BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influen...BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influence of PrPC expression in cholangiocarcinoma(CCA)on patient outcomes following surgical resection.METHODS Patients who underwent curative surgical resection for either intrahepatic or hilar CCA were enrolled in this retrospective study.Based on the immunohistochemical staining results of the surgical specimens,patients were categorized into two groups:The low PrPC group(negative or 1+)and the high PrPC group(2+or 3+).Survival analyses,including overall survival and recurrence-free survival,were conducted using the Kaplan-Meier method and compared using the log-rank test.RESULTS In total,seventy-six patients diagnosed with CCA(39 with intrahepatic and 37 with hilar CCA)underwent curative hepatectomy from January 2011 to November 2021.Among these patients,38(50%)demonstrated high PrPC expression,whereas the remaining 38(50%)showed low expression of PrPC.During a median follow-up period of 31.2 months(range:1 to 137 months),the high PrPC group had a significantly shorter median overall survival than the low PrPC group(40.4 months vs 137.9 months,respectively;P=0.041).Moreover,the high PrPC group had a significantly shorter median recurrence-free survival than the low PrPC group(13.3 months vs 23.8 months,respectively;P=0.026).CONCLUSION PrPC expression is significantly associated with early recurrence and decreased survival period in CCA patients following surgical resection.Thus,PrPC may be used as a prognostic factor in treatment planning.展开更多
Objective:Precision medicine approaches emphasize the importance of reliable prognostic tools for guiding individualized therapy decisions.In this study,we evaluated the clinical feasibility of the single patient clas...Objective:Precision medicine approaches emphasize the importance of reliable prognostic tools for guiding individualized therapy decisions.In this study,we evaluated the clinical feasibility of the single patient classifier(SPC)test,a new clinical-grade prognostic assay,in stageⅡ-Ⅲgastric cancer patients.Methods:A prospective multicenter study was conducted,involving 237 patients who underwent gastrectomy between September 2019 and August 2020 across nine hospitals.The SPC test was employed to stratify patients into risk groups,and its feasibility and performance were evaluated.The primary endpoint was the proportion of the cases in which the test results were timely delivered before selecting postoperative treatment.Furthermore,3-year disease-free survivals of risk groups were analyzed.Results:The SPC test met the primary endpoint criteria.The 99.5%of SPC tests were timely delivered to hospitals before the postoperative treatment started.In a clinical setting,the median time from the specimen transfer to laboratory to the result delivery to hospital was 4 d.Furthermore,3-year disease-free survivals were significantly different between risk groups classified with SPC tests.Conclusions:This study highlights the SPC test's feasibility in offering crucial information timely delivered for making informed decisions regarding postoperative treatment strategies.It also provides evidence to support the implementation of a future prospective clinical trial aimed at evaluating the clinical utility of the SPC test in guiding personalized treatment decisions for gastric cancer patients.展开更多
To review microbiome alterations associated with pancreatic cancer, its potential utility in diagnostics, risk assessment, and influence on disease outcomes.METHODSA comprehensive literature review was conducted by al...To review microbiome alterations associated with pancreatic cancer, its potential utility in diagnostics, risk assessment, and influence on disease outcomes.METHODSA comprehensive literature review was conducted by all-inclusive topic review from PubMed, MEDLINE, and Web of Science. The last search was performed in October 2016.RESULTSDiverse microbiome alterations exist among several body sites including oral, gut, and pancreatic tissue, in patients with pancreatic cancer compared to healthy populations.CONCLUSIONPilot study successes in non-invasive screening strategies warrant further investigation for future translational application in early diagnostics and to learn modifiable risk factors relevant to disease prevention. Pre-clinical investigations exist in other tumor types that suggest microbiome manipulation provides opportunity to favorably transform cancer response to existing treatment protocols and improve survival.展开更多
Adenosquamous carcinoma of the pancreas(ASCP)is a rare entity. Like adenocarcinoma of the pancreas,overall survival is poor. Characteristics of ASCP include central tumor necrosis, along with osteoclasts and hypercalc...Adenosquamous carcinoma of the pancreas(ASCP)is a rare entity. Like adenocarcinoma of the pancreas,overall survival is poor. Characteristics of ASCP include central tumor necrosis, along with osteoclasts and hypercalcemia. Various theories exist as to why this histological subtype exists, as normal pancreas tissue has no benign squamous epithelium. Due to the rarity of this disease, limited molecular analysis has been performed, and those reports indicate unique molecular features of ASCP. In this paper, we characterize 23 patients diagnosed with ASCP through molecular profiling using immunohistochemistry staining, fluorescent in situ hybridization, chromogenic in situ hybridization, and gene sequencing, Additionally, we provide a comprehensive literature review of what is known to date of ASCP.Molecular characterization revealed overexpression in MRP1(80%), MGMT(79%), TOP2A(75), RRM1(42%),TOPO1(42%), PTEN(45%), CMET(40%), and C-KIT(10%) among others. One hundred percent of samples tested were positive for KRAS mutations. This analysis shows heretofore unsuspected leads to be considered for treatments of this rare type of exocrine pancreas cancer. Molecular profiling may be appropriate to provide maximum information regarding the patient's tumor. Further work should be pursued to better characterize this disease.展开更多
Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation...Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as: SMAD4,BRAF,BRCA2,TP53,RB1,MEN1,JAK-1,BRCA-1,BRCA-2,and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore,molecular profiling of PACC should be an option for patients with refractory PACC.展开更多
Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease(NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the deve...Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease(NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known aboutthe underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs(mi RNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target m RNAs. Several mi RNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of mi RNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including mi RNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of mi RNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of mi RNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression.展开更多
Butyrate has been recently identified as a natural ligand of the G-protein-coupled receptor 41 （GPR41）. In addition, it is an inhibitor of histone deacetylase （HDAC）. Butyrate treatment results in the hyperacetyla...Butyrate has been recently identified as a natural ligand of the G-protein-coupled receptor 41 （GPR41）. In addition, it is an inhibitor of histone deacetylase （HDAC）. Butyrate treatment results in the hyperacetylation of histones, with resultant multiple biological effects including inhibition of proliferation, induction of cell cycle arrest, and apoptosis, in a variety of cultured mammalian cells. However, it is not clear whether GPR41 is actively involved in the above-mentioned processes. In this study, we generated a stable cell line expressing the hGPR41 receptor in order to investigate the involvement of GPR41 on butyrate-induced biochemical and physiologic processes. We found that GPR41 activation may be a compensatory mechanism to counter the increase in histone H3 acetylation levels induced by butyrate treatment. Moreover, GPR41 had an inhibitory effect on the anti-proliferative, pro-apoptotic effects of butyrate. GPR41 expression induced cell cycle arrest at the Gl-stage, while its activation by butyrate can cause more cells to pass the G1 checkpoint. These results indicated that GPR41 was associated with histone acetylation and might be involved in the acetylation-related regulation of cell processes including proliferation, apoptosis, and the cell cycle.展开更多
Background:Although bevacizumab is an important treatment for metastatic colorectal cancer(CRC),not allpatients with CRC benefit from it;in unselected patient populations,only modest survival benefits have been report...Background:Although bevacizumab is an important treatment for metastatic colorectal cancer(CRC),not allpatients with CRC benefit from it;in unselected patient populations,only modest survival benefits have been reported.Methods:We evaluated clinical outcomes in 110 patients using comprehensive molecular characterization to identifybiomarkers for a response to bevacizumab-containing treatment.The molecular analysis comprised whole-exomesequencing,ribonucleic acid sequencing,and a methylation array on patient tissues.Results:Genomic and molecularcharacterization was successfully conducted in 103 patients.Six of 103 CRC samples were hypermutated,and none ofthe non-hypermutant tumors were microsatellite unstable.Among those 103 patients,89 had adenocarcinoma(ADC),15 were diagnosed with mucinous ADC,and six had signet-ring cell carcinoma(SRCC).Consensus molecular subtype(CMS)2 was unique to ADC.Of the four SRCCs,two were CMS1,one was CMS4,and the other was CMS3.APCmutation status was a significantly enriched factor in responders to bevacizumab treatment.Fibroblast growth factorreceptor(FGFR)1/2 signaling was upregulated in non-responders,whereas cell cycle,transfer ribonucleic acidprocessing,nucleotide excision repair,and oxidative phosphorylation pathways were enriched in responders.Inaddition,IGF1 was differentially expressed in non-responders(log2 fold change=−1.43,p=4.11×10^(−5),falsediscovery rate=0.098),and FLT1 was highly methylated in non-responders(p=7.55×10^(−3)).When the molecularpathways were reanalyzed separately according to the backbone chemotherapy(FOLFOX vs.FOLFIRI),thesignificance of the molecular pathways varied according to the backbone chemotherapy.Conclusions:This studysought a subset of CRC patients with a distinct clinical response to chemotherapy containing bevacizumab.Ourresults need to be validated in a large group of homogenous patient cohort and examined according to the differentchemotherapy backbones to create personalized therapeutic opportunities in CRC.展开更多
