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PubMed2002

Detection of cathepsin B up-regulation in neoplastic thyroid tissues by proteomic analysis.

Nodular or multinodular goiter is the most common non-neoplastic thyroid disease and may be difficult to distinguish from true neoplastic thyroid diseases using microscopic criteria. We have used two-dimensional gel electrophoresis to study the protein patterns of thyroid tissues including normal thyroid, multinodular goiter, diffuse hyperplasia, follicular adenoma, follicular carcinoma and papillary carcinoma. Specific proteins, in the region of molecular mass 15-30 kDa and isoelectric point 4.5-6.5, were identified by electrospray tandem mass spectrometry and protein sequencing. The most distinctive protein found is cathepsin B, which could be detected as four spots, with differential expression in different thyroid diseases. In particular, two of these cathepsin B spots CB2 and CB3 are strongly up-regulated in neoplastic diseases, compared to non-neoplastic diseases. In addition, overexpression of ATP synthase D chain and prohibitin were observed in papillary carcinoma, which should allow it to be differentiated from follicular carcinoma. Changes in expression of other proteins were also observed in disease states compared to normal tissues, namely translationally controlled tumor protein, thioredoxin peroxidase 1, glutathione-S-transferase P, DJ-1 protein, superoxide dismutase (Cu, Zn), and heat shock protein 27, but these changes are less characteristic, so they do not allow the differentiation between neoplastic and non-neoplastic tissues. Thus, the proteomic approach is a useful diagnostic tool for studying diseases involving the thyroid nodule.

ATP Synthetase Complexes↗
PubMed2006

Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD-dependent genes.

Here, we present the first study of a human neuromuscular disorder at transcriptional and proteomic level. Autosomal dominant facio-scapulo-humeral muscular dystrophy (FSHD) is caused by a deletion of an integral number of 3.3-kb KpnI repeats inside the telomeric region D4Z4 at the 4q35 locus. We combined a muscle-specific cDNA microarray platform with a proteomic investigation to analyse muscle biopsies of patients carrying a variable number of KpnI repeats. Unsupervised cluster analysis divides patients into three classes, according to their KpnI repeat number. Expression data reveal a transition from fast-glycolytic to slow-oxidative phenotype in FSHD muscle, which is accompanied by a deficit of proteins involved in response to oxidative stress. Besides, FSHD individuals show a disruption in the MyoD-dependent gene network suggesting a coregulation at transcriptional level during myogenesis. We also discuss the hypothesis that D4Z4 contraction may affect in trans the expression of a set of genes involved in myogenesis, as well as in the regeneration pathway of satellite cells in adult tissue. Muscular wasting could result from the inability of satellite cells to successfully differentiate into mature fibres and from the accumulation of structural damages caused by a reactive oxygen species (ROS) imbalance induced by an increased oxidative metabolism in fibres.

Adolescent↗
PubMed2002

[Pharmacogenomics and pharmainformatics].

Pharmacogenomics is defined to identify the genes which are involved in determining the responsiveness and to distinguish responders and non-responders to a given drug. Genome sequencing, transcriptome and proteome analysis are of particular significance in pharmacogenomics. Sequencing is used to locate polymorphisms, and monitoring of gene expression can provide clue about the genomic response to disease and treatment. The transcriptome analysis can be done by methods of random cDNA sequencing (expressed sequence tag project, body map project, serial analysis of gene expression, et al), mRNA display (differential display, fluorescent differential display, RNA arbitraly primed PCR, molecular indexing, gene expression fingerprinting, et al) and differential hybridization(cDNA high density filter, cDNA microarray, oligomicrochip, et al). We used transcriptome analysis to identify therapeutic target genes by studying change of gene expression in animal models of cerebral vasospasm (1) and of hypoxia/ischemia and found novel drug target candidates through this pharmacogenomic strategy (2). We found remarkable up-regulation of heme oxygenase-1(HO-1) mRNA in the basilar artery and it might be closely related to the occurrence of delayed vasospasm after subarachnoid hemorrhage. In this report, we clearly demonstrate that intrathecal administration of antisense HO-1 oligodeoxynucleotide aggravates vasospasm, suggesting HO-1 gene induction has spasmolytic effects. Furthermore, we found the protective effects of HO-1 gene induction by endogenous or clinical compounds in cerebral vasospasm. Therapeutic gene induction of HO-1 could be a novel strategy for the prevention and treatment of Hb-induced pathologic conditions including delayed cerebral vasospasm. Our results suggest that the pharmacogenomic transcriptome analysis and pharmainformatics has the potential for strategy to define novel drug targets in various diseases (3). (1) J Clin Invest 104: 59-66, 1999. (2) J Biol Chem 276: 19921-19928, 2001. (3) J Cardiovasc Pharm 36: S1-S4, 2000.

