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Shu Zhang

Publications and source records attributed to Shu Zhang.

At least 19 recordsLinked to original sources

scAmp enables focal gene amplification analysis from single-cell data.

Oncogene amplification on extrachromosomal DNA is a common driver of tumor progression and is associated with acquired drug resistance and poor patient survival. While bulk whole genome sequencing studies have revealed the landscape of genes amplified on extrachromosomal DNA in tumors, it remains challenging to study the subclonal heterogeneity and functional (e.g., transcriptomic) consequences of extrachromosomal DNA on tumors. To address this, we introduce scAmp: a probabilistic algorithm for detecting and analyzing extrachromosomal DNA from single-cell datasets. Using well-characterized cell lines, we demonstrate that scAmp has improved specificity over bulk genome sequencing in predicting extrachromosomal DNA status and can resolve the status of chromosomal amplifications that were historically extrachromosomal. We further showcase scAmp by analyzing 73 patient tumors profiled with single-cell assay for transposase-accessible chromatin by sequencing, where we characterize the subclonal evolution of subclones with extrachromosomal DNA and identify the effect of these amplifications on the chromatin accessibility landscape of cancer cells. Finally, we provide proof-of-concept analyses that scAmp aids in the detection of extrachromosomal DNA from clinical histopathology assays. Together, we anticipate that scAmp will broadly enable further studies - both retrospective and prospective - that dissect critical questions of how extrachromosomal DNAs affect cancer cells and the tumors in which they reside.

Humans↗

Genetic Contributors to Postoperative Delirium and Their Implications for Dementia Outcomes.

BACKGROUND: Postoperative delirium (POD) is a perioperative neurocognitive disorder that substantially impairs patient recovery. Unfortunately, its genetic risk profile and relationship with subsequent dementia remain unclear. This study aimed to elucidate genetic contributors to POD identified via Hospital Episode Statistics codes and to examine its association with subsequent dementia. METHODS: The study included 230,179 noncardiac and 21,254 cardiac surgery subjects from the UK Biobank, defining POD using delirium codes from the International Classification of Diseases (10th revision) recorded within the first 7 postoperative days. Genome-wide association studies were performed in the noncardiac and cardiac cohorts and their prespecified subgroups, followed by functional annotation, gene prioritization and drug-target analyses. Associations between POD and subsequent dementia were estimated using Cox models. RESULTS: In the noncardiac cohort, one genome-wide significant locus was identified at the APOE region, with rs429358 as the lead variant ( P = 5.00 × 10 -28 ). Integrative gene prioritization analyses highlighted multiple genes within this locus. Exploratory drug-target analyses suggested potential subgroup-specific drug-target enrichment. In the cardiac cohort, no genome-wide significant signals were detected. POD was associated with all-cause dementia after both noncardiac (hazard ratio, 6.45; 95% CI, 5.45 to 7.63) and cardiac (hazard ratio, 2.95; 95% CI, 1.71 to 5.08) surgeries. CONCLUSIONS: This study demonstrates APOE as a genetic risk locus for International Classification of Diseases-coded POD in the noncardiac surgery setting and confirms an association between POD and subsequent dementia.

Humans↗

A MGMT Enhancer Variant is Associated with Glioma Susceptibility and Progression.

The O6-methylguanine-DNA methyltransferase (MGMT) plays a significant role in the pathogenesis and progression of glioma. Numerous enhancer variants, including those within the MGMT gene region and adjacent gene regions, have been found to be associated with cancer development and progression. We investigated the significance of enhancer variants located in the intergenic spacer far from the MGMT gene in relation to glioma susceptibility and progression. We recruited 402 glioma patients and 654 controls for this investigation using Sequenom MassARRAY genotyping. We identified a significantly elevated risk of glioma among carriers with the rs11016629 TG genotype compared to those with the GG genotype (OR = 1.41, 95% CI 1.03-1.93; P = 0.034). Subgroup analyses revealed that rs11016629 was significantly associated with glioma risk in subjects with WHO grade IV tumor (OR = 1.59, 95% CI 1.07-2.38; P = 0.023) and high-grade glioma (OR = 1.57, 95% CI 1.11-2.21; P = 0.011). Patients who underwent gross total resection with TG/TT genotypes exhibited a 2.66-fold higher risk of disease progression than GG carriers (HR = 2.66, 95% CI 1.23-5.79; P = 0.014). The study demonstrates that a MGMT enhancer variant rs11016629 contributes to both glioma susceptibility and progression.

