiles of bladder cancer using tissue microarrays.

BACKGROUND: The purpose of this study was to determine the clinical significance of Na,K-ATPase alpha- and beta-subunit expression in a histopathologically well-characterized group of patients representing a wide spectrum of tumor grades and disease stages with transitional cell carcinomas (TCC). METHODS: Na,K-ATPase alpha- and beta-subunit protein expression patterns were analyzed using immunohistochemistry on urothelial cancer tissue microarrays (TMA) of 146 patients diagnosed with urothelial carcinoma. For each subunit, the maximum staining intensity and the percentage of positive cells staining at the maximal intensity were analyzed. RESULTS: Compared with the benign fields, the mean protein expression for both Na,K-ATPase alpha- and beta-subunits were found to be decreased overall in in situ and invasive tumors, as well as in tumor-adjacent dysplastic fields. When Na,K-ATPase alpha- and beta-subunit expression levels were dichotomized into distinct groups, they were both found to be significant predictors of recurrence risk in multivariate logistic regression analysis (P = 0.0062, odds ratio [OR] = 2.6 and P = 0.013, OR = 0.43, for Na,K-ATPase alpha- and beta-subunits, respectively). The authors also found that patients with high alpha- and low beta-subunit expression had a high risk for early recurrence, whereas patients with a low alpha- and high beta-subunit expression had a significantly longer median recurrence-free time (17 months and 125 months, respectively, log rank statistics P = 0.0005). CONCLUSIONS: The results suggested that Na,K-ATPase alpha- and beta-subunit expression levels may be useful predictors of clinical outcomes such as recurrence-free time of bladder cancer patients.

Adult↗