High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma(HCC)cohorts confirmed previously identified frequently mutated somatic genes,such as TP53,CTNNB1 and ...High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma(HCC)cohorts confirmed previously identified frequently mutated somatic genes,such as TP53,CTNNB1 and AXIN1,and identified several novel genes with moderate mutation frequencies,including ARID1A,ARID2,MLL,MLL2,MLL3,MLL4,IRF2,ATM,CDKN2A,FGF19,PIK3CA,RPS6KA3,JAK1,KEAP1,NFE2L2,C16orf62,LEPR,RAC2,and IL6ST.Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling,Wnt/β-catenin signaling,JAK/STAT signaling,and oxidative stress play critical roles in HCC tumorigenesis.Nevertheless,because there are few druggable genes used in HCC therapy,the identification of new therapeutic targets through integrated genomic approaches remains an important task.Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain,copy number alteration(CNA)analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons,homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression.Moreover,integration of CNAs with other high-throughput genomic data,such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models,provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.展开更多
A major limitation of expression profiling is caused by the large number of variables assessed compared to relatively small sample sizes. In this study, we developed a multinomial Probit Bayesian model which utilizes ...A major limitation of expression profiling is caused by the large number of variables assessed compared to relatively small sample sizes. In this study, we developed a multinomial Probit Bayesian model which utilizes the double exponential prior to induce shrinkage and reduce the number of covariates in the model [1]. A hierarchical Sparse Bayesian Generalized Linear Model (SBGLM) was developed in order to facilitate Gibbs sampling which takes into account the progressive nature of the response variable. The method was evaluated using a published dataset (GSE6099) which contained 99 prostate cancer cell types in four different progressive stages [2]. Initially, 398 genes were selected using ordinal logistic regression with a cutoff value of 0.05 after Benjamini and Hochberg FDR correction. The dataset was randomly divided into training (N = 50) and test (N = 49) groups such that each group contained equal number of each cancer subtype. In order to obtain more robust results we performed 50 re-samplings of the training and test groups. Using the top ten genes obtained from SBGLM, we were able to achieve an average classification accuracy of 85% and 80% in training and test groups, respectively. To functionally evaluate the model performance, we used a literature mining approach called Geneset Cohesion Analysis Tool [3]. Examination of the top 100 genes produced an average functional cohesion p-value of 0.007 compared to 0.047 and 0.131 produced by classical multi-category logistic regression and Random Forest approaches, respectively. In addition, 96 percent of the SBGLM runs resulted in a GCAT literature cohesion p-value smaller than 0.047. Taken together, these results suggest that sparse Bayesian Multinomial Probit model applied to cancer progression data allows for better subclass prediction and produces more functionally relevant gene sets.展开更多
Objectives: Recent studies have introduced middle ear volume(MEV) as a novel determinant of perforation-induced conductive hearing loss(CHL) in a mechanism driven by trans-tympanic membrane pressure differences. The p...Objectives: Recent studies have introduced middle ear volume(MEV) as a novel determinant of perforation-induced conductive hearing loss(CHL) in a mechanism driven by trans-tympanic membrane pressure differences. The primary aims of this preliminary report are to: 1) correlate CHL with perforation size; 2) describe the relationship between CHL and MEV; and 3) compare CHL across a range of cholesteatoma involvement.Design: A retrospective pilot study was performed in 31 subjects with audiometry indicative of conductive hearing loss, temporal bone CT scans,and no prior middle ear surgery. Perforation size and MEV were analyzed with respect to CHL in a cohort of 10 perforated ears with no cholesteatoma. CHLs were compared in 3 groups defined by extent of cholesteatoma involvement.Results: Ears with large and small perforations showed mean ABG values of 32.0 ± 15.7 dB and 16.0 ± 16.4 dB, respectively. A direct relationship was observed between MEV and CHL for ears with large perforations across all frequencies, whereas this relationship for small perforations was frequency-dependent. Finally, a statistically significant increase in CHL was found across ears with increasing cholesteatoma involvement at 1000 Hz(X^2(2) = 9.786, p = 0.008),2000 Hz(x^2(2) = 8.455, p = 0.015),and 4000 Hz(x^2(2)= 8.253, p = 0.016).Conclusions: These pilot data suggest that greater perforation-induced conductive hearing losses may be associated with larger perforation sizes and cholesteatoma. The correlation between MEV and CHL may require additional study.展开更多
AIM To investigate the accuracy of fungal dysbiosis inmucosa and stool for predicting the diagnosis of Crohn's disease(CD).METHODS Children were prospectively enrolled in two medical centers:one university hospita...AIM To investigate the accuracy of fungal dysbiosis inmucosa and stool for predicting the diagnosis of Crohn's disease(CD).METHODS Children were prospectively enrolled in two medical centers:one university hospital and one private gastroenterology clinic in the city of Riyadh,Kingdom of Saudi Arabia.The children with confirmed diagnosis of CD by standard guidelines were considered cases,and the others were considered non-inflammatory bowel disease controls.Mucosal and stool samples were sequenced utilizing Illumina MiSeq chemistry following the manufacturer's protocols,and abundance and diversity of fungal taxa in mucosa and stool were analyzed.Sparse logistic regression was used to predict the diagnosis of CD.The accuracy of the classifier was tested by computing the receiver operating characteristic curves with 5-fold stratified cross-validation under 100 permutations of the training data partition and the mean area under the curve(AUC)was calculated.RESULTS All the children were Saudi nationals.There were 15 children with CD and 20 controls.The mean age was 13.9(range:6.7-17.8)years for CD children and 13.9(3.25-18.6)years for controls,and 10/15(67%)of the CD and 13/20(65%)of the control subjects were boys.CD locations at diagnosis were ileal(L1)in 4 and colonic(L3)in 11 children,while CD behavior was non-stricturing and non-penetrating(B1)in 12 and stricturing(B2)in 3 children.The mean AUC for the fungal dysbiosis classifier was significantly higher in stools(AUC=0.85±0.057)than in mucosa(AUC=0.71±0.067)(P<0.001).Most fungal species were significantly more depleted in stools than mucosal samples,except for Saccharomyces cerevisiae and S.bayanus,which were significantly more abundant.Diversity was significantly more reduced in stools than in mucosa.CONCLUSION We found high AUC of fungal dysbiosis in fecal samples of children with CD,suggesting high accuracy in predicting diagnosis of CD.展开更多