Humans↗

ST3GAL1 Promotes Malignant Phenotypes in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis, and elucidation of the molecular mechanisms underlying iCCA malignancy is of great significance. Glycosylation, an important post-translational modification, is closely associated with tumor progression. Altered glycosylation, including aberrant sialylation resulting from abnormal expression of sialyltransferases (STs) and neuraminidases (NEUs), is a significant feature of cancer cells. However, there is limited information on the roles of STs and NEUs in iCCA malignancy. Here, utilizing our proteogenomic resources from a cohort of 262 patients with iCCA, we identified ST3GAL1 as a prognostically relevant molecule in iCCA. Moreover, overexpression of ST3GAL1 promoted proliferation, migration, and invasion and inhibited apoptosis of iCCA cells in vitro. Through proteomic analyses, we identified the downstream pathway potentially regulated by ST3GAL1, which was the NF-κB signaling pathway, and further demonstrated that this pathway was positively correlated with malignancy in iCCA cells. Notably, glycoproteomics showed that O-glycosylation was changed in iCCA cells with high ST3GAL1 expression. Importantly, the altered O-glycopeptides underscored the potential utility of O-glycosylation profiling as a discriminatory marker for iCCA cells with ST3GAL1 overexpression. Additionally, miR-320b was identified as a post-transcriptional regulator of ST3GAL1, capable of suppressing ST3GAL1 expression and then reducing the proliferation, migration, and invasion abilities of iCCA cell lines. Taken together, these results suggest ST3GAL1 could serve as a promising therapeutic target for iCCA.

Female↗

Linear ablation of left atrium for the treatment of atrial fibrillation guided by double Lasso catheters and three dimensional electroanatomical mapping.

BACKGROUND: Linear ablation of left atrium (LA) guided by three dimensional (3-D) electroanatomical mapping (Carto) has been used in many centres worldwide for the treatment of atrial fibrillation (AF) instead of pure anatomical approaches. There were little data about linear ablation of LA guided by Carto and double Lasso catheters in China. We report the results of linear ablation of LA guided by both Carto and double Lasso catheters. METHODS: After the anatomical model of LA and all pulmonary veins (PVs) had been established, circumferential ablations of the left pulmonary vein antrum and the right pulmonary vein antrum were performed with 2 circumferential mapping catheters (Lasso) placed within the ipsilateral superior and inferior PVs. The endpoint of ablation was abolishment or dissociation of the pulmonary vein potentials (PVPs). Oral amiodarone or propafenone was taken for at least 3 months by patients with persistent AF, permanent AF or those whose PVPs had not been isolated completely. The recurrence of atrial tachyarrhythmias was observed 3 months after the procedure. RESULTS: There were 106 patients (mean age, 51.4 +/- 9.9 years). Seventy-eight patients had paroxysmal AF, 12 persistent AF and 16 permanent AF. Onset of atrial fibrillation occurred in 52 patients during ablation procedure. Thirty-two patients restored to sinus rhythm eventually after the procedure. Abolishment or dissociation of PVPs was accomplished during the procedure in 94 patients (88.7%). The duration of procedure and exposure to X-ray were (213 +/- 45) minutes and (32.5 +/- 12.8) minutes, respectively. Among the 87 patients followed up for over 3 months, 62 were free of atrial tachyarrhythmias (including 8 patients who were still taking oral amiodarone). The success rate was 71.3% in the first procedure. Two patients had pericardial effusion treated by pericardial puncture and effusion drainage. No pulmonary vein stenosis, atrioesophageal fistula, stroke or procedural death occurred. CONCLUSIONS: Combination of double Lasso catheters with 3-D electroanatomical mapping to guide the linear ablation of left atrium procedure can confirm the isolation of PVPs.

Adult↗

Effect of nifekalant on acute electrical remodelling in rapid atrial pacing canine model.

