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At least 379 records · Page 21Linked to original sources
PubMed2005

Noise and rank-dependent geometrical filter improves sensitivity of highly specific discovery by microarrays.

SUMMARY: MASH is a mathematical algorithm that discovers highly specific states of expression from genomic profiling by microarrays. The goal at the outset of this analysis was to improve the sensitivity of MASH. The geometrical representations of microarray datasets in the 3D space are rank-dependent and unique to each dataset. The first filter (F1) of MASH defines a zone of instability whose F1-sensitive ratios have large variations. A new filter (Fs) constructs in the 3D space rank-dependent lower and upper-bound contour surfaces, which are modeled based on the geometry of the unique noise intrinsic to each dataset. As compared with MASH, Fs increases sensitivity significantly without lowering the high specificity of discovery. Fs facilitates studies in functional genomics and systems biology.

Algorithms↗
PubMed2001

Inferring subnetworks from perturbed expression profiles.

Genome-wide expression profiles of genetic mutants provide a wide variety of measurements of cellular responses to perturbations. Typical analysis of such data identifies genes affected by perturbation and uses clustering to group genes of similar function. In this paper we discover a finer structure of interactions between genes, such as causality, mediation, activation, and inhibition by using a Bayesian network framework. We extend this framework to correctly handle perturbations, and to identify significant subnetworks of interacting genes. We apply this method to expression data of S. cerevisiae mutants and uncover a variety of structured metabolic, signaling and regulatory pathways.

Bayes Theorem↗
PubMed2026

Comprehensive Somatic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms.

BACKGROUND: The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is rising, yet their biological heterogeneity and variable response to treatments remain poorly understood. Comprehensive genomic characterization may uncover somatic drivers and inform biomarker-driven therapeutic strategies. METHODS: We retrospectively analyzed clinically ordered next-generation sequencing (NGS) results from tumor samples of 111 patients with confirmed GEP-NENs treated at Johns Hopkins Hospital between 2020 and 2022. Pathogenic and likely pathogenic mutations were identified using OncoKB, CHASMplus, and COSMIC databases. Mutational patterns were correlated with clinical characteristics and overall survival using univariate and multivariate analyses. RESULTS: In this retrospective study of 111 patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), somatic pathogenic or likely pathogenic mutations were identified in 79% of cases. The most frequent alterations involved TP53 (19%), MEN1 (17%), and chromatin remodeling genes such as DAXX (9%) and ATRX (6%). Notably, we also identified a subset of patients (9%) patients with mutations typically associated with hematologic malignancies. Distinct co-mutation and mutual exclusivity patterns were observed between pancreatic and non-pancreatic NENs. Poorly differentiated or high-grade tumors correlated with mutations in TP53, KRAS, and CDKN2A. Mutations in KRAS, DAXX/ATRX, and hematologic malignancy-associated genes were independently associated with worse overall survival. CONCLUSIONS: This study reveals distinct somatic mutation patterns in GEP-NENs associated with tumor differentiation, grade, primary site, and survival. The identification of hematologic malignancy-associated mutations in a subset of GEP-NENs suggests possible shared molecular phenotypes with poor prognostic implications. The presence of KRAS mutations supports exploring pan-RAS inhibitors as potential therapies in select patients. These findings highlight the clinical utility of genomic profiling in GEP-NENs.

Neuroendocrine neoplasms↗
PubMed2006

Identification of transcripts associated with cell wall metabolism and development in the stem of sugarcane by Affymetrix GeneChip Sugarcane Genome Array expression profiling.

Sugarcane is an important crop in tropical regions of the world, producing a very large biomass and accumulating large amounts of sucrose in the stem. In this study, we present the first report of transcript profiling using the GeneChip Sugarcane Genome Array. We have identified transcripts that are differentially expressed in the sugarcane stem during development by expression profiling using the array and total RNA derived from three disparate stem tissues (meristem, internodes 1-3, 8, and 20) from four replicates of the sugarcane variety Q117 grown in the field. We have identified 119 transcripts that were highly differentially expressed with development and have characterised members of the cellulose synthase (CesA) and cellulose synthase-like (Csl) gene families, which displayed coordinated expression during stem development. In addition, we determined that many other transcripts involved in cell wall metabolism and lignification were also co-expressed with members of the CesA and Csl gene families, offering additional insights into the dynamics of primary and secondary cell wall synthesis in the developing sugarcane stem.