Animals↗
PubMed2004

Proteomics characterization of different bran proteins between aromatic and nonaromatic rice (Oryza sativa L. ssp. indica).

Proteomic approach is applied for the analysis of seed brans of 14 rice varieties (Oryza sativa L. ssp. indica) which can classify to five aromatic rice and nine nonaromatic rice. The two-dimensional electrophoresis (2-DE) protein patterns for 14 rice varieties were similar within pH ranges of 3-10 and 4-7. To characterize aromatic group-specific proteins, we compared 2-D gels of aromatic rice to nonaromatic rice using PDQUEST image analysis. Four out of six differential spots were identified as hypothetical proteins, but one (SSP 7003) was identified by matrix assisted laser desoption/ionization-quardrupole-time of fight (MALDI-Q-TOF) as prolamin with three matching peptides based on NCBI database. Prolamin is a class of storage proteins with three different polypeptides of 10, 13, and 16 kDa. Spot SSP7003 was identified as a 13 kDa polypeptide of prolamin by combination of mass spectroscopy and N-terminal sequence analyses. In contrast, one sulfur-rich 16 kDa polypeptide of prolamin was found in extremely high intensity in brans of deep-water rice compared to nondeep-water rice. Our results suggest that proteomics is a powerful step to open the way for the identification of rice varieties.

2-Propanol↗
PubMed2004

Identification and proteomic profiling of exosomes in human urine.

Urine provides an alternative to blood plasma as a potential source of disease biomarkers. One urinary biomarker already exploited in clinical studies is aquaporin-2. However, it remains a mystery how aquaporin-2 (an integral membrane protein) and other apical transporters are delivered to the urine. Here we address the hypothesis that these proteins reach the urine through the secretion of exosomes [membrane vesicles that originate as internal vesicles of multivesicular bodies (MVBs)]. Low-density urinary membrane vesicles from normal human subjects were isolated by differential centrifugation. ImmunoGold electron microscopy using antibodies directed to cytoplasmic or anticytoplasmic epitopes revealed that the vesicles are oriented "cytoplasmic-side inward," consistent with the unique orientation of exosomes. The vesicles were small (<100 nm), consistent with studies of MVBs and exosomes from other tissues. Proteomic analysis of urinary vesicles through nanospray liquid chromatography-tandem mass spectrometry identified numerous protein components of MVBs and of the endosomal pathway in general. Full liquid chromatography-tandem MS analysis revealed 295 proteins, including multiple protein products of genes already known to be responsible for renal and systemic diseases, including autosomal dominant polycystic kidney disease, Gitelman syndrome, Bartter syndrome, autosomal recessive syndrome of osteopetrosis with renal tubular acidosis, and familial renal hypomagnesemia. The results indicate that exosome isolation may provide an efficient first step in biomarker discovery in urine.

Adult↗
PubMed2006

Identification of secreted and membrane proteins in the rat incisor enamel organ using a signal-trap screening approach.

The secretome represents the subset of proteins that are targeted by signal peptides to the endoplasmic reticulum. Among those, secreted proteins play a pivotal role because they regulate determinant cell activities such as differentiation and intercellular communication. In calcified tissues, they also represent key players in extracellular mineralization. This study was carried out to establish a secretome profile of rat enamel organ (EO) cells. A functional genomic technology, based on the signal trap methodology, was applied, starting with a library of 5'-enriched cDNA fragments prepared from rat incisor EOs. A total of 2,592 clones were analyzed by means of macroarray hybridizations and DNA sequencing. Ninety-four unique clones encoding a signal peptide were retrieved. Among those were 84 matched known genes, many not previously reported to be expressed by the EO. Most importantly, 10 clones were classified as being novel, with EO-009 identified as the rat homolog of human APin protein. These data indicate that many secreted and membrane-embedded EO proteins still remain to be identified, some of which may play crucial roles in regulating processes that create an optimal environment for the formation and organization of apatite crystals into a complex three-dimensional calcified matrix.

