Background:Few studies have assessed the relationship between multimorbidity patterns and mortality risk in the Chinese population.We aimed to identify multimorbidity patterns and examined the associations of multimor...Background:Few studies have assessed the relationship between multimorbidity patterns and mortality risk in the Chinese population.We aimed to identify multimorbidity patterns and examined the associations of multimorbidity patterns and the number of chronic diseases with the risk of mortality among Chinese middle-aged and older adults.Methods:We used data from the China Kadoorie Biobank and included 512,723 participants aged 30 to 79 years.Multimorbidity was defined as the presence of two or more of the 15 chronic diseases collected by self-report or physical examination at baseline.Multimorbidity patterns were identified using hierarchical cluster analysis.Cox regression was used to estimate the associations of multimorbidity patterns and the number of chronic diseases with all-cause and cause-specific mortality.Results:Overall,15.8%of participants had multimorbidity.The prevalence of multimorbidity increased with age and was higher in urban than rural participants.Four multimorbidity patterns were identified,including cardiometabolic multimorbidity(diabetes,coronary heart disease,stroke,and hypertension),respiratory multimorbidity(tuberculosis,asthma,and chronic obstructive pulmonary disease),gastrointestinal and hepatorenal multimorbidity(gallstone disease,chronic kidney disease,cirrhosis,peptic ulcer,and cancer),and mental and arthritis multimorbidity(neurasthenia,psychiatric disorder,and rheumatoid arthritis).During a median of 10.8 years of follow-up,49,371 deaths occurred.Compared with participants without multimorbidity,cardiometabolic multimorbidity(hazard ratios[HR]=2.20,95%confidence intervals[CI]:2.14-2.26)and respiratory multimorbidity(HR=2.13,95%CI:1.97-2.31)demonstrated relatively higher risks of mortality,followed by gastrointestinal and hepatorenal multimorbidity(HR=1.33,95%CI:1.22-1.46).The mortality risk increased by 36%(HR=1.36,95%CI:1.35-1.37)with every additional disease.Conclusion:Cardiometabolic multimorbidity and respiratory multimorbidity posed the highest threat on mortality risk and d展开更多
The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively s...The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy(PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids(BAs) are ligands of farnesoid X receptor(FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potentialuse of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.展开更多
Lung cancer is the leading cause of cancer mortality worldwide. Its high mortality is due to the poor prognosis of the disease caused by a late disease presentation, tumor heterogeneities within histological subtypes,...Lung cancer is the leading cause of cancer mortality worldwide. Its high mortality is due to the poor prognosis of the disease caused by a late disease presentation, tumor heterogeneities within histological subtypes, and the relatively limited understanding of tumor biology. Importantly, lung cancer histological subgroups respond differently to some chemotherapeutic substances and side effects of some therapies appear to vary between subgroups. Biomarkers able to stratify for the subtype of lung cancer, prognosticate the course of disease, or predict the response to treatment are in high demand. In the last decade, microR NAs(miR NAs), measured in resected tumor samples or in fine needle aspirate samples have emerged as biomarkers for tumor diagnosis, prognosis and prediction of response to treatment, due to the ease of their detection and in their extreme specificity. Moreover, miR NAs present in sputum, in plasma, in serum or in whole blood have increasingly been explored in the last five years as less invasive biomarkers for the early detection of cancers. In this review we cover the increasing amounts of datathat have accumulated in the last ten years on the use of miR NAs as lung cancer biomarkers.展开更多
Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveil...Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveillance. Methods The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonixl00 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis. Results In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 （53.1%） strains carried the blalMP gene, and IMP-4 and IMP-8 were detected in 92 （96.8%） and 3 （3.2%） IMP-producing isolates, respectively. 65 （36.3%） strains carried the blaNDM_1 gene. 6 （3.4%） strains carried the blaKpc gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 （NDM-1） producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%. Conclusion High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children＇s Hospital. The production of IMP-4 and NDM-1 metallo-13-1actamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae.展开更多
Objective： Triple-negative breast cancer（TNBC） is highly invasive and metastatic, which is in urgent need of transformative therapeutics. Tubeimu（TBM）, the rhizome of Bolbostemma paniculatum（Maxim.） Franquet, i...Objective： Triple-negative breast cancer（TNBC） is highly invasive and metastatic, which is in urgent need of transformative therapeutics. Tubeimu（TBM）, the rhizome of Bolbostemma paniculatum（Maxim.） Franquet, is one of the Chinese medicinal herbs used for breast diseases since the ancient times. The present study evaluated the efficacy, especially the anti-metastatic effects of the dichloromethane extract of Tubeimu（ETBM） on TNBC orthotopic mouse models and cell lines.Methods： We applied real-time imaging on florescent orthotopic TNBC mice model and tested cell migration and invasion abilities with MDA-MB-231 cell line. Digital gene expression sequencing was performed and Kyoto Encyclopedia of Genes and Genomes（KEGG） analysis applied to explore the pathways influenced by ETBM.Moreover, quantitative real-time polymerase chain reactions（q RT-PCR） and Western blot were delivered to confirm the gene expression changes.Results： ETBM exhibited noticeable control on tumor metastasis and growth of TNBC tumors with no obvious toxicity. In compliance with this, it also showed inhibition of cell migration and invasion in vitro. Its impact on the changed biological behavior in TNBC may be a result of decreased expression of integrin β1（ITGβ1）, integrin β8（ITGβ8） and Rho GTPase activating protein 5（ARHGAP5）, which disabled the focal adhesion pathway and caused change in cell morphology.Conclusions： This study reveals that ETBM has anti-metastatic effects on MDA-MB-231-GFP tumor and may lead to a new therapeutic agent for the integrative treatment of highly invasive TNBC.展开更多
