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PubMed2025

PMkbase (version 1.0): an interactive web-based tool for tracking bacterial metabolic traits using phenotype microarrays made interoperable with sequence information and visualizing/processing PM data.

Bacteria showcase remarkable metabolic diversity and traits, even among strains of the same species. In recent years, a large number of bacterial genomes have been sequenced, leading to the elucidation and documentation of genomic differences and commonalities across and within species. Genome-scale metabolic reconstructions, which are often defined and curated using data from phenotype microarrays, elucidate the differences in metabolic traits resulting from genomic diversity. These microarrays measure cellular respiration on a variety of carbon, nitrogen, phosphorus, and sulfur sources and various stressors and inhibitors over a period of time to determine the metabolic activity of a given strain. Despite their popularity in measuring bacterial metabolic activity and traits, no public databases that allow researchers to warehouse, access, and analyze this information currently exist. Additionally, there are no publicly available tools that allow researchers to view the variance of these metabolic traits across bacterial strains. To address this need, we present Phenotype Microarray Knowledgebase (PMkbase [version 1.0], https://pmkbase.com/), an interactive database that acts as a repository of phenotype microarray (PM) data with integrated sequence information. Binarized activity calls, along with associated kinetic parameters, are made for all metabolic substrates and inhibitors. Users can upload their own data for analysis and visualization and to perform quality checks on their experiments. PMkbase will address an unmet need to track and view bacterial metabolic traits and provide researchers with valuable information to develop metabolic models, enrich pangenomic analyses, and design new experiments.IMPORTANCEBacterial species can be differentiated by their metabolic profiles or the type of nutrients they consume. Interestingly, strains within the same species also display differences in nutrient consumption. Phenotype microarrays are a high-throughput, widely used technology to measure which substrates can be metabolized by various microbial strains and the extent to which inhibitors can affect it. Despite their widespread use, public databases to parse and access this data type at scale do not exist. PMkbase, which contains 9,024 data points for nitrogen substrate utilization, 41,664 data points for carbon substrate utilization, 8,448 data points for phosphorus/sulfur substrate utilization, and 27,264 data points on various antibiotics across three species (Escherichia coli, Pseudomonas putida, and Staphylococcus aureus), has been developed to allow researchers to freely access PM data, along with enriching the data with sequence information.

Bacteria↗

PubMed2026

Hybrid genome assembly and phenotypic assays reveal carbohydrate metabolism diversity in Lacticaseibacillus strains.

Investigation of carbohydrate metabolism in lactic acid bacteria is essential for the rational selection of strains for fermentation processes, particularly in emerging applications involving non-conventional substrates or building of synthetic microbial consortia. However, establishing robust genotype-phenotype relationships remains challenging, as gene presence alone often fails to explain observed metabolic traits without considering the genomic context and regulatory architecture. In the present study, we combined hybrid genome assembly (Illumina and Oxford Nanopore) with high-throughput phenotype profiling (Biolog GENIII and PM2A) to investigate carbohydrate utilization in five Lacticaseibacillus strains. Phenotypic assays revealed clear intra- and inter-specific variability in substrate utilization. We therefore investigated whether such differences could be attributed to the organization and regulatory context of carbohydrate-associated loci, rather than to gene presence alone. Functional annotation based on COG and CAZyme databases revealed candidate genomic regions potentially involved in carbohydrate metabolism. Comparative analysis between predicted and experimentally observed substrate usage highlighted specific loci associated with carbohydrate utilization profile. The trehalose (tre) operon was conserved across all strains, while at least two distinct cellobiose-associated loci were detected in each genome. Despite the presence of these loci, L. paracasei strains were unable to metabolize cellobiose, a phenotype likely linked to the presence of a downstream TetR-type transcriptional repressor within the cellobiose (cel) operon. Additionally, a genomic region uniquely found in L. rhamnosus strains was associated with gentiobiose utilization, consistent with phenotypic observations. Overall, these findings highlight the importance of integrating phenotypic validation with complete genome context to support the identification of candidate structural and regulatory determinants of carbohydrate utilization in lactic acid bacteria. KEY POINTS: • Phenotype microarrays reveal metabolic traits of interest in isolated strains. • Regulatory context is key to understanding carbohydrate metabolism differences. • Basis of subspecies-dependent cellobiose metabolism in L. paracasei is provided.