Personalized medicine will improve heath outcomes and patient satisfaction. However, implementing personalized medicine based on individuals’ biological information is far from simple, requiring genetic biomarkers th...Personalized medicine will improve heath outcomes and patient satisfaction. However, implementing personalized medicine based on individuals’ biological information is far from simple, requiring genetic biomarkers that are mainly developed and used by the pharmaceutical companies for selecting those patients who benefit more, or have less risk of adverse drug reactions, from a particular drug. Genome-wide Association Studies (GWAS) aim to identify genetic variants across the human genome that might be utilized as genetic biomarkers for diagnosis and prognosis. During the last several years, high-density genotyping SNP arrays have facilitated GWAS that successfully identified common genetic variants associated with a variety of phenotypes. However, each of the identified genetic variants only explains a very small fraction of the underlying genetic contribution to the studied phenotypic trait. The replication studies demonstrated that only a small portion of associated loci in the initial GWAS can be replicated, even within the same populations. Given the complexity of GWAS, multiple sources of Type I (false positive) and Type II (false negative) errors exist. The inconsistency in genotypes that caused either by the genotypeing experiment or by genotype calling process is a major source of the false GWAS findings. Accurate and reproducible genotypes are paramount as inconsistency in genotypes can lead to an inflation of false associations. This article will review the sources of inconsistency in genotypes and discuss its effect in GWAS findings.展开更多
The genetic diversity of the banana shrimp Fenneropenaeus merguiensis is at risk because of over-harvesting,which consequently reduces food security.This endangerment is exacerbated because this species is not commonl...The genetic diversity of the banana shrimp Fenneropenaeus merguiensis is at risk because of over-harvesting,which consequently reduces food security.This endangerment is exacerbated because this species is not commonly cultivated by farmers.Overall,these factors necessitate conservation of this shrimp species across its natural habitat.Information on the migration of primordial germ cells(PGCs)to form a gonad is essential for shrimp preservation techniques such as broodstock preparation,sex differentiation,and germ cell transplantation.In this study,histological analysis and in situ hybridization of vasa expression(from embryo to testis development)were used to demonstrate the movement of PGCs.Hematoxylin and Eosin staining and in situ hybridization with the VASA probe revealed that the PGCs migrated retrogradely along the midgut,colonizing the area between the hepatopancreas and heart,a region that becomes the genital ridge in the postlarval stage.External sexual organs appeared at approximately 4 months of age.Through real-time PCR,the expression of the vasa gene was detected early on postlarval day 7,whereas its abundant expression was detected in the ovaries and testes of adult shrimp.This study could help with the identification and monitoring of PGCs or spermatogonia in banana shrimp and facilitate the implementation of other germ cell-relevant techniques in the future.展开更多
Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in ...Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.展开更多
The morphology of inflorescences is regulated in part by the temporal and spatial events that regulate flower specification.In Arabidopsis,an endogenous flowering time pathway mediated by a subset of SQUAMOSA PROMOTER...The morphology of inflorescences is regulated in part by the temporal and spatial events that regulate flower specification.In Arabidopsis,an endogenous flowering time pathway mediated by a subset of SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE(SPL)transcription factors,including SPL3,SPL4,and SPL5,function to specify flowers by activating floral meristem identity genes.During shoot development,SPL3,SPL4,and SPL5 are post-transcriptionally regulated by microRNA156(miR156).The photoperiod regulated florigenic signal,FLOWERING LOCUS T(FT),promotes floral induction,in part by activating SPL3,SPL4,and SPL5.In turn,these SPLs function in parallel with FT to specify flower meristems.Two related BELLl-like homeobox genes PENNYWISE(PNY)and POUND-FOOLISH(PNF)expressed in the shoot apical meristem are absolutely required for the specification of floral meristems.Genetic studies show that the floral specification function of FT depends upon PNYand PNF;however,the interplay between these homeodomain proteins and SPLs is not known.In this manuscript,we show that the photoperiodic floral induction of SPL3,SPL4,and SPL5 is dependent upon PNY and PNE Further,PNY and PNF also control SPL3,SPL4,and SPL5 expression by negatively regulating miR156.Lastly,ectopic expres-sion of SPL4 partially rescues the pny pnf non-flower-producing phenotype,while overexpression of SPL3 or SPL5 in pny pnf plants was unable to restore flower specification.These results suggest that:(1)SPL3,SPL4,and SPL5 function is dependent upon PNY and PNF,or(2)expression of multiple SPLs is required for floral specification in pny pnf plants.展开更多
Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes an...Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.展开更多
Background and Aims:The perinatal transmission of hepatitis B virus(HBV)remains an important global health problem.Here,a systematic review and meta-analysis were conducted to evaluate the evidence regarding the effic...Background and Aims:The perinatal transmission of hepatitis B virus(HBV)remains an important global health problem.Here,a systematic review and meta-analysis were conducted to evaluate the evidence regarding the efficacy and maternal/fetal safety of treating pregnant women with lamivudine,telbivudine(LdT),and tenofovir(TDF).Methods:A PubMed and Scopus search resulted in 1,076 records,which were reduced to 36,containing 7,717 pregnant women with chronic HBV infection and 7467 infants meeting the inclusion criteria.The latest search was in August 2019.Results:Treatment with LdT,but not lamivudine and TDF,could significantly reduce the hepatitis B virus surface antigen-positive rate(odds ratio(OR)=0.37)in infants;it also led to higher rates of hepatitis B e antigen loss(OR=12.14),hepatitis B e antigen seroconversion(OR=8.93),and alanine