The role of chronic inflammation,acting as an independent factor,on the onset of gastrointestinal carcinogenesis is now well accepted.However,even if there is an increase in the number of elements directly involving p...The role of chronic inflammation,acting as an independent factor,on the onset of gastrointestinal carcinogenesis is now well accepted.However,even if there is an increase in the number of elements directly involving polymorphonuclear leukocytes (PMNL),as a major actor in digestive carcinogenesis,the different cellular and molecular events occurring in this process are still not completely understood.The transepithelial migration of PMNL,which is the ultimate step of the afflux of PMNL into the digestive mucosa,is a complex phenomenon involving sequential interaction of molecules expressed both on PMNL and on digestive epithelial cells.Chronic inflammatory areas rich in PMNL [so-called (chronic active inflammation)] and iterative transepithelial migration of PMNL certainly evoke intracellular signals,which lead toward progressive transformation of epithelia.Among these different signals,the mutagenic effect of reactive oxygen species and nitrates,the activation of the nuclear factor-κB pathway,and the modulation of expression of certain microRNA are key actors.Following the initiation of carcinogenesis,PMNL are involved in the progression and invasion of digestive carcinomas,with which they interact.It is noteworthy that different subpopulations of PMNL,which can have some opposite effects on tumor growth,in association with different levels of transforming growth factor-β and with the number of CD8 positive T lymphocytes,could be present during the development of digestive carcinoma.Other factors that involve PMNL,such as massive elastase release,and the production of angiogenic factors,can participate in the progression of neoplastic cells through tissues.PMNL may play a major role in the onset of metastases,since they allow the tumor cells to cross the endothelial barrier and to migrate into the blood stream.Finally,PMNL play a role,alone or in association with other cell parameters,in the initiation,promotion,progression and dissemination of digestive carcinomas.This review focuses on the main currently acce展开更多
MTUS1 （microtubule-associated tumor suppressor 1） has been identified that can function as a tumor sup- pressor gene in many malignant tumors. However, the function and mechanisms underlying the regulation of MTUS1 ...MTUS1 （microtubule-associated tumor suppressor 1） has been identified that can function as a tumor sup- pressor gene in many malignant tumors. However, the function and mechanisms underlying the regulation of MTUS1 are unclear. In the present study, we reported that miR-19a and miR-19b （miR-19a/b） promote prolifer- ation and migration of lung cancer cells by targeting MTUS1. First, MTUS1 was proved to function as a tumor suppressor in lung cancer and was linked to cell prolif- eration and migration promotion. Second, an inverse correlation between miR-19a/b expression and MTUS1 mRNA/protein expression was noted in human lung cancer tissues. Third, MTUS1 was appraised as a direct target of miR-19a/b by bioinformatics analysis. Fourth, direct MTUS1 regulation by miR-19a/b in lung cancer cells was experimentally affirmed by cell transfection assay and luciferase reporter assay. Finally, miR-19a/b were shown to cooperatively repress MTUS1 expression and synergistically regulate MTUS1 expression to pro- mote lung cancer cell proliferation and migration. In conclusion, our findings have provided the first cluesregarding the roles of miR-19a/b, which appear to func- tion as oncomirs in lung cancer by downregulating MTUSI.展开更多
Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeuti...Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.Methods:RNA sequencing of cisplatin-resistant and sensitive(chemoresis-tant and chemosensitive,respectively)ovarian cancer organoids was performed,followed by detection of the expression level of fibrillin-1(FBN1)in organoids and clinical specimens of ovarian cancer.Subsequently,glucose metabolism,angiogenesis,and chemosensitivity were analyzed in structural glycoprotein FBNl-knockout cisplatin-resistant ovarian cancer organoids and cell lines.To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer,immunoprecipitation,silver nitrate staining,mass spectrometry,immunofluorescence,Western blotting,and Forister resonance energy transfer-fluorescence lifetime imaging analyses were performed,followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.Results:FBN1 expression was significantly enhanced in cisplatin-resistant ovar-ian cancer organoids and tissues,indicating that FBNI might be a key factor in chemoresistance of ovarian cancer.We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo,which promoted the cisplatin-resistance of ovarian cancer.Knockout of FBN1 combined with treat-ment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells.Mechanistically,FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2)at the Tyrl054 residue,which activated its downstream focal adhesion kinase(FAK)/protein kinase B(PKB or AKT)pathway,induced the phosphorylation of signal transducer and activator of transcription 2(STAT2)at the tyrosine residue 690(Tyr690),pro-moted the nuclear translocation of STAT2,and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.Conclusions:T展开更多
Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder(MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitiv...Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder(MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia(FES), 125 with MDD, and 237 demographically-matched healthy controls(HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with aone-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD.Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.展开更多
Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factor...Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.展开更多
Background It remains unclear about the association of muscle mass,strength,and quality with death in the general Chinese population of diverse economical and geographical backgrounds.The present study aimed to compre...Background It remains unclear about the association of muscle mass,strength,and quality with death in the general Chinese population of diverse economical and geographical backgrounds.The present study aimed to comprehensively examine such associations across different regions in China.Methods Based on the China Kadoorie Biobank study,the present study included 23,290 participants who were aged 38 to 88 years and had no prevalent cardiovascular diseases or cancer.Muscle mass and grip strength were measured using calibrated instruments.Arm muscle quality was defined as the ratio of grip strength to arm muscle mass.Low muscle mass,grip strength,and arm muscle quality were defined as the sex-specific lowest quintiles of muscle mass index,grip strength,and arm muscle quality,respectively.Cox proportional hazards models yielded hazard ratios(HRs)and 95%confidence intervals(CIs)for risks of all-cause mortality in relation to muscle mass,strength,and quality.Results During a median follow-up of 3.98 years,739 participants died.The HR(95%CI)of all-cause mortality risk was 1.28(1.08–1.51)for low appendicular muscle mass index,1.38(1.16–1.62)for low total muscle mass index,1.68(1.41–2.00)for low grip strength,and 1.41(1.20–1.66)for low arm muscle quality in models adjusted for sociodemographic characteristics,lifestyle factors,and medical histories.Conclusion Low muscle mass,grip strength,and arm muscle quality are all associated with short-term increased risks of mortality,indicating the importance of maintaining normal muscle mass,strength,and quality for general Chinese adults.展开更多