Objective:Benefits of adjuvant treatment in pT1 N1 gastric cancer(GC)remain controversial.Additionally,an effective biomarker for early GC is the need of the hour.The prognostic and predictive roles of single patient ...Objective:Benefits of adjuvant treatment in pT1 N1 gastric cancer(GC)remain controversial.Additionally,an effective biomarker for early GC is the need of the hour.The prognostic and predictive roles of single patient classifier(SPC)were validated in stageⅡ/ⅢGC.In this study,we aimed to elucidate the role of SPC as a biomarker for pT1 N1 GC.Methods:The present retrospective biomarker study(NCT03485105)enrolled patients treated for pT1 N1 GC between 1996 and 2012 from two large hospitals(the Y cohort and S cohort).For SPC,mRNA expression of four classifier genes(GZMB,WARS,SFRP4 and CDX1)were evaluated by real-time reverse transcription-polymerase chain reaction assay.The SPC was revised targeting pT1 stages and the prognosis was stratified as high-and lowrisk group by the expression of SFRP4,a representative epithelial-mesenchymal transition marker.Results:SPC was evaluated in 875 patients(n=391 and 484 in the Y and S cohorts,respectively).Among 864 patients whose SPC result was available,41(4.7%)patients experience GC recurrence.According to revised SPC,254(29.4%)patients were classified as high risk[123(31.5%)and 131(27.1%)in the Y and S cohorts,respectively].The high risk was related to frequent recurrence in both Y and S cohort(log-rank P=0.023,P<0.001,respectively),while there was no difference by GZMB and WARS expression.Multivariable analyses of the overall-cohort confirmed the high risk of revised SPC as a significant prognostic factor[hazard ratio(HR):4.402(2.293-8.449),P<0.001]of GC.A significant difference was not detected by SPC in the prognosis of patients in the presence and absence of adjuvant treatment(log-rank P=0.670).Conclusions:The present study revealed the revised SPC as a prognostic biomarker of pT1 N1 GC and suggested the use of the revised SPC for early-stage GC as like stageⅡ/Ⅲ.展开更多
After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrat...After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.展开更多
Background/Purpose: Hispanic/Latinos in the US are at increased risk for type 2 diabetes (T2D). Data suggest that avocado intake is associated with better glycemic control, but whether this translates to protection fr...Background/Purpose: Hispanic/Latinos in the US are at increased risk for type 2 diabetes (T2D). Data suggest that avocado intake is associated with better glycemic control, but whether this translates to protection from T2D has not been studied. The goal of the current analyses was to examine whether consuming avocados at baseline is associated with lower incident T2D over a six-year period, compared to not consuming avocados at baseline. Subjects/Methods: Using data from a large population of US adults with Hispanic ancestry, without known or unknown T2D at baseline (N = 6159), participants were classified as avocado consumers (N = 983) or non-consumers (N = 5176) based on the mean of two 24-hour dietary recalls. Cox proportional hazard models estimated the association of avocado consumption with incident T2D (N = 656 cases) over a six-year follow-up period, in the population as a whole, and separately in those with normoglycemia vs. prediabetes at baseline. A set of three sequential models were run: the first controlling only for sociodemographic factors (“minimally adjusted” models), the second for these and health behaviors (“fully adjusted” models), and a third for both sets of covariates and also body mass index (BMI;“fully adjusted + BMI” models). Results: In the population as a whole, avocado intake at baseline was associated with reduced incident T2D in both the minimally adjusted (hazard ratio [HR] (±95% confidence intervals [CIs]): 0.70 (0.52 - 0.94), P = 0.04) and the fully adjusted models (HR: 0.72 (0.54 - 0.97), P = 0.03). This association was observed in both those with prediabetes and with normoglycemia at baseline, but only reached significance in those with prediabetes (minimally adjusted model: HR: 0.68 (0.48 - 0.97), P = 0.03;fully adjusted model: HR: 0.69 (0.48 - 0.98), P = 0.04), not in those with normoglycemia (minimally adjusted model: HR: 0.86 (0.45 - 1.65), P = 0.65;fully adjusted model: HR: 0.80 (0.41 - 1.55), P = 0.50). In models which additionally controlled for BMI (“fully adjusted + BMI model”), the associations were slightly attenuated (overall population: HR: 0.79 (0.59 - 1.06), P = 0.60;normoglycemia: HR: 0.83 (0.42 - 1.64), P = 0.60;prediabetes: HR = 0.75 (0.54 - 1.05), P = 0.09). Conclusions: In our longitudinal analyses, adults with Hispanic/Latino ancestry who consumed avocado were less likely to develop T2D than those who did not consume avocado at baseline, especially if they had prediabetes at baseline.展开更多
Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemor...Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemoresistance[1,2].Mutations in tumor protein 53(TP53)occur in over 96%of HGSOC cases,impairing itstumor-suppressive functions,including cell cycle control,DNA repair,and apoptosis.Mutant TP53 promotes tumorprogression,genomic instability,and resistance to stan-dard therapies,thereby worsening patient outcomes[3,4].Death-associated protein kinase 1(DAPK1)is a key reg-ulator of apoptosis and autophagy[5,6].展开更多
Although breast cancer(BC)predominantly affects women over 50,about 5%of cases occur in very young women,aged 35 years or younger,presenting significant clinical challenges and poor outcomes.To explore ageassociated m...Although breast cancer(BC)predominantly affects women over 50,about 5%of cases occur in very young women,aged 35 years or younger,presenting significant clinical challenges and poor outcomes.To explore ageassociated molecular differences in BC,we evaluated the transcriptomic profiles of tumors from very young and older patients,focusing on the tumor microenvironment(TME).Methods are described in the Supplementary file.This study enrolled 66 patients from Hospital Clínico Universitario of Valencia,stratified into very young(≤35 years,premenopausal)and older(>50 years,postmenopausal)BC patients.RNA-sequencing was performed on untreated primary tumors,and data were collected from 22 very young(median:32.5 years;range:22-35 years)and 27 older(median:66 years;range:50-94 years)BC patients who met quality criteria(clinicopathological characteristics in Supplementary Table S1).Principal component analysis illustrated increased heterogeneity among very young HR^(+)/HER2^(−)BC samples(Figure 1A).Differential expression analysis revealed 82 downregulated and 12 upregulated genes in very young BC samples(log2 fold change≥|2|;adjusted P<0.05)(Figure 1B-C,Supplementary Table S2).展开更多
Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits t...Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.展开更多
With the growing incidence of obesity-related malignancies,glucagon-like peptide-1(GLP-1)receptor agonists represent an intriguing potential clinical avenue for cancer prevention and treatment.Population-based data su...With the growing incidence of obesity-related malignancies,glucagon-like peptide-1(GLP-1)receptor agonists represent an intriguing potential clinical avenue for cancer prevention and treatment.Population-based data suggest that individuals who have taken GLP-1 receptor agonists have a decreased incidence of obesity-related cancers.Moreover,in vivo and in vitro studies have demonstrated the antitumor activity of these agents independent of other antineoplastic therapeutics.Additionally,other pre-clinical studies have shown that GLP-1 receptor agonists may help overcome resistance to chemotherapy-refractory cancer cells,thus demonstrating a plausible role in cancer treatment.Randomized controlled trials utilizing GLP-1 receptor agonists in both cancer prevention and treatment may allow for a better understanding of the role of these agents in modern oncology.展开更多
Alzheimer’s disease(AD)is a common neurodegenerative disease characterized clinically by progressive deterioration of memory,and pathologically by histopathological changes including extracellular deposits of amyloid...Alzheimer’s disease(AD)is a common neurodegenerative disease characterized clinically by progressive deterioration of memory,and pathologically by histopathological changes including extracellular deposits of amyloid-beta(A-beta)peptides forming senile plaques(SP)and the intracellular neurofibrillary tangles(NFT)of hyperphosphorylated tau in the brain.This review focused on the new developments of amyloid cascade hypothesis with details on the production,metabolism and clearance of A-beta,and the key roles of some important A-beta-related genes in the pathological processes of AD.The most recent research advances in genetics,neuropathology and pathogenesis of the disease were also discussed.展开更多
Background： The dilemma of pathogens identification in patients with unidentified clinical symptoms such as lever of unknown origin exists, which not only poses a challenge to both the diagnostic and therapeutic proc...Background： The dilemma of pathogens identification in patients with unidentified clinical symptoms such as lever of unknown origin exists, which not only poses a challenge to both the diagnostic and therapeutic process by itself, but also to expert physicians. Methods： In this report, we have attempted to increase the awareness of unidentified pathogens by developing a method to investigate hitherto unidentified infectious pathogens based on unbiased high-throughput sequencing. Results： Our observations show that this method supplements current diagnostic technology that predominantly relies on information derived five cases from the intensive care unit. This methodological approach detects viruses and corrects the incidence of false positive detection rates of pathogens in a much shorter period. Through our method is followed by polymerase chain reaction validation, we could identify infection with Epstein-Barr virus, and in another case, we could identify infection with Streptococcus viridians based on the culture, which was false positive. Conclusions： This technology is a promising approach to revolutionize rapid diagnosis of infectious pathogens and to guide therapy that might result in the improvement of personalized medicine.展开更多
The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia ...The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.展开更多
Background:Single-cell RNA-sequencing(scRNA-seq)is a rapidly evolving technology that enables measurement of gene expression levels at an unprecedented resolution.Despite the explosive growth in the number of cells th...Background:Single-cell RNA-sequencing(scRNA-seq)is a rapidly evolving technology that enables measurement of gene expression levels at an unprecedented resolution.Despite the explosive growth in the number of cells that can be assayed by a single experiment,scRNA-seq still has several limitations,including high rates of dropouts,which result in a large number of genes having zero read count in the scRNA-seq data,and complicate downstream analyses.Methods:To overcome this problem,we treat zeros as missing values and develop nonparametric deep learning methods for imputation.Specifically,our LATE(Learning with AuToEncoder)method trains an autoencoder with random initial values of the parameters,whereas our TRANSLATE(TRANSfer learning with LATE)method further allows for the use of a reference gene expression data set to provide LATE with an initial set of parameter estimates.Results:On both simulated and real data,LATE and TRANSLATE outperform existing scRNA-seq imputation methods,achieving lower mean squared error in most cases,recovering nonlinear gene-gene relationships,and better separating cell types.They are also highly scalable and can efficiently process over 1 million cells in just a few hours on a GPU.Conclusions:We demonstrate that our nonparametric approach to imputation based on autoencoders is powerful and highly efficient.展开更多
基金Supported by National Research Foundation of Korea Grant Funded by the Korea Government,No.RS-2023-00213951.
