The KCNQ family of genes(KCNQ1–KCNQ5),encoding voltage-gated K+(Kv)channels,have been demonstrated to play potential pathophysiological roles in cancers.However,the associations between genetic variants located in KC...The KCNQ family of genes(KCNQ1–KCNQ5),encoding voltage-gated K+(Kv)channels,have been demonstrated to play potential pathophysiological roles in cancers.However,the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear.In this study,a large-scale cohort comprising 1135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival(OS).Based on the survival evaluation of all five KCNQ family genes,KCNQ1 was selected for subsequent genetic analysis.In both Cox regression model and stepwise Cox regression model used to evaluate survival-related genetic variants,we found that KCNQ1 rs10832417G>T was associated with an increased OS in gastric cancer patients(adjusted hazards ratio[HR]=0.84,95%confidence interval[CI]:0.72–0.98,P=0.023).Subsequently,a nomogram was constructed to enhance the prognostic capacity and clinical translation of rs10832417 variants.The rs10832417 T allele was predicted to increase the minimum free energy of the secondary structure.Furthermore,we observed that gastric cancer patients with downregulated KCNQ1expression had a poorer survival across multiple public datasets.The findings of the present study indicate that KCNQ1 rs10832417 may serve as an independent prognostic predictor of gastric cancer,providing novel insights into the progression and survival of the disease.展开更多
The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant...The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.展开更多
Inflammatory bowel diseases (IBD) are complex multifactorial disorders that include Crohn’s disease (CD) and ulcerative colitis (UC). Considering that IBD is a genetic and multifactorial disease, we screened for the ...Inflammatory bowel diseases (IBD) are complex multifactorial disorders that include Crohn’s disease (CD) and ulcerative colitis (UC). Considering that IBD is a genetic and multifactorial disease, we screened for the distribution dynamism of IBD pathogenic genetic variants (single nucleotide polymorphisms;SNPs) and risk factors in four (4) IBD pediatric patients, by integrating both clinical exome sequencing and computational statistical approaches, aiming to categorize IBD patients in CD and UC phenotype. To this end, we first aligned genomic read sequences of these IBD patients to hg19 human genome by using bowtie 2 package. Next, we performed genetic variant calling analysis in terms of single nucleotide polymorphism (SNP) for genes covered by at least 20 read genomic sequences. Finally, we checked for biological and genomic functions of genes exhibiting statistically significant genetic variant (SNPs) by introducing Fitcon genomic parameter. Findings showed Fitcon parameter as normalizing IBD patient’s population variability, as well as inducing a relative good clustering between IBD patients in terms of CD and UC phenotypes. Genomic analysis revealed a random distribution of risk factors and as well pathogenic SNPs genetic variants in the four IBD patient’s genome, claiming to be involved in: i) Metabolic disorders, ii) Autoimmune deficiencies;iii) Crohn’s disease pathways. Integration of genomic and computational statistical analysis supported a relative genetic variability regarding IBD patient population by processing IBD pathogenic SNP genetic variants as opposite to IBD risk factor variants. Interestingly, findings clearly allowed categorizing IBD patients in CD and UC phenotypes by applying Fitcon parameter in selecting IBD pathogenic genetic variants. Considering as a whole, the study suggested the efficiency of integrating clinical exome sequencing and computational statistical tools as a right approach in discriminating IBD phenotypes as well as improving inflammatory bowel disease (IBD) molecular diagnostic process.展开更多
Background:Bonducellin is one of the bioactive compounds present in Caesalpinia bonduc Roxb(L).It is a homoisoflavonoid recognized for its anti-cancer,anti-androgenic,and anti-estrogenic properties and could potential...Background:Bonducellin is one of the bioactive compounds present in Caesalpinia bonduc Roxb(L).It is a homoisoflavonoid recognized for its anti-cancer,anti-androgenic,and anti-estrogenic properties and could potentially treat polycystic ovary syndrome(PCOS).However,the underlying molecular mechanism remains unexplored.This study aims to elucidate the potential molecular mechanisms of bonducellin in treating PCOS and its associated symptoms through an integrated approach combining network pharmacology,molecular docking,molecular dynamics simulation,and in vivo validation.Methods:Bonducellin-associated and PCOS-related genes were intersected using VENN analysis to determine common gene targets.KEGG pathway analysis was conducted to investigate the biological pathways involving the co-targeted genes.The protein-protein interactions of the target genes were performed to identify the key proteins interacting with bonducellin.Molecular docking and 100 ns molecular simulations were carried out to evaluate the binding affinity and conformational stability of bonducellin with the target proteins.Additionally,the acute toxicity of bonducellin was assessed on zebrafish embryos and in vivo gene expression studies were performed to examine its regulatory effect on the top co-targeted gene.Results:The intersection of bonducellin-associated and PCOS-related genes identified 76 co-targeted genes.KEGG pathway analysis revealed their involvement in 15 critical pathways,including steroid hormone biosynthesis.Protein-protein interaction and pathway enrichment analysis highlighted key targets,including MMP9,AR,KDR,PRKACA,KIT,CYP19A1,HSD11B1,ESR1,STAT3,ESR2,PRKCA,ROCK1,BRAF,HSD17B2,PIK3R1,and RAF1,all of which exhibited strong binding to bonducellin.Molecular simulations confirmed the stability of bonducellin to the top proteins,MMP9 and AR,with high binding scores.Acute toxicity studies in zebrafish embryos determined the LC50 value of bonducellin as 0.8μg/mL at 48 hpf.Gene expression analysis revealed that bonducellin differentially regulates the MMP9 gene that is involved in modulating PCOS-related pathways.Conclusion:This study suggests potential gene pathways and protein interactions through which bonducellin could exert therapeutic effects on PCOS and its associated disorders.This provides valuable insights for future research into understanding and developing bonducellin-based treatments for PCOS.展开更多
The zebrafish has emerged as a powerful model organism in life science owing to its remarkable biological characteristics and wide-ranging applications.This review provides a comprehensive overview of the recent advan...The zebrafish has emerged as a powerful model organism in life science owing to its remarkable biological characteristics and wide-ranging applications.This review provides a comprehensive overview of the recent advancements in research on zebrafish within the field of environmental toxicology,highlighting specific studies where this species was used to investigate various pollutants to elucidate their impacts and underlying mechanisms.The findings of these studies underscore the significant potential of zebrafish as a model to gain crucial insights into the ecological consequences of environmental contamination and toxicity pathways.By incorporating cutting-edge technologies such as artificial intelligence(Al),high-throughput screening,and omics approaches,the use of zebrafish as a model organism is poised to significantly accelerate toxicological investigations,promote environmental conservation efforts,contribute to safeguarding human health,and advance sustainable development objectives.展开更多