aminotransferase normalization in mothers(OR=1.49).Each of these treatments was able to significantly reduce HBV DNA positivity at birth(total OR=0.19)and mother-to-child-transmission of HBV(total OR=0.15),and to cause higher rates of HBV DNA suppression in mothers(total OR=25.53).However,nucleos(t)ide analogues might also be involved in creatine kinase elevation(total OR=7.48).In contrast,no significant association was found between nucleos(t)ide analogue therapy and preterm/premature births,congenital malformation,low birth weight,and abortion or fetal/infant death.The results suggested LdT's high capability of preventing mother-to-childtransmission.However,TDF failed to show significant associations to a reduced risk of mother-to-child-transmission,probably due to the low number of patients included.Conclusions:Although using either lamivudine,LdT,orTDF could lead to more favorable maternal/fetal outcomes,LdT seemed to show more potential in resolving certain infant-and maternal-related outcomes.More studies on the safety profile of such treatments are required.展开更多
We present in this paper an ab initio method, named KnotFold, for RNA H-type pseudoknot prediction. Our method employs an ensemble of RNA folding tools and a filtering heuristic to generate a set of pseudoknot-free st...We present in this paper an ab initio method, named KnotFold, for RNA H-type pseudoknot prediction. Our method employs an ensemble of RNA folding tools and a filtering heuristic to generate a set of pseudoknot-free stems, and then predicts pseudoknots by utilizing a search technique with a pseudo-probability scoring scheme. Experimental results show that KnotFold achieves higher sensitivity than existing methods. The KnotFold package with documentation is freely available at http：//bioinformatics.njit.edu/KnotFold.展开更多
Aim:CD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia(BPL)cells.The purpose of the present study was to identify the CD22ΔE12-specific signature transcr...Aim:CD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia(BPL)cells.The purpose of the present study was to identify the CD22ΔE12-specific signature transcriptome in human BPL cells and evaluate the clinical potential of a nanoscale formulation of CD22ΔE12-siRNA as an RNAi therapeutic against drug-resistant BPL.CD22ΔE12-siRNA nanoparticles significantly improved the event-free survival(EFS)outcome of NOD/SCID(NS)mice challenged with human BPL xenograft cells.Methods:Gene expression and translational bioinformatics methods were applied to examine the expression of the CD22ΔE12-specific signature transcriptome in human BPL cells in subsets of BPL patients.Survival analysis for mice challenged with BPL cells and treated with CD22ΔE12 siRNA was performed using standard methods.Results:Leukemia cells from CD22ΔE12-Tg mice exhibit gene and protein expression profiles consistent with constitutive activation of multiple signaling networks,mimicking the profiles of relapsed BPL patients as well as newly diagnosed high-risk patients with BCR-ABL+/Philadelphia chromosome(Ph)+BPL as well as Ph-like BPL.A nanoscale formulation of CD22ΔE12-siRNA abrogated the in vivo clonogenicity of the leukemia-initiating leukemic cell fraction in xenograft specimens derived from patients with relapsed BPL and significantly improved the EFS outcome of NS mice challenged with drug-resistant human BPL xenograft cells.Conclusion:The CD22-RNAi technology is applicable to all BPL patients both high risk and standard risk.That is because CD22ΔE12 is a characteristic feature of drug-resistant leukemic clones that escape chemotherapy and cause relapse in both high risk and low risk subgroups of patients.The technology therefore has the potential(1)for prevention of relapses by selectively killing the clones that are most likely to escape chemotherapy and cause relapse as well(2)for treatment of relapses in BPL.This research project may also lead to innovative salvage regimens against other forms of CD22ΔE12-positive relapsed B-lineage leukemias and lymphomas.展开更多
We have developed a comprehensive software suite for bioinformatics research of cDNAs; it is aimed at rapid characterization of the features of genes and the proteins they code. Methods implemented include the detecti...We have developed a comprehensive software suite for bioinformatics research of cDNAs; it is aimed at rapid characterization of the features of genes and the proteins they code. Methods implemented include the detection of translation initia- tion and termination signals, statistical analysis of codon usage, comparative study of amino acid composition, comparative modeling of the structures of product proteins, prediction of alternative splice forms, and metabolic pathway reconstruction. The software package is freely available under the GNU General Public License at http： / /www.g-language.org/ data/cdna/.展开更多
In their manuscript,“Whole-Grain Intake and Pancreatic Cancer Risk-The Danish,Diet,Cancer and Health Cohort”,Schacht et al.(1)report that total whole-grain product(per 50 g/d serving)intake was significantly associa...In their manuscript,“Whole-Grain Intake and Pancreatic Cancer Risk-The Danish,Diet,Cancer and Health Cohort”,Schacht et al.(1)report that total whole-grain product(per 50 g/d serving)intake was significantly associated with lower incidence of pancreatic cancer(HR:0.93;95%CI:0.86,1.00).A sex-specific analysis revealed that this association only held among men.However,neither total whole-grain(per 16-g serving)or specific individual whole-grain products and cereals were significantly associated with lower pancreatic cancer risk.In this commentary,I will describe some of the assumptions and biases associated with assessing dietary intake and attempting to find associations with disease.展开更多
Plants are constantly under attack by pathogens,pests,and parasites,resulting in severe consequences on global food production and human health.While pathogens and pests find their ways to invade and communicate with ...Plants are constantly under attack by pathogens,pests,and parasites,resulting in severe consequences on global food production and human health.While pathogens and pests find their ways to invade and communicate with their hosts,plants have evolved sophisticated immune systems to fight infections.展开更多