Amelogenesis↗
PubMed2001

Identification of disease genes by expression profiling.

The human genome has been completely sequenced. The development of innovative methodologies and tools to understand the functions of human genes in health and disease will allow the data of the human genome project to be utilized. This paper reviews methods that can be used to detect and isolate genes that are specifically expressed in certain diseases or that are specific to cell types. First, classical methods, such as differential screening of complementary deoxyribonucleic acid libraries and subtractive techniques, are described. Methods based on polymerase chain reaction (PCR), such as differential display PCR or serial analysis of gene expression, will then be discussed. Finally, recent developments in gene chip technology and basic principles of functional genomics will be illustrated. Future developments will link the results of genomic approaches to data obtained by other systematic methods, such as proteomics (i.e. the systematic, large scale analysis of proteins), and will allow the production of a detailed molecular characterization of diseases, disease stages, tissues, or cell types. Methods to detect disease or cell type-specific gene expression patterns will play an important role in the future of basic research, as well as the development of novel diagnostic procedures and identification of therapeutic targets.

DNA Fingerprinting↗
PubMed2003

Integrative analysis of intraerythrocytic differentially expressed transcripts yields novel insights into the biology of Plasmodium falciparum.

BACKGROUND: The intraerythrocytic development of Plasmodium falciparum, the most virulent human malaria parasite involves asexual and gametocyte stages. There has been a significant increase in disparate datasets derived from genomic and post-genomic analysis of the parasite that necessitates delivery of integrated analysis from which biological processes important to the survival of the parasite can be determined. METHODS: In order to resolve genes associated with stage differentially expressed transcripts, we have developed and implemented an integrative approach that combines evidence from P. falciparum expressed sequence tags (ESTs), genomic, microarray, proteomic and gene ontology data. RESULTS: A total of 143 gametocyte-overexpressed and 51 asexual-overexpressed transcripts were identified. A subset of 74 genes associated with these transcripts showed evidence of stage-correlated protein expression, of which 53 have not been experimentally characterised. Our study has revealed (1) possible regulatory mechanisms in malaria parasites' gametocyte maturation, (2) correlation between EST and microarray data for a P. falciparum gene family to present unique EST-derived information, (3) candidate drug and antigenic targets on which computational and experimental studies can be performed, and (4) the need for more empirical studies on gene and protein expression in malaria parasites. CONCLUSION: Applying different domains of data to the same underlying gene set has yielded novel insights into the biology of the parasite and presents an approach to appraise critically the data quality of post-genomic datasets from malaria parasites.

Journal Article↗
PubMed2003

Proteomics in the discovery of new therapeutic targets for psychiatric disease.

In terms of impact on and cost to society psychiatric disorders are among the most important health problems of today. Current estimates from the US suggest that the collective cost of psychiatric diseases could amount to one-third of the total health care budget with a cumulative lifetime prevalence of 30%. While undoubtedly improvements have been made in the diagnosis and treatment of at least the symptoms of mental illness, there has been frustratingly little progress in elucidating the molecular mechanisms. However, a fundamentally different approach to study molecular mechanisms of psychiatric diseases is emerging as a result of technological advances in expression profiling methods. This comprises the investigation of the expressed disease 'phenotypes', developing from the differential gene and protein expression in the central nervous system as a result of the complex interaction between genetic predisposition and environmental modulation. This paper will focus on proteomics, expression profiling at the protein level, reviewing some of the available tools and their application in the molecular analysis of psychiatric disease.

Antipsychotic Agents↗
PubMed2003

[Therapeutic gene clusters as drug action mechanisms].

Pharmacogenomics is defined to identify the therapeutic gene clusters which are involved in determining the responsiveness and to distinguish responders and non-responders to a given drug. Genome sequencing, transcriptome, proteome and metabolome analysis are of particular significance in pharmacogenomics. Sequencing is used to locate polymorphisms, and monitoring of functional gene expression can provide clue about the genomic response to disease and treatment. The transcriptome analysis can be done by methods of random cDNA sequencing, mRNA display(fluorescent differential display et al.) and differential hybridization(cDNA microarray, oligomicrochip et al.). We used transcriptome/proteome/metabolome analysis to identify therapeutic target genes by studying change of gene expression in animal models and human model cells of various diseases and found novel drug target candidates through this pharmacogenomic strategy. The present study describes combined transcriptome and metabolome analysis for therapeutic target validation in hypoxia-induced vascular remodeling. The pharmacogenomic analysis and pharmainformatics has the potential for strategy to define novel therapeutic gene clusters in various diseases and holds the promise that drugs might be tailor-maid for individuals and adapted to each person's own genetic makeup. These techniques provided an excellent strategy for screening and validation of targets.