Background Necrotic enteritis(NE)is an economically important disease of broiler chickens caused by Clostridium perfringens(CP).The pathogenesis,or disease process,of NE is still not clear.This study aimed to identify...Background Necrotic enteritis(NE)is an economically important disease of broiler chickens caused by Clostridium perfringens(CP).The pathogenesis,or disease process,of NE is still not clear.This study aimed to identify the alterations of metabolites and metabolic pathways associated with subclinical or clinical NE in CP infected birds and to investi-gate the possible variations in the metabolic profile of birds infected with different isolates of CP.Methodology Using a well-established NE model,the protein content of feed was changed abruptly before expos-ing birds to CP isolates with different toxin genes combinations(cpa,cpb2,netB,tpeL;cpa,cpb2,netB;or cpa,cpb2).Metabolomics analysis of jejunal contents was performed by a targeted,fully quantitative LC-MS/MS based assay.Results This study detected statistically significant differential expression of 34 metabolites including organic acids,amino acids,fatty acids,and biogenic amines,including elevation of butyric acid at onset of NE in broiler chickens.Subsequent analysis of broilers infected with CP isolates with different toxin gene combinations confirmed an eleva-tion of butyric acid consistently among 21 differentially expressed metabolites including organic acids,amino acids,and biogenic amines,underscoring its potential role during the development of NE.Furthermore,protein-metabolite network analysis revealed significant alterations in butyric acid and arginine-proline metabolisms.Conclusion This study indicates a significant metabolic difference between CP-infected and non-infected broiler chickens.Among all the metabolites,butyric acid increased significantly in CP-infected birds compared to non-infected healthy broilers.Logistic regression analysis revealed a positive association between butyric acid(coefficient:1.23,P<0.01)and CP infection,while showing a negative association with amino acid metabolism.These findings suggest that butyric acid could be a crucial metabolite linked to the occurrence of NE in broiler chickens and may serve as an early indicator of the disease at the farm level.Further metabolomic experiments using different NE animal models and field studies are needed to determine the specificity and to validate metabolites associated with NE,regardless of predisposing factors.展开更多
Most papillary thyroid carcinoma(PTC) patients have a good prognosis. However, lymph node metastasis(LNM), the most common manifestation of disease progression, is frequently associated with a poor prognosis.Neverthel...Most papillary thyroid carcinoma(PTC) patients have a good prognosis. However, lymph node metastasis(LNM), the most common manifestation of disease progression, is frequently associated with a poor prognosis.Nevertheless, few studies have focused on the underlying mechanisms of LNM. In the current study, we aimed to investigate the potential role of exosomal circRNAs that contribute to LNM in PTC. We identified 9 000 differentially expressed exosomal circRNAs in PTC patients with LNM, including 684 upregulated and 2 193 downregulated circRNAs. Functional enrichment analysis revealed that these differentially expressed circRNAs were primarily involved in a variety of molecular and signaling pathways correlated with PTC progression and LNM. Through bioinformatics analysis, we identified 14 circRNA-miRNA-mRNA networks related to LNM-associated signaling pathways in PTC. Moreover, both circTACC2-miR-7-EGFR and circBIRC6-miR-24-3p-BCL2L11 axes were verified for their potential involvement in PTC with LNM. Additionally, we identified four upregulated circRNA-related hub genes and eight hub genes correlated with downregulated circRNAs, some of which were validated as being potentially involved in LNM in PTC. Collectively, our findings provide a novel framework for an in-depth investigation of the function of dysregulated exosomal circRNAs and their potential as biomarkers in PTC patients with LNM.展开更多
Obesity,a global health concern,is associated with severe health issues like type 2 diabetes,heart disease,and respiratory complications.It also increases the risk of various cancers,including melanoma,endometrial,pro...Obesity,a global health concern,is associated with severe health issues like type 2 diabetes,heart disease,and respiratory complications.It also increases the risk of various cancers,including melanoma,endometrial,prostate,pancreatic,esophageal adenocarcinoma,colorectal carcinoma,renal adenocarcinoma,and pre-and post-menopausal breast cancer.Obesity-induced cellular changes,such as impaired CD8^(+)T cell function,dyslipi-demia,hypercholesterolemia,insulin resistance,mild hyperglycemia,and fluctuating levels of leptin,resistin,adiponectin,and IL-6,contribute to cancer development by promoting inflammation and creating a tumor-promoting microenvironment rich in adipocytes.Adipocytes release leptin,a pro-inflammatory substance that stimulates cancer cell proliferation,inflammation,and invasion,altering the tumor cell metabolic pathway.Adiponectin,an insulin-sensitizing adipokine,is typically downregulated in obese individuals.It has antipro-liferative,proapoptotic,and antiangiogenic properties,making it a potential cancer treatment.This narrative review offers a comprehensive examination of the molecular interconnections between obesity and cancer,draw-ing on an extensive,though non-systematic,survey of the recent literature.This approach allows us to integrate and synthesize findings from various studies,offering a cohesive perspective on emerging themes and potential therapeutic targets.The review explores the metabolic disturbances,cellular alterations,inflammatory responses,and shifts in the tumor microenvironment that contribute to the obesity-cancer link.Finally,it discusses poten-tial therapeutic strategies aimed at disrupting these connections,offering valuable insights into future research directions and the development of targeted interventions.展开更多
Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained...Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained largely unknown.In this study,we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study(GWAS),including 9674 East Asians and 10,115 Europeans,quantitatively assessing 78 facial traits using 3D facial images.We identify 71 genomic loci associated with facial features,including 21 novel loci.We develop a facial polygenic score(FPS)that enables the prediction of facial features based on genetic information.Interestingly,the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features.Furthermore,we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records.Our results suggest that Neanderthals and Denisovans likely share similar facial features,such as a wider but shorter nose and a wider endocanthion distance.The decreased mouth width is characterized specifically in Denisovans.The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.展开更多
