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PubMed1995

Impaired mitochondrial function in idiopathic dilated cardiomyopathy: biochemical and molecular analysis.

Mitochondrial defects at the biochemical and molecular levels are increasingly recognized in diseases involving the heart. The objective of this study was to assess the frequency and extent of mitochondrial defects in idiopathic dilated cardiomyopathy. Left ventricular tissues of 27 patients with idiopathic dilated cardiomyopathy undergoing orthotopic cardiac transplantation because of severe cardiac failure were examined to assess the specific activity levels of mitochondrial respiratory enzymes and changes in mtDNA structure and copy number. Abnormal specific activities of several mitochondrial enzymes were found in 55% of the cardiomyopathic tissues examined (15 patients), with six patients displaying single enzyme defects, including five in complex III and one in complex I. Multiple mitochondrial enzyme defects were found in nine patients, with the most frequent combination of defects seen in complex III and complex IV (5 cases). These enzymatic changes were shown not to be accompanied by changes in mtDNA copy number. In seven cases, however, including three young adults, there was a marked decrease in the levels of polymerase chain reaction products derived from specific mtDNA regions, which may be an indication of specific mtDNA damage. Specific mitochondrial abnormalities are frequently found in idiopathic dilated cardiomyopathy, with a variety of mitochondrial loci affected. These findings are not age dependent.

Adult↗
PubMed2001

Structural features and methylation patterns associated with paramutation at the r1 locus of Zea mays.

In paramutation, two alleles of a gene interact and, during the interaction, one of them becomes epigenetically silenced. The various paramutation systems that have been studied to date exhibit intriguing differences in the physical complexity of the loci involved. B and Pl alleles that participate in paramutation are simple, single genes, while the R haplotypes that participate in paramutation contain multiple gene copies and often include rearrangements. The number and arrangement of the sequences in particular complex R haplotypes have been correlated with paramutation behavior. Here, the physical structures of 28 additional haplotypes of R were examined. A specific set of physical features is associated with paramutability (the ability to be silenced). However, no physical features were strongly correlated with paramutagenicity (the ability to cause silencing) or neutrality (the inability to participate in paramutation). Instead, paramutagenic haplotypes were distinguished by high levels of cytosine methylation over certain regions of the genes while neutral haplotypes were distinguished by lack of C-methylation over these regions. These findings suggest that paramutability of r1 is determined by the genetic structure of particular haplotypes, while paramutagenicity is determined by the epigenetic state.

Alleles↗
PubMed1996

Characterization of Mycobacterium tuberculosis complex direct repeat sequence for use in cycling probe reaction.

Cycling probe technology (CPT) is a unique and simple method for the detection of specific target sequences. CPT utilizes a chimeric DNA-RNA-DNA probe providing an RNase H-sensitive scissile linkage when bound to a complementary target sequence. For this study a diagnostic assay based on CPT was developed for the detection of the 36-bp direct repeat (DR) region in Mycobacterium tuberculosis. To determine the feasibility of using the DR for detecting M. tuberculosis by CPT, a wide variety of mycobacteria were tested by Southern blot hybridization with three DR probes to verify their specificity. The entire DR region of Mycobacterium bovis 401 was sequenced, and the data were used to design a PCR assay that would allow us to estimate the number of DRs present in a variety of strains. A CPT assay which uses a probe complementary to the DR region was developed and evaluated with synthetic targets and genomic DNA from mycobacteria. In summary, the 36-bp DR provides an attractive target for detecting M. tuberculosis because the sequence is present in high copy numbers in the genome, is specific for the M. tuberculosis complex, and is found in strains that lack IS6110.

Animals↗
PubMedDate not supplied

A paradigm for oncogene complementation in human breast cancer.