Aim:The purpose of the present study was to perform a comprehensive analysis of WT1 gene expression in high-risk pediatric acute lymphoblastic leukemia(ALL).Methods:We performed a meta-analysis of WT1 gene expression ...Aim:The purpose of the present study was to perform a comprehensive analysis of WT1 gene expression in high-risk pediatric acute lymphoblastic leukemia(ALL).Methods:We performed a meta-analysis of WT1 gene expression for normal hematopoietic cells vs.primary leukemia cells from 801 pediatric ALL samples deposited in the Oncomine database combined with an in-depth gene expression analysis using our in-house database of gene expression profiles of primary leukemia cells from 1416 pediatric ALL cases.We also examined the expression of WT1 in primary leukemic cells from 299 T-lineage ALL patients in the Oncomine database and 189 T-lineage ALL patients in the archived datasets GSE13159,GSE13351,and GSE13159.Results:Our data provide unprecedented evidence that primary leukemia cells from patients with MLL gene rearrangements(MLL-R)express highest levels of WT1 expression within the high-risk subsets of pediatric B-lineage ALL.Notably,MLL-R^(+)patients exhibited>6-fold higher expression levels of the WT1 gene compared to the other B-lineage ALL subtypes combined(P<0.0001).Our findings in 97 MLL-R^(+)infant B-lineage ALL cases uniquely demonstrated that WT1 is expressed at 1.5-4.2-fold higher levels in MLL-R^(+)infant leukemia cells than in normal hematopoietic cells and revealed that WT1 expression level was substantially higher in steroid-resistant infant leukemia cells when compared to non-leukemic healthy bone marrow cells.Furthermore,our study demonstrates for the first time that the WT1-regulated EWSR1,TP53,U2AF2,and WTAP genes(i.e.,WT1 interactome)were differentially upregulated in MLL-R^(+)leukemia cells illustrating that the MLL-regulatory pathway is aberrantly upregulated in MLL-R^(+)pediatric B-lineage ALL.These novel insights provide a compelling rationale for targeting WT1 in second line treatment of MLL-R^(+)pediatric B-lineage ALL,including MLL-R^(+)infant ALL.Furthermore,our study is the first to demonstrate that leukemia cells from 370 Ph-like patients had significantly higher WT1 expression when compared to normal hematopoietic cells.Finally,our findings demonstrate for the first time that chemotherapy-resistant primarily leukemic cells from relapsed B-lineage ALL patients exhibit higher expression levels of WT1 than primary leukemia cells from newly diagnosed B-lineage ALL patients(P=0.001).Conclusion:Our findings indicate that the WT1 gene product may serve as a target for immunotherapy in high risk/poor prognosis subsets of newly diagnosed as well as relapsed pediatric B-lineage ALL.Our findings also significantly expand the current knowledge of WT1 expression in T-lineage ALL and provide new evidence that WT1 gene and its interactome are expressed in T-lineage ALL cells at significantly higher levels than in normal hematopoietic cells.This previously unknown differential expression profile uniquely indicates that the protein product of WT1 would be an attractive molecular target for treatment of T-lineage ALL as well.展开更多
Advances in mass spectrometry(MS)have enabled high-throughput analysis of proteomes in biological systems.The state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying ...Advances in mass spectrometry(MS)have enabled high-throughput analysis of proteomes in biological systems.The state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide–spectrum matches(PSMs),which convert mass spectra to peptide sequences.Different database search algorithms use distinct search strategies and thus may identify unique PSMs.However,no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and a control on the false discovery rate(FDR).To fill in this gap,we proposed a statistical framework,Aggregation of Peptide Identification Results(APIR),that is universally compatible with all database search algorithms.Notably,under an FDR threshold,APIR is guaranteed to identify at least as many,if not more,peptides as individual database search algorithms do.Evaluation of APIR on a complex proteomics standard dataset showed that APIR outpowers individual database search algorithms and empirically controls the FDR.Real data studies showed that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search algorithms.The APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis,e.g.,differential gene expression analysis on RNA sequencing data.The APIR R package is available at https://github.com/yiling0210/APIR.展开更多
This year （2018） marks the 60th anniversary of the ＂central dogma＂, summarized as ＂DNA makes RNA makes protein＂, which was originally proposed by Francis Crick in 1958. Three years later, messenger RNA was ident...This year （2018） marks the 60th anniversary of the ＂central dogma＂, summarized as ＂DNA makes RNA makes protein＂, which was originally proposed by Francis Crick in 1958. Three years later, messenger RNA was identified as the template of protein synthesis. After 60 years of discovery, including discovery of the split nature of eukaryotic genes （Le., splicing）, it becomes evident that messenger RNAs are not merely messengers, but a hub of co- and post-transcriptional regulation, which is fundamental to amplify the complexity encoded in the genome of higher eukaryotic organisms. The mature forms of RNA of protein-coding genes and their abundance have to be tightly regulated through multiple steps of sophisticated processing, including capping, splicing and polyadenylation. In addition, their function also critically depends on proper localization -- sometimes trafficking to the remote parts of the cell such as dendrites and axons of neurons -- and proper control of their stability. Furthermore, thousands of long and small noncoding RNAs are produced to play a wide range of roles in gene regulation. From our perspective, two overarching goals for RNA biology include （i） characterizing the spatial-temporal regulation of various RNA species and elucidating the underlying regulatory mechanisms; （ii） understanding the functional impact of such regulation on human physiology and disease.展开更多
基金Supported by The National Research Program for Biopharmaceuticalsby the National Science Council,Taiwan with grant numbers No.101-2320-B-010-066-MY3,No.101-2325-B-001-011 and No.101-2320-B-001-029-MY3
文摘High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma(HCC)cohorts confirmed previously identified frequently mutated somatic genes,such as TP53,CTNNB1 and AXIN1,and identified several novel genes with moderate mutation frequencies,including ARID1A,ARID2,MLL,MLL2,MLL3,MLL4,IRF2,ATM,CDKN2A,FGF19,PIK3CA,RPS6KA3,JAK1,KEAP1,NFE2L2,C16orf62,LEPR,RAC2,and IL6ST.Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling,Wnt/β-catenin signaling,JAK/STAT signaling,and oxidative stress play critical roles in HCC tumorigenesis.Nevertheless,because there are few druggable genes used in HCC therapy,the identification of new therapeutic targets through integrated genomic approaches remains an important task.Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain,copy number alteration(CNA)analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons,homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression.Moreover,integration of CNAs with other high-throughput genomic data,such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models,provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.