Cell Wall↗
PubMed2004

Efficient targeting of plant disease resistance loci using NBS profiling.

The conserved sequences in the nucleotide-binding sites of the nucleotide-binding site-leucine-rich repeat (NBS-LRR) class of disease resistance (R) genes have been used for PCR-based R-gene isolation and subsequent development of molecular markers. Here we present a PCR-based approach (NBS profiling) that efficiently targets R genes and R-gene analogs (RGAs) and, at the same time, produces polymorphic markers in these genes. In NBS profiling, genomic DNA is digested with a restriction enzyme, and an NBS-specific (degenerate) primer is used in a PCR reaction towards an adapter linked to the resulting DNA fragments. The NBS profiling protocol generates a reproducible polymorphic multilocus marker profile on a sequencing gel that is highly enriched for R genes and RGAs. NBS profiling was successfully used in potato with several restriction enzymes, and several primers targeted to different conserved motifs in the NBS. Across primers and enzymes, the NBS profiles contained 50-90% fragments that were significantly similar to known R-gene and RGA sequences. The protocol was similarly successful in other crops (including tomato, barley, and lettuce) without modifications. NBS profiling can thus be used to produce markers tightly linked to R genes and R-gene clusters for genomic mapping and positional cloning and to mine for new alleles and new sources of disease resistance in available germplasm.

Amino Acid Sequence↗
PubMed2026

Integrated Clinicopathologic and Multiomic Profiling Reveals MEIS1-Rearranged Sarcoma as a Distinct Entity With 2 Prognostic Subgroups.

Sarcomas with MEIS1 fusions represent a rare, recently recognized group of mesenchymal neoplasms with a predilection for genitourinary and gynecologic sites. A subset exhibits skeletal muscle differentiation resembling spindle cell rhabdomyosarcoma. Existing literature is limited to case reports and small series, with scant comprehensive clinicopathologic, molecular, and outcome data. In this study, we analyzed a multi-institutional cohort of 20 MEIS1-rearranged sarcomas using integrated clinicopathologic review, genomic profiling, and DNA methylation analysis. The tumors occurred in 17 females and 3 males (median age, 41 years; range, 6-58 years), arising mainly in the uterus/vagina (n = 12), vulva/perineum (n = 4), bone (n = 2), and kidney (n = 2), with a median size of 9 cm (range, 2.5-20 cm). Histology showed mostly bland spindle cells in fascicles/storiform patterns, alternating cellularity, fibromyxoid stroma, prominent vascularity, and adipose metaplasia (45%). A subset of cases featured high-grade morphology with epithelioid cells and increased mitotic activity. Skeletal muscle markers were variably positive in 9 cases. Fusions involved MEIS1 with NCOA2 (16/20), NCOA1 (3/20), or FOXO1 (1/20). Recurrent additional genomic alterations included CTNNB1 mutations (31.6%) and MDM2 amplification (15%). DNA methylation profiling showed that MEIS1-rearranged sarcomas formed a unifying cluster comprising 2 subgroups, regardless of rhabdomyosarcomatous phenotype, clearly separated from other mesenchymal neoplasms, including various rhabdomyosarcoma subtypes and uterine sarcomas. The 2 DNA methylation (Meth) subgroups correlated with differences in genome-wide copy number variation (CNV) status (Meth-CNV high vs Meth-CNV low), with Meth-CNV high tumors characterized by high mitotic rate, frequent tumor necrosis, recurrent co-occurring CTNNB1 and MDM2 alterations, and recurrent chromosomal arm-level changes. Most importantly, this subgroup exhibited significantly worse overall survival (P = .027) and disease-free survival (median, 5 vs 99 months; P = .017). This study establishes MEIS1-rearranged sarcoma as a distinct entity with generally indolent but potentially aggressive behavior. The 2 methylation/CNV subgroups provide potential utility for prognostic stratification and highlight actionable molecular targets in high-risk cases.