Carbohydrate Metabolism↗

PubMed2025

Phenotypic profiling of carbon utilization of Pectobacterium brasiliense (Pbr1692).

Pectobacterium brasiliense 1692 (Pbr1692) is a necrotrophic pathogen that infects many crops such as potatoes and ornamental plants and derives nutrients from degraded plant tissue. Previous studies have identified Pbr1692 genes required for ecological fitness and virulence, however there is a lack of information on nutrient utilization in Pbr1692. Carbon source utilization profiling in Pbr1692 could provide a platform to decipher its metabolic flexibility and adaptation. This study assessed the nutrient utilization of Pbr1692 in different carbon sources, using Biolog Phenotypic Microarray (PM). An array of carbon sources utilized by Pbr1692 were identified, 32 carbohydrates and 8 carboxylic acids were among the preferred carbon nutrients utilized by Pbr1692. The PM results also revealed that the citric acid cycle, amino acid metabolism, and pentose phosphate metabolic pathways might be used to produce energy for Pbr1692. In addition, growth of Pbr1692 cells in minimal medium supplemented with citric acid, glucose, and aspartic acid retained the typical rod shape, suggesting that nutrient variation did not influence Pbr1692 cell morphology adaptation. This study provides an understanding on the adaptation of Pbr1692 and lays a foundation for understanding carbon metabolism of Pbr1692.

Carbon↗

PubMed2024

Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort.

PURPOSE: The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort. METHODS: We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis. RESULTS: Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift. CONCLUSION: This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort.

Humans↗

PubMed2024

Prenatal diagnosis and molecular cytogenetic analysis of pure chromosome 10p15.3 microdeletion using chromosomal microarray analysis.

BACKGROUND: The literature contains exceedingly limited reports on chromosome 10p15.3 microdeletions. In the present study, two cases of fetuses with pure terminal 10p15.3 microdeletion syndrome in a Chinese population were examined, with the objective of enhancing understanding of the genotype-phenotype correlation associated with 10p15.3 microdeletions. METHODS: Two fetuses with chromosome 10p15.3 microdeletion were identified from a cohort of 5,258 cases undergoing amniocentesis. Karyotyping and chromosomal microarray analysis (CMA) was conducted to assess chromosomal abnormalities and detect copy number variations (CNVs) within the families, respectively. RESULTS: In Family 1, the fetus exhibited a 556.2-Kb deletion in the 10p15.3 region, encompassing OMIM genes such as DIP2C and ZMYND11, and presented with increased nuchal translucency on prenatal ultrasound examination. Parental CMA analysis revealed that the 10p15.3 microdeletion was inherited from the father, who displayed mild language impairment. In Family 2, a comparable 10p15.3 microdeletion was identified in a fetus presenting with asymmetric butterfly vertebrae at T10 and T12, along with mild scoliosis of the spine. Family 1 elected to terminate the pregnancy, while Family 2 chose to continue. At a follow-up conducted at one year and eight months, the child demonstrated delays in both speech and motor development. CONCLUSION: The present study is the first to report two cases of pure terminal chromosome 10p15.3 microdeletion syndrome in fetuses, offering valuable insights for the prenatal diagnosis of 10p15.3 microdeletion syndrome. Further, it is the first to describe mild clinical features, specifically limited to language impairment, in a patient with 10p15.3 microdeletion syndrome.

Female↗

PubMed2026

Expanding the Clinical Spectrum of DHX30-Related Neurodevelopmental Disorder: A Case Report and a Scoping Review.