Objective:This study aimed to evaluate the prognostic value of preoperative radiomics and establish an integrated model for esophageal squamous cell cancer(ESCC).Methods:A total of 931 patients were retrospectively en...Objective:This study aimed to evaluate the prognostic value of preoperative radiomics and establish an integrated model for esophageal squamous cell cancer(ESCC).Methods:A total of 931 patients were retrospectively enrolled in this study(training cohort,n=624;validation cohort,n=307).Radiomics features were obtained by contrast-enhanced computed tomography(CT)before esophagectomy.A radiomics index was set based on features of tumor and reginal lymph nodes by using the least absolute shrinkage and selection operator(LASSO)Cox regression.Prognostic nomogram was built based on radiomics index and other independent risk factors.The prognostic value was assessed by using Harrell’s concordance index,time-dependent receiver operating characteristics and Kaplan-Meier curves.Results:Twelve radiomic features from tumor and lymph node regions were identified to build a radiomics index,which was significantly associated with overall survival(OS)in both training cohort and validation cohort.The radiomics index was highly correlated with clinical tumor-node-metastasis(cTNM)and pathologic TNM(pTNM)stages,but it demonstrated a better prognostic value compared with cTNM stage and was almost comparable with pTNM stage.Multivariable Cox regression showed that the radiomics index was an independent prognostic factor.An integrated model was constructed based on gender,preoperative serum sodium concentration,pTNM and the radiomics index for clinical usefulness.The integrated model demonstrated discriminatory ability better compared with the traditional clinical-pathologic model and pTNM alone,indicating incremental value for prognosis.Conclusions:CT-based radiomics for primary tumor and reginal lymph nodes was sufficient in predicting OS for patients with ESCC.The integrated model demonstrated incremental value for prognosis and was robust for clinical applications.展开更多
Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is k...Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is known about the long-term stability of these biomarker proteins in plasma samples stored at-80°C.We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort.Plasma samples from 229 cognitively unimpaired individuals,encompassing healthy controls and those experiencing subjective cognitive decline,as well as 99 patients with cognitive impairment,comprising those with mild cognitive impairment and dementia,were acquired from the Sino Longitudinal Study on Cognitive Decline project.These samples were stored at-80°C for up to 6 years before being used in this study.Our results showed that plasma levels of Aβ42,Aβ40,neurofilament light chain,and glial fibrillary acidic protein were not significantly correlated with sample storage time.However,the level of total tau showed a negative correlation with sample storage time.Notably,in individuals without cognitive impairment,plasma levels of total protein and tau phosphorylated protein threonine 181(p-tau181)also showed a negative correlation with sample storage time.This was not observed in individuals with cognitive impairment.Consequently,we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time.Therefore,caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases,such as Alzheimer's disease.Furthermore,in cohort studies,it is important to consider the impact of storage time on the overall results.展开更多
AIM: To develop a safe and effective agent for cholangiocarcinoma(CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in c o m b i n a t i o n w i t h c h e m o...AIM: To develop a safe and effective agent for cholangiocarcinoma(CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in c o m b i n a t i o n w i t h c h e m o t h e ra p y o n C C A c e l l s. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of β-escin and common chemotherapeutics on the proliferation of human CCA cells(QBC939, Sk-Ch A-1, and MZ-Ch A-1). Immunocytochemistry was used to detect the expression of P-glycoprotein(P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/β-catenin pathway. The protein levels of P-gp, p S9-GSK3β, p T216-GSK3β, GSK3β, β-catenin, and p-β-catenin were further confirmed by western blotting.RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil(5-FU) cells to 5-FU, vincristine sulfate(VCR), or mitomycin C was significantly enhanced by β-escin compared with either agent alone(P < 0.05). In addition, the combination of β-escin(20 μmol/L) with 5-FU and VCR was synergic with a combination index < 1. Further investigation found that the m RNA and protein expression of P-gp was downregulated by β-escin. Moreover, β-escin induced GSK3β phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of β-catenin. Interestingly, activation of the GSK3β/β-catenin pathway induced by Wnt3 a resulted in upregulation of P-gp, which was effectively abolished by β-escin, indicating that β-escin down-regulated P-gp expression in a GSK3β-dependent manner.CONCLUSION: β-escin was a potent reverser of P-gpdependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3β/β-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.展开更多
Substantial evidence supports the neurodevelopmental hypothesis of schizophrenia.Meanwhile,progressive neurodegenerative processes have also been reported,leading to the hypothesis that neurodegeneration is a characte...Substantial evidence supports the neurodevelopmental hypothesis of schizophrenia.Meanwhile,progressive neurodegenerative processes have also been reported,leading to the hypothesis that neurodegeneration is a characteristic component in the neuropathology of schizophrenia.However,a major challenge for the neurodegenerative hypothesis is that antipsychotic drugs used by patients have profound impact on brain structures.To clarify this potential confounding factor,we measured the cortical thickness across the whole brain using highresolution T1-weighted magnetic resonance imaging in 145 first-episode and treatment-naive patients with schizophrenia and 147 healthy controls.The results showed that,in the patient group,the frontal,temporal,parietal,and cingulate gyri displayed a significant age-related reduction of cortical thickness.In the control group,age-related cortical thickness reduction was mostly located in the frontal,temporal,and cingulate gyri,albeit to a lesser extent.Importantly,relative to healthy controls,patients exhibited a significantly smaller age-related cortical thickness in the anterior cingulate,inferior temporal,and insular gyri in the right hemisphere.These results provide evidence supporting the existence of neurodegenerative processes in schizophrenia and suggest that these processes already occur in the early stage of the illness.展开更多
Lung cancer is the most common and fatal malignant disease worldwide and has the highest mortality rate among tumor-related causes of death.Early diagnosis and precision medicine can significantly improve the survival...Lung cancer is the most common and fatal malignant disease worldwide and has the highest mortality rate among tumor-related causes of death.Early diagnosis and precision medicine can significantly improve the survival rate and prognosis of lung cancer patients.At present,the clinical diagnosis of lung cancer is challenging due to a lack of effective non-invasive detection methods and biomarkers,and treatment is primarily hindered by drug resistance and high tumor heterogeneity.Liquid biopsy is a method for detecting circulating biomarkers in the blood and other body fluids containing genetic information from primary tumor tissues.Bronchoalveolar lavage fluid(BALF)is a potential liquid biopsy medium that is rich in a variety of bioactive substances and cell components.BALF contains information on the key characteristics of tumors,including the tumor subtype,gene mutation type,and tumor environment,thus BALF may be used as a diagnostic supplement to lung biopsy.In this review,the current research on BALF in the diagnosis,treatment,and prognosis of lung cancer is summarized.The advantages and disadvantages of different components of BALF,including cells,cell-free DNA,extracellular vesicles,and micro RNA are introduced.In particular,the great potential of extracellular vesicles in precision diagnosis and detection of drug-resistant for lung cancer is highlighted.In addition,the performance of liquid biopsies with different body fluid sources in lung cancer detection are compared to facilitate more selective studies involving BALF,thereby promoting the application of BALF for precision medicine in lung cancer patients in the future.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