文摘BACKGROUND The cellular prion protein(PrPC),traditionally associated with neurodegenerative disorders,plays an important role in cancer progression and metastasis by inhibiting apoptosis.AIM To investigate the influence of PrPC expression in cholangiocarcinoma(CCA)on patient outcomes following surgical resection.METHODS Patients who underwent curative surgical resection for either intrahepatic or hilar CCA were enrolled in this retrospective study.Based on the immunohistochemical staining results of the surgical specimens,patients were categorized into two groups:The low PrPC group(negative or 1+)and the high PrPC group(2+or 3+).Survival analyses,including overall survival and recurrence-free survival,were conducted using the Kaplan-Meier method and compared using the log-rank test.RESULTS In total,seventy-six patients diagnosed with CCA(39 with intrahepatic and 37 with hilar CCA)underwent curative hepatectomy from January 2011 to November 2021.Among these patients,38(50%)demonstrated high PrPC expression,whereas the remaining 38(50%)showed low expression of PrPC.During a median follow-up period of 31.2 months(range:1 to 137 months),the high PrPC group had a significantly shorter median overall survival than the low PrPC group(40.4 months vs 137.9 months,respectively;P=0.041).Moreover,the high PrPC group had a significantly shorter median recurrence-free survival than the low PrPC group(13.3 months vs 23.8 months,respectively;P=0.026).CONCLUSION PrPC expression is significantly associated with early recurrence and decreased survival period in CCA patients following surgical resection.Thus,PrPC may be used as a prognostic factor in treatment planning.
基金partial financial support provided by Novomics (Seoul, Korea)
文摘Objective:Precision medicine approaches emphasize the importance of reliable prognostic tools for guiding individualized therapy decisions.In this study,we evaluated the clinical feasibility of the single patient classifier(SPC)test,a new clinical-grade prognostic assay,in stageⅡ-Ⅲgastric cancer patients.Methods:A prospective multicenter study was conducted,involving 237 patients who underwent gastrectomy between September 2019 and August 2020 across nine hospitals.The SPC test was employed to stratify patients into risk groups,and its feasibility and performance were evaluated.The primary endpoint was the proportion of the cases in which the test results were timely delivered before selecting postoperative treatment.Furthermore,3-year disease-free survivals of risk groups were analyzed.Results:The SPC test met the primary endpoint criteria.The 99.5%of SPC tests were timely delivered to hospitals before the postoperative treatment started.In a clinical setting,the median time from the specimen transfer to laboratory to the result delivery to hospital was 4 d.Furthermore,3-year disease-free survivals were significantly different between risk groups classified with SPC tests.Conclusions:This study highlights the SPC test's feasibility in offering crucial information timely delivered for making informed decisions regarding postoperative treatment strategies.It also provides evidence to support the implementation of a future prospective clinical trial aimed at evaluating the clinical utility of the SPC test in guiding personalized treatment decisions for gastric cancer patients.
文摘To review microbiome alterations associated with pancreatic cancer, its potential utility in diagnostics, risk assessment, and influence on disease outcomes.METHODSA comprehensive literature review was conducted by all-inclusive topic review from PubMed, MEDLINE, and Web of Science. The last search was performed in October 2016.RESULTSDiverse microbiome alterations exist among several body sites including oral, gut, and pancreatic tissue, in patients with pancreatic cancer compared to healthy populations.CONCLUSIONPilot study successes in non-invasive screening strategies warrant further investigation for future translational application in early diagnostics and to learn modifiable risk factors relevant to disease prevention. Pre-clinical investigations exist in other tumor types that suggest microbiome manipulation provides opportunity to favorably transform cancer response to existing treatment protocols and improve survival.
基金Supported by In part the Lee T.Hanley Fund for Pancreatic Cancer Research
文摘Adenosquamous carcinoma of the pancreas(ASCP)is a rare entity. Like adenocarcinoma of the pancreas,overall survival is poor. Characteristics of ASCP include central tumor necrosis, along with osteoclasts and hypercalcemia. Various theories exist as to why this histological subtype exists, as normal pancreas tissue has no benign squamous epithelium. Due to the rarity of this disease, limited molecular analysis has been performed, and those reports indicate unique molecular features of ASCP. In this paper, we characterize 23 patients diagnosed with ASCP through molecular profiling using immunohistochemistry staining, fluorescent in situ hybridization, chromogenic in situ hybridization, and gene sequencing, Additionally, we provide a comprehensive literature review of what is known to date of ASCP.Molecular characterization revealed overexpression in MRP1(80%), MGMT(79%), TOP2A(75), RRM1(42%),TOPO1(42%), PTEN(45%), CMET(40%), and C-KIT(10%) among others. One hundred percent of samples tested were positive for KRAS mutations. This analysis shows heretofore unsuspected leads to be considered for treatments of this rare type of exocrine pancreas cancer. Molecular profiling may be appropriate to provide maximum information regarding the patient's tumor. Further work should be pursued to better characterize this disease.