Fifty-seven bacteria were isolated from Southern Ocean （Indian sector） water samples which were collected from different latitude and longitude of the ocean. All the isolates were able to grow at 4℃, 20℃, 37℃ and...Fifty-seven bacteria were isolated from Southern Ocean （Indian sector） water samples which were collected from different latitude and longitude of the ocean. All the isolates were able to grow at 4℃, 20℃, 37℃ and tolerable NaCI concentration up to 13.5% （w/v）. 29 out of 57 isolates were identified using 16S rDNA amplification and the sequences were submitted to National Center for Biotechnology Information （NCBI）. All the isolates were classified by using Ribosomal Database Project （RDP） and found that isolates belongs to Proteobacteria and Bacteriodes. The average G＋C content was 56.4%. The isolates were screened for the presence of extracellular enzymes, viz. amylase, catalase, urease, esterase, lipase and protease. The disc diffusion method is used to screen antibiotic production by the isolates against four pathogenic bacteria, viz. Salmonella typhimurium （NCIM 2501）, Staphylococcus aureus （NCIM 2122）, Bacillus subtilis （NCIM 2193）, and Pseudomonas aeruginosa （NCIM 2036）. Nine out of 29 were found to be antibiotic producer.展开更多
α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons,respectively.Previous works have revealed that intracellular deposition...α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons,respectively.Previous works have revealed that intracellular deposition ofα-synuclein and/or tau causes many neurodegenerative disorders,including Alzheimer’s disease and Parkinson’s disease.Despite intense investigation,the normal physiological functions and roles ofα-synuclein and tau are still unclear,owing to the fact that mice with knockout of either of these proteins do not present apparent phenotypes.Interestingly,the co-occurrence ofα-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies,some of which share similarities in clinical manifestations.Furthermore,the direct interaction ofα-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in vivo.On the other hand,our recent findings have revealed thatα-synuclein and tau are cooperatively involved in brain development in a stage-dependent manner.These findings indicate strong cross-talk between the two proteins in physiology and pathology.In this review,we provide a summary of the recent findings on the functional roles ofα-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases.A deep understanding of the interplay betweenα-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.展开更多
To obtain the helper plasmids for a reverse genetics system of rabies virus, the cDNAs of the complete open reading frames of the N, P, G, and L genes of rabies street virus stain HN10 were each cloned into expression...To obtain the helper plasmids for a reverse genetics system of rabies virus, the cDNAs of the complete open reading frames of the N, P, G, and L genes of rabies street virus stain HN10 were each cloned into expression vector pVAX1, These four plasmids were identified by restriction enzyme digestion and gene sequencing. The plasmid encoding the N protein was selected to determine the expression effect of these plasmids in NA cells. The results showed that the helper plasmids for a reverse genetics system of rabies street virus strain HN10 had been successfully constructed.展开更多
The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alteration...The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.展开更多
Objective:Numerous single nucleotide polymorphisms(SNPs)have been identified as genetic contributors to atrial fibrillation(AF).The aim of this study was to investigate the effects of genome-wide N6-methyladenosine(m^...Objective:Numerous single nucleotide polymorphisms(SNPs)have been identified as genetic contributors to atrial fibrillation(AF).The aim of this study was to investigate the effects of genome-wide N6-methyladenosine(m^(6)A)-SNPs on AF.Method:m^(6)A-SNPs were identified by analysis of raw data from published AF GWAS datasets and the list of m^(6)A-SNPs from the m^(6)AVar database.Expression quantitative trait loci(eQTL)analysis was conducted to evaluate the effects of m^(6)A-SNPs on gene expression.The expression of linked genes was validated in three independent AF-associated gene expression datasets(GSE14975,GSE108660 and GSE2240).Results:A total of 1429(6.2%)unique m^(6)A-SNPs that were significantly associated with AF were identified.Sev-enteen m^(6)A-SNPs in 14 genes reached genome-wide significance.Eight m^(6)A-SNPs demonstrated eQTL signals.Four m^(6)A-SNPs(rs383692,rs3211105,rs1061259 and rs1152582)exhibited strong cis-eQTL signals associated with the gene expression levels of SMIM8,JMJD1C and SYNE2.SYNE2 and SMIM8 had differential gene expression levels between the AF and sinus rhythm groups.In addition,SYNE2 expression was uniformly downregulated in AF samples compared with normal control samples in the three datasets.Conclusions:Our results provide the first demonstration that m^(6)A-SNPs are strongly associated with AF,and extend understanding of m^(6)A modification as a potential biological pathway underlying AF.展开更多
Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk....Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk.Currently,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular mechanisms.In the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10^(-5)).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r^(2)=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics analysis.We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene.Biologically,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate cancer.The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.展开更多
Ginger (Zingiber officinale Roscoe) is an important culinary and medicinal spice but is rarely cultivated due to the unavailability of seeds. Given the difficulties in adapting to plantlets produced in natural environ...Ginger (Zingiber officinale Roscoe) is an important culinary and medicinal spice but is rarely cultivated due to the unavailability of seeds. Given the difficulties in adapting to plantlets produced in natural environments, it is important to analyze the survival conditions of ginger plantlets. For this reason, we varied the incubation temperature and humidity as well as the substrate during the weaning phase. Then, we varied the nutrients contained in the watering solution during the hardening phase. The statistical analysis showed that physical factors and substrates significantly influenced (p < 0.0001) plantlet survival. Nutrient solutions significantly influenced the phylogenesis, rhizogenesis, and height growth of the plantlets. The suitable physical factors for good development of plantlets are a temperature of 26.54˚C and a humidity of 96.16%. The 1C2T2TC substrate (1 Compost + 2 Soil + 2 Coconut Peat) had a significant survival rate of approximately 92.5%. During hardening, the Plantzym solution promoted good growth in terms of plantlet height (0.6 cm) and good development of roots (30 roots) and leaves (03 leaves). This work will make it possible to develop a technical seed production sheet for better development of ginger cultivation in Benin.展开更多
BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA misma...BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA mismatch repair(MMR)genes.This phenomenon is defined as microsatellite instability(MSI).Immunohistochemistry(IHC)is a widely used,practical,and cost-effective method for the screening of MSI.However,using IHC alone may be insufficient to identify patients with MSI and LS.AIM To determine the clinicopathological features in EOCRC,IHC performance,and the frequency of genetic testing for EOCRC patients.METHODS A retrospective review was conducted on patients with CRC aged≤50 years who underwent surgery at our center between January 2014 and July 2021.MMR proteins were screened using IHC.Of the 131 patients included,IHC was performed on 130.Patients were classified as MSI or microsatellite-stable(MSS),and their features were compared.Additionally,data from patients who received genetic counseling were analyzed.RESULTS Thirty patients with MSI were designated as group 1,whereas 100 with MSS were defined as group 2.The mean age in group 1 was the lowest(median age:42 vs 46,P<0.05).Group 1 exhibited a higher frequency of tumors in the right colon and a lower frequency in the rectum.Lymph node involvement and distant metastases were less common in group 1,and in group 2,tumors were generally diagnosed at a more advanced stage.Genetic testing was performed in 53 patients(40%),with a definitive LS diagnosis established in 13/17 patients(76.4%)in group 1 and 1/36(2.7%)patients in group 2,resulting in a total of 14 patients(26.4%)with confirmed LS.CONCLUSION MSI tumors show a better prognosis.IHC is very effective for screening MSI,but may not be sufficient alone.Low genetic counseling rates highlight the need for hospital-based surveillance programs.展开更多
BACKGROUND Duchenne muscular dystrophy(DMD)is a neuromuscular disorder caused by mutations in the dystrophin gene.DMD is reported to coexist with other comorbidities,although the occurrence of the triad,autism spectru...BACKGROUND Duchenne muscular dystrophy(DMD)is a neuromuscular disorder caused by mutations in the dystrophin gene.DMD is reported to coexist with other comorbidities,although the occurrence of the triad,autism spectrum disorder(ASD),and epilepsy is very rare.Indeed,only one case of the triad has currently been reported.Here,we present a detailed case report of a ten-year-old boy with DMD,ASD,and epilepsy.We also investigated the dysregulation of miRNAs in this unusual triad(represented as DMD++)compared with a healthy individual and a DMD patient(represented as DMD+)without autism.AIM To understand the differential expression of miRNAs in rare comorbid DMD cases.METHODS The Sequin Form Board test,Gesell's drawing test,multiplex ligation probe amplification,and Vineland Social Maturity Scale were applied to confirm the DMD and ASD.Total RNA was isolated from samples using TRIzol.cDNA was synthesized using the Mir-X^(TM)miRNA First-Strand Synthesis kit.qRT-PCR was performed using SYBR Advantage qPCR Premix.The results were statistically analyzed using one-way analysis of variance with Tukey's ttest.RESULTS miR-146a-5p and miR-132-5p showed significant downregulation in both patient samples.miR-199a-5p and miR-146a-3p showed no change in expression between the diseased and controls.miR-132-3p showed downregulation only in the DMD+sample(0.21±0.04).The decrease in miR-132-3p can result in failed silencing of the phosphatase and tensin homolog-mediated apoptotic pathway,leading to severe skeletal muscle atrophy.Here,the downregulation of miR-132-3p in DMD+is consistent with severe muscle loss and higher disease progression than that in DMD++.DMD++has slower disease progression,and the expression of miRNA involved in inflammatory and apoptotic responses is more similar to that of the control.CONCLUSION Our study shows marked difference in miRNA expression in this rare case of DMD with autism and epilepsy.These miRNAs also serve as regulators of several muscle regeneration,apoptosis,and inflammatory pathways.This study shows the significance of studying miRNAs in such rare cases in a larger cohort to progress in several intervention treatments utilizing miRNAs.展开更多
Pharmacogenomic landscapes and related databases are important for identifying the biomarkers of drug response and toxicity.However,these data are still lacking for the Chinese population.In this study,we constructed ...Pharmacogenomic landscapes and related databases are important for identifying the biomarkers of drug response and toxicity.However,these data are still lacking for the Chinese population.In this study,we constructed a pharmacogenomic landscape and an associated database using whole-genome sequencing data generated by non-invasive prenatal testing in 206,640 Chinese individuals.In total,1,577,513 variants(including 331,610 novel variants)were identified among 3,538 pharmacogenes related to 2,086 drugs.We found that the variant spectrum in the Chinese population differed among the seven major regions.Regional differences also exist among provinces in China.The average numbers of drug enzyme,transporter,and receptor variants were 258,557,and 632,respectively.Subsequent correlation analysis indicated that the pharmacogenes affecting multiple drugs had fewer variants.Among the 16 categories of drugs,we found that nervous system,cardiovascular system,and genitourinary system/sex hormone drugs were more likely to be affected by variants of pharmacogenes.Characteristics of the variants in the enzyme,transporter,and receptor subfamilies showed specificity.To explore the clinical utility of these data,a genetic association study was conducted on 1,019 lung cancer patients.Two novel variants,AKT2 chr19:40770621 C>G and SLC19A1 chr21:46934171 A>C,were identified as novel platinum response biomarkers.Finally,a pharmacogenomic database,named the Chinese Pharmacogenomic Knowledge Base(CNPKB:http://www.cnpkb.com.cn/),was constructed to collect all the data.In summary,a pharmacogenomic landscape and database for the Chinese population were constructed in this study,which could support personalized Chinese medicine in the future.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.82273458 to Jinfei Chen)the Start-up Fund for the Recruited Talents of the First Affiliated Hospital of Wenzhou Medical University(Grant No.2021QD025 to Jinfei Chen)。
文摘The KCNQ family of genes(KCNQ1–KCNQ5),encoding voltage-gated K+(Kv)channels,have been demonstrated to play potential pathophysiological roles in cancers.However,the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear.In this study,a large-scale cohort comprising 1135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival(OS).Based on the survival evaluation of all five KCNQ family genes,KCNQ1 was selected for subsequent genetic analysis.In both Cox regression model and stepwise Cox regression model used to evaluate survival-related genetic variants,we found that KCNQ1 rs10832417G>T was associated with an increased OS in gastric cancer patients(adjusted hazards ratio[HR]=0.84,95%confidence interval[CI]:0.72–0.98,P=0.023).Subsequently,a nomogram was constructed to enhance the prognostic capacity and clinical translation of rs10832417 variants.The rs10832417 T allele was predicted to increase the minimum free energy of the secondary structure.Furthermore,we observed that gastric cancer patients with downregulated KCNQ1expression had a poorer survival across multiple public datasets.The findings of the present study indicate that KCNQ1 rs10832417 may serve as an independent prognostic predictor of gastric cancer,providing novel insights into the progression and survival of the disease.