BACKGROUND: Whole exome sequencing (WES) has improved diagnostic rates for neurodevelopmental disorders (NDDs) while introducing challenges in novel variant interpretation. DHX30-related NDD (DHX30-NDD) is a recently described condition with an evolving phenotypic spectrum. OBJECTIVES: To expand the understanding of the DHX30-NDD genotype-phenotype spectrum by integrating a case-based WES interpretation with a scoping review. METHODS: We performed comprehensive genetic analysis (karyotyping, microarray, WES) on a proband with global developmental delay (GDD). A systematic literature search of PubMed/MEDLINE, Scopus and Google Scholar from database inception to April 2026 identified 10 publications including 51 individuals with DHX30-NDD. Clinical and genetic data were extracted to characterize the genotype-phenotype spectrum. RESULTS: The proband presented with GDD and right microtia, harbouring a de novo heterozygous pathogenic DHX30 missense variant (c.1478G > A; p.Arg493His), confirming DHX30-NDD. To our knowledge, this is the first reported individual with DHX30-NDD and microtia. The scoping review confirmed DHX30 variants are formed predominantly de novo and affected both sexes (22 males; 29 females). Hallmark manifestations were motor delay (50/51; 98.0%), GDD/ID (48/49; 98.0%), hypotonia (48/51; 94.1%), feeding difficulties (38/51; 74.5%), ataxia (17/23; 73.9%), abnormal brain imaging (36/49; 73.5%) and absent expressive language (35/48; 72.9%). Digital anomalies (31/51; 60.8%), eye anomalies (28/51; 54.9%), autistic behaviours (24/44; 54.5%), sleep disturbances (26/51; 51.0%), joint hypermobility (25/51; 49.0%), microcephaly (23/51; 45.1%) and ear anomalies (22/51; 43.1%) were also frequent. CONCLUSIONS: This study potentially expands the phenotypic spectrum of DHX30-NDD, highlights the clinical utility of WES for diagnosing GDD and underscores the importance of ongoing WES reanalysis for evolving variant interpretation.

DHX30↗

PubMed2026

Ocular Nystagmus as the Initial Presenting Feature in a Patient with Complete CLTC Deletion: Expanding the Genotype-Phenotype Spectrum of CLTC-Related Disorder.

Background: CLTC-related neurodevelopmental disorder is a rare condition primarily characterized by global developmental delay (GDD) and intellectual disability (ID). To date, approximately 41 cases involving CLTC gene alterations have been reported. We present the first individual with a complete deletion of the CLTC gene. Methods: The proband is a male from a non-consanguineous family, presenting with congenital nystagmus, hypotonia, GDD, and autism spectrum disorder (ASD). Chromosomal microarray analysis and trio exome sequencing were performed. A systematic review of previously reported CLTC variant cases was conducted to delineate the phenotypic spectrum. Results: A de novo 363-kb heterozygous deletion at 17q23.1 spanning the entire CLTC gene was identified. The systematic review confirmed GDD/ID as core features and revealed various ocular abnormalities in a subset of cases. These findings indicate that the clinical phenotype extends beyond neurodevelopment, with multi-system involvement. Conclusions: The phenotypic heterogeneity of CLTC-related disorders underscores the need for comprehensive physical examination to identify extra-neurological manifestations. Accurate diagnosis relies on integrating detailed clinical phenotyping with comprehensive genomic testing. Early, precise diagnosis facilitates multidisciplinary management, informed genetic counseling, and the establishment of long-term surveillance protocols.

Humans↗

PubMed2025

Detection of copy number variations by chromosomal microarray analysis in disorders of sex development of unexplained molecular etiology and association with clinical findings.

PURPOSE: Despite advances in genetic diagnostics, the molecular cause of a significant proportion of DSDs remains unknown. The aim of this study was to identify copy number variations (CNVs) using chromosomal microarray analysis (CMA) technology in DSD patients with previously undetected molecular genetic etiology and to investigate their phenotypic associations with these variations. METHODS: This study included DSD cases without chromosomal abnormalities and without any variants detected by sequence analysis methods, including whole-exome sequencing analysis. We evaluated variant pathogenicity according to the American College of Medical Genetics and Genomics guidelines and recorded the phenotypic findings of the cases. All pathogenic variants were subjected to segregation analysis. RESULTS: Of the 20 patients included in the study, 16 (80%) were classified as 46,XY DSD and 4 (20%) as 46,XX DSD. Initial clinical diagnoses in this 46,XX DSD group included gonadal dysgenesis in two patients (50%) and androgen excess in the remaining two (50%). Among the 46,XY DSD patients, five patients (31.25%) were presumed to be androgen insensitive, nine (56.25%) were diagnosed with defects in androgen biosynthesis, and two (12.5%) had gonadal dysgenesis. CMA detected 38 CNVs in 16 patients (80%), comprising 12 deletions (31.6%) and 26 duplications (68.4%). Three pathogenic CNVs were detected in 3 patients (15%), whereas 27 variants of uncertain significance were identified in 13 patients (65%). CONCLUSION: In selected cases, the diagnostic approach should incorporate CMA to elucidate the molecular etiology of DSD. Furthermore, CMA may prove to be an invaluable tool in the search for new genes responsible for DSD.