文摘Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as: SMAD4,BRAF,BRCA2,TP53,RB1,MEN1,JAK-1,BRCA-1,BRCA-2,and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore,molecular profiling of PACC should be an option for patients with refractory PACC.
基金Supported by The National Institutes of Health DK091601(JKD and GSG),P30 DK072488(GSG and CDS)the Translational Genomics Research Institute
文摘Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease(NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known aboutthe underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs(mi RNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target m RNAs. Several mi RNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of mi RNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including mi RNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of mi RNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of mi RNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression.
基金supported by the grant from the National High-tech R&D Program(863 Program)(No.2007AA02Z163)the National Natural Science Foundation of China(No. 31000574)the Fundamental Research Fund for the Central Universities(No.78210042)
文摘Butyrate has been recently identified as a natural ligand of the G-protein-coupled receptor 41 （GPR41）. In addition, it is an inhibitor of histone deacetylase （HDAC）. Butyrate treatment results in the hyperacetylation of histones, with resultant multiple biological effects including inhibition of proliferation, induction of cell cycle arrest, and apoptosis, in a variety of cultured mammalian cells. However, it is not clear whether GPR41 is actively involved in the above-mentioned processes. In this study, we generated a stable cell line expressing the hGPR41 receptor in order to investigate the involvement of GPR41 on butyrate-induced biochemical and physiologic processes. We found that GPR41 activation may be a compensatory mechanism to counter the increase in histone H3 acetylation levels induced by butyrate treatment. Moreover, GPR41 had an inhibitory effect on the anti-proliferative, pro-apoptotic effects of butyrate. GPR41 expression induced cell cycle arrest at the Gl-stage, while its activation by butyrate can cause more cells to pass the G1 checkpoint. These results indicated that GPR41 was associated with histone acetylation and might be involved in the acetylation-related regulation of cell processes including proliferation, apoptosis, and the cell cycle.
基金supported by a grant of the Korean Health Technology R&D Project through the Korean Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(Grant Number:HR20C0025).
文摘Background:Although bevacizumab is an important treatment for metastatic colorectal cancer(CRC),not allpatients with CRC benefit from it;in unselected patient populations,only modest survival benefits have been reported.Methods:We evaluated clinical outcomes in 110 patients using comprehensive molecular characterization to identifybiomarkers for a response to bevacizumab-containing treatment.The molecular analysis comprised whole-exomesequencing,ribonucleic acid sequencing,and a methylation array on patient tissues.Results:Genomic and molecularcharacterization was successfully conducted in 103 patients.Six of 103 CRC samples were hypermutated,and none ofthe non-hypermutant tumors were microsatellite unstable.Among those 103 patients,89 had adenocarcinoma(ADC),15 were diagnosed with mucinous ADC,and six had signet-ring cell carcinoma(SRCC).Consensus molecular subtype(CMS)2 was unique to ADC.Of the four SRCCs,two were CMS1,one was CMS4,and the other was CMS3.APCmutation status was a significantly enriched factor in responders to bevacizumab treatment.Fibroblast growth factorreceptor(FGFR)1/2 signaling was upregulated in non-responders,whereas cell cycle,transfer ribonucleic acidprocessing,nucleotide excision repair,and oxidative phosphorylation pathways were enriched in responders.Inaddition,IGF1 was differentially expressed in non-responders(log2 fold change=−1.43,p=4.11×10^(−5),falsediscovery rate=0.098),and FLT1 was highly methylated in non-responders(p=7.55×10^(−3)).When the molecularpathways were reanalyzed separately according to the backbone chemotherapy(FOLFOX vs.FOLFIRI),thesignificance of the molecular pathways varied according to the backbone chemotherapy.Conclusions:This studysought a subset of CRC patients with a distinct clinical response to chemotherapy containing bevacizumab.Ourresults need to be validated in a large group of homogenous patient cohort and examined according to the differentchemotherapy backbones to create personalized therapeutic opportunities in CRC.