Humans↗
PubMed1995

Application of pulsed-field gel electrophoresis for differentiation of vaccine strain RB51 from field isolates of Brucella abortus from cattle, bison, and elk.

Restriction endonuclease patterns of genomic fragments separated by use of pulsed-field gel electrophoresis were used to differentiate Brucella abortus strain RB51, a rifampin-resistant mutant of the standard virulent strain 2308, from other brucellae. Results were compared with results obtained by use of standard methods for characterizing brucellae. Electrophoretic patterns of the ATCC type strains allowed identification of the strains to the level of species. Genomic profiles of B abortus biovars 1, 2, and 4 were similar, as were those of biovars 5, 6, and of biovar 3 was similar to that of biovars 5, 6, and 9, except for a missing band at 93 kb and additional bands at 65 and 67 kb. A different fingerprint was detected in B abortus strain RB51, using the pulsed-field gel electrophoresis patterns of genomic DNA digested with restrictive endonuclease Xba I. The profile of B abortus strain RB51 contained a band at 104 kb, as opposed to a 109-kb fragment within profiles of B abortus isolates from naturally infected cattle, bison, and elk. Despite known biochemical and biological differences between RB51 and its parent strain (2308), restriction endonuclease analysis results were similar.

Animals↗
PubMed2007

Global genome expression analysis of rice in response to drought and high-salinity stresses in shoot, flag leaf, and panicle.

To elucidate genome-level responses to drought and high-salinity stress in rice, a 70 mer oligomer microarray covering 36,926 unique genes or gene models was used to profile genome expression changes in rice shoot, flag leaf and panicle under drought or high-salinity conditions. While patterns of gene expression in response to drought or high-salinity stress within a particular organ type showed significant overlap, comparison of expression profiles among different organs showed largely organ-specific patterns of regulation. Moreover, both stresses appear to alter the expression patterns of a significant number of genes involved in transcription and cell signaling in a largely organ-specific manner. The promoter regions of genes induced by both stresses or induced by one stress in more than one organ types possess relative enrichment of two cis-elements (ABRE core and DRE core) known to be associated with water stress. An initial computational analysis indicated that novel promoter motifs are present in the promoters of genes involved in rehydration after drought. This analysis suggested that rice might possess a mechanism that actively detects rehydration and facilitates rapid recovery. Overall, our data supports a notion that organ-specific gene regulation in response to the two abiotic stresses may primarily be mediated by organ-specific transcription responses.

DNA Primers↗
PubMed1993

Clonal differentiation of uropathogenic Escherichia coli isolates of serotype O6:K5 by fimbrial antigen typing and DNA long-range mapping techniques.

Escherichia coli isolates of serotype O6:K5 are the most common causative agents of cystitis and pyelonephritis in adults. To answer the question, as to whether strains of this particular serotype represent one special clonal group, out of a collection of 34 serotype O6:K5 isolates [Zingler et al. (1990) Zentralbl. Bakteriol Mikrobiol Hyg [A] 274:372-381] 15 strains were selected and analyzed in detail. The flagellar (H) antigen and the outer membrane protein (OMP) pattern were determined. Further serum resistance properties and the genetic presence and expression of other virulence factors, including hemolysin, aerobactin, P fimbriae, S/F1C fimbriae and type 1 fimbriae was evaluated. In addition the XbaI-macrorestriction pattern of ten representative isolates was elaborated and the fimbrial (F) antigen type of the P fimbriae was determined, to obtain the complete O:K:H:F pattern. These analyses could clearly show that the O6:K5 isolates do not represent one clonal group. The XbaI-macrorestriction profiles were heterogeneous and marked differences in the hybridization patterns, using virulence-associated gene probes in Southern hybridization of long-range-separated genomic DNA, were observed among the strains. However, some of strains showed similarities in the genomic profiles, arguing for clonal groupings among the O6:K5 isolates. Interestingly the strains grouped together exhibited the same fimbrial F type that many indicate a coincidence of this phenotypic trait with clonality.