Multiple cellular oncogenes are amplified in malignant tumours, and it is possible to invoke gene dosage as a possible base for product activity. In vitro data have shown that two different oncogenes can cooperate in converting a normal cell into one that is tumorigenic. This suggested that multiple cooperative alterations might be involved in cancer progression. Breast cancers have a broad spectrum of clinical behaviours ranging from highly aggressive neoplasms to almost chronic diseases. Fifty months of clinical follow-up were studied in 143 patients with primary breast cancers. Uni- and multivariate analyses were performed in order to determine any synergistic effect of amplified c-myc, erbB-2 and int-2 genes on the disease-free state and overall survival. We showed that c-myc amplification was associated with early recurrence and shorter survival; in contrast, erbB-2 and int-2 extra copies resulted in later relapse events, especially in patients whose tumours showed a normal copy number of c-myc genes. This pointed out sequential activation of complex regulatory cascades within the cell. Such particular behaviour enabled us to categorize erbB-2 and int-2 oncogenes into a group showing delayed action, in contrast to c-myc involvement in rapid spread of the tumour. As expected, co-amplified c-myc and erbB-2 genes showed positive cooperation with respect to recurrence and shortening of overall survival. Finally, the harmful effects of amplified c-myc and erbB-2 oncogenes were dramatically increased in patient subgroups showing a normal copy number of the int-2 gene. Multivariate analysis was used to evaluate disease-free survival and to test for potential interactions of oncogene covariates. It pointed out multiple independent combinations which enabled us to define complementation groups with respect to clinical patient behaviour.

Blotting, Southern↗
PubMed2025

CNV-Finder: Streamlining Copy Number Variation Discovery.

Copy Number Variations (CNVs) play pivotal roles in the etiology of complex diseases and are variable across diverse populations. Understanding the association between CNVs and disease susceptibility is significant in disease genetics research and often requires analysis of large sample sizes. One of the most cost-effective and scalable methods for detecting CNVs is based on normalized signal intensity values, such as Log R Ratio (LRR) and B Allele Frequency (BAF), from Illumina genotyping arrays. In this study, we present CNV-Finder, a novel pipeline integrating deep learning techniques on array data, specifically a Long Short-Term Memory (LSTM) network, to expedite the large-scale identification of CNVs within predefined genomic regions. This facilitates efficient prioritization of samples for time-consuming or costly subsequent analyses such as Multiplex Ligation-dependent Probe Amplification (MLPA), short-read, and long-read whole genome sequencing. We incorporate four genes to establish our methods-Parkin (PRKN), Leucine Rich Repeat And Ig Domain Containing 2 (LINGO2), Microtubule Associated Protein Tau (MAPT), and alpha-Synuclein (SNCA)-which may be relevant to neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), or related disorders such as essential tremor (ET). By training our models on expert-annotated samples and validating them across diverse cohorts, including those from the Global Parkinson's Genetics Program (GP2) and additional dementia-specific databases, we demonstrate the efficacy of CNV-Finder in accurately detecting deletions and duplications. Our pipeline outputs app-compatible files for visualization within CNV-Finder's interactive web application. This interface enables researchers to review predictions and filter displayed samples by model prediction values, LRR range, and variant count in order to explore or confirm results. Our pipeline integrates this human feedback to enhance model performance and reduce false positive rates. Through a series of comprehensive analyses and validations using visual inspection, MLPA, short-read, and long-read sequencing data, we demonstrate the robustness and adaptability of CNV-Finder in identifying CNVs with regions of varied size, probe density, and noise. Our findings highlight the significance of contextual understanding and human expertise in enhancing the precision of CNV identification, particularly in complex genomic regions like 17q21.31. The CNV-Finder pipeline is a scalable, publicly available resource for the scientific community, available on GitHub (https://github.com/GP2code/CNV-Finder; DOI 10.5281/zenodo.14182563). CNV-Finder not only expedites accurate candidate identification but also significantly reduces the manual workload for researchers, enabling future targeted validation and downstream analyses in regions or phenotypes of interest.

Copy Number Variation (CNV)↗
PubMed1980

The yeast mitochondrial adenosine triphosphatase complex. Subunit stoichiometry and physical characterization.