Background Necrotizing enterocolitis(NEC)is the most common severe gastrointestinal emergency in neonates.We designed this study to identify the pathogenic microorganisms of NEC in the microbiota of the small intestin...Background Necrotizing enterocolitis(NEC)is the most common severe gastrointestinal emergency in neonates.We designed this study to identify the pathogenic microorganisms of NEC in the microbiota of the small intestine of neonates.Methods Using the 16S ribosomal DNA(rDNA)sequencing method,we compared and analyzed the structure and diversity of microbiotas in the intestinal feces of different groups of neonates:patients undergoing jejunostomy to treat NEC(NP group),neonates undergoing jejunostomy to treat other conditions(NN group),and neonates with NEC undergoing conservative treatment(NC group).We took intestinal feces and saliva samples from patients at different time points.Results The beta diversities of the NP,NN,and NC groups were all similar.When comparing the beta diversities between different time points in the NP group,we found similar beta diversities at time points El to E3 but significant differences between the E2-E3 and E4 time points:the abundances of Klebsiella and Enterococcus(Proteobacteria)were higher at the E1-E3 time points;the abundance of Escherichia-Shigella(Proteobacteria)increased at the E2 time point,and the abundance of Klebsiella decreased significantly,whereas that of Streptococcus increased significantly at the E4 time point.Conclusions Our results suggest that the pathological changes of intestinal necrosis in the small intestine of infants with NEC are not directly caused by excessive proliferation of pathogenic bacteria in the small intestine.The sources of microbiota in the small intestine of neonates,especially in premature infants,may be affected by multiple factors.展开更多
Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment options.Although inhibiting xanthine oxidase(XO)in the treatment of AP has been studied in several experimental models and clinical tri...Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment options.Although inhibiting xanthine oxidase(XO)in the treatment of AP has been studied in several experimental models and clinical trials,whether XO is a target of AP and what its the main mechanism of action is remains unclear.Here,we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP.We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models.We also found that allopurinol and febuxostat,as purine-like and non-purine XO inhibitors,respectively,exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points.Moreover,we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity.Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha(HIF-1α)-regulated lactate dehydrogenase A(LDHA)and NOD-like receptor family pyrin domain containing 3(NLRP3)signaling pathways and reduced the enrichment of^(13)C_(6)-glucose to^(13)C_(3)-lactate.Lastly,we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels,while pancreatic XO and urate were also increased in severe AP patients.These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.展开更多
While precision medicine driven by genome sequencing has revolutionized cancer care,such as lung cancer,its impact on gastric cancer(GC)has been minimal.GC patients are routinely treated with chemotherapy,but only a f...While precision medicine driven by genome sequencing has revolutionized cancer care,such as lung cancer,its impact on gastric cancer(GC)has been minimal.GC patients are routinely treated with chemotherapy,but only a fraction of them receive the clinical benefit.There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy.Here,we carried out retrospective analyses of 1,020 formalin-fixed,paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC.We identified two proteomic subtypes:the chemo-sensitive group(CSG)and the chemo-insensitive group(CIG)in the discovery set.The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only(64.2%vs.49.6%;Cox P-value=0.002),whereas no such improvement was observed in CIG(50.0%vs.58.6%;Cox P-value=0.495).We validated these results in an independent validation set.Further,differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC.A prospective study is warranted to test these findings for future GC patient care.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81941018)The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong,China.The long-term follow-up is supported by grants from the UK Wellcome Trust(Nos.212946/Z/18/Z,202922/Z/16/Z,104085/Z/14/Z,and 088158/Z/09/Z)+2 种基金grants from the National Key R&D Program of China(Nos.2016YFC0900500 and 2016YFC1303904)National Natural Science Foundation of China(No.81390540)Chinese Ministry of Science and Technology(No.2011BAI09B01)。
文摘Background:Few studies have assessed the relationship between multimorbidity patterns and mortality risk in the Chinese population.We aimed to identify multimorbidity patterns and examined the associations of multimorbidity patterns and the number of chronic diseases with the risk of mortality among Chinese middle-aged and older adults.Methods:We used data from the China Kadoorie Biobank and included 512,723 participants aged 30 to 79 years.Multimorbidity was defined as the presence of two or more of the 15 chronic diseases collected by self-report or physical examination at baseline.Multimorbidity patterns were identified using hierarchical cluster analysis.Cox regression was used to estimate the associations of multimorbidity patterns and the number of chronic diseases with all-cause and cause-specific mortality.Results:Overall,15.8%of participants had multimorbidity.The prevalence of multimorbidity increased with age and was higher in urban than rural participants.Four multimorbidity patterns were identified,including cardiometabolic multimorbidity(diabetes,coronary heart disease,stroke,and hypertension),respiratory multimorbidity(tuberculosis,asthma,and chronic obstructive pulmonary disease),gastrointestinal and hepatorenal multimorbidity(gallstone disease,chronic kidney disease,cirrhosis,peptic ulcer,and cancer),and mental and arthritis multimorbidity(neurasthenia,psychiatric disorder,and rheumatoid arthritis).During a median of 10.8 years of follow-up,49,371 deaths occurred.Compared with participants without multimorbidity,cardiometabolic multimorbidity(hazard ratios[HR]=2.20,95%confidence intervals[CI]:2.14-2.26)and respiratory multimorbidity(HR=2.13,95%CI:1.97-2.31)demonstrated relatively higher risks of mortality,followed by gastrointestinal and hepatorenal multimorbidity(HR=1.33,95%CI:1.22-1.46).The mortality risk increased by 36%(HR=1.36,95%CI:1.35-1.37)with every additional disease.Conclusion:Cardiometabolic multimorbidity and respiratory multimorbidity posed the highest threat on mortality risk and d
基金supported by the National Institutes of Health Fund (Nos.DK081343,DK090036 and GM104037 to Grace L.Guo)the National Natural Science Foundation of China (No.81302059)+2 种基金the Natural Science Foundation of Heilongjiang Province of China (No.LC2013C35)the Foundation of Educational Committee of Heilongjiang Province of China (No.12541300)supported by the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry and Science Foundation for The Excellent Youth Scholars of the Fourth Hospital of Harbin Medical University in China
文摘The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy(PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids(BAs) are ligands of farnesoid X receptor(FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potentialuse of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.