Humans↗

PubMed2026

Integrated multi-omics analysis and functional experiments reveals PPAP2C as a potential prognostic biomarker and therapeutic target in breast cancer.

BACKGROUND: This study aims to systematically elucidate the clinical significance and biological function of the phospholipid phosphatase (PLPP) family member (PPAP2C) phosphatidic acid phosphatase type 2C in breast cancer, and to evaluate its potential as a prognostic biomarker and therapeutic target. METHODS: Gene expression data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases were integrated to characterize the expression profile of PLPP family members, focusing on PPAP2C in breast cancer. The prognostic value of PPAP2C, initially identified at the mRNA level (TCGA, (METABRIC) Molecular Taxonomy of Breast Cancer International Consortium, Gene Expression Omnibus (GEO)), was confirmed at the protein level by immunohistochemistry (IHC) on tissue microarrays (TMA). The oncogenic functions of PPAP2C were investigated in triple-negative breast cancer (TNBC) cells through CRISPR-Cas9-mediated knockout and ectopic overexpression, with assessment of key phenotypes including proliferation, colony formation, migration, and invasion. In vivo validation was subsequently performed using an MDA-MB-231 xenograft model. RESULTS: PPAP2C exhibits the most significant overexpression pattern across 33 cancer types (upregulated in 16 cancers, downregulated in only 3). Compared with normal tissues, PPAP2C showed specific overexpression in breast cancer tissues and was significantly associated with advanced clinical stages and aggressive subtypes (HER2+ and TNBC). Survival analysis demonstrated that high PPAP2C expression correlated with significantly shorter overall survival and disease-free survival, which was further validated in METABRIC and GEO cohorts. Tissue microarray analysis confirmed higher PPAP2C protein positivity in tumor tissues (94.7%) than in adjacent normal tissues (59.7%), with worse OS and RFS in high-expression groups. Multivariate analysis identified PPAP2C as an independent prognostic factor for OS. Functional experiments revealed that PPAP2C knockout (via 5-bp/1-bp frameshift mutations) suppressed TNBC cell proliferation, colony formation, migration, and invasion, while overexpression enhanced these phenotypes. In vivo studies further demonstrated complete tumor regression in MDA-MB-231 xenografts upon PPAP2C knockout. CONCLUSION: This study identifies PPAP2C as a key oncogenic driver and a robust independent prognostic biomarker in breast cancer. The findings provide compelling evidence that PPAP2C represents a promising therapeutic target, offering a new strategic avenue for precision therapy, particularly for aggressive breast cancer subtypes.

PLPP2↗

PubMed2026

Three-Year Experience of Cytogenetic and Molecular Genetic Evaluation in Patients With Disorders of Sex Development at a Tertiary Care Centre in Eastern India.

OBJECTIVES: Disorders of sex development (DSD) include a range of conditions in which chromosomal, gonadal, or anatomical sex deviates from the typical developmental pathway. The diagnostic approach to DSD has shifted from karyotyping to molecular genetic tools. This study evaluated the clinical presentation, cytogenetic spectrum, and diagnostic utility of conventional and advanced molecular genetic investigations in patients with suspected DSD managed at a tertiary care facility in Eastern India over a three-year period. METHODS: A retrospective observational study was conducted at the Genetics Laboratory of a tertiary care teaching hospital in Eastern India. Consecutive patients with clinically suspected DSD referred between January 2022 and December 2024 were included. Demographic and clinical data were obtained from referral records, and peripheral blood samples were analysed using standard G-banded karyotyping according to the International System for Human Cytogenomic Nomenclature (ISCN 2020). Fluorescence in situ hybridisation (FISH), chromosomal microarray analysis (CMA), and whole-genome sequencing (WGS) were selectively performed in cases with inconclusive cytogenetic findings, suspected structural chromosomal abnormalities, or complex phenotypes. RESULTS: A total of 98 suspected DSD cases were evaluated during the study period. The most frequent chromosomal constitution was 46,XY DSD (37, 37.8%), followed by 46,XX DSD (30, 30.6%) and sex chromosome DSD (21, 21.4%). Culture failure occurred in 10 (10.2%) samples. Advanced genetic techniques, including FISH, CMA, and WGS, improved diagnostic clarification in selected complex cases. CONCLUSION: This experience highlights the importance of integrating contemporary high-resolution technologies with conventional cytogenetics to enhance the assessment, counselling, and treatment of individuals with DSD.

