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PubMed2025

Integrated Multiomics Analysis of Microsatellite Instability-High Colorectal Cancer Identifies a Subtype With Poor Outcome.

Up to 50% of patients with metastatic microsatellite instability-high (MSI-H) colorectal cancer (CRC) are resistant to immunotherapy and experience progression or recurrence after treatment. We integrated the genomic, epigenomic, transcriptomic, and proteomic data for 99 patients in a Chinese MSI-H CRC cohort. Proteomic profiling of primary tumors clearly classified MSI-H tumors into 2 subtypes. We found that the 2 subtypes have different mutational signatures, enriched pathways, gene fusion networks, and clinical outcomes. Notably, NCAM1 could serve as a potential biomarker for checkpoint inhibitor response in MSI-H CRC. Thus, there is an urgent need to stratify the MSI-H group into different subtypes and adopt more targeted therapies to prolong patient survival.

Humans↗

PubMed2026

Time- and Dose-Resolved DIA-PASEF Proteomics Maps the Transition from Adaptive Stress to Apoptotic Collapse in Melittin-Treated MDA-MB-231 Cells.

Melittin, the cytolytic peptide of honeybee venom, exhibits potent anticancer activity in triple-negative breast cancer (TNBC), yet the molecular programs underlying its cytotoxic effects remain incompletely defined. To address this gap, MDA-MB-231 TNBC cells were exposed to melittin at half-maximal inhibitory concentration(half IC50) and IC50 across early(0.5, 1, and 2 h), mid(3, 4 h), and late (12, 24 h) time windows. Proteomic profiling was performed using label-free data-independent acquisition(DIA) parallel accumulation-serial fragmentation(PASEF). Approximately 5800 proteins were quantified, revealing distinct dose-dependent stress responses. An integrative exploratory framework combining time-resolved log2 fold-change trajectories, area-under-the-curve(AUC) based temporal prioritization, and independent heatmap visualization identified proteins associated with melittin-induced stress remodeling. Half IC50 exposure showed a transient stress-adaptive signature characterized by chromatin remodeling(HMGN2, H2AZ1), structural and RNA-associated buffering(LRRC7), and indirect mitochondrial quality-control signaling(CPAMD8, SPATA4), which progressively weakened over time. In contrast, IC50 treatment induced rapid chromatin remodeling dominated by histone H1 variants(H1.4, H1.2), early RNA instability(LRRC7), and late-stage cytoskeletal disassembly marked by MICAL3 induction, consistent with progression toward apoptosis. These trajectories paralleled dose-dependent apoptotic phenotypes. Overall, data suggest that melittin elicits dose- and time-dependent proteomic stress responses in TNBC cells and identify candidate trajectory-associated proteins and pathways linked to adaptive stress remodeling or progression toward cytotoxic collapse.

Melitten↗

PubMed2006

Proteomic analysis of the effects of cocaine on the enhancement of HIV-1 replication in normal human astrocytes (NHA).

The US is experiencing an epidemic of cocaine use entangled with HIV-1 infection. Normal human astrocytes (NHA) are susceptible to HIV-1 infection. We utilized LTR-R/U5 amplification, p24 antigen assay and the proteomic method of difference gel electrophoresis (DIGE) combined with protein identification through HPLC-MS/MS to investigate the effect of cocaine on HIV-1 infectivity and the proteomic profile of NHA, respectively. Data demonstrate that cocaine significantly upregulates HIV-1 infection in NHA as measured by LTR-R/U5 amplification and p24 antigen assay. Further, our results show for the first time that cocaine differentially regulates the expression of a number of proteins by NHA that may play a role in the neuropathogenesis of HIV-1 disease.

Astrocytes↗

PubMed2025

iTRAQ-based quantitative proteomics reveals reduced expression of KRT19, KRT7, and PSTDG in cutaneous specimens after kidney transplantation.