Immunoprecipitation of uniformly labeled yeast submitochondrial preparations using a subunit-specific or a holoenzyme antiserum has been employed to determine the subunit stoichiometry of the oligomycin-sensitive ATPase complex. The Triton-solubilized enzyme consists of 10 types of subunits. The number of copies of each subunit, in order of decreasing molecular weight, is 3:3:1:2:1:2:2:1:2:3. on the basis of the stoichiometry data, the ATPase complex has a molecular weight of 5.8 x 10(5) and contains a minimum of 20 polypeptide chains. Analysis of water-soluble ATPase (F1-ATPase) indicates that the stoichiometry of the three largest subunits of the enzyme is preserved in the absence of the other subunits. The molecular weights of both forms of the ATPase, derived from stoichiometry data, agree well with measurements obtained from gel filtration and sedimentation studies. The implications of these data for the structure, function, and assembly of the complex are discussed.

Adenosine Triphosphatases↗
PubMed2002

Polymorphism in the subtelomeric regions of chromosomes of Kinetoplastida.

Leishmania spp. and the related kinetoplastid Trypanosoma brucei are single-celled parasites. In Leishmania, the nuclear genome comprises 36 diploid chromosomes and occasional amplified minichromosomes, while the T. brucei nucleus contains 11 larger diploid chromosomes and a variable number of intermediate-sized and minichromosomes. This paper primarily describes the subtelomeric structure of the larger diploid chromosomes of L. major and T. brucei, although some aspects may also apply to smaller chromosomes. The diploid chromosomes contain most protein-coding genes and vary in size. The telomeric sequence is common to both species, but adjacent subtelomeric repeats vary between species and chromosomes. It is possible that some of the complex repeats described here play a role in stabilizing replication and copy number of the chromosomes. The subtelomeric regions of T. brucei chromosomes differ from those of other protozoan parasites, as they are dedicated to expression sites for variant surface glycoprotein genes, used by the parasite to evade immune destruction by antigenic variation. Variation in these sites creates segmental aneuploidy in many T. brucei chromosomes.

Animals↗
PubMed1986

The binding of Pseudomonas aeruginosa outer membrane ghosts to human buccal epithelial cells.

The binding of outer membrane (OM) ghosts derived from Pseudomonas aeruginosa strain 492c to human buccal epithelial cells (BECs) was examined. Electron microscopic examination of the binding of OM ghosts to BECs revealed direct OM ghost-BEC interaction. Equilibrium analysis of the binding of OM ghosts to trypsinized BECs employing the Langmuir adsorption isotherm indicated the number of binding sites (N) to be 1.3 X 10(-4) micrograms protein per BEC with an apparent association constant (Ka) of 3.4 X 10(-2) mL/microgram protein. The Langmuir analysis of binding of OM ghosts to untrypsinized BECs was complex, suggesting two possible classes of receptors, a high affinity-low copy number class (Ka, 7.8 X 10(-2)mL/microgram protein; N, 8.6 X 10(-5) microgram protein per BEC) and a low affinity-high copy number class (Ka, 3.7 X 10(-3)mL/microgram protein; N, 9.2 X 10(-4)microgram protein per BEC). Sugar inhibition studies incorporating D-galactose enhanced binding to each BEC type. N-Acetylneuraminic acid and N-acetylglucosamine both enhanced binding of OM ghosts to untrypsinized BECs, while inhibiting binding to trypsinized BECs. D-Arabinose inhibited binding to both BEC types. Binding of OM ghosts to both BEC types was greatly inhibited by D-fucose, while L-fucose only greatly inhibited binding to untrypsinized BECs. These sugar inhibition data demonstrated a difference in the binding of OM ghosts to trypsinized and untrypsinized BECs and possibly reveal the nature of the receptor(s), free of possible bacterial metabolic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adhesiveness↗
PubMed1992

Two hemes in Bacillus subtilis succinate:menaquinone oxidoreductase (complex II).