chromosomal analysis↗

PubMed2026

Analysis of end-stage renal disease mediated by cuproptosis-related genes.

OBJECTIVE: The complex pathophysiological mechanism of end-stage renal disease (ESRD) has not been fully understood. Cuproptosis is a newly discovered type of programmed cell death. Therefore, this study attempts to clarify the relationship between cuproptosis-related genes (CRGs) and the phenotype of ESRD. MATERIALS AND METHODS: The National Center for Biological Information Gene Expression Omnibus database was applied to obtain the GSE37171 dataset comprising whole-genome microarray analysis of peripheral blood samples. A 3 : 1 case-control design was employed with 75 ESRD patients and 20 healthy controls who were frequency-matched for age, sex, and ethnicity. Based on differentially expressed genes (DEGs) and genes related to cuproptosis, CRGs were identified. Thereafter, we explored two different subpopulations based on the cuproptosis gene and analyzed their expression and immune infiltration. Genes specific to the CRG cluster were identified through the weighted gene co-expression network analysis algorithm, and the best prediction model was determined and verified by four machine learning methods. RESULTS: The study identified 14 differentially expressed CRGs, among which ATP7B, SLC31A1, LIAS, LIPT1, DLD, MTF1, CDKN2A, DBT, and DLST had relatively high expression levels in the ESRD samples. Compared with the control group, expression levels of FDX1, DLAT, PDHA1, PDHB, and GLS were significantly lower in the ESRD group, and CRGs played a key role in the regulation of immune infiltration in ESRD. Two cuproptosis-related molecular clusters were identified in the ESRD samples. Cluster2 was more correlated with the immune infiltration of ESRD. By analyzing the intersection points between CRG cluster and key genes of ESRD, a total of 888 specific DEGs were identified. Functional differences related to specific DEGs were further explored using gene set variation analysis. Five significant genes (SMC5, USP47, USP53, AGA, and DMXL1) were identified by the support vector machine model as key predictors for ESRD disease risk, achieving an area under the curve (AUC) of 1.00 in internal validation. However, external validation in independent cohorts is required prior to clinical application. Individual gene analysis showed an AUC > 0.81 in discriminating ESRD patients from healthy controls, and the expression of all 5 genes in ESRD patients was significantly lower than in the control group. CONCLUSION: This study clarified the relationship between CRGs and the phenotype of ESRD, analyzed their specific roles in the immune microenvironment, and obtained a predictive model, providing new insights for the study of its potential therapeutic targets.

Humans↗

PubMed2026

Beyond Rett syndrome: a case series expanding the neurological spectrum associated with pathogenic MECP2 variants.