BACKGROUND: Nifekalant may prevent atrial fibrillation (AF) and possibly be useful in treatment of atrial tachyarrhythmia in patients with severe heart failure. This study investigated the electophysiologic effect of nifekalant on the acute atrial remodeling in rapid atrial pacing (RAP) model of canine. METHODS: Twelve mongrel dogs subjected to rapid stimulation (400 beats/min) at left atrial appendage (LAA) for 24 hours, were randomized into the control group (rapid pacing only, n = 6) and the nifekalant group (intravenous nifekalant therapy immediately after RAP, n = 6). Atrial electrophysiological parameters were measured in right atrium, coronary sinus, LAA, posterior wall of left atrium (PWLA) and left superior pulmonary vein (LSPV), before and after the RAP. RESULTS: In the control group, the effective refractory periods (ERP) were shortened greatly at all sites, paced dogs had substantially shorter ERPs in the high right atrium, LAA, and LSPV, but fewer changes in the PWLA, the coefficient variation of ERP (COV ERP) was increased significantly. After rapid atrial stimulation, the inducibility of AF increased significantly [induction number: pre-RAP vs post-RAP, 1.00 +/- 0.89 vs 8.17 +/- 2.79, P < 0.01; duration of AF: pre-RAP vs post-RAP, (450.34 +/- 362.59) ms vs (9975.77 +/- 4376.99) ms, P < 0.01]. In the nifekalant group, although the ERPs were prolonged at all sites compared with those in pre-RAP state, only the value at LSPV differed significantly from that in pre-RAP state [pre-RAP vs post-RAP, (102.50 +/- 5.24) ms vs (132.51 +/- 5.20) ms, P < 0.01]; the COV ERP did not change statistically in this group. The inducibility of AF slightly increased but insignificantly after pacing [induction number: pre-RAP vs post-RAP, 0.83 +/- 0.75 vs 1.67 +/- 0.82, P = 0.19; duration of AF: pre-RAP vs post-RAP, (378.67 +/- 317.88) ms vs (1124.08 +/- 1109.77) ms, P = 0.06]. Conduction time values did not alter significantly in either of the two groups after RAP. CONCLUSIONS: In canine RAP model, nifekalant inhibited ERP shortening and ERP heterogeneity increasing, decreased AF induction. Nifekalant can reverse acute electrical remodeling effect in this model.

Animals↗

Acceleration after-effects on learning and memory in rats: +10 Gz or +6 Gz for 3 min.

High sustained positive Gz (+Gz) exposures have been shown to have a pathophysiological impact on the brain in rats. However, the consequence for brain function such as learning and memory remains elusive. In the present study, we investigated locomotor activity, learning ability and memory in rats over 6 days (d) following +6 Gz/3 min and +10 Gz/3 min exposures. In an open field test, rats treated with +10 Gz showed a significant increase in the time spent in the center square immediately and 2d after exposure compared with control rats. In contrast, the number of grid crosses and number of rears of rats decreased significantly immediately after +6 Gz and +10 Gz exposures. In addition, a Y-maze test revealed that +Gz exposures reduced the number of correct responses and increased total reaction time in rats, and the number of correct responses was negatively correlated with the total reaction time in all groups throughout the period of study. Moreover, the passive avoidance test exhibited that the latency increased significantly on 0 d and decreased significantly on 6 d after +Gz exposures compared with control. Thus, +6 Gz/3 min and +10 Gz/3 min exposures may transiently decrease locomotor activity, impair learning, and induce a deficit in memory retention in rats.

Acceleration↗

The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population.

Recent studies suggest that genetic mutation of the slow delayed rectifier potassium channel (I(Ks)) may underlie atrial fibrillation (AF). We investigated the association between AF and the single nucleotide polymorphisms (SNPs) of genes KCNQ1, KCNE1 and KCNE4 associated with this channel. Common non-synonymous SNPs in KCNQ1 and KCNE1 known to be frequent in Asian people were selected and direct sequencing of KCNE4 was performed to identify possible SNPs. The AF group consisted of 142 hospitalized patients with AF, the community control group consisted of 120 subjects, and a ward control group consisted of 118 hospitalized patients without AF. Restriction fragment length polymorphism analysis was performed to determine the genotypes. The minor allele frequencies of P448R, R519H, G643S for KCNQ1 and G38S and D85N for KCNE1 in the AF group, the community control group and the ward control group were 9.9, 7.9, 9.3%; 0, 0, -; 4.3, 4.2, 1.7%; 28.4, 31.7, 29.7%; 0.7, 0.4%, -, respectively. There was no significant association between these SNPs and AF phenotype. There were eight SNPs in the whole length of KCNE4 plus 1,000 bases upstream of this gene including the non-synonymous SNP E145D. Logistical regression analysis revealed a difference in the distribution of KCNE4 E145D in the AF and the community control group (minor allele frequency was 34.0 versus 27.1% respectively, OR = 1.66, p = 0.044). We provided the frequencies of non-synonymous SNPs of KCNQ1 and KCNE1 in Chinese population; none of these SNPs was associated with AF. But KCNE4 E145D may be associated with the AF phenotype.