基金supported by the National Natural Science Foundation of China(Grant No.82173601)Yili&Jiangsu Joint Institute of Health(Grant No.yl2021ms02).
文摘The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.
文摘Inflammatory bowel diseases (IBD) are complex multifactorial disorders that include Crohn’s disease (CD) and ulcerative colitis (UC). Considering that IBD is a genetic and multifactorial disease, we screened for the distribution dynamism of IBD pathogenic genetic variants (single nucleotide polymorphisms;SNPs) and risk factors in four (4) IBD pediatric patients, by integrating both clinical exome sequencing and computational statistical approaches, aiming to categorize IBD patients in CD and UC phenotype. To this end, we first aligned genomic read sequences of these IBD patients to hg19 human genome by using bowtie 2 package. Next, we performed genetic variant calling analysis in terms of single nucleotide polymorphism (SNP) for genes covered by at least 20 read genomic sequences. Finally, we checked for biological and genomic functions of genes exhibiting statistically significant genetic variant (SNPs) by introducing Fitcon genomic parameter. Findings showed Fitcon parameter as normalizing IBD patient’s population variability, as well as inducing a relative good clustering between IBD patients in terms of CD and UC phenotypes. Genomic analysis revealed a random distribution of risk factors and as well pathogenic SNPs genetic variants in the four IBD patient’s genome, claiming to be involved in: i) Metabolic disorders, ii) Autoimmune deficiencies;iii) Crohn’s disease pathways. Integration of genomic and computational statistical analysis supported a relative genetic variability regarding IBD patient population by processing IBD pathogenic SNP genetic variants as opposite to IBD risk factor variants. Interestingly, findings clearly allowed categorizing IBD patients in CD and UC phenotypes by applying Fitcon parameter in selecting IBD pathogenic genetic variants. Considering as a whole, the study suggested the efficiency of integrating clinical exome sequencing and computational statistical tools as a right approach in discriminating IBD phenotypes as well as improving inflammatory bowel disease (IBD) molecular diagnostic process.
文摘Background:Bonducellin is one of the bioactive compounds present in Caesalpinia bonduc Roxb(L).It is a homoisoflavonoid recognized for its anti-cancer,anti-androgenic,and anti-estrogenic properties and could potentially treat polycystic ovary syndrome(PCOS).However,the underlying molecular mechanism remains unexplored.This study aims to elucidate the potential molecular mechanisms of bonducellin in treating PCOS and its associated symptoms through an integrated approach combining network pharmacology,molecular docking,molecular dynamics simulation,and in vivo validation.Methods:Bonducellin-associated and PCOS-related genes were intersected using VENN analysis to determine common gene targets.KEGG pathway analysis was conducted to investigate the biological pathways involving the co-targeted genes.The protein-protein interactions of the target genes were performed to identify the key proteins interacting with bonducellin.Molecular docking and 100 ns molecular simulations were carried out to evaluate the binding affinity and conformational stability of bonducellin with the target proteins.Additionally,the acute toxicity of bonducellin was assessed on zebrafish embryos and in vivo gene expression studies were performed to examine its regulatory effect on the top co-targeted gene.Results:The intersection of bonducellin-associated and PCOS-related genes identified 76 co-targeted genes.KEGG pathway analysis revealed their involvement in 15 critical pathways,including steroid hormone biosynthesis.Protein-protein interaction and pathway enrichment analysis highlighted key targets,including MMP9,AR,KDR,PRKACA,KIT,CYP19A1,HSD11B1,ESR1,STAT3,ESR2,PRKCA,ROCK1,BRAF,HSD17B2,PIK3R1,and RAF1,all of which exhibited strong binding to bonducellin.Molecular simulations confirmed the stability of bonducellin to the top proteins,MMP9 and AR,with high binding scores.Acute toxicity studies in zebrafish embryos determined the LC50 value of bonducellin as 0.8μg/mL at 48 hpf.Gene expression analysis revealed that bonducellin differentially regulates the MMP9 gene that is involved in modulating PCOS-related pathways.Conclusion:This study suggests potential gene pathways and protein interactions through which bonducellin could exert therapeutic effects on PCOS and its associated disorders.This provides valuable insights for future research into understanding and developing bonducellin-based treatments for PCOS.
基金supported by the Leading Goose R&D Program of Zhejiang(No.2024C03230)the Fundamental Research Funds for the Central Universities。
文摘The zebrafish has emerged as a powerful model organism in life science owing to its remarkable biological characteristics and wide-ranging applications.This review provides a comprehensive overview of the recent advancements in research on zebrafish within the field of environmental toxicology,highlighting specific studies where this species was used to investigate various pollutants to elucidate their impacts and underlying mechanisms.The findings of these studies underscore the significant potential of zebrafish as a model to gain crucial insights into the ecological consequences of environmental contamination and toxicity pathways.By incorporating cutting-edge technologies such as artificial intelligence(Al),high-throughput screening,and omics approaches,the use of zebrafish as a model organism is poised to significantly accelerate toxicological investigations,promote environmental conservation efforts,contribute to safeguarding human health,and advance sustainable development objectives.
基金support for the project was provided by Chicken Farmers of Saskatchewan(424357)Canadian Poultry Research Council(424854)+1 种基金Natural Sciences and Engineering Research Council of Canada(424679)Saskatchewan Agriculture Development Fund(426954).