Clinical improvement in pigmentation is frequently observed after kidney transplantation. However, the underlying molecular and histological mechanisms remain unclear. We conducted a study to quantify the skin color change using a handheld reflected light colorimeter and to investigate protein expression changes in the skin before and after kidney transplantation. Paired skin biopsies were obtained from three patients who underwent kidney transplantation before and one month after transplantation. Protein expression was analyzed using iTRAQ-based quantitative proteomics. Differentially expressed proteins were identified and visualized using hierarchical clustering and volcano plots. Histopathological evaluation included hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical (IHC) staining for keratin (KRT) 7, KRT19, and MelanA. Skin pigmentation of the arms, ankles, and abdomen had significant L-value improvement after kidney transplantation. Proteomic profiling identified 2148 proteins, with six proteins showing significant differential expression after transplantation. Among them, KRT7, KRT19, and prostaglandin D2 synthase (PTGDS) were significantly downregulated, potentially reflecting reduced epithelial stress and systemic inflammation. H&E and Masson's trichrome staining revealed a post-transplantation reduction in dermal pigmentation and collagen content. IHC showed decreased KRT7, KRT19, and MelanA expression after transplantation. Our results suggest that targeting KRT or prostaglandin pathways may offer new treatments for ESRD-related skin symptoms.

Humans↗

PubMed2004

Use of two-dimensional gel electrophoresis proteome reference maps of dinoflagellates for species recognition of causative agents of harmful algal blooms.

The sample preparation procedures established for Prorocentrum triestinum were adapted to cover both thecate and athecate dinoflagellates. Further, whether trichloroacetic acid (TCA) precipitation can be used to fix and preserve the harmful or nuisance species from local waters that they infest was tested. Optimized technical procedures developed were used to generate proteome reference maps for eight other local causative species of harmful algal blooms (HABs): Prorocentrum micans, Prorocentrum minimum, Prorocentrum sigmoides, Prorocentrum dentatum, Scrippsiella trochoidea, Karenia longicanalis, Karenia digitata and Karenia mikimotoi; together with one American species Karenia brevis (Florida, USA). These proteome maps were used to test their ability for species recognition in a mixed culture of dinoflagellates and whether such investigations will provide a comparative view at a global level. Comparisons of proteome profiles were made (i). between closely related species within the same family; (ii). between distantly related species belonging to different types, i.e., gymnodinioids, prorocentroids or peridinioids, or (iii). between different groups, i.e., thecate (armored) dinoflagellate cells against athecate (naked or unarmored) dinoflagellate cells. Species-specific two-dimensional electrophoresis (2-DE) protein profiles were observed in all ten species and it was possible to distinguish between even closely related species within the same family. To demonstrate the extent of reproducibility and usefulness of these 2-DE reference maps, 2-DE has been used to analyze three geographically distinct isolates of Prorocentrum dentatum, and to distinguish species composition in a mixed culture. Application of 2-D PAGE analysis to differentiate between taxonomically confused strains of a single species could be a powerful taxonomic tool.

Animals↗

PubMed2005

Proteomic identification of differentially expressed proteins in the aging murine olfactory system and transcriptional analysis of the associated genes.

Decline in olfactory ability has been associated with aging as well as neurodegenerative disorders. The aim of this study was to gain fundamental insight into molecular events associated with the aging olfactory system. We report a comparative proteomic analysis of the olfactory epithelium (OE) and olfactory bulb (OB) of old (80-week old) and young (6-week old) mice with further analysis of age-related differences in differentially expressed proteins at the mRNA level using real-time RT-PCR. Nine proteins in the OE and 20 in the OB were differentially expressed in old and young mice; of these, aldolase 1, peptidyl prolyl isomerase A, mitochondrial aconitase 2, mitochondrial aldehyde dehydrogenase 2 and albumin 1 were identified in the OE; and ATP synthase isoform 1, enolase 1, ferritin heavy chain, malate dehydrogenase 1, tropomyosin alpha 3 chain and dynamin 1 were identified in the OB. At the transcriptional level, aconitase 2 in the OE and ferritin heavy chain 1 in the OB were differentially expressed with aging, in concordance with the proteomic data. Our results demonstrate an altered proteomic profile of the aged murine olfactory system. The identified proteins fall into three broadly defined functional categories: (i) metabolism, (ii) transport/motility and (iii) stress response. Our transcriptional analysis provides insight into possible mechanisms by which protein expression may be regulated in the OE and OB. The results are discussed in relation to the decrement in olfactory sensitivity with aging.

Age Factors↗

PubMed2026

Early life sugar rationing and ageing related diseases, biological ageing and mortality.