Aged↗

snoSeeker: an advanced computational package for screening of guide and orphan snoRNA genes in the human genome.

Small nucleolar RNAs (snoRNAs) represent an abundant group of non-coding RNAs in eukaryotes. They can be divided into guide and orphan snoRNAs according to the presence or absence of antisense sequence to rRNAs or snRNAs. Current snoRNA-searching programs, which are essentially based on sequence complementarity to rRNAs or snRNAs, exist only for the screening of guide snoRNAs. In this study, we have developed an advanced computational package, snoSeeker, which includes CDseeker and ACAseeker programs, for the highly efficient and specific screening of both guide and orphan snoRNA genes in mammalian genomes. By using these programs, we have systematically scanned four human-mammal whole-genome alignment (WGA) sequences and identified 54 novel candidates including 26 orphan candidates as well as 266 known snoRNA genes. Eighteen novel snoRNAs were further experimentally confirmed with four snoRNAs exhibiting a tissue-specific or restricted expression pattern. The results of this study provide the most comprehensive listing of two families of snoRNA genes in the human genome till date.

Algorithms↗

Short-term effect of cardiac resynchronization therapy in patients with ischaemic or nonischaemic cardiomyopathy.

BACKGROUND: Patients with heart failure were candidates for cardiac resynchronization therapy (CRT) regardless of underlying aetiology. This study observed the effect of CRT in patients with ischaemic or nonischaemic cardiomyopathy. METHODS: One hundred and forty-two patients with refractory chronic heart failure and left bundle branch block received cardiac resynchronization therapy, 91 men and 51 women, average age 60 years. Left ventricular ejection fraction (LVEF) was severely depressed (mean 29%), left ventricular end diastolic diameter (LVEDD) enlarged (mean 72 mm) and QRS width was lengthened (mean 147 ms). Ninety-eight had nonischaemic cardiomyopathy and 44 had ischaemic cardiomyopathy. RESULTS: After cardiac resynchronization therapy, the heart function was significantly improved. The mean LVEF increased from 29% to 36% after pacing. In patients with nonischaemic cardiomyopathy, the LVEF was improved from 28% to 37%, and in patients with ischaemic cardiomyopathy, the LVEF was improved from 30% to 36%. No significant difference of the improvement was found between the two groups (P > 0.05). CONCLUSIONS: Cardiac resynchronization therapy could significantly improve cardiac function in patients with chronic heart failure regardless of the underlying heart disease.

Bundle-Branch Block↗

Molecular characterization and anticoagulant activity of a novel annexin derived from the Taenia solium.

A novel annexin gene was isolated from the Taenia solium cDNA library by degenerate PCR. The purified protein was generated by hydrolysis with thrombin in glutathione S-transferase (GST) affinity chromatography following expression in GST tagged pGEX-5T vector. It shares the common structural features of the annexin family and specially possesses two unique fragments between repeating domains II and III which do not exist in other annexin family members revealed by aligning and homology modeling, hence it was designated as Tso ANXB2 according to the new nomenclature of annexins. According to the parasitic behaviors of the origin, a series of coagulation assays was performed, indicating that Tso ANXB2 inhibits extrinsic blood coagulation pathway and platelet aggregation also has platelet binding activity. Nevertheless, the mutant protein deleting the consensus coagulation-related KGD motif of Tso ANXB2 showed significant decreasing platelet binding and anticoagulation activity.

Amino Acid Sequence↗

Prevalence and clinical characteristics of sleep apnea in Chinese patients with heart failure.