文摘Lung cancer is the leading cause of cancer mortality worldwide. Its high mortality is due to the poor prognosis of the disease caused by a late disease presentation, tumor heterogeneities within histological subtypes, and the relatively limited understanding of tumor biology. Importantly, lung cancer histological subgroups respond differently to some chemotherapeutic substances and side effects of some therapies appear to vary between subgroups. Biomarkers able to stratify for the subtype of lung cancer, prognosticate the course of disease, or predict the response to treatment are in high demand. In the last decade, microR NAs(miR NAs), measured in resected tumor samples or in fine needle aspirate samples have emerged as biomarkers for tumor diagnosis, prognosis and prediction of response to treatment, due to the ease of their detection and in their extreme specificity. Moreover, miR NAs present in sputum, in plasma, in serum or in whole blood have increasingly been explored in the last five years as less invasive biomarkers for the early detection of cancers. In this review we cover the increasing amounts of datathat have accumulated in the last ten years on the use of miR NAs as lung cancer biomarkers.
基金supported by Scientific Research Project of Beijing Children's Hospital(2012MS08)Beijing Municipal Science and Technology Project(D131100005313014)
文摘Objective To characterize carbapenem （CPM）-non-susceptible Klebsiella pneumoniae （K. pneumoniae） and carbape-nemase produced by these strains isolated from Beijing Children＇s Hospital based on a five-year surveillance. Methods The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonixl00 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis. Results In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 （53.1%） strains carried the blalMP gene, and IMP-4 and IMP-8 were detected in 92 （96.8%） and 3 （3.2%） IMP-producing isolates, respectively. 65 （36.3%） strains carried the blaNDM_1 gene. 6 （3.4%） strains carried the blaKpc gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 （NDM-1） producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%. Conclusion High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children＇s Hospital. The production of IMP-4 and NDM-1 metallo-13-1actamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae.
基金supported by National Natural Science Foundation of China Grant (No. 81303129)Beijing University of Chinese Medicine Grant (Project ID: 2016-jxs-548)
文摘Objective： Triple-negative breast cancer（TNBC） is highly invasive and metastatic, which is in urgent need of transformative therapeutics. Tubeimu（TBM）, the rhizome of Bolbostemma paniculatum（Maxim.） Franquet, is one of the Chinese medicinal herbs used for breast diseases since the ancient times. The present study evaluated the efficacy, especially the anti-metastatic effects of the dichloromethane extract of Tubeimu（ETBM） on TNBC orthotopic mouse models and cell lines.Methods： We applied real-time imaging on florescent orthotopic TNBC mice model and tested cell migration and invasion abilities with MDA-MB-231 cell line. Digital gene expression sequencing was performed and Kyoto Encyclopedia of Genes and Genomes（KEGG） analysis applied to explore the pathways influenced by ETBM.Moreover, quantitative real-time polymerase chain reactions（q RT-PCR） and Western blot were delivered to confirm the gene expression changes.Results： ETBM exhibited noticeable control on tumor metastasis and growth of TNBC tumors with no obvious toxicity. In compliance with this, it also showed inhibition of cell migration and invasion in vitro. Its impact on the changed biological behavior in TNBC may be a result of decreased expression of integrin β1（ITGβ1）, integrin β8（ITGβ8） and Rho GTPase activating protein 5（ARHGAP5）, which disabled the focal adhesion pathway and caused change in cell morphology.Conclusions： This study reveals that ETBM has anti-metastatic effects on MDA-MB-231-GFP tumor and may lead to a new therapeutic agent for the integrative treatment of highly invasive TNBC.