文摘A major limitation of expression profiling is caused by the large number of variables assessed compared to relatively small sample sizes. In this study, we developed a multinomial Probit Bayesian model which utilizes the double exponential prior to induce shrinkage and reduce the number of covariates in the model [1]. A hierarchical Sparse Bayesian Generalized Linear Model (SBGLM) was developed in order to facilitate Gibbs sampling which takes into account the progressive nature of the response variable. The method was evaluated using a published dataset (GSE6099) which contained 99 prostate cancer cell types in four different progressive stages [2]. Initially, 398 genes were selected using ordinal logistic regression with a cutoff value of 0.05 after Benjamini and Hochberg FDR correction. The dataset was randomly divided into training (N = 50) and test (N = 49) groups such that each group contained equal number of each cancer subtype. In order to obtain more robust results we performed 50 re-samplings of the training and test groups. Using the top ten genes obtained from SBGLM, we were able to achieve an average classification accuracy of 85% and 80% in training and test groups, respectively. To functionally evaluate the model performance, we used a literature mining approach called Geneset Cohesion Analysis Tool [3]. Examination of the top 100 genes produced an average functional cohesion p-value of 0.007 compared to 0.047 and 0.131 produced by classical multi-category logistic regression and Random Forest approaches, respectively. In addition, 96 percent of the SBGLM runs resulted in a GCAT literature cohesion p-value smaller than 0.047. Taken together, these results suggest that sparse Bayesian Multinomial Probit model applied to cancer progression data allows for better subclass prediction and produces more functionally relevant gene sets.
基金supported by the National Institutes of Health under Award Numbers 5T32DC013018-03 and TL1TR001116
文摘Objectives: Recent studies have introduced middle ear volume(MEV) as a novel determinant of perforation-induced conductive hearing loss(CHL) in a mechanism driven by trans-tympanic membrane pressure differences. The primary aims of this preliminary report are to: 1) correlate CHL with perforation size; 2) describe the relationship between CHL and MEV; and 3) compare CHL across a range of cholesteatoma involvement.Design: A retrospective pilot study was performed in 31 subjects with audiometry indicative of conductive hearing loss, temporal bone CT scans,and no prior middle ear surgery. Perforation size and MEV were analyzed with respect to CHL in a cohort of 10 perforated ears with no cholesteatoma. CHLs were compared in 3 groups defined by extent of cholesteatoma involvement.Results: Ears with large and small perforations showed mean ABG values of 32.0 ± 15.7 dB and 16.0 ± 16.4 dB, respectively. A direct relationship was observed between MEV and CHL for ears with large perforations across all frequencies, whereas this relationship for small perforations was frequency-dependent. Finally, a statistically significant increase in CHL was found across ears with increasing cholesteatoma involvement at 1000 Hz(X^2(2) = 9.786, p = 0.008),2000 Hz(x^2(2) = 8.455, p = 0.015),and 4000 Hz(x^2(2)= 8.253, p = 0.016).Conclusions: These pilot data suggest that greater perforation-induced conductive hearing losses may be associated with larger perforation sizes and cholesteatoma. The correlation between MEV and CHL may require additional study.
基金supported by a grant from the Simons Foundation[No.409704]to Kirill Korolev)the startup fund from Boston University to Kirill Korolev+2 种基金Simulations were carried out on Shared Computing Cluster at Boston UniversityRajita Menon was partially supported by a Hariri Graduate Fellowship from Boston UniversityHarland Winter,MD received support from Martin Schlaff and the Diane and Dorothy Brooks Foundation
文摘AIM To investigate the accuracy of fungal dysbiosis inmucosa and stool for predicting the diagnosis of Crohn's disease(CD).METHODS Children were prospectively enrolled in two medical centers:one university hospital and one private gastroenterology clinic in the city of Riyadh,Kingdom of Saudi Arabia.The children with confirmed diagnosis of CD by standard guidelines were considered cases,and the others were considered non-inflammatory bowel disease controls.Mucosal and stool samples were sequenced utilizing Illumina MiSeq chemistry following the manufacturer's protocols,and abundance and diversity of fungal taxa in mucosa and stool were analyzed.Sparse logistic regression was used to predict the diagnosis of CD.The accuracy of the classifier was tested by computing the receiver operating characteristic curves with 5-fold stratified cross-validation under 100 permutations of the training data partition and the mean area under the curve(AUC)was calculated.RESULTS All the children were Saudi nationals.There were 15 children with CD and 20 controls.The mean age was 13.9(range:6.7-17.8)years for CD children and 13.9(3.25-18.6)years for controls,and 10/15(67%)of the CD and 13/20(65%)of the control subjects were boys.CD locations at diagnosis were ileal(L1)in 4 and colonic(L3)in 11 children,while CD behavior was non-stricturing and non-penetrating(B1)in 12 and stricturing(B2)in 3 children.The mean AUC for the fungal dysbiosis classifier was significantly higher in stools(AUC=0.85±0.057)than in mucosa(AUC=0.71±0.067)(P<0.001).Most fungal species were significantly more depleted in stools than mucosal samples,except for Saccharomyces cerevisiae and S.bayanus,which were significantly more abundant.Diversity was significantly more reduced in stools than in mucosa.CONCLUSION We found high AUC of fungal dysbiosis in fecal samples of children with CD,suggesting high accuracy in predicting diagnosis of CD.
文摘Personalized medicine will improve heath outcomes and patient satisfaction. However, implementing personalized medicine based on individuals’ biological information is far from simple, requiring genetic biomarkers that are mainly developed and used by the pharmaceutical companies for selecting those patients who benefit more, or have less risk of adverse drug reactions, from a particular drug. Genome-wide Association Studies (GWAS) aim to identify genetic variants across the human genome that might be utilized as genetic biomarkers for diagnosis and prognosis. During the last several years, high-density genotyping SNP arrays have facilitated GWAS that successfully identified common genetic variants associated with a variety of phenotypes. However, each of the identified genetic variants only explains a very small fraction of the underlying genetic contribution to the studied phenotypic trait. The replication studies demonstrated that only a small portion of associated loci in the initial GWAS can be replicated, even within the same populations. Given the complexity of GWAS, multiple sources of Type I (false positive) and Type II (false negative) errors exist. The inconsistency in genotypes that caused either by the genotypeing experiment or by genotype calling process is a major source of the false GWAS findings. Accurate and reproducible genotypes are paramount as inconsistency in genotypes can lead to an inflation of false associations. This article will review the sources of inconsistency in genotypes and discuss its effect in GWAS findings.