Animals↗
PubMed2005

Proteomic analysis of colonic myofibroblasts and effect on colon cancer cell proliferation.

BACKGROUND: The stromal microenvironment influences many steps of tumor progression through the elaboration of signals from myofibroblasts. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway transduces signals initiated by growth factors and is involved in colonic epithelial proliferation. The purpose of this study was to determine (1) the influence of myofibroblasts on colon cancer cell proliferation and PI3K activity, and (2) the protein alterations associated with myofibroblasts derived from polyp versus normal margins. METHODS: Myofibroblasts were derived from polyps and corresponding normal mucosa. Myofibroblasts were cocultured with colon cancer cells HT29 stably transfected with green fluorescent protein and KM20 cells. Proliferation was quantitated by green fluorescent protein count and cytokeratin enzyme-linked immunosorbent assay. HT29 cells were incubated with conditioned medium from myofibroblasts, and the effect on proliferation and PI3K activity was determined by 5-bromo 2-deoxyuridine incorporation and Akt kinase assay, respectively. Protein profiles were obtained by SELDI-TOF MS analysis. RESULTS: In coculture experiments, all myofibroblasts significantly enhanced HT29 and KM20 cell proliferation. However, polyp myofibroblasts enhanced proliferation of the cancer cells to a greater extent than normal myofibroblasts. Conditioned medium from all myofibroblasts stimulated Akt kinase activity. SELDI-TOF MS profiles showed more than 40 protein peaks for each isolate. One protein was differentially expressed in polyps versus normal cells. CONCLUSIONS: Utilizing a novel proteomic approach, we identify distinct protein profiles in myofibroblasts of polyps compared with stromal cells of normal mucosa. Moreover, myofibroblasts can stimulate indirectly PI3K activity and enhance colon cancer cell proliferation. These findings suggest that targeted therapy to signaling pathways in myofibroblasts may be useful in colorectal cancer chemoprevention and possible treatment.

Adenomatous Polyps↗
PubMed2006

Establishment of a 2-D human urinary proteomic map in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common form of immune complex-mediated glomerulonephritis worldwide. Although chronic renal failure develops in considerable numbers of IgAN patients, the exact etiology has not yet been clearly elucidated. To establish the urinary protein map of IgAN, we performed a urinary proteomic analysis. Thirteen patients with IgAN and 12 normal controls were recruited. Morning midstream spot urine samples were used with Centriprep ultrafiltration for concentration and desalting. 2-DE was performed and compared between IgAN and normal control, and urinary proteins were identified by MALDI-TOF MS. A large number of protein spots were identified in IgAN and normal control samples, with means of 311 spots and 174 spots, respectively. Approximately 216 protein spots were detected as differentially expressed in IgAN. Among these, 82 spots were over-expressed, and 134 spots were under-expressed compared to normal controls. A total of 84 differentially expressed spots, representing 59 different proteins, were finally identified in IgAN. We have established a urinary proteomic map of IgAN and this result helps in the identification. Further study is needed to determine the potential pathogenic role of these proteins.

Adolescent↗
PubMed2026

Large-Scale Proteomic Profiling of Incident Heart Failure and Its Subtypes in Older Adults.