文摘The role of chronic inflammation,acting as an independent factor,on the onset of gastrointestinal carcinogenesis is now well accepted.However,even if there is an increase in the number of elements directly involving polymorphonuclear leukocytes (PMNL),as a major actor in digestive carcinogenesis,the different cellular and molecular events occurring in this process are still not completely understood.The transepithelial migration of PMNL,which is the ultimate step of the afflux of PMNL into the digestive mucosa,is a complex phenomenon involving sequential interaction of molecules expressed both on PMNL and on digestive epithelial cells.Chronic inflammatory areas rich in PMNL [so-called (chronic active inflammation)] and iterative transepithelial migration of PMNL certainly evoke intracellular signals,which lead toward progressive transformation of epithelia.Among these different signals,the mutagenic effect of reactive oxygen species and nitrates,the activation of the nuclear factor-κB pathway,and the modulation of expression of certain microRNA are key actors.Following the initiation of carcinogenesis,PMNL are involved in the progression and invasion of digestive carcinomas,with which they interact.It is noteworthy that different subpopulations of PMNL,which can have some opposite effects on tumor growth,in association with different levels of transforming growth factor-β and with the number of CD8 positive T lymphocytes,could be present during the development of digestive carcinoma.Other factors that involve PMNL,such as massive elastase release,and the production of angiogenic factors,can participate in the progression of neoplastic cells through tissues.PMNL may play a major role in the onset of metastases,since they allow the tumor cells to cross the endothelial barrier and to migrate into the blood stream.Finally,PMNL play a role,alone or in association with other cell parameters,in the initiation,promotion,progression and dissemination of digestive carcinomas.This review focuses on the main currently acce
文摘MTUS1 （microtubule-associated tumor suppressor 1） has been identified that can function as a tumor sup- pressor gene in many malignant tumors. However, the function and mechanisms underlying the regulation of MTUS1 are unclear. In the present study, we reported that miR-19a and miR-19b （miR-19a/b） promote prolifer- ation and migration of lung cancer cells by targeting MTUS1. First, MTUS1 was proved to function as a tumor suppressor in lung cancer and was linked to cell prolif- eration and migration promotion. Second, an inverse correlation between miR-19a/b expression and MTUS1 mRNA/protein expression was noted in human lung cancer tissues. Third, MTUS1 was appraised as a direct target of miR-19a/b by bioinformatics analysis. Fourth, direct MTUS1 regulation by miR-19a/b in lung cancer cells was experimentally affirmed by cell transfection assay and luciferase reporter assay. Finally, miR-19a/b were shown to cooperatively repress MTUS1 expression and synergistically regulate MTUS1 expression to pro- mote lung cancer cell proliferation and migration. In conclusion, our findings have provided the first cluesregarding the roles of miR-19a/b, which appear to func- tion as oncomirs in lung cancer by downregulating MTUSI.
基金Shanghai Municipal Health Commission,Grant/Award Number:20194Y0039Natural Science Foundation of China,Grant/Award Numbers:81872117,81502235funded by Project of the Shanghai Municipal Health Com-mission(No.20194Y0039 to HZ.S)and Natural Science Foundation of China(No.81872117 and 81502235 to ZL.W).
文摘Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.Methods:RNA sequencing of cisplatin-resistant and sensitive(chemoresis-tant and chemosensitive,respectively)ovarian cancer organoids was performed,followed by detection of the expression level of fibrillin-1(FBN1)in organoids and clinical specimens of ovarian cancer.Subsequently,glucose metabolism,angiogenesis,and chemosensitivity were analyzed in structural glycoprotein FBNl-knockout cisplatin-resistant ovarian cancer organoids and cell lines.To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer,immunoprecipitation,silver nitrate staining,mass spectrometry,immunofluorescence,Western blotting,and Forister resonance energy transfer-fluorescence lifetime imaging analyses were performed,followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.Results:FBN1 expression was significantly enhanced in cisplatin-resistant ovar-ian cancer organoids and tissues,indicating that FBNI might be a key factor in chemoresistance of ovarian cancer.We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo,which promoted the cisplatin-resistance of ovarian cancer.Knockout of FBN1 combined with treat-ment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells.Mechanistically,FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2)at the Tyrl054 residue,which activated its downstream focal adhesion kinase(FAK)/protein kinase B(PKB or AKT)pathway,induced the phosphorylation of signal transducer and activator of transcription 2(STAT2)at the tyrosine residue 690(Tyr690),pro-moted the nuclear translocation of STAT2,and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.Conclusions:T
基金funded by National Nature Science Foundation of China Key Projects(81130024,91332205,and 81630030)the National Key Technology R&D Program of the Ministry of Science and Technology of China(2016YFC0904300)+4 种基金the National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme(8141101084)the Natural Science Foundation of China(8157051859)the Sichuan Science&Technology Department(2015JY0173)the Canadian Institutes of Health Research,Alberta Innovates:Centre for Machine Learningthe Canadian Depression Research&Intervention Network
文摘Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder(MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia(FES), 125 with MDD, and 237 demographically-matched healthy controls(HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with aone-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD.Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.
基金supported by National Natural Science Foundation of China (81670874, 81500354, and 81772999)Shenzhen Science Foundation (JCYJ20160308104109234)
文摘Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.
基金This work was supported by grants from the Natural Science Foundation of China (Nos. 81941018, 91846303) , and the National Key Research and Development Program of China (Nos. 2016YFC0900500, 2016YFC0900501, 2016YFC0900504) . The CKB baseline survey was supported by a grant from the Kadoorie Charitable Foundation in Hong Kong of China.
文摘Background It remains unclear about the association of muscle mass,strength,and quality with death in the general Chinese population of diverse economical and geographical backgrounds.The present study aimed to comprehensively examine such associations across different regions in China.Methods Based on the China Kadoorie Biobank study,the present study included 23,290 participants who were aged 38 to 88 years and had no prevalent cardiovascular diseases or cancer.Muscle mass and grip strength were measured using calibrated instruments.Arm muscle quality was defined as the ratio of grip strength to arm muscle mass.Low muscle mass,grip strength,and arm muscle quality were defined as the sex-specific lowest quintiles of muscle mass index,grip strength,and arm muscle quality,respectively.Cox proportional hazards models yielded hazard ratios(HRs)and 95%confidence intervals(CIs)for risks of all-cause mortality in relation to muscle mass,strength,and quality.Results During a median follow-up of 3.98 years,739 participants died.The HR(95%CI)of all-cause mortality risk was 1.28(1.08–1.51)for low appendicular muscle mass index,1.38(1.16–1.62)for low total muscle mass index,1.68(1.41–2.00)for low grip strength,and 1.41(1.20–1.66)for low arm muscle quality in models adjusted for sociodemographic characteristics,lifestyle factors,and medical histories.Conclusion Low muscle mass,grip strength,and arm muscle quality are all associated with short-term increased risks of mortality,indicating the importance of maintaining normal muscle mass,strength,and quality for general Chinese adults.