One hundred twenty-six eligible consecutive Chinese heart failure (HF) patients classified by New York Heart Association (NYHA) Classes II-IV underwent historic data collection and a sleep study. Seventy-one percent of HF patients were diagnosed with sleep apnea (SA), of which 65% were central sleep apnea (CSA) and 35% were obstructive sleep apnea (OSA). Higher body mass index (BMI), metabolic syndrome, habitual snoring, and nocturia were independent risk factors for OSA; NYHA classes III and IV were independent risk factors for CSA in the HF patients. There was a high prevalence of SA in Chinese patients with HF. HF patients with obesity, metabolic syndrome, snoring, nocturia and NYHA classes III and IV were more susceptible to OSA and CSA.

China↗

Diagnostic yield and therapeutic impact of double-balloon enteroscopy in a large cohort of patients with obscure gastrointestinal bleeding.

OBJECTIVES: Double-balloon enteroscopy (DBE) is a novel endoscopic technique developed to investigate small bowel disease. There are limited available data on its impact in the diagnosis and management of obscure gastrointestinal bleeding (OGIB). The aim of this study was to evaluate the diagnostic yield and therapeutic impact of DBE in the management of patients with OGIB. METHODS: This study is a retrospective analysis of patients referred to our hospital from December 2003 to January 2005 for the investigation of overt or occult OGIB who underwent DBE after negative upper endoscopy and colonoscopy. Demographic, clinical, procedural, and outcome data were collected for analysis. RESULTS: One hundred fifty-two patients (73 women and 79 men) were studied, with a mean age of 48.2 yr. Seventeen patients presented with occult OGIB while 135 patients had overt OGIB. A total of 191 DBEs was performed. Antegrade and retrograde approaches were performed in 60 and 53 patients, respectively, and 39 patients had a combination of both routes. DBE demonstrated a potential bleeding site in 115 (75.7%) patients (102 overt, 13 occult). The more common abnormalities detected were small bowel tumors (39.1%) and angioectasia (30.4%). DBE altered management in 83.5% of patients with positive findings. Follow-up was obtained on 119 patients (mean 16 months, range 8-23 months). Of the 95 patients with follow-up and a positive DBE finding, 85 (89%) had no further rebleeding. The procedure was well tolerated with 23 patients (15.1%) experiencing mild self-limited bleeding during the procedure. CONCLUSIONS: DBE appears to have a high diagnostic yield and therapeutic impact in patients with OGIB with previously negative upper endoscopy and colonoscopy.

Adolescent↗

An unconventional nuclear localization motif is crucial for function of the Drosophila Wnt/wingless antagonist Naked cuticle.

Wnt/beta-catenin signals orchestrate cell fate and behavior throughout the animal kingdom. Aberrant Wnt signaling impacts nearly the entire spectrum of human disease, including birth defects, cancer, and osteoporosis. If Wnt signaling is to be effectively manipulated for therapeutic advantage, we first must understand how Wnt signals are normally controlled. Naked cuticle (Nkd) is a novel and evolutionarily conserved inducible antagonist of Wnt/beta-catenin signaling that is crucial for segmentation in the model genetic organism, the fruit fly Drosophila melanogaster. Nkd can bind and inhibit the Wnt signal transducer Dishevelled (Dsh), but the mechanism by which Nkd limits Wnt signaling in the fly embryo is not understood. Here we show that nkd mutants exhibit elevated levels of the beta-catenin homolog Armadillo but no alteration in Dsh abundance or distribution. In the fly embryo, Nkd and Dsh are predominantly cytoplasmic, although a recent report suggests that vertebrate Dsh requires nuclear localization for activity in gain-of-function assays. While Dsh-binding regions of Nkd contribute to its activity, we identify a conserved 30-amino-acid motif, separable from Dsh-binding regions, that is essential for Nkd function and nuclear localization. Replacement of the 30-aa motif with a conventional nuclear localization sequence rescued a small fraction of nkd mutant animals to adulthood. Our studies suggest that Nkd targets Dsh-dependent signal transduction steps in both cytoplasmic and nuclear compartments of cells receiving the Wnt signal.

Active Transport, Cell Nucleus↗

[Effect of human beta defensin 2 on Staphylococcus aureus infection: in vivo study with transgenic mice].