基金supported by the Alumni Association of the Department of Surgery at the Yonsei University Health System(No.2017-01)。
文摘Objective:Benefits of adjuvant treatment in pT1 N1 gastric cancer(GC)remain controversial.Additionally,an effective biomarker for early GC is the need of the hour.The prognostic and predictive roles of single patient classifier(SPC)were validated in stageⅡ/ⅢGC.In this study,we aimed to elucidate the role of SPC as a biomarker for pT1 N1 GC.Methods:The present retrospective biomarker study(NCT03485105)enrolled patients treated for pT1 N1 GC between 1996 and 2012 from two large hospitals(the Y cohort and S cohort).For SPC,mRNA expression of four classifier genes(GZMB,WARS,SFRP4 and CDX1)were evaluated by real-time reverse transcription-polymerase chain reaction assay.The SPC was revised targeting pT1 stages and the prognosis was stratified as high-and lowrisk group by the expression of SFRP4,a representative epithelial-mesenchymal transition marker.Results:SPC was evaluated in 875 patients(n=391 and 484 in the Y and S cohorts,respectively).Among 864 patients whose SPC result was available,41(4.7%)patients experience GC recurrence.According to revised SPC,254(29.4%)patients were classified as high risk[123(31.5%)and 131(27.1%)in the Y and S cohorts,respectively].The high risk was related to frequent recurrence in both Y and S cohort(log-rank P=0.023,P<0.001,respectively),while there was no difference by GZMB and WARS expression.Multivariable analyses of the overall-cohort confirmed the high risk of revised SPC as a significant prognostic factor[hazard ratio(HR):4.402(2.293-8.449),P<0.001]of GC.A significant difference was not detected by SPC in the prognosis of patients in the presence and absence of adjuvant treatment(log-rank P=0.670).Conclusions:The present study revealed the revised SPC as a prognostic biomarker of pT1 N1 GC and suggested the use of the revised SPC for early-stage GC as like stageⅡ/Ⅲ.
文摘After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.
文摘Background/Purpose: Hispanic/Latinos in the US are at increased risk for type 2 diabetes (T2D). Data suggest that avocado intake is associated with better glycemic control, but whether this translates to protection from T2D has not been studied. The goal of the current analyses was to examine whether consuming avocados at baseline is associated with lower incident T2D over a six-year period, compared to not consuming avocados at baseline. Subjects/Methods: Using data from a large population of US adults with Hispanic ancestry, without known or unknown T2D at baseline (N = 6159), participants were classified as avocado consumers (N = 983) or non-consumers (N = 5176) based on the mean of two 24-hour dietary recalls. Cox proportional hazard models estimated the association of avocado consumption with incident T2D (N = 656 cases) over a six-year follow-up period, in the population as a whole, and separately in those with normoglycemia vs. prediabetes at baseline. A set of three sequential models were run: the first controlling only for sociodemographic factors (“minimally adjusted” models), the second for these and health behaviors (“fully adjusted” models), and a third for both sets of covariates and also body mass index (BMI;“fully adjusted + BMI” models). Results: In the population as a whole, avocado intake at baseline was associated with reduced incident T2D in both the minimally adjusted (hazard ratio [HR] (±95% confidence intervals [CIs]): 0.70 (0.52 - 0.94), P = 0.04) and the fully adjusted models (HR: 0.72 (0.54 - 0.97), P = 0.03). This association was observed in both those with prediabetes and with normoglycemia at baseline, but only reached significance in those with prediabetes (minimally adjusted model: HR: 0.68 (0.48 - 0.97), P = 0.03;fully adjusted model: HR: 0.69 (0.48 - 0.98), P = 0.04), not in those with normoglycemia (minimally adjusted model: HR: 0.86 (0.45 - 1.65), P = 0.65;fully adjusted model: HR: 0.80 (0.41 - 1.55), P = 0.50). In models which additionally controlled for BMI (“fully adjusted + BMI model”), the associations were slightly attenuated (overall population: HR: 0.79 (0.59 - 1.06), P = 0.60;normoglycemia: HR: 0.83 (0.42 - 1.64), P = 0.60;prediabetes: HR = 0.75 (0.54 - 1.05), P = 0.09). Conclusions: In our longitudinal analyses, adults with Hispanic/Latino ancestry who consumed avocado were less likely to develop T2D than those who did not consume avocado at baseline, especially if they had prediabetes at baseline.
基金supported by grants from Deutsche Kreb-shilfe(70116875)the German Cancer Consortium(DKTK,Heidelberg).
文摘Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemoresistance[1,2].Mutations in tumor protein 53(TP53)occur in over 96%of HGSOC cases,impairing itstumor-suppressive functions,including cell cycle control,DNA repair,and apoptosis.Mutant TP53 promotes tumorprogression,genomic instability,and resistance to stan-dard therapies,thereby worsening patient outcomes[3,4].Death-associated protein kinase 1(DAPK1)is a key reg-ulator of apoptosis and autophagy[5,6].
基金supported by grants from Fundación FERO,Asociación Española Contra el Cáncer(PRYCO211372RODR)the Biomedical Research Networking Centre for Oncology(CIBERONC)(CB16/12/00481).I.Garrido-Cano.was funded by the Margarita Salas postdoctoral grant(European Union-Next generation EU),M.Tapia was funded by SEOM-Río Hortega 2023,and A.L.and A.A.were funded by predoctoral fellowships from Asociación Española Contra el Cancer.J.M.Cejalvo was funded by Joan Rodes contract.