BACKGROUND: Heart failure (HF) and its main subtypes, heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF), impose an enormous health burden on elders. Assessment of the circulating proteome to illuminate pathogenesis could open new opportunities for treatment. METHODS: We conducted a plasma proteomics screen of incident HF and its subtypes in 2 older population-based cohorts, the CHS (Cardiovascular Health Study) and the AGES-RS (Aging, Gene/Environment Susceptibility-Reykjavik Study). The 2 studies used SomaLogic platforms, with 4404 aptamers in common. Multivariable Cox models were fit to evaluate individual-protein associations with HF, HFpEF, and HFrEF separately in each cohort, and study-specific associations were combined by fixed-effects meta-analysis. Replication was performed in the ARIC (Atherosclerosis Risk in Communities) cohort. Two-sample Mendelian randomization of HF and its subtypes, along with colocalization analysis, was performed to support causal inference. RESULTS: Among 8599 participants, 1590 experienced incident HF (536 HFpEF, 471 HFrEF). There were 119 proteins associated with HF, 15 proteins with HFpEF, and 11 proteins with HFrEF, at Bonferroni-corrected significance. Among these, 9 have never previously been identified for cardiovascular diseases, and another 61 represent new associations with incident HF or its subtypes. Of these 70 proteins, 55 of the 66 available replicated externally. Mendelian randomization analysis revealed 7 proteins genetically associated with HF at nominal significance; 2 were separately associated with HFpEF, and another 2 with HFrEF. Seven of these 9 proteins (NPDC1 [neural proliferation differentiation and control protein 1], APOF [apolipoprotein F], LMAN2 [lectin, mannose-binding 2], ADIPOQ [adiponectin], CD14 [cluster of differentiation 14], ARHGAP1 [Rho GTPase-activating protein 1], C9 [complement 9]) showed new, possibly causal associations, although we did not detect evidence for colocalization. CONCLUSIONS: In this large-scale proteomic study involving 3 longitudinal cohorts of older adults, we identified and replicated 55 novel protein markers of HF or its subtypes, and 7 new, possibly causal proteins. These proteins may enhance risk prediction, improve understanding of pathobiology, and help prioritize targets for therapeutic development of these foremost disorders in elders.

Humans↗
PubMed2000

Identification of differentially expressed proteins between human hepatoma and normal liver cell lines by two-dimensional electrophoresis and liquid chromatography-ion trap mass spectrometry.

In the previous study, the proteomes of the human hepatoma cell line BEL-7404 and the normal human liver cell line L-02 were separated by high resolution two-dimensional electrophoresis (2-DE). Image analysis revealed that 99 protein spots showed quantitative and qualitative variations that were significant (P < 0.01) and reproducible. Here we report the identification results of some of these protein spots. Protein spots excised from 2-D gels were subjected to in-gel digestion with trypsin, and the resulting peptides were measured by microbore high performance liquid chromatography - ion trap - mass spectrometry (LC-IT-MS) to obtain the tandem mass (MS/MS) spectra. Twelve protein spots were identified with high confidence using SEQUEST with uninterpreted MS/MS raw data. Besides inosine-5'-monophosphate dehydrogenase 2, heat shock 27 kDa protein, calreticulin and calmodulin, whose expression was elevated in hepatoma cells, glutathione-S-transferase P was identified from hepatoma cells in which its level was 18-fold higher compared to human liver cells. Two spots were identified as the homologs of reticulocalbin for the first time in hepatoma cells and their expression increased compared to liver cells. However, tubulin beta-1 chain and natural killer cell enhancing factor B were downregulated in hepatoma cells. A tumor suppressing serpin, maspin precursor, was identified from one spot whose quantity was much higher in the normal liver cell line. More interestingly, epidermal fatty acid-binding protein (E-FABP) and fatty acid-binding protein, adipocyte-type (A-FABP), were detected in liver cells but not in hepatoma cells. The functional implication of the identified proteins was discussed.

Chromatography, Liquid↗
PubMed2006

Identification and functional analysis of damage-induced neuronal endopeptidase (DINE), a nerve injury associated molecule.

Nerve regeneration is a complex process associated with the expression of hundreds of genes. To elucidate the molecular mechanism responsible for nerve regeneration, hundreds of nerve regeneration-associated genes have been hunted using differential display polymerase chain reaction (DD-PCR), random cloning, microarray and proteomics. Damage-induced neuronal endopeptidase (DINE) is a newly identified nerve regeneration-related molecule derived from normal and axotomized hypoglosssal nuclei using DD-PCR. After full-length cloning, we have found that DINE is a neuron-specific membrane-bound metalloprotease. Damage-induced neuronal endopeptidase shares homology with neprilysin and endothelin-converting enzyme, which degrade or process neuropeptides. Although DINE has some neuroprotective effects, the physiological function of, as well as the substrate for, DINE remains obscure. The most intriguing property of DINE is its extreme transcriptional response against various types of nerve injuries, including that of the peripheral and central nervous systems. Thus, a more detailed expression profile of DINE mRNA was investigated using the dorsal root ganglion (DRG) after sciatic nerve injury. In the DRG, DINE mRNA was observed in small-sized DRG neurons after axotomy. This expression profile was similar to that of the neuropeptide galanin. Both in vitro and in vivo studies revealed that leukemia inhibitory factor and nerve growth factor withdrawal additively enhanced the expression of DINE, as well as that of galanin. Damage-induced neuronal endopeptidase and galanin may use common transcriptional regulation machinery. Although functional correlation of these molecules remains unclear, their simultaneous induction may provide more successful protection for injured neurons.