OBJECTIVE: To investigate the effect of human beta defensin 2 (HBD-2) on Staphylococcus aureus infection. METHODS: A minigene of HBD-2 containing pCMV promoter, full length of HBD-2 cDNA, and BGH polyA tail was generated by PCR amplification and introduced into the fertilized oocytes of C57/ICR hybridized mouse by microinjection. After gestation of 3 - 4 weeks, immunohistochemistry was used to detect the expression of HBD-2 peptide in different tissues of the transgenic young mice. Staphylococcus aureus was cultured and injected intraperitoneally to wild type mice and transgenic mice to observe their surviving status. RESULTS: PCR showed that the HBD-2 fragment had been successfully integrated into the chromosome of the mice. A widespread expression of HBD-2 gene was found in many tissues of the transgenic mice: trachea, lung, intestine, esophagus, testis, spleen, skin, endothelium, brain, etc. Four of the 7 transgenic mice survived the Staphylococcus aureus infection, and 10 wild type mice all died within 24 hours. CONCLUSION: HBD-2 may play an important role ion the host defense against Staphylococcus aureus infection.

Animals↗

Focal atrial tachycardia originating from the non-coronary aortic sinus: electrophysiological characteristics and catheter ablation.

OBJECTIVES: We sought to investigate electrophysiological characteristics and catheter ablation in patients with focal atrial tachycardia (AT) originating from the non-coronary aortic sinus (AS). BACKGROUND: In patients with failed ablation of focal AT near the His bundle (HB) region, an origin from the non-coronary AS should be considered because of the close anatomical relationship. METHODS: This study included 9 patients with focal AT, in 6 of whom attempted radiofrequency (RF) ablation had previously failed. Activation mapping was performed during tachycardia to identify an earliest activation in the atria and the AS. The aortic root angiography was performed to identify the origin in the AS before RF ablation. RESULTS: Focal AT was reproducibly induced by atrial pacing. Mapping in atria demonstrated that the earliest atrial activation was located at the HB region, whereas mapping in the non-coronary AS demonstrated that an earliest atrial activation preceded the atrial activation at the HB by 12.2 +/- 6.9 ms and was anatomically located superoposterior to the HB in all 9 patients. Also, His potentials were not found at the successful site in the non-coronary AS in all 9 patients. The focal AT was terminated in <8 s in all 9 patients. Junctional beats and PR prolongation did not occur during RF application in all 9 patients. No complications occurred in any of the nine patients. All 9 patients were free of arrhythmias without antiarrhythmic drugs during a follow-up of 9 +/- 3 months. CONCLUSIONS: In patients with focal AT near the HB region, mapping in the non-coronary AS can improve clinical outcome.

Adult↗

Impact of automatic threshold capture on pulse generator longevity.

BACKGROUND: The automatic, threshold tracking, pacing algorithm developed by St. Jude Medical, verifies ventricular capture beat by beat by recognizing the evoked response following each pacemaker stimulus. This function was assumed to be not only energy saving but safe. This study estimated the extension in longevity obtained by AutoCapture (AC) compared with pacemakers programmed to manually optimized, nominal output. METHODS: Thirty-four patients who received the St. Jude Affinity series pacemaker were included in the study. The following measurements were taken: stimulation and sensing threshold, impedance of leads, evoked response and polarization signals by 3501 programmer during followup, battery current and battery impedance under different conditions. For longevity comparison, ventricular output was programmed under three different conditions: (1) AC on; (2) AC off with nominal output, and (3) AC off with pacing output set at twice the pacing threshold with a minimum of 2.0 V. Patients were divided into two groups: chronic threshold is higher or lower than 1 V. The efficacy of AC was evaluated. RESULTS: Current drain in the AC on group, AC off with optimized programming or nominal output was (14.33 +/- 2.84) mA, (16.74 +/- 2.75) mA and (18.4 +/- 2.44) mA, respectively (AC on or AC off with optimized programming vs. nominal output, P < 0.01). Estimated longevity was significantly extended by AC on when compared with nominal setting [(103 +/- 27) months, (80 +/- 24) months, P < 0.01). Furthermore, compared with the optimized programming, AC extends the longevity when the pacing threshold is higher than 1 V. CONCLUSION: AC could significantly prolong pacemaker longevity; especially in the patient with high pacing threshold.

Aged↗