Succinate:menaquinone-7 oxidoreductase (complex II) of the Gram-positive bacterium Bacillus subtilis consists of equimolar amounts of three polypeptides; a 65-kDa FAD-containing polypeptide, a 28-kDa iron-sulfur cluster containing polypeptide, and a 23-kDa membrane-spanning cytochrome b558 polypeptide. The enzyme complex was overproduced 2-3-fold in membranes of B. subtilis cells containing the sdhCAB operon on a low copy number plasmid and was purified in the presence of detergent. The cytochrome b558 subunit alone was similarly overexpressed in a complex II deficient mutant and partially purified. Isolated complex II catalyzed the reduction of various quinones and also quinol oxidation. Both activities were efficiently albeit not completely blocked by 2-n-heptyl-4-hydroxyquinoline N-oxide. Chemical analysis demonstrated two protoheme IX per complex II. One heme component was found to have an Em,7.4 of +65 mV and an EPR gmax signal at 3.68, to be fully reducible by succinate, and showed a symmetrical alpha-band absorption peak at 555 nm at 77 K. The other heme component was found to have an Em,7.4 of -95 mV and an EPR gmax signal at 3.42, was not reducible by succinate under steady-state conditions, and showed in the reduced state an apparent split alpha-band absorption peak with maxima at 553 and 558 nm at 77 K. Potentiometric titrations of partially purified cytochrome b558 subunit demonstrated that the isolated cytochrome b558 also contains two hemes. Some of the properties, i.e., the alpha-band light absorption peak at 77 K, the line shapes of the EPR gmax signals, and reactivity with carbon monoxide were observed to be different in B. subtilis cytochrome b558 isolated and in complex II. This suggests that the bound flavoprotein and iron-sulfur protein subunits protect or affect the heme environment in the assembled complex.

Bacillus subtilis↗
PubMed2025

PARTAGE: Parallel analysis of replication timing and gene expression.

The human genome is partitioned into functional compartments that replicate at specific times during the S-phase. This temporal program, referred to as replication timing (RT), is co-regulated with the 3D genome organization, is cell type-specific, and changes during development in coordination with gene expression. Moreover, RT alterations are linked to abnormal gene expression, genome instability, and structural variation in multiple diseases, including cancer. However, mechanistic links between RT, large-scale 3D genome architecture, and transcriptional regulation remain poorly understood. A major limitation is that current approaches require the separate profiling of RT and transcriptomes from independent batches of samples, obscuring the complex co-regulation between the epigenome and transcriptome. Here, we developed PARTAGE, a multiomics approach that enables joint profiling of copy number variation (CNV), RT, and gene expression from the same sample, providing a more accurate integrative view of the complex relationships between RT and gene regulation.

Journal Article↗
PubMed2000

Mitochondrial genome-encoded ATPase subunit 6+8 mRNA increases in human hepatoblastoma cells in response to nonfatal cold stress.

Cellular responses to cold stress have not been well clarified, compared with heat shock responses, especially in mammalian cells. We investigated cold-stress responses in human hepatoblastoma cells (HepG2) exposed to a nonfatal temperature of 17 degrees C. Under the condition, RNA and protein syntheses in the cells were highly, but incompletely, depressed and cell growth was impaired. A cDNA subtraction method was used to isolate mRNAs for which the levels were increased in cold-stressed cells compared with cells cultured at 37 degrees C. A transcript isolated by the screening was identified as ATPase subunit 6+8 mRNA that encodes components of a mitochondrial ATPase complex and that is transcribed from a mitochondrial genome. The copy number of the mitochondrial genome in cells was not changed by cold stress. Thus, HepG2 cells were treated with various concentrations of actinomycin D and chloramphenicol to assess the effects of transcriptional and translational reduction on the increased level of the ATPase subunit 6+8 mRNA. The mRNA level was increased in cells treated with low concentrations of the RNA or protein synthesis inhibitors. These results indicate that the increase in ATPase subunit 6+8 mRNA stimulated by cold stress could be mediated by a partial decline of transcription and/or translation in the cells. In addition, the degradation of ATPase subunit 6+8 mRNA was suppressed in cold-stressed cells compared with that in 37 degrees C-cultured cells. This result implies that posttranscriptional regulation is also involved in the cold-stimulated increase in ATPase subunit 6+8 mRNA in HepG2 cells.