基金funding from the Fundamental Fund,Prince of Songkla University(Contact No.SCI6405032b)funding support from the NSRF via the Program Management Unit for Human Resources&Institutional Development,Research and Innovation[grant number B05F630026]+1 种基金Science and Technology Research Partnership for Sustainable Development(SATREPS),Japan Science and Technology Agency(JST,JPMJSA1806)/Japan International Cooperation Agency(JICA)the Faculty of Science Research Fund,Prince of Songkla University[grant number 1-2565-02-001].
文摘The genetic diversity of the banana shrimp Fenneropenaeus merguiensis is at risk because of over-harvesting,which consequently reduces food security.This endangerment is exacerbated because this species is not commonly cultivated by farmers.Overall,these factors necessitate conservation of this shrimp species across its natural habitat.Information on the migration of primordial germ cells(PGCs)to form a gonad is essential for shrimp preservation techniques such as broodstock preparation,sex differentiation,and germ cell transplantation.In this study,histological analysis and in situ hybridization of vasa expression(from embryo to testis development)were used to demonstrate the movement of PGCs.Hematoxylin and Eosin staining and in situ hybridization with the VASA probe revealed that the PGCs migrated retrogradely along the midgut,colonizing the area between the hepatopancreas and heart,a region that becomes the genital ridge in the postlarval stage.External sexual organs appeared at approximately 4 months of age.Through real-time PCR,the expression of the vasa gene was detected early on postlarval day 7,whereas its abundant expression was detected in the ovaries and testes of adult shrimp.This study could help with the identification and monitoring of PGCs or spermatogonia in banana shrimp and facilitate the implementation of other germ cell-relevant techniques in the future.
基金supported in part by the Outsmarting Osteosarcoma Hero Award(Because of Sydney)the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Rose Hill Foundation Innovator Award+23 种基金supported by NCI R01CA201035,R01CA240711,R01CA229893DoD W81XWH-18-1-0223UCLA SPORE in Prostate Cancer(P50 CA092131)JCCC Cancer support grant from NIH P30 CA016042(PI:Teitell)Knut and Alice Wallenberg FoundationBertha Kamprad FoundationDavid H.Koch Prostate Cancer Foundation Young Investigator AwardSwedish Research CouncilSwedish Cancer SocietySIPEA FoundationSwedish Childhood Cancer FoundationJohn and Augusta Perssons FoundationRoyal Physiographic Society of LundFranke and Margareta Bergqvist FoundationCrafoord FoundationLund University Medical Faculty research time allocation award,IngaBrittArne Lundberg Research Foundation,the German Research Foundation(552440240)the German Cancer Consortium(DKTK)the German Federal Ministry of Education and Research(BMBFgrant no.01KD2206A/SATURN3)funding support from the Children’s Discovery Institute of the St.Louis Children’s Hospital.Confocal laser scanning microscopy was performed at the Advanced Light Microscopy/Spectroscopy Laboratory(RRID:SCR_022789)the Leica Microsystems Center of Excellence at the California NanoSystems Institute at UCLA with funding support from NIH Shared Instrumentation Grant S10OD025017Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center(JCCC)Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697。
文摘Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.
文摘The morphology of inflorescences is regulated in part by the temporal and spatial events that regulate flower specification.In Arabidopsis,an endogenous flowering time pathway mediated by a subset of SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE(SPL)transcription factors,including SPL3,SPL4,and SPL5,function to specify flowers by activating floral meristem identity genes.During shoot development,SPL3,SPL4,and SPL5 are post-transcriptionally regulated by microRNA156(miR156).The photoperiod regulated florigenic signal,FLOWERING LOCUS T(FT),promotes floral induction,in part by activating SPL3,SPL4,and SPL5.In turn,these SPLs function in parallel with FT to specify flower meristems.Two related BELLl-like homeobox genes PENNYWISE(PNY)and POUND-FOOLISH(PNF)expressed in the shoot apical meristem are absolutely required for the specification of floral meristems.Genetic studies show that the floral specification function of FT depends upon PNYand PNF;however,the interplay between these homeodomain proteins and SPLs is not known.In this manuscript,we show that the photoperiodic floral induction of SPL3,SPL4,and SPL5 is dependent upon PNY and PNE Further,PNY and PNF also control SPL3,SPL4,and SPL5 expression by negatively regulating miR156.Lastly,ectopic expres-sion of SPL4 partially rescues the pny pnf non-flower-producing phenotype,while overexpression of SPL3 or SPL5 in pny pnf plants was unable to restore flower specification.These results suggest that:(1)SPL3,SPL4,and SPL5 function is dependent upon PNY and PNF,or(2)expression of multiple SPLs is required for floral specification in pny pnf plants.
基金supported by grants of U01CA175315 and R01GM113888 from the U.S.National Institutes of Health(NIH)supported by grants of ES006694 and ES007091 from NIH+8 种基金supported by grants of ES021800,ES020522,and ES005022 from NIHsupported by the Robert Bosch Foundation,Stuttgart,Germanysupported by grants of ES023438 and DK083952 from NIHsupported by grant of R01HL122593 from NIH and the Searle Scholars Program,USAsupported by grant of R01ES025708 from NIHsupported by grants of CA098468 and T32DK007737 from NIHsupported by grants of R01DK33765 and R01ES024421 from NIHsupported by grants of R01DK104656,R01DK080440,R01ES025909,R21AA022482,and R21AA024935 from NIH,grant of 1I01BX002634 from VA Merit Award,USA,grant of No.81572443 from National Natural Science Foundation of China,and grant of P30 DK34989 from Yale Liver Center,USAsupported by grants of R01ES019487,R01GM087367,and R01GM118367 from NIH
文摘Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.