Adhesins, Escherichia coli↗
PubMed2002

Towards an integrated classification of adult acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) represents a biologically and clinically heterogeneous group of diseases characterized by the abnormal proliferation and accumulation of immature lymphoid cells within the bone marrow and lymphoid tissues. Following a diagnostic work-up, prognostic data are routinely achieved through physical examination, serum biochemical profiles, peripheral blood count and bone marrow morphology. Over the years, information obtained through karyotype, molecular genetics, extensive immunophenotype, multidrug resistance and, more recently, genomic profiling is progressively contributing to a better understanding of the biology of this complex disease, to the identification of subgroups of patients with a different clinical outcome, to the more precise monitoring of minimal residual disease, to the use of different therapeutic protocols based on prognostic indicators and, recently, also to the design of innovative and specific treatment strategies. In the present review, we will discuss how an integrated approach is now mandatory for the optimal management of adult ALL.

Adult↗
PubMed2005

Real-time quantitative PCR analysis of viral transcription.

Whole-genome profiling using DNA arrays has led to tremendous advances in our understanding of cell biology. It has had similar success when applied to large viral genomes, such as the herpesviruses. Unfortunately, most DNA arrays still require specialized and expensive resources and, generally, large amounts of input RNA. An alternative approach is to query entire viral genomes using real-time quantitative PCR. We have designed such PCR-based arrays for every open reading frame of human herpesvirus 8 and describe here the general design criteria, validation procedures, and detailed application to quantify viral mRNAs. This should provide a useful resource either for whole-genome arrays or just to measure transcription of any one particular mRNA of interest. Because these arrays are RT-PCR-based, they are inherently more sensitive and robust than current hybridization-based approaches and are ideally suited to query viral gene expression in models of pathogenesis.

Base Sequence↗
PubMed2006

Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro.

TZT-1027 is an antimicrotubule agent targeting beta-tubulin that is undergoing clinical development. The genomic response of cancer cells to TZT-1027 was profiled to evaluate its biochemical activity. A lung cancer cell line, PC-14, was exposed to antimicrotubule agents including dolastatins, Vinca alkaloids and taxanes at an equivalent toxicity level. Alterations in the TZT-1027-induced gene expression of approximately 600 genes were then examined using microarray technology and the resulting gene profiles were compared with those for cells exposed to the other antimicrotubule agents. A principle component analysis using the whole gene set demonstrated that TZT-1027 produced similar gene profiles to those produced by dolastatin 10, but that these gene profiles differed from those produced by other agents. The agents were classified according to their induced genomic response in a molecular structure-dependent manner. Genes whose expression profiles differed according to drug class included intermediate filaments, extracellular matrix protein and Rho regulatory genes that may be involved in cytoskeletal and angiogenesis processes that are regulated by microtubule dynamics. TZT-1027 produces a unique genomic response profile distinct from that of Vinca alkaloids and taxanes, suggesting that this agent has a different mechanism of action. The selected genes may act as pharmacodynamic biomarkers allowing the unique mode of action of TZT-1027 to be discriminated from those of other antimicrotubule agents.

Antineoplastic Agents↗
PubMed2005

Genome-wide mRNA profiling in glucose starved Bacillus subtilis cells.

In this study global changes in gene expression were monitored in Bacillus subtilis cells entering stationary growth phase owing to starvation for glucose. Gene expression was analysed in growing and starving cells at different time points by full-genome mRNA profiling using DNA macroarrays. During the transition to stationary phase we observed extensive reprogramming of gene expression, with approximately 1,000 genes being strongly repressed and approximately 900 strongly up-regulated in a time-dependent manner. The genes involved in the response to glucose starvation can be assigned to two main classes: (i) general stress/starvation genes which respond to various stress or starvation stimuli, and (ii) genes that respond specifically to starvation for glucose. The first class includes members of the sigma(B)-dependent general stress regulon, as well as 90 vegetative genes, which are strongly down regulated in the course of the stringent response. Among the genes in the second class, we observed a decrease in the expression of genes encoding proteins required for glucose uptake, glycolysis and the tricarboxylic acid cycle. Conversely, many carbohydrate utilisation systems that depend on phosphotransferase systems (PTS) or ABC transporters were activated. The expression of genes required for utilisation or generation of acetate indicates that acetate constitutes an important energy source for B. subtilis during periods of glucose starvation. Finally, genome wide mRNA profiling data can be used to predict new metabolic pathways in B. subtilis. Thus, our data suggest that glucose-starved cells are able to degrade branched-chain fatty acids to pyruvate and succinate via propionyl-CoA using the methylcitrate pathway. This pathway appears to link lipid degradation to gluconeogenesis in glucose-starved cells.