BACKGROUND: Although pathogenic variants in MECP2 are classically associated with Rett syndrome (RTT), increasing evidence suggests that they can underlie a broader spectrum of neurological phenotypes. Clinical manifestations may vary according to sex, variant type, residual protein function, and pattern of X-chromosome inactivation. METHODS: We describe five unrelated individuals carrying pathogenic MECP2 variants identified through multiplex ligation-dependent probe amplification, chromosomal microarray analysis, and next-generation sequencing. Clinical, neuroradiological, neurophysiological, and molecular findings were retrospectively reviewed. RESULTS: Two unrelated girls carrying large de novo Xq28 deletions encompassing the entire MECP2 locus presented with mild neurodevelopmental impairment and epilepsy, but no developmental regression or classic RTT features. Both girls showed borderline cognitive functioning and normal brain MRI. A 9-year-old boy carrying a maternally inherited MECP2 frameshift variant presented with intellectual disability, autism spectrum disorder, and focal epilepsy, whereas carriers in his family exhibited milder neuropsychiatric manifestations. A 44-year-old man carrying a MECP2 missense variant presented with an early-onset spastic-ataxic syndrome, peripheral neuropathy, and cerebellar dysfunction, while a 16-year-old girl patient carrying a distinct de novo MECP2 missense variant displayed isolated mild motor incoordination and subtle cerebellar signs with preserved cognitive functioning. CONCLUSIONS: Our findings expand the evidence that pathogenic MECP2 variants can produce neurological phenotypes distinct from classic RTT, including mild neurodevelopmental impairment without regression, and predominantly cerebellar or spastic-ataxic manifestations associated with limited cognitive involvement. Allelic heterogeneity seems to correlate with clinical phenotypes, at least in our small cohort. In conjunction with established diagnostic criteria, these observations support testing MECP2 in a selection of atypical neurodevelopmental and movement disorder presentations.

Humans↗

PubMed2004

Function-informed transcriptome analysis of Drosophila renal tubule.

BACKGROUND: Comprehensive, tissue-specific, microarray analysis is a potent tool for the identification of tightly defined expression patterns that might be missed in whole-organism scans. We applied such an analysis to Drosophila melanogaster Malpighian (renal) tubule, a defined differentiated tissue. RESULTS: The transcriptome of the D. melanogaster Malpighian tubule is highly reproducible and significantly different from that obtained from whole-organism arrays. More than 200 genes are more than 10-fold enriched and over 1,000 are significantly enriched. Of the top 200 genes, only 18 have previously been named, and only 45% have even estimates of function. In addition, 30 transcription factors, not previously implicated in tubule development, are shown to be enriched in adult tubule, and their expression patterns respect precisely the domains and cell types previously identified by enhancer trapping. Of Drosophila genes with close human disease homologs, 50 are enriched threefold or more, and eight enriched 10-fold or more, in tubule. Intriguingly, several of these diseases have human renal phenotypes, implying close conservation of renal function across 400 million years of divergent evolution. CONCLUSIONS: From those genes that are identifiable, a radically new view of the function of the tubule, emphasizing solute transport rather than fluid secretion, can be obtained. The results illustrate the phenotype gap: historically, the effort expended on a model organism has tended to concentrate on a relatively small set of processes, rather than on the spread of genes in the genome.

Animals↗

PubMed2024

Assessment of Gene Set Enrichment Analysis using curated RNA-seq-based benchmarks.

Pathway enrichment analysis is a ubiquitous computational biology method to interpret a list of genes (typically derived from the association of large-scale omics data with phenotypes of interest) in terms of higher-level, predefined gene sets that share biological function, chromosomal location, or other common features. Among many tools developed so far, Gene Set Enrichment Analysis (GSEA) stands out as one of the pioneering and most widely used methods. Although originally developed for microarray data, GSEA is nowadays extensively utilized for RNA-seq data analysis. Here, we quantitatively assessed the performance of a variety of GSEA modalities and provide guidance in the practical use of GSEA in RNA-seq experiments. We leveraged harmonized RNA-seq datasets available from The Cancer Genome Atlas (TCGA) in combination with large, curated pathway collections from the Molecular Signatures Database to obtain cancer-type-specific target pathway lists across multiple cancer types. We carried out a detailed analysis of GSEA performance using both gene-set and phenotype permutations combined with four different choices for the Kolmogorov-Smirnov enrichment statistic. Based on our benchmarks, we conclude that the classic/unweighted gene-set permutation approach offered comparable or better sensitivity-vs-specificity tradeoffs across cancer types compared with other, more complex and computationally intensive permutation methods. Finally, we analyzed other large cohorts for thyroid cancer and hepatocellular carcinoma. We utilized a new consensus metric, the Enrichment Evidence Score (EES), which showed a remarkable agreement between pathways identified in TCGA and those from other sources, despite differences in cancer etiology. This finding suggests an EES-based strategy to identify a core set of pathways that may be complemented by an expanded set of pathways for downstream exploratory analysis. This work fills the existing gap in current guidelines and benchmarks for the use of GSEA with RNA-seq data and provides a framework to enable detailed benchmarking of other RNA-seq-based pathway analysis tools.