Apoptosis↗
PubMed1995

Functional differences and interactions among the putative RecA homologs Rad51, Rad55, and Rad57.

The genes of the Saccharomyces cerevisiae RAD52 epistasis group are required for the repair of ionizing radiation-induced DNA damage. Three of these genes, RAD51, RAD55, and RAD57, have been identified as putative RecA homologs. An important feature of RecA is its ability to bind and hydrolyze ATP. RAD55 and RAD57 contain putative nucleotide binding motifs, and the importance of these motifs was determined by constructing site-directed mutations of the conserved lysine residue within the Walker A-box. Changing the lysine residue to arginine or alanine resulted in a mutant phenotype in DNA repair and sporulation for Rad55 but not for Rad57. Protein-protein interactions among Rad51, Rad55, and Rad57 were tested for by the two-hybrid system. Rad55 was shown to interact with Rad51 and Rad57 but not with itself. Additionally, no interaction between Rad57 and Rad51 or between Rad57 and itself was detected. Consistent with the hypothesis that Rad55 and Rad57 may function within, or stabilize, a protein complex, we found that RAD51 expressed from a high-copy-number plasmid suppresses the DNA repair defect of strains carrying rad55 and rad57 mutations. These data, in conjunction with other reports, demonstrate the importance of protein-protein interactions in the process of DNA repair.

Adenosine Triphosphatases↗
PubMed2005

Epithelial-mesenchymal transition in gastric cancer (Review).

Endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), surgical gastrectomy, and chemotherapy are therapeutic options of gastric cancer; how-ever, prognosis of advanced gastric cancer patients is still poor. Gastric cancer cells with fibroblastoid morphological changes show increased motility and invasiveness due to decreased cell-cell adhesion, which are reminiscent of epithelial-mesenchymal transition (EMT) during embryonic development. Here, EMT signaling networks in gastric cancer were reviewed. E-cadherin at adherens junction is a key molecular target of EMT. CDH1 gene at human chromosome 16q22.1 encodes E-cadherin. Familial diffuse type gastric cancer occurs due to germ-line mutations of the CDH1 gene. Down-regulation of E-cadherin function due to mutation, deletion, CpG hyper-methylation, and SNAIL (SNAI1)- or SIP1-mediated transcriptional repression of the CDH1 gene leads to EMT in gastric cancer. Amplification of ERBB2, MET, FGFR2, PIK3CA, AKT1 genes, up-regulation of WNT2, WNT2B, WNT8B, and down-regulation of SFRP1 lead to EMT in gastric cancer through GSK3beta inhibition and following SNAIL-mediated CDH1 repression. Claudin (CLDN) and PAR3/PAR6/aPKC complex at tight junction are other key molecular targets of EMT. CLDN23 gene is down-regulated in intestinal type gastric cancer. Down-regulation of PAR3/PAR6/aPKC complex also leads to EMT. Single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) of genes encoding EMT signaling molecules will be identified as novel risk factors of gastric cancer. In addition, antibodies, RNAi compounds, and small molecular inhibitors for EMT signaling molecules will be developed as novel therapeutic agents for gastric cancer. Personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of gastric cancer patients in the future.

Cadherins↗
PubMed2005

hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer.

In a majority of malignant human tumors telomerase activity can be detected, suggesting an immortal phenotype. Expression of the reverse transcriptase subunit, hTERT, in the human telomerase complex is required for telomerase activity. The regulation of hTERT, from gene level to a fully functional protein, is still a poorly understood process. Increased copy number of the hTERT gene has been demonstrated in a significant portion of established cell lines and tumors of different origin but its relevance for telomerase activity levels is unclear. In the present study, we examined the hTERT gene copy number using fluorescence in situ hybridization (FISH) in samples from 64 colorectal carcinomas and an increased copy number (> or = 3 hTERT gene copies/nucleus) was observed in 31 cases (48%). No statistical association existed between hTERT gene copy number and hTERT RNA expression or telomerase activity. However, a significant relationship was found between an increase in hTERT gene copy number and p53 protein accumulation (p = 0.002) and aneuploidy (p = 0.036). Only 4 tumors showed microsatellite instability, 3 of which had a normal hTERT gene copy number. The data indicated that the increased copy number of the hTERT gene in colorectal carcinoma was a result of genomic instability with no obvious consequence for telomerase activity levels.