基金supported by Science and Technology Department of Sichuan Province(No.22NSFSC1483,2019YFS0378 and 2018JY0277)CSCO-Genecast Oncology Research Found(No.Y-2019Genecast-041)。
文摘Objective:This study aimed to evaluate the prognostic value of preoperative radiomics and establish an integrated model for esophageal squamous cell cancer(ESCC).Methods:A total of 931 patients were retrospectively enrolled in this study(training cohort,n=624;validation cohort,n=307).Radiomics features were obtained by contrast-enhanced computed tomography(CT)before esophagectomy.A radiomics index was set based on features of tumor and reginal lymph nodes by using the least absolute shrinkage and selection operator(LASSO)Cox regression.Prognostic nomogram was built based on radiomics index and other independent risk factors.The prognostic value was assessed by using Harrell’s concordance index,time-dependent receiver operating characteristics and Kaplan-Meier curves.Results:Twelve radiomic features from tumor and lymph node regions were identified to build a radiomics index,which was significantly associated with overall survival(OS)in both training cohort and validation cohort.The radiomics index was highly correlated with clinical tumor-node-metastasis(cTNM)and pathologic TNM(pTNM)stages,but it demonstrated a better prognostic value compared with cTNM stage and was almost comparable with pTNM stage.Multivariable Cox regression showed that the radiomics index was an independent prognostic factor.An integrated model was constructed based on gender,preoperative serum sodium concentration,pTNM and the radiomics index for clinical usefulness.The integrated model demonstrated discriminatory ability better compared with the traditional clinical-pathologic model and pTNM alone,indicating incremental value for prognosis.Conclusions:CT-based radiomics for primary tumor and reginal lymph nodes was sufficient in predicting OS for patients with ESCC.The integrated model demonstrated incremental value for prognosis and was robust for clinical applications.
基金supported by the National Key Research&Development Program of China,Nos.2021YFC2501205(to YC),2022YFC24069004(to JL)the STI2030-Major Project,Nos.2021ZD0201101(to YC),2022ZD0211800(to YH)+2 种基金the National Natural Science Foundation of China(Major International Joint Research Project),No.82020108013(to YH)the Sino-German Center for Research Promotion,No.M-0759(to YH)a grant from Beijing Municipal Science&Technology Commission(Beijing Brain Initiative),No.Z201100005520018(to JL)。
文摘Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is known about the long-term stability of these biomarker proteins in plasma samples stored at-80°C.We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort.Plasma samples from 229 cognitively unimpaired individuals,encompassing healthy controls and those experiencing subjective cognitive decline,as well as 99 patients with cognitive impairment,comprising those with mild cognitive impairment and dementia,were acquired from the Sino Longitudinal Study on Cognitive Decline project.These samples were stored at-80°C for up to 6 years before being used in this study.Our results showed that plasma levels of Aβ42,Aβ40,neurofilament light chain,and glial fibrillary acidic protein were not significantly correlated with sample storage time.However,the level of total tau showed a negative correlation with sample storage time.Notably,in individuals without cognitive impairment,plasma levels of total protein and tau phosphorylated protein threonine 181(p-tau181)also showed a negative correlation with sample storage time.This was not observed in individuals with cognitive impairment.Consequently,we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time.Therefore,caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases,such as Alzheimer's disease.Furthermore,in cohort studies,it is important to consider the impact of storage time on the overall results.
基金Supported by National Nature Science Foundation of China,No.81101502the National Science Foundation for Fostering Talents in Basic Research of the National Natural Science Foundation of China,No.J1310027
文摘AIM: To develop a safe and effective agent for cholangiocarcinoma(CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in c o m b i n a t i o n w i t h c h e m o t h e ra p y o n C C A c e l l s. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of β-escin and common chemotherapeutics on the proliferation of human CCA cells(QBC939, Sk-Ch A-1, and MZ-Ch A-1). Immunocytochemistry was used to detect the expression of P-glycoprotein(P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/β-catenin pathway. The protein levels of P-gp, p S9-GSK3β, p T216-GSK3β, GSK3β, β-catenin, and p-β-catenin were further confirmed by western blotting.RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil(5-FU) cells to 5-FU, vincristine sulfate(VCR), or mitomycin C was significantly enhanced by β-escin compared with either agent alone(P < 0.05). In addition, the combination of β-escin(20 μmol/L) with 5-FU and VCR was synergic with a combination index < 1. Further investigation found that the m RNA and protein expression of P-gp was downregulated by β-escin. Moreover, β-escin induced GSK3β phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of β-catenin. Interestingly, activation of the GSK3β/β-catenin pathway induced by Wnt3 a resulted in upregulation of P-gp, which was effectively abolished by β-escin, indicating that β-escin down-regulated P-gp expression in a GSK3β-dependent manner.CONCLUSION: β-escin was a potent reverser of P-gpdependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3β/β-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.