文摘Background and Aims:The perinatal transmission of hepatitis B virus(HBV)remains an important global health problem.Here,a systematic review and meta-analysis were conducted to evaluate the evidence regarding the efficacy and maternal/fetal safety of treating pregnant women with lamivudine,telbivudine(LdT),and tenofovir(TDF).Methods:A PubMed and Scopus search resulted in 1,076 records,which were reduced to 36,containing 7,717 pregnant women with chronic HBV infection and 7467 infants meeting the inclusion criteria.The latest search was in August 2019.Results:Treatment with LdT,but not lamivudine and TDF,could significantly reduce the hepatitis B virus surface antigen-positive rate(odds ratio(OR)=0.37)in infants;it also led to higher rates of hepatitis B e antigen loss(OR=12.14),hepatitis B e antigen seroconversion(OR=8.93),and alanine aminotransferase normalization in mothers(OR=1.49).Each of these treatments was able to significantly reduce HBV DNA positivity at birth(total OR=0.19)and mother-to-child-transmission of HBV(total OR=0.15),and to cause higher rates of HBV DNA suppression in mothers(total OR=25.53).However,nucleos(t)ide analogues might also be involved in creatine kinase elevation(total OR=7.48).In contrast,no significant association was found between nucleos(t)ide analogue therapy and preterm/premature births,congenital malformation,low birth weight,and abortion or fetal/infant death.The results suggested LdT's high capability of preventing mother-to-childtransmission.However,TDF failed to show significant associations to a reduced risk of mother-to-child-transmission,probably due to the low number of patients included.Conclusions:Although using either lamivudine,LdT,orTDF could lead to more favorable maternal/fetal outcomes,LdT seemed to show more potential in resolving certain infant-and maternal-related outcomes.More studies on the safety profile of such treatments are required.
文摘We present in this paper an ab initio method, named KnotFold, for RNA H-type pseudoknot prediction. Our method employs an ensemble of RNA folding tools and a filtering heuristic to generate a set of pseudoknot-free stems, and then predicts pseudoknots by utilizing a search technique with a pseudo-probability scoring scheme. Experimental results show that KnotFold achieves higher sensitivity than existing methods. The KnotFold package with documentation is freely available at http：//bioinformatics.njit.edu/KnotFold.
基金The project described was supported by the DHHS grant R43CA177067(Uckun FM)from the National Cancer Institute.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.Uckun FM was also supported in part by DHHS grants P30CA014089,U01-CA-151837,R01CA-154471 and R21-CA-164098(Uckun FM)from the National Cancer Instituteby the V-Foundation,Nautica Triathlon as well as the Ronald McDonald House Charities of Southern California.
文摘Aim:CD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia(BPL)cells.The purpose of the present study was to identify the CD22ΔE12-specific signature transcriptome in human BPL cells and evaluate the clinical potential of a nanoscale formulation of CD22ΔE12-siRNA as an RNAi therapeutic against drug-resistant BPL.CD22ΔE12-siRNA nanoparticles significantly improved the event-free survival(EFS)outcome of NOD/SCID(NS)mice challenged with human BPL xenograft cells.Methods:Gene expression and translational bioinformatics methods were applied to examine the expression of the CD22ΔE12-specific signature transcriptome in human BPL cells in subsets of BPL patients.Survival analysis for mice challenged with BPL cells and treated with CD22ΔE12 siRNA was performed using standard methods.Results:Leukemia cells from CD22ΔE12-Tg mice exhibit gene and protein expression profiles consistent with constitutive activation of multiple signaling networks,mimicking the profiles of relapsed BPL patients as well as newly diagnosed high-risk patients with BCR-ABL+/Philadelphia chromosome(Ph)+BPL as well as Ph-like BPL.A nanoscale formulation of CD22ΔE12-siRNA abrogated the in vivo clonogenicity of the leukemia-initiating leukemic cell fraction in xenograft specimens derived from patients with relapsed BPL and significantly improved the EFS outcome of NS mice challenged with drug-resistant human BPL xenograft cells.Conclusion:The CD22-RNAi technology is applicable to all BPL patients both high risk and standard risk.That is because CD22ΔE12 is a characteristic feature of drug-resistant leukemic clones that escape chemotherapy and cause relapse in both high risk and low risk subgroups of patients.The technology therefore has the potential(1)for prevention of relapses by selectively killing the clones that are most likely to escape chemotherapy and cause relapse as well(2)for treatment of relapses in BPL.This research project may also lead to innovative salvage regimens against other forms of CD22ΔE12-positive relapsed B-lineage leukemias and lymphomas.
基金This research was supported by the Japan Society for the Promotion of Science(JSPS)a grant from the Ministry of Education,Culture,Sports,Science and Technology of Japan(The 21st Century COE Program).
文摘We have developed a comprehensive software suite for bioinformatics research of cDNAs; it is aimed at rapid characterization of the features of genes and the proteins they code. Methods implemented include the detection of translation initia- tion and termination signals, statistical analysis of codon usage, comparative study of amino acid composition, comparative modeling of the structures of product proteins, prediction of alternative splice forms, and metabolic pathway reconstruction. The software package is freely available under the GNU General Public License at http： / /www.g-language.org/ data/cdna/.
基金This work was supported through NIH funds from the NDSU COBRE Center for Diagnostic and Therapeutic Strategies in Pancreatic Cancer(P20GM109024).
文摘In their manuscript,“Whole-Grain Intake and Pancreatic Cancer Risk-The Danish,Diet,Cancer and Health Cohort”,Schacht et al.(1)report that total whole-grain product(per 50 g/d serving)intake was significantly associated with lower incidence of pancreatic cancer(HR:0.93;95%CI:0.86,1.00).A sex-specific analysis revealed that this association only held among men.However,neither total whole-grain(per 16-g serving)or specific individual whole-grain products and cereals were significantly associated with lower pancreatic cancer risk.In this commentary,I will describe some of the assumptions and biases associated with assessing dietary intake and attempting to find associations with disease.
文摘Plants are constantly under attack by pathogens,pests,and parasites,resulting in severe consequences on global food production and human health.While pathogens and pests find their ways to invade and communicate with their hosts,plants have evolved sophisticated immune systems to fight infections.