Bacillus subtilis↗
PubMed2002

Evaluation of the random amplified polymorphic DNA (RAPD) assay for the detection of DNA damage and mutations.

The random amplified polymorphic DNA (RAPD) assay and related techniques like the arbitrarily primed polymerase chain reaction (AP-PCR) have been shown to detect genotoxin-induced DNA damage and mutations. The changes occurring in RAPD profiles following genotoxic treatments include variation in band intensity as well as gain or loss of bands. However, the interpretation of the molecular events responsible for differences in the RAPD patterns is not an easy task since different DNA alterations can induce similar type of changes. In this study, we evaluated the effects of a number of DNA alterations on the RAPD profiles. Genomic DNA from different species was digested with restriction enzymes, ultrasonicated, treated with benzo[a]pyrene (B[a]P) diol epoxide (BPDE) and the resulting RAPD profiles were evaluated. In comparison to the enzymatic DNA digestions, sonication caused greater changes in the RAPD patterns and induced a dose-related disappearance of the high molecular weight amplicons. A DNA sample substantially modified with BPDE caused very similar changes but amplicons of low molecular weight were also affected. Appearance of new bands and increase in band intensity were also evident in the RAPD profiles generated by the BPDE-modified DNA. Random mutations occurring in mismatch repair-deficient strains did not cause any changes in the banding patterns whereas a single base change in 10-mer primers produced substantial differences. Finally, further research is required to better understand the potential and limitations of the RAPD assay for the detection of DNA damage and mutations.

Base Pair Mismatch↗
PubMed2026

MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer.

MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m6A) of messenger RNA (mRNA). MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Reestablishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Last, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.

Humans↗
PubMed1983

Molecular characterization of rotaviruses with distinct group antigens.

Comparative serological and nucleic acid studies were carried out on rotavirus isolates, with and without the original group antigen. Indirect immunofluorescence allowed the atypical isolates to be divided into two groups each with its own distinct group antigen hence giving a total of at least three distinct rotavirus groups. Genome profile analysis of the atypical isolates again divided them into two groups which corresponded with those obtained by immunofluorescence and within which the overall pattern of genome segments was similar. A more rigorous examination of the degree of difference between the three virus groups was carried out using single-dimension terminal fingerprint analysis. This indicated that the viruses in the three groups did not carry any genome segments in common with each other. Therefore, experimental criteria have been established which allow the division of rotaviruses into three groups. Analysis of further atypical isolates, as they become available, will establish whether the division of rotaviruses into a number of separate groups, of the type seen in influenza virus, is justified.

Animals↗
PubMed2025

MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic ductal adenocarcinoma.

MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m6A) of mRNA. MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Re-establishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Lastly, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.

Cell Biology↗
PubMed2026

Deficiency in POLE Exonuclease Causes Synthetic Lethality in Highly Aneuploid Cancer Cells.

UNLABELLED: Aneuploidy is a hallmark of cancer and is associated with drug resistance and poor clinical outcomes across diverse cancer types. However, no therapies have been clinically established to target highly aneuploid tumors. By analyzing nearly half a million tumor samples subjected to comprehensive genomic profiling, we identified a striking mutual exclusivity between POLE exonuclease domain mutations and high aneuploidy burden. This observation was independently validated using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Probabilistic modeling revealed that the elevated quantity and unique spectrum of mutations induced by POLE exonuclease deficiency increase the likelihood of inactivating essential genes on chromosome arms harboring losses, leading to a synthetic lethal phenotype in highly aneuploid cells. Functional experiments demonstrated that POLE exonuclease activity is essential for the viability of highly aneuploid cancer cell lines but dispensable in diploid cells. These findings suggest that selective inhibition of POLE exonuclease activity may represent a promising therapeutic strategy for targeting highly aneuploid tumors. SIGNIFICANCE: An integrated approach using large-scale genomic analyses, probabilistic modeling and functional validation identified POLE exonuclease as a potential synthetic lethal target to overcome cancer aneuploidy.

Humans↗