基金supported by the National Basic Research Development Program of China (2016YFC0904300)National Natural Science Foundation of China (81630030, 81130024 and 81528008)+1 种基金the National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme (81461168029)the ‘‘135’’ Project for Disciplines of Excellence, West China Hospital of Sichuan University, China (ZY2016103 and ZY2016203)
文摘Substantial evidence supports the neurodevelopmental hypothesis of schizophrenia.Meanwhile,progressive neurodegenerative processes have also been reported,leading to the hypothesis that neurodegeneration is a characteristic component in the neuropathology of schizophrenia.However,a major challenge for the neurodegenerative hypothesis is that antipsychotic drugs used by patients have profound impact on brain structures.To clarify this potential confounding factor,we measured the cortical thickness across the whole brain using highresolution T1-weighted magnetic resonance imaging in 145 first-episode and treatment-naive patients with schizophrenia and 147 healthy controls.The results showed that,in the patient group,the frontal,temporal,parietal,and cingulate gyri displayed a significant age-related reduction of cortical thickness.In the control group,age-related cortical thickness reduction was mostly located in the frontal,temporal,and cingulate gyri,albeit to a lesser extent.Importantly,relative to healthy controls,patients exhibited a significantly smaller age-related cortical thickness in the anterior cingulate,inferior temporal,and insular gyri in the right hemisphere.These results provide evidence supporting the existence of neurodegenerative processes in schizophrenia and suggest that these processes already occur in the early stage of the illness.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82173182)the Sichuan Science and Technology Program(Grant No.2021YJ0117 to Weiya Wang+1 种基金Grant No.2023NSFSC1939 to Dan Liu)the 1·3·5 project for Disciplines of Excellence–Clinical Research Incubation Project,West China Hospital,Sichuan University(Grant Nos.2019HXFH034 and ZYJC21074)。
文摘Lung cancer is the most common and fatal malignant disease worldwide and has the highest mortality rate among tumor-related causes of death.Early diagnosis and precision medicine can significantly improve the survival rate and prognosis of lung cancer patients.At present,the clinical diagnosis of lung cancer is challenging due to a lack of effective non-invasive detection methods and biomarkers,and treatment is primarily hindered by drug resistance and high tumor heterogeneity.Liquid biopsy is a method for detecting circulating biomarkers in the blood and other body fluids containing genetic information from primary tumor tissues.Bronchoalveolar lavage fluid(BALF)is a potential liquid biopsy medium that is rich in a variety of bioactive substances and cell components.BALF contains information on the key characteristics of tumors,including the tumor subtype,gene mutation type,and tumor environment,thus BALF may be used as a diagnostic supplement to lung biopsy.In this review,the current research on BALF in the diagnosis,treatment,and prognosis of lung cancer is summarized.The advantages and disadvantages of different components of BALF,including cells,cell-free DNA,extracellular vesicles,and micro RNA are introduced.In particular,the great potential of extracellular vesicles in precision diagnosis and detection of drug-resistant for lung cancer is highlighted.In addition,the performance of liquid biopsies with different body fluid sources in lung cancer detection are compared to facilitate more selective studies involving BALF,thereby promoting the application of BALF for precision medicine in lung cancer patients in the future.
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sponsored by the National Key R&D Program of China(No.2022YFC2703400,to Yan Wang)funded by the Health Bureau of the Logistics Support Department of the Military Commission(Grant no.21JSZ18,to Liu-Ming Huang).
文摘Background Necrotizing enterocolitis(NEC)is the most common severe gastrointestinal emergency in neonates.We designed this study to identify the pathogenic microorganisms of NEC in the microbiota of the small intestine of neonates.Methods Using the 16S ribosomal DNA(rDNA)sequencing method,we compared and analyzed the structure and diversity of microbiotas in the intestinal feces of different groups of neonates:patients undergoing jejunostomy to treat NEC(NP group),neonates undergoing jejunostomy to treat other conditions(NN group),and neonates with NEC undergoing conservative treatment(NC group).We took intestinal feces and saliva samples from patients at different time points.Results The beta diversities of the NP,NN,and NC groups were all similar.When comparing the beta diversities between different time points in the NP group,we found similar beta diversities at time points El to E3 but significant differences between the E2-E3 and E4 time points:the abundances of Klebsiella and Enterococcus(Proteobacteria)were higher at the E1-E3 time points;the abundance of Escherichia-Shigella(Proteobacteria)increased at the E2 time point,and the abundance of Klebsiella decreased significantly,whereas that of Streptococcus increased significantly at the E4 time point.Conclusions Our results suggest that the pathological changes of intestinal necrosis in the small intestine of infants with NEC are not directly caused by excessive proliferation of pathogenic bacteria in the small intestine.The sources of microbiota in the small intestine of neonates,especially in premature infants,may be affected by multiple factors.
基金supported by the National Natural Science Foundation of China(Dan Du,82170905)the Program of Science and Technology Department of Sichuan Province(Dan Du,2023NSFSC1755,China)+2 种基金the State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College(Dan Du,GTZK202107,China)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(Qing Xia,ZYJC18005,China)the West China,Nursing Discipline Development Special Fund Project,Sichuan University(Xia Li,HXHL21060,China).
文摘Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment options.Although inhibiting xanthine oxidase(XO)in the treatment of AP has been studied in several experimental models and clinical trials,whether XO is a target of AP and what its the main mechanism of action is remains unclear.Here,we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP.We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models.We also found that allopurinol and febuxostat,as purine-like and non-purine XO inhibitors,respectively,exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points.Moreover,we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity.Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha(HIF-1α)-regulated lactate dehydrogenase A(LDHA)and NOD-like receptor family pyrin domain containing 3(NLRP3)signaling pathways and reduced the enrichment of^(13)C_(6)-glucose to^(13)C_(3)-lactate.Lastly,we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels,while pancreatic XO and urate were also increased in severe AP patients.These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.
基金supported by the National Key Research and Development Program of China(2017YFC1308900,2017YFC0908404,2018YFA0507503,2017YFA0505103)Beijing Municipal Government Key Research and Development Program(Z181100001918020,Z161100002616036)+4 种基金the National Natural Science Foundation of China(31870828,81972790,81672319)the Guangdong Provincial Key R&D Programmes(2019B020229002)the Science and Technology Program of Guangzhou(201902020009)the National Key Basic Research Program of China(2014CBA02002)the National Key Technology Support Program(2015BAI13B07).
文摘While precision medicine driven by genome sequencing has revolutionized cancer care,such as lung cancer,its impact on gastric cancer(GC)has been minimal.GC patients are routinely treated with chemotherapy,but only a fraction of them receive the clinical benefit.There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy.Here,we carried out retrospective analyses of 1,020 formalin-fixed,paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC.We identified two proteomic subtypes:the chemo-sensitive group(CSG)and the chemo-insensitive group(CIG)in the discovery set.The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only(64.2%vs.49.6%;Cox P-value=0.002),whereas no such improvement was observed in CIG(50.0%vs.58.6%;Cox P-value=0.495).We validated these results in an independent validation set.Further,differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC.A prospective study is warranted to test these findings for future GC patient care.
