Anti-p21 autoantibodies detected in colorectal cancer patients: A proof of concept study.
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ABSTRACT:
SUBMITTER: Bishehsari F
PROVIDER: S-EPMC4368126 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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Project description:Today, novel candidate therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. We present a strategy that allows biological relevance to be assessed in the early stages of drug discovery. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. The technique was applicable to compounds with a range of binding specificities and detected false-positive hits missed by classical phenotypic assays. Our results advocate application of molecular phenotyping in drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade.
2017-05-24 | GSE89972 | GEO
Project description:In this proof-of-concept study, spatial transcriptomics combined with public single-cell RNA sequencing data were used to explore the potential of this technology to study kidney allograft rejection. We aimed to map gene expression patterns within diverse pathological states by examining biopsies classified across non-rejection, T cell-mediated acute rejection, and interstitial fibrosis and tubular atrophy (IFTA). Our results revealed distinct immune cell signatures, including those of T and B lymphocytes, monocytes, mast cells, and plasma cells, and their spatial organization within the renal interstitium. We also mapped chemokine receptors and ligands to study immune-cell migration and recruitment. Finally, our analysis demonstrated differential spatial enrichment of transcription signatures associated with kidney allograft rejection across various biopsy regions. Interstitium regions displayed higher enrichment scores for rejection-associated gene expression patterns than did tubular areas, which had negative scores. This implies that these signatures are primarily driven by processes unfolding in the renal interstitium. Overall, this study highlights the value of spatial transcriptomics for revealing cellular heterogeneity and immune signatures in renal transplant biopsies, and demonstrates its potential for studying the molecular and cellular mechanisms associated with rejection. However, certain limitations must be borne in mind regarding the development and future applications of this technology.
2024-05-02 | GSE245870 | GEO
Project description:BackgroundLonger patient intervals can lead to more late-stage cancer diagnoses and higher mortality rates. Individuals may delay presenting to primary care with red flag symptoms and instead turn to the internet to seek information, purchase over-the-counter medication, and change their diet or exercise habits. With advancements in machine learning, there is the potential to explore this complex relationship between a patient's symptom appraisal and their first consultation at primary care through linkage of existing datasets (eg, health, commercial, and online).ObjectiveHere, we aimed to explore feasibility and acceptability of symptom appraisal using commercial- and health-data linkages for cancer symptom surveillance.MethodsA proof-of-concept study was developed to assess the general public's acceptability of commercial- and health-data linkages for cancer symptom surveillance using a qualitative focus group study. We also investigated self-care behaviors of ovarian cancer patients using high-street retailer data, pre- and postdiagnosis.ResultsUsing a high-street retailer's data, 1118 purchases-from April 2013 to July 2017-by 11 ovarian cancer patients and one healthy individual were analyzed. There was a unique presence of purchases for pain and indigestion medication prior to cancer diagnosis, which could signal disease in a larger sample. Qualitative findings suggest that the public are willing to consent to commercial- and health-data linkages as long as their data are safeguarded and users of this data are transparent about their purposes.ConclusionsCancer symptom surveillance using commercial data is feasible and was found to be acceptable. To test efficacy of cancer surveillance using commercial data, larger studies are needed with links to individual electronic health records.
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Project description:Quantitative mass spectrometry has transformed proteomics by allowing the simultaneous quantification of thousands of proteins. To boost statistical power, it is necessary to increase sample sizes by combining patient-derived data from various institutions. However, this practice raises significant privacy concerns. We created this dataset comtaining 30 healthy donors and 30 patients suffering from focal segmental glomerulosclerosis - a rare kidney disease - and distributed them to three independent proteomics centers. This distributed data were used as a proof of concept to introduce FedProt - the first privacy-preserving tool for collaborative differential protein abundance analysis of distributed data.
2024-08-08 | PXD053560 | Pride
Project description:Colorectal cancer remains the leading cause of cancer death worldwide. The 5-year annual survival is less than half of the incidence rate that is predominantly due to late diagnosis of the disease striking the very urgent clinical necessity for biomarkers capable of detecting cancer malignancy at an early onset. During neoplastic transformation, cells undergo several behavioral changes that subsequently result in defects in cell division, immune tolerance, inflammation, and cellular death mechanisms. These processes lead to the development of tumor antigens (TA) that evoke an immune response and subsequent generation of antibodies against self-proteins, called autoantibodies (AAbs). This study aims to identify autoantibody biomarkers in patient’s sera for early screening of the cancer. High-density human proteome array having approximately 17,000 full-length recombinant human proteins were used in the study. The generation of an autoimmune response against important cancer-linked pathways could be important in terms of screening for the disease. The process of immune surveillance starts as tumorigenesis begins and hence autoantibodies can be detected in a very early stage of cancer. Moreover, AAbs can be easily extracted from blood serum through the least invasive test for disease screening.