文摘Background Necrotic enteritis(NE)is an economically important disease of broiler chickens caused by Clostridium perfringens(CP).The pathogenesis,or disease process,of NE is still not clear.This study aimed to identify the alterations of metabolites and metabolic pathways associated with subclinical or clinical NE in CP infected birds and to investi-gate the possible variations in the metabolic profile of birds infected with different isolates of CP.Methodology Using a well-established NE model,the protein content of feed was changed abruptly before expos-ing birds to CP isolates with different toxin genes combinations(cpa,cpb2,netB,tpeL;cpa,cpb2,netB;or cpa,cpb2).Metabolomics analysis of jejunal contents was performed by a targeted,fully quantitative LC-MS/MS based assay.Results This study detected statistically significant differential expression of 34 metabolites including organic acids,amino acids,fatty acids,and biogenic amines,including elevation of butyric acid at onset of NE in broiler chickens.Subsequent analysis of broilers infected with CP isolates with different toxin gene combinations confirmed an eleva-tion of butyric acid consistently among 21 differentially expressed metabolites including organic acids,amino acids,and biogenic amines,underscoring its potential role during the development of NE.Furthermore,protein-metabolite network analysis revealed significant alterations in butyric acid and arginine-proline metabolisms.Conclusion This study indicates a significant metabolic difference between CP-infected and non-infected broiler chickens.Among all the metabolites,butyric acid increased significantly in CP-infected birds compared to non-infected healthy broilers.Logistic regression analysis revealed a positive association between butyric acid(coefficient:1.23,P<0.01)and CP infection,while showing a negative association with amino acid metabolism.These findings suggest that butyric acid could be a crucial metabolite linked to the occurrence of NE in broiler chickens and may serve as an early indicator of the disease at the farm level.Further metabolomic experiments using different NE animal models and field studies are needed to determine the specificity and to validate metabolites associated with NE,regardless of predisposing factors.
基金National Natural Science Foundation of China (Grant No. 81800698)Jiangsu Provincial Medical Key Discipline Cultivation Unit (Grant No. JSDW202241)+1 种基金Research Project of Jiangsu Commission of Health (Grant No. H2023053)Zhenjiang Science and the Technology Planning Project (Grant Nos. SH2023006and SH2023008)。
文摘Most papillary thyroid carcinoma(PTC) patients have a good prognosis. However, lymph node metastasis(LNM), the most common manifestation of disease progression, is frequently associated with a poor prognosis.Nevertheless, few studies have focused on the underlying mechanisms of LNM. In the current study, we aimed to investigate the potential role of exosomal circRNAs that contribute to LNM in PTC. We identified 9 000 differentially expressed exosomal circRNAs in PTC patients with LNM, including 684 upregulated and 2 193 downregulated circRNAs. Functional enrichment analysis revealed that these differentially expressed circRNAs were primarily involved in a variety of molecular and signaling pathways correlated with PTC progression and LNM. Through bioinformatics analysis, we identified 14 circRNA-miRNA-mRNA networks related to LNM-associated signaling pathways in PTC. Moreover, both circTACC2-miR-7-EGFR and circBIRC6-miR-24-3p-BCL2L11 axes were verified for their potential involvement in PTC with LNM. Additionally, we identified four upregulated circRNA-related hub genes and eight hub genes correlated with downregulated circRNAs, some of which were validated as being potentially involved in LNM in PTC. Collectively, our findings provide a novel framework for an in-depth investigation of the function of dysregulated exosomal circRNAs and their potential as biomarkers in PTC patients with LNM.
基金supported by Sidra Medicine Research Fund to Ajaz A.Bhat(grant number:SDR400190)Ammira S.Al-Shabeeb Akil(grant number:SDR400175).
文摘Obesity,a global health concern,is associated with severe health issues like type 2 diabetes,heart disease,and respiratory complications.It also increases the risk of various cancers,including melanoma,endometrial,prostate,pancreatic,esophageal adenocarcinoma,colorectal carcinoma,renal adenocarcinoma,and pre-and post-menopausal breast cancer.Obesity-induced cellular changes,such as impaired CD8^(+)T cell function,dyslipi-demia,hypercholesterolemia,insulin resistance,mild hyperglycemia,and fluctuating levels of leptin,resistin,adiponectin,and IL-6,contribute to cancer development by promoting inflammation and creating a tumor-promoting microenvironment rich in adipocytes.Adipocytes release leptin,a pro-inflammatory substance that stimulates cancer cell proliferation,inflammation,and invasion,altering the tumor cell metabolic pathway.Adiponectin,an insulin-sensitizing adipokine,is typically downregulated in obese individuals.It has antipro-liferative,proapoptotic,and antiangiogenic properties,making it a potential cancer treatment.This narrative review offers a comprehensive examination of the molecular interconnections between obesity and cancer,draw-ing on an extensive,though non-systematic,survey of the recent literature.This approach allows us to integrate and synthesize findings from various studies,offering a cohesive perspective on emerging themes and potential therapeutic targets.The review explores the metabolic disturbances,cellular alterations,inflammatory responses,and shifts in the tumor microenvironment that contribute to the obesity-cancer link.Finally,it discusses poten-tial therapeutic strategies aimed at disrupting these connections,offering valuable insights into future research directions and the development of targeted interventions.
基金funded by the following grants and contracts:Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38020400 to S.W.)the National Natural Science Foundation of China(32325013 to S.W.,32271186 to J.T.,31900408 to M.Z.)+5 种基金the CAS Project for Young Scientists in Basic Research(YSBR-077 to S.W.)Shanghai Science and Technology Commission Excellent Academic Leaders Program(22XD1424700 to S.W.)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-066 to L.J.and J.W.)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01 to L.J.and S.W.)the National Science and Technology Basic Research Project(2015FY111700 to L.J.)the 111 Project(B13016 to L.J.).
文摘Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained largely unknown.In this study,we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study(GWAS),including 9674 East Asians and 10,115 Europeans,quantitatively assessing 78 facial traits using 3D facial images.We identify 71 genomic loci associated with facial features,including 21 novel loci.We develop a facial polygenic score(FPS)that enables the prediction of facial features based on genetic information.Interestingly,the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features.Furthermore,we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records.Our results suggest that Neanderthals and Denisovans likely share similar facial features,such as a wider but shorter nose and a wider endocanthion distance.The decreased mouth width is characterized specifically in Denisovans.The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.