Humans↗

PubMed2026

Diversified cell origin of Helicobacter pylori eradication-responsive gastric diffuse large B-cell lymphomas.

A significant proportion of gastric diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue [DLBCL(MALT)] and without MALT ('pure' DLBCL) can be resolved by Helicobacter pylori eradication (HPE). Gastric MALT lymphoma is an indolent lymphoma derived from memory B cells in the marginal zone. In the present study, we aimed to explore the origin of large cells in HPE-responsive gastric DLBCLs (complete remission after HPE). We investigated gastric lymphoma biopsies from 31 patients with HPE-responsive DLBCLs [15 'pure' DLBCLs, 16 DLBCL(MALT)s]. We used the Hans algorithm (CD10, BCL-6, and MUM1) to define the origins of germinal center B cell (GCB) and non-GCB. To further ascertain the cellular origin, 11 'pure' DLBCLs were examined using an Agilent whole-human genome microarray. Eleven DLBCLs [eight with 'pure' DLBCL and three with DLBCL(MALT)] were also assessed using Lymph2Cx. Specific GCB markers, including BACH2, AID, and BCL2 rearrangement and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) codon 641 mutations, were evaluated in 31 patients with HPE-responsive gastric DLBCLs. According to the Hans algorithm, 53% (8/15) of gastric 'pure' DLBCLs and 50% (8/16) of DLBCL(MALT)s were of the GCB phenotype. Gene expression assays revealed that five of six patients with 'Hans' GCB had GCB genetic signatures, whereas four of five patients with 'Hans' non-GCB had activated B-cell genetic signatures. The Lymph2Cx assay revealed the GCB subtype in seven of eight patients with 'Hans' GCB. The expression patterns of BACH2 (p = 0.005) and AID (p = 0.038) closely correlated with the 'Hans' GCB phenotype. BCL2 rearrangements and EZH2 codon 641 mutations were detected in 44% (7/16) and 13% (2/16) of patients with 'Hans' GCB, respectively. In another cohort of 29 HPE-unresponsive gastric DLBCLs [19 'pure' DLBCLs and 10 DLBCL(MALT)s], we found a close association between the 'Hans' GCB subtype and the GCB subtype as determined by the Agilent whole-human genome microarray and Lymph2Cx in lymphoma cells of these patients. In conclusion, more than half of HPE-responsive large cell lymphoma cases in the stomach were of GCB origin. © 2026 The Pathological Society of Great Britain and Ireland.

Humans↗

PubMed2018

Thioredoxin interacting protein promotes invasion in hepatocellular carcinoma.

BACKGROUND: Considerable evidence suggests that oxidative stress plays an essential role in the progression of hepatocellular carcinoma (HCC). While acquired resistance to oxidative stress is the main driver of aggressive cell phenotype, the underlying mechanisms remain unknown. Here, we tested the hypothesis that elevated expression of Thioredoxin-interacting protein (TXNIP) is a main regulator of the aggressive phenotype in HCC. MATERIALS AND METHODS: To test this hypothesis, we measured TXNIP expression levels in 11 HCC cell lines by qPCR and western blotting. In addition, 80 pairs of HCC tissues and matched liver tissues of 73 cases, as well as 11 normal liver tissue samples were examined by immunohistochemistry. Besides, TXNIP expression levels were analyzed by Oncomine Platform in seven independent microarray datasets. Finally, the functional role of TXNIP in HCC was investigated in vitro and in vivo by silencing and overexpression studies. RESULTS: Our results show that TXNIP expression is significantly increased in HCC compared to non-tumor counterparts (p < 0.0001) as well as to normal (p < 0.0001) and cirrhotic (p < 0.0001) liver tissues. Moreover, stable overexpression of TXNIP in HCC cells (i) significantly increases ROS levels, (ii) induces EMT phenotype, (iii) increases motility, invasion and 3D branching tubulogenesis, (iv) decreases apoptosis, and (v) elevates in vivo metastasis in zebrafish embryos. Finally, we identify sinusoidal/stromal and cytoplasmic TXNIP staining patterns as risk factors for intrahepatic vascular invasion (p:0.0400). CONCLUSION: Our results strongly suggest that overexpression of TXNIP has a pivotal role in HCC progression by inducing cell survival, invasion, and metastasis.