2022-12-07 | E-MTAB-12081 | biostudies-arrayexpress
Project description:BackgroundCogMed Working Memory Training (CWMT) is a computer-based program shown to improve working memory (WM) among those with cognitive impairments. No study to date has investigated its feasibility, acceptability, and satisfaction in adult patients with glioma, despite the well-documented incidence of WM impairment in this population.MethodsTwenty patients with glioma and objective and/or perceived WM deficits enrolled in the study: 52% high-grade, 60% female, Mage = 47 (range = 21-72 years). Adverse events were monitored to determine safety. Feasibility and acceptability were assessed based on established metrics. Satisfaction was explored by exit-interviews. Neurocognitive tests and psychological symptoms were analyzed at baseline and post-CWMT to estimate effect sizes.ResultsOf 20 enrolled patients, 16 completed the intervention (80% retention rate). Reasons for withdrawal included time burden (n = 2); tumor-related fatigue (n = 1) or loss to follow-up (n = 1). No adverse events were determined to be study-related. Adherence was 69% with reasons for nonadherence similar to those for study withdrawal. The perceived degree of benefit was only moderate. Baseline to post-CWMT assessments showed medium to large effects on neurocognitive tasks. Psychological symptoms remained stable throughout the study period.ConclusionsCWMT was found to be safe and acceptable in adult patients with glioma. Enrollment, retention rates, and treatment adherence were all adequate and comparable to studies recruiting similar populations. Only moderate perceived benefit was reported despite demonstrated improvements in objectively-assessed WM. This may indicate that the time commitment and intervention intensity (5 weeks of 50-min training sessions on 5 days/week) outweighed the perceived benefits of the program. (Trial Registration Number: NCT03323450 registered on 10/27/2017).
| S-EPMC9720894 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-12-21 | GSE109514 | GEO
Project description:BackgroundTo identify subjects with rupture-prone atherosclerotic plaques before thrombotic events occur is an unmet clinical need. Thus, this proof-of-concept study aims to determine which rupture-prone plaque features can be detected using clinically available photon-counting computed tomography (PCCT).MethodsIn this retrospective study, advanced atherosclerotic plaques (ex vivo, paraffin-embedded) from the Carotid Plaque Imaging Project were scanned by PCCT with reconstructed energy levels (45, 70, 120, 190 keV). Density in HU was measured in 97 regions of interest (ROIs) representing rupture-prone plaque features as demonstrated by histopathology (thrombus, lipid core, necrosis, fibrosis, intraplaque haemorrhage, calcium). The relationship between HU and energy was then assessed using a mixed-effects model for each plaque feature.ResultsPlaques from five men (age 79 ± 8 [mean ± standard deviation]) were included in the study. Comparing differences in coefficients (b1diff) of matched ROIs on plaque images obtained by PCCT and histology confirmed that calcium was distinguishable from all other analysed features. Of greater novelty, additional rupture-prone plaque features proved discernible from each other, particularly when comparing haemorrhage with fibrous cap (p = 0.017), lipids (p = 0.003) and necrosis (p = 0.004) and thrombus compared to fibrosis (p = 0.048), fibrous cap (p = 0.028), lipids (p = 0.015) and necrosis (p = 0.017).ConclusionsClinically available PCCT detects not only calcification, but also other rupture-prone features of human carotid plaques ex vivo.Relevance statementImproved atherosclerotic plaque characterisation by photon-counting CT provides the ability to distinguish not only calcium, but also rupture-prone plaque features such as haemorrhage and thrombus. This may potentially improve monitoring and risk stratification of atherosclerotic patients in order to prevent strokes.Key points• CT of atherosclerotic plaques mainly detects calcium. • Many components, such as intra-plaque haemorrhage and lipids, determine increased plaque rupture risk. • Ex vivo carotid plaque photon-counting CT distinguishes haemorrhage and thrombus. • Improved plaque photon-counting CT evaluation may refine risk stratification accuracy to prevent strokes.
| S-EPMC10825079 | biostudies-literature
Project description:Innovative single cell technologies such as mass cytometry (CyTOF) widen possibilities to deeply improve characterisation of immune alterations mechanisms in human diseases. So far, CyTOF has not been used in sepsis - a condition characterized by complex immune disorders. Here, we evaluated feasibility of CyTOF analysis in patients with septic shock. We designed a mass cytometry panel of 25 extracellular markers to study mononuclear cells from 5 septic shock patients and 5 healthy donors. We explored single-cell data with global and specific unsupervised approaches such as heatmaps, SPADE and viSNE. We first validated relevance of our CyTOF results by highlighting established immune hallmarks of sepsis, such as decreased monocyte HLA-DR expression and increased expressions of PD1 and PD-L1 on CD4 T cells and monocytes. We then showed that CyTOF analysis reveals novel aspects of sepsis-induced immune alterations, e.g. B cell shift towards plasma cell differentiation and uniform response of several monocyte markers defining an immune signature in septic patients. This proof of concept study demonstrates CyTOF suitability to analyse immune features of septic patients. Mass cytometry could thus represent a powerful tool to identify novel pathophysiological mechanisms and therapeutic targets for immunotherapy in septic shock patients.
| S-EPMC6251894 | biostudies-other
Project description:SettingAnti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues.Objectiveniazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI).DesignPBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval.ResultsThe PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing.ConclusionWe identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed.
| S-EPMC6166436 | biostudies-literature