基金This work was supported by departmental funds of the Ares Pharmaceuticals Biotherapy Program.No external funding sources or sponsored research grants were used.
文摘Aim:The purpose of the present study was to perform a comprehensive analysis of WT1 gene expression in high-risk pediatric acute lymphoblastic leukemia(ALL).Methods:We performed a meta-analysis of WT1 gene expression for normal hematopoietic cells vs.primary leukemia cells from 801 pediatric ALL samples deposited in the Oncomine database combined with an in-depth gene expression analysis using our in-house database of gene expression profiles of primary leukemia cells from 1416 pediatric ALL cases.We also examined the expression of WT1 in primary leukemic cells from 299 T-lineage ALL patients in the Oncomine database and 189 T-lineage ALL patients in the archived datasets GSE13159,GSE13351,and GSE13159.Results:Our data provide unprecedented evidence that primary leukemia cells from patients with MLL gene rearrangements(MLL-R)express highest levels of WT1 expression within the high-risk subsets of pediatric B-lineage ALL.Notably,MLL-R^(+)patients exhibited>6-fold higher expression levels of the WT1 gene compared to the other B-lineage ALL subtypes combined(P<0.0001).Our findings in 97 MLL-R^(+)infant B-lineage ALL cases uniquely demonstrated that WT1 is expressed at 1.5-4.2-fold higher levels in MLL-R^(+)infant leukemia cells than in normal hematopoietic cells and revealed that WT1 expression level was substantially higher in steroid-resistant infant leukemia cells when compared to non-leukemic healthy bone marrow cells.Furthermore,our study demonstrates for the first time that the WT1-regulated EWSR1,TP53,U2AF2,and WTAP genes(i.e.,WT1 interactome)were differentially upregulated in MLL-R^(+)leukemia cells illustrating that the MLL-regulatory pathway is aberrantly upregulated in MLL-R^(+)pediatric B-lineage ALL.These novel insights provide a compelling rationale for targeting WT1 in second line treatment of MLL-R^(+)pediatric B-lineage ALL,including MLL-R^(+)infant ALL.Furthermore,our study is the first to demonstrate that leukemia cells from 370 Ph-like patients had significantly higher WT1 expression when compared to normal hematopoietic cells.Finally,our findings demonstrate for the first time that chemotherapy-resistant primarily leukemic cells from relapsed B-lineage ALL patients exhibit higher expression levels of WT1 than primary leukemia cells from newly diagnosed B-lineage ALL patients(P=0.001).Conclusion:Our findings indicate that the WT1 gene product may serve as a target for immunotherapy in high risk/poor prognosis subsets of newly diagnosed as well as relapsed pediatric B-lineage ALL.Our findings also significantly expand the current knowledge of WT1 expression in T-lineage ALL and provide new evidence that WT1 gene and its interactome are expressed in T-lineage ALL cells at significantly higher levels than in normal hematopoietic cells.This previously unknown differential expression profile uniquely indicates that the protein product of WT1 would be an attractive molecular target for treatment of T-lineage ALL as well.
基金supported by the following grants:the National Cancer Institute,USA(a part of the National Institutes of Health,USAGrant No.T32LM012424)to Yiling Elaine Chen+8 种基金the National Cancer Institute,USA(Grant No.K08CA201591)the Margaret E Early Medical Research Trust,USAthe Pediatric Cancer Research Foundation,USA to Leo David Wangthe National Cancer Institute under Cancer Center Support Grant,USA(Grant No.P30CA033572)to the MS facility at the City of Hopethe National Institute of General Medical Sciences,USA(a part of the National Institutes of Health,USAGrant Nos.R01GM120507 and R35GM140888)the National Science Foundation,USA(Grant Nos.DBI-1846216 and DMS-2113754)the Johnson&Johnson WiSTEM2D Award,USA,the Sloan Research Fellowship,USAthe UCLA David Geffen School of Medicine W.M.Keck Foundation Junior Faculty Award,USA,to Jingyi Jessica Li.
文摘Advances in mass spectrometry(MS)have enabled high-throughput analysis of proteomes in biological systems.The state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide–spectrum matches(PSMs),which convert mass spectra to peptide sequences.Different database search algorithms use distinct search strategies and thus may identify unique PSMs.However,no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and a control on the false discovery rate(FDR).To fill in this gap,we proposed a statistical framework,Aggregation of Peptide Identification Results(APIR),that is universally compatible with all database search algorithms.Notably,under an FDR threshold,APIR is guaranteed to identify at least as many,if not more,peptides as individual database search algorithms do.Evaluation of APIR on a complex proteomics standard dataset showed that APIR outpowers individual database search algorithms and empirically controls the FDR.Real data studies showed that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search algorithms.The APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis,e.g.,differential gene expression analysis on RNA sequencing data.The APIR R package is available at https://github.com/yiling0210/APIR.
文摘This year （2018） marks the 60th anniversary of the ＂central dogma＂, summarized as ＂DNA makes RNA makes protein＂, which was originally proposed by Francis Crick in 1958. Three years later, messenger RNA was identified as the template of protein synthesis. After 60 years of discovery, including discovery of the split nature of eukaryotic genes （Le., splicing）, it becomes evident that messenger RNAs are not merely messengers, but a hub of co- and post-transcriptional regulation, which is fundamental to amplify the complexity encoded in the genome of higher eukaryotic organisms. The mature forms of RNA of protein-coding genes and their abundance have to be tightly regulated through multiple steps of sophisticated processing, including capping, splicing and polyadenylation. In addition, their function also critically depends on proper localization -- sometimes trafficking to the remote parts of the cell such as dendrites and axons of neurons -- and proper control of their stability. Furthermore, thousands of long and small noncoding RNAs are produced to play a wide range of roles in gene regulation. From our perspective, two overarching goals for RNA biology include （i） characterizing the spatial-temporal regulation of various RNA species and elucidating the underlying regulatory mechanisms; （ii） understanding the functional impact of such regulation on human physiology and disease.