Early-life nutrition may influence lifelong ageing, yet human evidence is scarce. Using Britain's postwar sugar rationing as a natural experiment, we examine its long-term effects in 64,809 United Kingdom Biobank participants. Exposure to sugar rationing during the first 1,000 days of life is associated with a 9% lower incidence of hallmark-related disease, with a hazard ratio of 0.91 and a 95% confidence interval of 0.88-0.94, and a 19% lower risk of all-cause mortality, with a hazard ratio of 0.81 and a 95% confidence interval of 0.69-0.93. Mediation analysis indicates that the survival association is statistically mediated, by approximately 60%, through differences in incident hallmark-related disease. Rationed individuals show 1.0-1.2-year younger biological ages across multiple clocks and lower organ ages, particularly in the lung, heart, and liver. Proteomic profiling identifies 47 altered proteins, with enrichment of adenosine monophosphate-activated protein kinase and longevity pathways and suppression of mechanistic target of rapamycin signaling. These findings are consistent with international recommendations to limit free or added sugars from the World Health Organization, United States Dietary Guidelines, and American Heart Association, and may inform policy discussions related to sugar taxation and infant food and marketing policies under the United Nations 2030 Agenda.

Humans↗

PubMed2005

Identification of reproducible low mass SELDI protein profiles specific to cisplatin resistance in human ovarian cancer cells.

Platinum compounds are the most effective drugs in the fight against ovarian cancer. Unfortunately, many ovarian tumors are not eradicated by chemotherapy due to the emergence of drug-resistant clones during therapy, and hence 5-year survival rate of women afflicted with this disease is just 18%. In the continued absence of an effective early detection test for ovarian cancer, there is a considerable need to develop treatment strategies that can either circumvent (e.g. gene therapy) or prevent the development of platinum resistance. A prerequisite for the development of such treatments is a detailed knowledge of factors that confer tumor cell resistance to platinum compounds. We have used surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS or SELDI) to identify low mass proteins that are uniquely expressed in ovarian tumor cells that are platinum-resistant. Only two polypeptide peaks (m/z 5041 and 7324) were consistently altered following the induction of cisplatin resistance in the OAW42 and 2780 cell lines. These peaks appear to be specific to cisplatin resistance as they are not altered in the same manner in a melphalan-resistant variant of OAW42. The exact identity of the polypeptide peaks is unknown, but appears to be unrelated to changes in several proteins that have been historically associated with cisplatin resistance. These data suggest that SELDI-based proteomic profiling may be useful in monitoring the emergence of cisplatin-resistant tumor cell clones.

Antineoplastic Agents↗

PubMed2005

Functional analysis of two divalent metal-dependent regulatory genes dmdR1 and dmdR2 in Streptomyces coelicolor and proteome changes in deletion mutants.

In Gram-positive bacteria, the expression of iron-regulated genes is mediated by a class of divalent metal-dependent regulatory (DmdR) proteins. We cloned and characterized two dmdR genes of Streptomyces coelicolor that were located in two different nonoverlapping cosmids. Functional analysis of dmdR1 and dmdR2 was performed by deletion of each copy. Deletion of dmdR1 resulted in the derepression of at least eight proteins and in the repression of three others, as shown by 2D proteome analysis. These 11 proteins were characterized by MALDI-TOF peptide mass fingerprinting. The proteins that show an increased level in the mutant correspond to a DNA-binding hemoprotein, iron-metabolism proteins and several divalent metal-regulated enzymes. The levels of two other proteins--a superoxide dismutase and a specific glutamatic dehydrogenase--were found to decrease in this mutant. Complementation of the dmdR1-deletion mutant with the wild-type dmdR1 allele restored the normal proteome profile. By contrast, deletion of dmdR2 did not affect significantly the protein profile of S. coelicolor. One of the proteins (P1, a phosphatidylethanolamine-binding protein), overexpressed in the dmdR1-deleted mutant, is encoded by ORF3 located immediately upstream of dmdR2; expression of both ORF3 and dmdR2 is negatively controlled by DmdR1. Western blot analysis confirmed that dmdR2 is only expressed when dmdR1 is disrupted. Species of Streptomyces have evolved an elaborated regulatory mechanism mediated by the DmdR proteins to control the expression of divalent metal-regulated genes.

Amino Acid Sequence↗

PubMed2005

Practical proteomic biomarker discovery: taking a step back to leap forward.

There is a pressing need for radically improved proteomic screening methods that allow for earlier diagnosis of disease, for systematic monitoring of physiological responses and for uncovering the fundamental mechanisms of drug action. Recent developments in proteomic technology offer tremendous, yet untapped, potential to yield novel biomarkers that are translatable to routine clinical use. Despite the significant conceptual promise of comparative proteomic profiling as a research platform for biomarker discovery, however, major hurdles remain for practical and clinical implementation. In particular, there is growing recognition that rigorous experimental design principles are urgently required to validate conclusively the unproven methodologies currently being touted. Debate and confusion persist about where the burden of proof lies: statistically, biologically or clinically? Moreover, there is no consensus about what constitutes a meaningful benchmark. An important question is how to achieve a scientifically rigorous, and therefore convincing, proof-of-concept that can be accepted by the field. Key analytical challenges related to these issues that must be addressed by the burgeoning biomarker community are discussed here.