文摘Although breast cancer(BC)predominantly affects women over 50,about 5%of cases occur in very young women,aged 35 years or younger,presenting significant clinical challenges and poor outcomes.To explore ageassociated molecular differences in BC,we evaluated the transcriptomic profiles of tumors from very young and older patients,focusing on the tumor microenvironment(TME).Methods are described in the Supplementary file.This study enrolled 66 patients from Hospital Clínico Universitario of Valencia,stratified into very young(≤35 years,premenopausal)and older(>50 years,postmenopausal)BC patients.RNA-sequencing was performed on untreated primary tumors,and data were collected from 22 very young(median:32.5 years;range:22-35 years)and 27 older(median:66 years;range:50-94 years)BC patients who met quality criteria(clinicopathological characteristics in Supplementary Table S1).Principal component analysis illustrated increased heterogeneity among very young HR^(+)/HER2^(−)BC samples(Figure 1A).Differential expression analysis revealed 82 downregulated and 12 upregulated genes in very young BC samples(log2 fold change≥|2|;adjusted P<0.05)(Figure 1B-C,Supplementary Table S2).
基金This work was supported by grants from the Deutsche Krebshilfe(70114007)Wilhelm Sander Stiftung(Nr.2021.023.1),German Cancer Consortium(DKTK),Heidelberg.
文摘Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.
文摘With the growing incidence of obesity-related malignancies,glucagon-like peptide-1(GLP-1)receptor agonists represent an intriguing potential clinical avenue for cancer prevention and treatment.Population-based data suggest that individuals who have taken GLP-1 receptor agonists have a decreased incidence of obesity-related cancers.Moreover,in vivo and in vitro studies have demonstrated the antitumor activity of these agents independent of other antineoplastic therapeutics.Additionally,other pre-clinical studies have shown that GLP-1 receptor agonists may help overcome resistance to chemotherapy-refractory cancer cells,thus demonstrating a plausible role in cancer treatment.Randomized controlled trials utilizing GLP-1 receptor agonists in both cancer prevention and treatment may allow for a better understanding of the role of these agents in modern oncology.
基金This work was supported by the grants from the National Natural Science Foundation of China(No.31171019,No.81173108 and No.31000574)the Opening Projects of Shanghai Key Laboratory of Brain Functional Genomics and Key Laboratory of Brain Functional Genomics(East China Normal University),Ministry of Education.
文摘Alzheimer’s disease(AD)is a common neurodegenerative disease characterized clinically by progressive deterioration of memory,and pathologically by histopathological changes including extracellular deposits of amyloid-beta(A-beta)peptides forming senile plaques(SP)and the intracellular neurofibrillary tangles(NFT)of hyperphosphorylated tau in the brain.This review focused on the new developments of amyloid cascade hypothesis with details on the production,metabolism and clearance of A-beta,and the key roles of some important A-beta-related genes in the pathological processes of AD.The most recent research advances in genetics,neuropathology and pathogenesis of the disease were also discussed.
文摘Background： The dilemma of pathogens identification in patients with unidentified clinical symptoms such as lever of unknown origin exists, which not only poses a challenge to both the diagnostic and therapeutic process by itself, but also to expert physicians. Methods： In this report, we have attempted to increase the awareness of unidentified pathogens by developing a method to investigate hitherto unidentified infectious pathogens based on unbiased high-throughput sequencing. Results： Our observations show that this method supplements current diagnostic technology that predominantly relies on information derived five cases from the intensive care unit. This methodological approach detects viruses and corrects the incidence of false positive detection rates of pathogens in a much shorter period. Through our method is followed by polymerase chain reaction validation, we could identify infection with Epstein-Barr virus, and in another case, we could identify infection with Streptococcus viridians based on the culture, which was false positive. Conclusions： This technology is a promising approach to revolutionize rapid diagnosis of infectious pathogens and to guide therapy that might result in the improvement of personalized medicine.
基金the Arizona Biomedical Research Commission(ABRC)young investigator awardthe Fred Hutchinson Cancer Research Center(0000917241)Tulane University Startup fund。
文摘The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.
文摘Background:Single-cell RNA-sequencing(scRNA-seq)is a rapidly evolving technology that enables measurement of gene expression levels at an unprecedented resolution.Despite the explosive growth in the number of cells that can be assayed by a single experiment,scRNA-seq still has several limitations,including high rates of dropouts,which result in a large number of genes having zero read count in the scRNA-seq data,and complicate downstream analyses.Methods:To overcome this problem,we treat zeros as missing values and develop nonparametric deep learning methods for imputation.Specifically,our LATE(Learning with AuToEncoder)method trains an autoencoder with random initial values of the parameters,whereas our TRANSLATE(TRANSfer learning with LATE)method further allows for the use of a reference gene expression data set to provide LATE with an initial set of parameter estimates.Results:On both simulated and real data,LATE and TRANSLATE outperform existing scRNA-seq imputation methods,achieving lower mean squared error in most cases,recovering nonlinear gene-gene relationships,and better separating cell types.They are also highly scalable and can efficiently process over 1 million cells in just a few hours on a GPU.Conclusions:We demonstrate that our nonparametric approach to imputation based on autoencoders is powerful and highly efficient.