Animals↗
PubMed2005

Comparing the protein expression profiles of human mesenchymal stem cells and human osteoblasts using gene ontologies.

One of the hallmark events regulating the process of osteogenesis is the transition of undifferentiated human mesenchymal stem cells (hMSCs) found in the bone marrow into mineralized-matrix producing osteoblasts (hOSTs) through mechanisms that are not entirely understood. With recent developments in mass spectrometry and its potential application to the systematic definition of the stem cell proteome, proteins that govern cell fate decisions can be identified and tracked during this differentiation process. We hypothesize that protein profiling of hMSCs and hOSTs will identify potential osteogenic marker proteins associated with hMSC commitment and hOST differentiation. To identify markers for each cell population, we analyzed the expression of hMSC proteins and compared them to that of hOST by two-dimensional gel electrophoresis and two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS). The 2D LC-MS/MS data sets were analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Only 34% of the spots in 2D gels were found in both cell populations; of those that differed between populations, 65% were unique to hOST cells. Of the 755 different proteins identified by 2D LCMS/ MS in both cell populations, two sets of 247 and 158 proteins were found only in hMSCs and hOST cells, respectively. Differential expression of some of the identified proteins was further confirmed by Western blot analyses. Substantial differences in clusters of proteins responsible for calcium- based signaling and cell adhesion were found between the two cell types. Osteogenic differentiation is accompanied by a substantial change in the overall protein expression profile of hMSCs. This study, using gene ontology analysis, reveals that these changes occur in clusters of functionally related proteins. These proteins may serve as markers for identifying stem cell differentiation into osteogenic fates because they promote differentiation by mechanisms that remain to be defined.

Blotting, Western↗
PubMed2006

Proteomic analysis of malignant ovarian cancer effusions as a tool for biologic and prognostic profiling.

PURPOSE: Malignant epithelial ovarian cancer effusions are important in disease dissemination and clinical outcome. The identification of biochemical events active in effusions may improve our identification and application of targeted therapeutics. EXPERIMENTAL DESIGN: Archival effusion samples for which outcome information was known were studied. Clinical variables were comparable between these groups. Two cohorts of patients with malignant effusion were assessed: those with effusion at presentation (Tap1) or at first recurrence (Tap2). Expression and activated fraction of selected signaling proteins were quantitated on serial protein microarrays using validated antibodies. Proteomic results and clinical variables were analyzed by univariate analysis followed by Cox proportional hazards model analysis. RESULTS: Malignant effusions (>80% malignant cells) were distinguished from benign effusions by higher expression of AKT, activated extracellular signal-regulated kinase, activated (P < or = 0.001) and total cAMP-responsive element binding protein (P = 0.01), and JNK (P = 0.03). Malignant pleural effusions could not be differentiated from ascites by signaling profiles. Both had signal expression clusters for survival, proliferation and metastasis, and injury pathways. Cox proportional hazards model analysis revealed high p38 and pEGFR/EGFR ratio as jointly associated with poor survival in Tap1 cases (both P < or = 0.002). Phospho-JNK quantity was associated with worse outcome in Tap2 patients (P = 0.004), when taking other factors into consideration. CONCLUSIONS: Proliferation, survival, and apoptosis signaling dysregulation can be identified in ovarian cancer effusion samples. Biochemical characterization of clinical effusions may provide either predictive and/or correlative information on patient outcome from which to further understand the mechanisms of effusion development and target clinical intervention.

Apoptosis↗
PubMed2025

Malonate promotes CD8+ T cell memory formation via protein malonylation.

Protein malonylation represents a recently identified posttranslational modification whose role in CD8+ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8+ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8+ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8+ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8+ T cell memory formation.

Animals↗