Animals↗

PubMed2004

Mass spectrometry as a diagnostic and a cancer biomarker discovery tool: opportunities and potential limitations.

Serum proteomic profiling, by using surfaced-enhanced laser desorption/ionization-time-of-flight mass spectrometry, is one of the most promising new approaches for cancer diagnostics. Exceptional sensitivities and specificities have been reported for some cancer types such as prostate, ovarian, breast, and bladder cancers. These sensitivities/specificities are far superior to those obtained by using classical cancer biomarkers. In this review, I concentrate more on questions that cast doubt on the results reported and propose experiments to investigate these questions in detail, before the technique is used at the clinic. It is clear that the method needs to be externally and thoroughly validated before clinical implementation is warranted.

Biomarkers, Tumor↗

PubMed2026

Proteomics identify disease-associated variants in patients with rare diseases undiagnosed after genome sequencing.

Despite the introduction of genome sequencing (GS) for rare disease diagnostics, a genetic cause is not identified in most patients. Here, we explored the potential of proteomics to improve the diagnostic yield in 424 patients with rare diseases from the 100,000 Genomes Project (100kGP) without a genetic diagnosis. Serum proteomic profiling was performed using the Olink Explore 1536 assay (N = 1463 proteins). For 13 patients without genetic diagnoses, detection of lower serum protein "outliers" (z-score < -2) led to confirmed genetic diagnoses by resolving variants of uncertain significance or prioritizing genes for targeted GS reanalysis. For 23 additional patients without genetic diagnoses (64% of findings), we identified candidate gene-disease links and variants through convergent evidence from lower protein outliers and variants ranked through the variant prioritization tool Exomiser. For example, we identified a candidate heterozygous missense variant [Genome Aggregation Database (gnomAD) minor allele frequency = 0.006%] in tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains 1 (TIE1) that was only present in a patient with lower TIE1 serum abundance (z-score = -5.12) and their father, both of whom were affected by the same monogenic cardiac disorder, but in no other individuals from the 100kGP. Missense (52.5%) and splice region (27.5%) variants accounted for most diagnostic or candidate variants prioritized. This proof-of-principle study demonstrated that serum proteomics can support rare disease diagnosis and identify disease-causing genes in patients undiagnosed after GS, although successful implementation will likely depend on tissue specificity of protein expression, detectability in blood, proteomic platform coverage, and sensitivity.

Humans↗

PubMed2005

Protein sequence tags: a novel solution for comparative proteomics.

Comparative proteome profiling using stable isotope peptide labelling and mass spectrometry has emerged as a promising strategy. Here, we show the broad potential of our proprietary protein sequence tag (PST) technology. A special feature of PST is its ability to detect a wide variety of proteins including the pharmaceutically relevant membrane and nuclear proteins. This procedure addresses a similar number of proteins, compared to the multidimensional protein identification technology approach, but offers additionally a quantitative analysis with its recently developed quantitative PST version.

Amino Acid Sequence↗

PubMed2006

IgA nephropathy associated with Hodgkin's disease in children: a case report, literature review and urinary proteome analysis.

We report herein a rare case of IgAN associated with Hodgkin's disease in a 14-year-old boy. Clinical manifestations and laboratory parameters were improved after treatment with CHOP chemotherapy and enalapril. Urinary proteins were isolated and examined using state-of-the-art proteomic technology, before and during the treatment course. Two-dimensional gel electrophoresis showed obvious alterations in the urinary proteome profile in response to such therapy. Quantitative intensity analysis and gel mapping revealed 14 altered proteins with reduced excretion levels during the treatment course, including albumin, albumin complexed with decanoic acid, alpha-1 antitrypsin, cadherin-11 precursor, collagen alpha 1 (VI) chain precursor, complement C1q tumor necrosis factor-related protein, Ig heavy chain, Ig light chain, kininogen, inter-alpha-trypsin inhibitor (alpha-1 microglobulin), inter-alpha-trypsin inhibitor heavy chain, leucine-rich alpha-2 glycoprotein, beta-2 microglobulin, and transferrin precursor. Their potential roles in the pathogenesis and pathophysiology of IgAN are discussed.