基金the Expedition support to MoES, New Delhi and NCAOR, Goa (No. Mo ES/NCAOR/SOS/1/2007-PC-I dated January 4, 2011)+5 种基金the Cumulative Professional Development Grant (CPDG Ref No. GO/PD/2011-12/269/3523 dated, August 04, 2011) from BIT, MesraBTISNet Sub DIC (BT/BI/065/2004) for providing internet facilities and the Government of JharkhandDepartment of Agriculture for providing infrastructure development fund (5/B.K.V/Misc/12/2001)the financial support as research fellowship to Centre of Excellence (COE) (Ref No. NPIU/TEQIP II/FIN/31/158, dated April 16, 2013) at the Department of BioEngineering
文摘Fifty-seven bacteria were isolated from Southern Ocean （Indian sector） water samples which were collected from different latitude and longitude of the ocean. All the isolates were able to grow at 4℃, 20℃, 37℃ and tolerable NaCI concentration up to 13.5% （w/v）. 29 out of 57 isolates were identified using 16S rDNA amplification and the sequences were submitted to National Center for Biotechnology Information （NCBI）. All the isolates were classified by using Ribosomal Database Project （RDP） and found that isolates belongs to Proteobacteria and Bacteriodes. The average G＋C content was 56.4%. The isolates were screened for the presence of extracellular enzymes, viz. amylase, catalase, urease, esterase, lipase and protease. The disc diffusion method is used to screen antibiotic production by the isolates against four pathogenic bacteria, viz. Salmonella typhimurium （NCIM 2501）, Staphylococcus aureus （NCIM 2122）, Bacillus subtilis （NCIM 2193）, and Pseudomonas aeruginosa （NCIM 2036）. Nine out of 29 were found to be antibiotic producer.
基金supported by the Natural Science Foundation of Guangxi Zhuang Autonomous Region,Nos.2022GXNSFAA035622(to MJ),2020GXNSFAA297048(to ZZ)the National Natural Science Foundation of China,No.82060268(to ZZ)。
文摘α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons,respectively.Previous works have revealed that intracellular deposition ofα-synuclein and/or tau causes many neurodegenerative disorders,including Alzheimer’s disease and Parkinson’s disease.Despite intense investigation,the normal physiological functions and roles ofα-synuclein and tau are still unclear,owing to the fact that mice with knockout of either of these proteins do not present apparent phenotypes.Interestingly,the co-occurrence ofα-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies,some of which share similarities in clinical manifestations.Furthermore,the direct interaction ofα-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in vivo.On the other hand,our recent findings have revealed thatα-synuclein and tau are cooperatively involved in brain development in a stage-dependent manner.These findings indicate strong cross-talk between the two proteins in physiology and pathology.In this review,we provide a summary of the recent findings on the functional roles ofα-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases.A deep understanding of the interplay betweenα-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.
基金National High Technology Research and Development Program of China (2006AA02Z110, 2007AA02Z402)Major Program of the National Natural Science Foundation of China (30630049)
文摘To obtain the helper plasmids for a reverse genetics system of rabies virus, the cDNAs of the complete open reading frames of the N, P, G, and L genes of rabies street virus stain HN10 were each cloned into expression vector pVAX1, These four plasmids were identified by restriction enzyme digestion and gene sequencing. The plasmid encoding the N protein was selected to determine the expression effect of these plasmids in NA cells. The results showed that the helper plasmids for a reverse genetics system of rabies street virus strain HN10 had been successfully constructed.
文摘The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.
基金The study was supported by the Natural Science Foundation of China(31860320 and 32060154)Jiangxi National Natural Science Foundation(20181BAB215030 and 20192BAB215013).
文摘Objective:Numerous single nucleotide polymorphisms(SNPs)have been identified as genetic contributors to atrial fibrillation(AF).The aim of this study was to investigate the effects of genome-wide N6-methyladenosine(m^(6)A)-SNPs on AF.Method:m^(6)A-SNPs were identified by analysis of raw data from published AF GWAS datasets and the list of m^(6)A-SNPs from the m^(6)AVar database.Expression quantitative trait loci(eQTL)analysis was conducted to evaluate the effects of m^(6)A-SNPs on gene expression.The expression of linked genes was validated in three independent AF-associated gene expression datasets(GSE14975,GSE108660 and GSE2240).Results:A total of 1429(6.2%)unique m^(6)A-SNPs that were significantly associated with AF were identified.Sev-enteen m^(6)A-SNPs in 14 genes reached genome-wide significance.Eight m^(6)A-SNPs demonstrated eQTL signals.Four m^(6)A-SNPs(rs383692,rs3211105,rs1061259 and rs1152582)exhibited strong cis-eQTL signals associated with the gene expression levels of SMIM8,JMJD1C and SYNE2.SYNE2 and SMIM8 had differential gene expression levels between the AF and sinus rhythm groups.In addition,SYNE2 expression was uniformly downregulated in AF samples compared with normal control samples in the three datasets.Conclusions:Our results provide the first demonstration that m^(6)A-SNPs are strongly associated with AF,and extend understanding of m^(6)A modification as a potential biological pathway underlying AF.
文摘Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk.Currently,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular mechanisms.In the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10^(-5)).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r^(2)=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics analysis.We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene.Biologically,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate cancer.The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.
文摘Ginger (Zingiber officinale Roscoe) is an important culinary and medicinal spice but is rarely cultivated due to the unavailability of seeds. Given the difficulties in adapting to plantlets produced in natural environments, it is important to analyze the survival conditions of ginger plantlets. For this reason, we varied the incubation temperature and humidity as well as the substrate during the weaning phase. Then, we varied the nutrients contained in the watering solution during the hardening phase. The statistical analysis showed that physical factors and substrates significantly influenced (p < 0.0001) plantlet survival. Nutrient solutions significantly influenced the phylogenesis, rhizogenesis, and height growth of the plantlets. The suitable physical factors for good development of plantlets are a temperature of 26.54˚C and a humidity of 96.16%. The 1C2T2TC substrate (1 Compost + 2 Soil + 2 Coconut Peat) had a significant survival rate of approximately 92.5%. During hardening, the Plantzym solution promoted good growth in terms of plantlet height (0.6 cm) and good development of roots (30 roots) and leaves (03 leaves). This work will make it possible to develop a technical seed production sheet for better development of ginger cultivation in Benin.