Aneuploidy↗
PubMed1998

New Australian aboriginal complotypes characterised by increased C4 gene copy number.

Complement component C4 genes are located within the central region of the human MHC. The genomic arrangement of these genes is complex, with each chromosome usually encoding either one or two C4 genes. C4 allotyping of a group of Western Australian Aborigines demonstrated certain discrepancies in the densitometric ratios between the C4A4 and the C4A3 protein bands; however, the mechanism causing the increase in density of the C4A4 band was unknown. Our aim was to determine whether the increase in densitometry was due to an increase in the expression of the C4A4 isotype, or whether these individuals carried a new complotype characterised by an increased gene copy number. Using pulsed-field gel electrophoresis and Taq I RFLP analysis we will show that the apparent increase in C4A4 protein expression was due to the existence of new, previously uncharacterised Aboriginal complotypes defined by at least three C4 genes. Segregation analysis from an extensive family suggests that one of the new C4 complotypes is likely to contain the duplicated C4A4 isotype together with a C4B2 gene (C4A4, C4A4, C4B2) and is the first such chromosomal arrangement seen in this population group.

Australia↗
PubMed1987

The plasmids of Acetobacter xylinum and their interaction with the host chromosome.

Acetobacter xylinum contains a complex system of plasmid DNA molecules. Plasmids of molecular weights or copy numbers different from the original wild-type, are found in different types of mutants. Restriction endonuclease digestion and DNA/DNA hybridization analysis, showed that the plasmids often contained partly, but not completely the same DNA sequences. Two of these plasmid classes were analysed in more detail, and could be shown to differ in size by about 5 kb. Hybridization analysis using cloned DNA fragments as probes, showed that sequences lacking in the smallest plasmid were still present in a DNA fraction co-migrating with linearized chromosomal DNA. In addition, at least part of the DNA in the smallest plasmid was present both in the plasmid and chromosomal DNA fraction. Analysis of a particular strain containing an insertion of transposon Tn1, also indicated the existence of complex interactions between plasmids and chromosomal DNA. Together with experiments on conjugative transfer and curing of the plasmids, the results indicate that at least part of the genetic system of A. xylinum is unusual when compared to that of other genetically characterized bacteria.

Cellulose↗
PubMed1992

What is the selective pressure that maintains the gene loci encoding the antigen receptors of T and B cells? A hypothesis.

The dominant view is that the gene loci encoding the B cell antigen receptor (BAr) or the T cell antigen receptor (TAr) specify a vast array of combining sites. The 'germline' repertoire is estimated to be > 10(10) by multiplying numbers of subunit complements by DN-region variability. This implies that the germline can be maintained by a selection imposed by all or most of the antigenic universe. Its unchallenged popularity, notwithstanding, this neo-germline view is untenable and hence the need for a competing concept, as presented here. The immunoglobulin (Ig) loci are under a totally different selection from the T loci. The Ig loci are selected upon largely by carbohydrate determinants on pathogens that vary more slowly than the proteins produced by the Ig loci, which are necessary to rid these selective antigens. By contrast, the T loci are selected to recognize the allele-specific determinants on restricting elements encoded in the major histocompatibility complex (MHC). The expression of the germline results in a high copy number (HCN) repertoire; this repertoire is the substrate for 'mutation' that yields the low copy number (LCN) repertoire. For the B cell, these two repertoires interact to optimize the response to the unexpected. For the T cell, only the LCN repertoire is functional. The immunoglobulin (Ig) loci are selected upon as light(L)-heavy (H) pairs; the T loci are selected upon as single units alpha or beta (i.e. the VT-gene segments act as a single pool). This competing concept carries with it many important and testable consequences.

Alleles↗
PubMed2024

Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

Humans↗