Adolescent↗

PubMed2005

An overview of chemosensitivity testing.

This overview chapter presents the importance of chemosensitivity testing for screening new therapeutic agents, identifying patterns of chemosensitivity for different types of tumors, establishing patterns of cross-resistance and sensitivity in treatment naive and relapsing tumors; identifying genomic and proteomic profiles associated with sensitivity; correlating in vitro response, preclinical in vivo effect, and clinical outcome associated with a particular therapeutic agent, and tailoring chemotherapy regimens to individual patients. Various assays are available to achieve these end points, including several in vitro clonogenic and proliferation assays, cell metabolic activity assays, molecular assays to monitor expression of markers for responsiveness, development of drug resistance and induction of apoptosis, in vivo tumor growth and survival assays in metastatic and orthotopic models, and in vivo imaging assays. The advantages and disadvantages of the specific assays are discussed. A summary of research areas related to chemo sensitivity testing is also included.

Animals↗

PubMed2005

Proteomic analysis of corticobasal degeneration: a case study of corticobasal degeneration at the proteome level.

Corticobasal degeneration (CBD) is an adult-onset progressive neurodegenerative disorder. However, its pathogenic mechanisms underlying this disorder remain poorly understood. The authors examined changes of proteome profiles between three nondemented comparison brains and a CBD brain based on two-dimensional gel electrophoresis. Two up-regulated proteins in the CBD brain were identified as protein-L-isoaspartate (D-aspartate) O-methyltransferase and cofilin 1 (non-muscle), and six down-regulated proteins were identified as carbonyl reductase [NADPH] 1, two of peptidyl-prolyl cis-trans isomerase A, ubiquitin carboxyl-terminal hydrolase isozyme L1, phosphoglycerate mutase 1 (brain) and chain A of human peroxiredoxin 5. Subsequently, the possible relevance of these changes was analyzed.

Aged↗

PubMed2005

Adaptation of Corynebacterium glutamicum to ammonium limitation: a global analysis using transcriptome and proteome techniques.

Theresponse of Corynebacterium glutamicum to ammonium limitation was studied by transcriptional and proteome profiling of cells grown in a chemostat. Our results show that ammonium-limited growth of C. glutamicum results in a rearrangement of the cellular transport capacity, changes in metabolic pathways for nitrogen assimilation, amino acid biosynthesis, and carbon metabolism, as well as a decreased cell division. Since transcription at different growth rates was studied, it was possible to distinguish specific responses to ammonium limitation and more general, growth rate-dependent alterations in gene expression. The latter include a number of genes encoding ribosomal proteins and genes for F(o)F(1)-ATP synthase subunits.

Adaptation, Physiological↗

PubMed2005

Proteomic analysis of nipple aspirate fluid using SELDI-TOF-MS.

Proteomic analysis of body fluids, including breast nipple aspirate fluid (NAF), holds promise to aid in early cancer detection. We conducted a prospective trial that collected NAF from women scheduled for diagnostic breast surgery to determine 1) the consistency of proteomic results, 2) protein masses associated with breast cancer, 3) subsets of women with a unique proteomic profile and 4) a breast cancer predictive model. NAF was collected preoperatively in 114 women and analyzed by SELDI-TOF mass spectrometry over a 3-50 kDa range using H4, NP and SAX ProteinChips. For all 3 chips, the same protein peaks were detected over 90% of the time in duplicate samples. The overall coefficient of variation was < or = 0.17% for each chip for the internal standard and < or = 0.29% for the unknown proteins. Seven candidate protein ion masses frequently expressed in NAF were identified. Three (5,200-H4, p=.04, 11,880-H4, p=.07 and 13,880 Da-SAX, p=.03) were differentially expressed in women with/without breast cancer. Protein expression differed between women with/without pathologic nipple discharge (PND), but the 5,200, 11,880 and 13,880 proteins remained associated with breast cancer even if PND samples were excluded. Subset analysis identified differences in expression between benign disease and DCIS and between DCIS and invasive cancer for the 5,200 and 33,400 Da proteins. The best cancer detection model included age, parity and the 11,880 Da protein, and excluded women with PND. 1) NAF proteomic analysis using SELDI-TOF is reproducible with the same sample set across different platforms, 2) differential proteomic expression exists between women/without breast cancer and 3) combining proteomic and clinical information that are available before surgery optimizes the prediction of which women have breast cancer.

Adult↗