EMT↗

PubMed2022

Phenotypic Impact of Rare Potentially Damaging Copy Number Variation in Obsessive-Compulsive Disorder and Chronic Tic Disorders.

BACKGROUND: Recent studies report an important-and previously underestimated-role of rare variation in risk of obsessive-compulsive disorder (OCD) and chronic tic disorders (CTD). Using data from a large epidemiological study, we evaluate the distribution of potentially damaging copy number variation (pdCNV) in OCD and CTD, examining associations between pdCNV and the phenotypes of probands, including a consideration of early- vs. late-diagnoses. METHOD: The Obsessive-Compulsive Inventory-Revised (OCI-R) questionnaire was used to ascertain psychometric profiles of OCD probands. CNV were identified genome-wide using chromosomal microarray data. RESULTS: For 993 OCD cases, 86 (9%) were identified as pdCNV carriers. The most frequent pdCNV found was at the 16p13.11 region. There was no significant association between pdCNV and the OCI-R total score. However, pdCNV was associated with Obsessing and Checking subscores. There was no significant difference in pdCNV frequency between early- vs. late-diagnosed OCD probands. Of the 217 CTD cases, 18 (8%) were identified as pdCNV carriers. CTD probands with pdCNV were significantly more likely to have co-occurring autism spectrum disorder (ASD). CONCLUSIONS: pdCNV represents part of the risk architecture for OCD and CTD. If replicated, our findings suggest pdCNV impact some OCD symptoms. Genes within the 16p13.11 region are potential OCD risk genes.

Humans↗

PubMed2026

Prenatal exome sequencing of fetuses with central nervous system anomalies based on prenatal ultrasound and magnetic resonance imaging diagnosis: A retrospective cohort study with a systematic review and meta-analysis.

INTRODUCTION: Fetal central nervous system (CNS) abnormalities have diverse etiologies, with genetic factors as a major contributor. Prenatal exome sequencing (ES) is a powerful tool for precise molecular diagnosis of CNS anomalies, but its diagnostic yield varies among studies. This study aimed to evaluate the additional diagnostic yield of prenatal ES compared with chromosomal microarray analysis (CMA) in fetuses with CNS anomalies detected by prenatal imaging. MATERIAL AND METHODS: We collected ES results from fetuses diagnosed with CNS anomalies by prenatal imaging (2019-2024) who had negative results. Subgroup analyses assessed phenotype-specific ES diagnostic yield for associated genes and variants. A systematic review and meta-analysis incorporating our data and published studies further explored the association between phenotype and diagnostic yield. RESULTS: In the cohort study of 219 cases, ES identified pathogenic/likely pathogenic single nucleotide variations in 36 cases (16%). The highest diagnostic yield of ES was in cases with multisystem malformations (25%, 14/55), followed by multiple CNS anomalies (15%, 2/13) and isolated CNS anomalies (13%, 20/151). The most commonly identified isolated CNS anomaly was agenesis of the corpus callosum (31%, 5/16). Neural tube defects with urogenital anomalies were associated with a positive ES finding in 57% (4/7) of cases. The meta-analysis of 989 cases from 22 studies showed a pooled diagnostic yield of ES of 27% (95% CI, 21%-34%). The highest diagnostic yield of ES was in cases of corpus callosum anomalies with facial abnormalities (75%, 8/11) and neural tube defects with urogenital malformations (80%, 12/15). The diagnostic yield of ES for three or more CNS abnormalities was 43% (95% CI, 31%-58%), significantly higher than that for only two abnormalities (10%, 95% CI, 4%-18%). No significant difference in diagnostic yield was found between cases identified by prenatal MRI combined with ultrasound (27%, 95% CI, 20%-36%) and those identified by ultrasound alone (25%, 95% CI, 17%-35%). CONCLUSIONS: ES provided a significantly higher diagnostic yield than CMA for fetal CNS abnormalities, with diagnostic yields varying by phenotype. The systematic review and meta-analysis confirmed that the complexity and combination of malformations are key factors associated with differences in ES diagnostic yield.

Humans↗