文摘BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA mismatch repair(MMR)genes.This phenomenon is defined as microsatellite instability(MSI).Immunohistochemistry(IHC)is a widely used,practical,and cost-effective method for the screening of MSI.However,using IHC alone may be insufficient to identify patients with MSI and LS.AIM To determine the clinicopathological features in EOCRC,IHC performance,and the frequency of genetic testing for EOCRC patients.METHODS A retrospective review was conducted on patients with CRC aged≤50 years who underwent surgery at our center between January 2014 and July 2021.MMR proteins were screened using IHC.Of the 131 patients included,IHC was performed on 130.Patients were classified as MSI or microsatellite-stable(MSS),and their features were compared.Additionally,data from patients who received genetic counseling were analyzed.RESULTS Thirty patients with MSI were designated as group 1,whereas 100 with MSS were defined as group 2.The mean age in group 1 was the lowest(median age:42 vs 46,P<0.05).Group 1 exhibited a higher frequency of tumors in the right colon and a lower frequency in the rectum.Lymph node involvement and distant metastases were less common in group 1,and in group 2,tumors were generally diagnosed at a more advanced stage.Genetic testing was performed in 53 patients(40%),with a definitive LS diagnosis established in 13/17 patients(76.4%)in group 1 and 1/36(2.7%)patients in group 2,resulting in a total of 14 patients(26.4%)with confirmed LS.CONCLUSION MSI tumors show a better prognosis.IHC is very effective for screening MSI,but may not be sufficient alone.Low genetic counseling rates highlight the need for hospital-based surveillance programs.
文摘BACKGROUND Duchenne muscular dystrophy(DMD)is a neuromuscular disorder caused by mutations in the dystrophin gene.DMD is reported to coexist with other comorbidities,although the occurrence of the triad,autism spectrum disorder(ASD),and epilepsy is very rare.Indeed,only one case of the triad has currently been reported.Here,we present a detailed case report of a ten-year-old boy with DMD,ASD,and epilepsy.We also investigated the dysregulation of miRNAs in this unusual triad(represented as DMD++)compared with a healthy individual and a DMD patient(represented as DMD+)without autism.AIM To understand the differential expression of miRNAs in rare comorbid DMD cases.METHODS The Sequin Form Board test,Gesell's drawing test,multiplex ligation probe amplification,and Vineland Social Maturity Scale were applied to confirm the DMD and ASD.Total RNA was isolated from samples using TRIzol.cDNA was synthesized using the Mir-X^(TM)miRNA First-Strand Synthesis kit.qRT-PCR was performed using SYBR Advantage qPCR Premix.The results were statistically analyzed using one-way analysis of variance with Tukey's ttest.RESULTS miR-146a-5p and miR-132-5p showed significant downregulation in both patient samples.miR-199a-5p and miR-146a-3p showed no change in expression between the diseased and controls.miR-132-3p showed downregulation only in the DMD+sample(0.21±0.04).The decrease in miR-132-3p can result in failed silencing of the phosphatase and tensin homolog-mediated apoptotic pathway,leading to severe skeletal muscle atrophy.Here,the downregulation of miR-132-3p in DMD+is consistent with severe muscle loss and higher disease progression than that in DMD++.DMD++has slower disease progression,and the expression of miRNA involved in inflammatory and apoptotic responses is more similar to that of the control.CONCLUSION Our study shows marked difference in miRNA expression in this rare case of DMD with autism and epilepsy.These miRNAs also serve as regulators of several muscle regeneration,apoptosis,and inflammatory pathways.This study shows the significance of studying miRNAs in such rare cases in a larger cohort to progress in several intervention treatments utilizing miRNAs.
基金supported by the National Natural Science Foundation of China(82073943,82373962,and 82450103 to J-Y.Y. and 82204533 to J.J.C.)a Scientific Research Project of the Furong Laboratory of Central South University (2023SK2083 to J-Y.Y.)+4 种基金the Natural Science Foundation of Hunan Province(2023JJ40931 to JJ.C 2023JU50251 to J.-C.W,and 2024JJ6633 to Y.W.)the Postdoctoral Fellowship Programof CPSF (GZB20240878 to Y.W.)the Hunan Innovation platform and talent program(2020RC3086 to C.-P.L)the Non-profit Central Research Institute Fund of the Chinese Academyof Medical Scienoes (2020 PT320-004to J.-G.L)the Open Fund for ScientificResearch ofNHC Key Laboratory of Personalized Diagnosis and Treatment of Nasopharyn-geal Carcinoma (2021NPCK01 to J.-Y.Y.).
文摘Pharmacogenomic landscapes and related databases are important for identifying the biomarkers of drug response and toxicity.However,these data are still lacking for the Chinese population.In this study,we constructed a pharmacogenomic landscape and an associated database using whole-genome sequencing data generated by non-invasive prenatal testing in 206,640 Chinese individuals.In total,1,577,513 variants(including 331,610 novel variants)were identified among 3,538 pharmacogenes related to 2,086 drugs.We found that the variant spectrum in the Chinese population differed among the seven major regions.Regional differences also exist among provinces in China.The average numbers of drug enzyme,transporter,and receptor variants were 258,557,and 632,respectively.Subsequent correlation analysis indicated that the pharmacogenes affecting multiple drugs had fewer variants.Among the 16 categories of drugs,we found that nervous system,cardiovascular system,and genitourinary system/sex hormone drugs were more likely to be affected by variants of pharmacogenes.Characteristics of the variants in the enzyme,transporter,and receptor subfamilies showed specificity.To explore the clinical utility of these data,a genetic association study was conducted on 1,019 lung cancer patients.Two novel variants,AKT2 chr19:40770621 C>G and SLC19A1 chr21:46934171 A>C,were identified as novel platinum response biomarkers.Finally,a pharmacogenomic database,named the Chinese Pharmacogenomic Knowledge Base(CNPKB:http://www.cnpkb.com.cn/),was constructed to collect all the data.In summary,a pharmacogenomic landscape and database for the Chinese population were constructed in this study,which could support personalized Chinese medicine in the future.
