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Journal of the American Heart... Jun 2024Cardiac troponin is extensively used as a biomarker in modern medicine due to its diagnostic capability for myocardial injury, as well as its predictive and prognostic... (Review)
Review
Cardiac troponin is extensively used as a biomarker in modern medicine due to its diagnostic capability for myocardial injury, as well as its predictive and prognostic value for cardiac diseases. However, heterophile antibodies, antitroponin antibodies, and macrotroponin complexes can be observed both in seemingly healthy individuals and patients with cardiac diseases, potentially leading to false positive or disproportionate elevation of cTn (cardiac troponin) assay results and introducing discrepancies in clinical interpretations with impact on medical management. In this review article, we describe the possible mechanisms of cTn release and the sources of variations in the assessment of circulating cTn levels. We also explore the pathophysiological mechanisms underlying antitroponin antibody development and discuss the influence exerted by macrotroponin complexes on the results of immunoassays. Additionally, we explore approaches to detect these complexes by presenting various clinical scenarios encountered in routine clinical practice. Finally, unsolved questions about the development, prevalence, and clinical significance of cardiac autoantibodies are discussed.
Topics: Humans; Biomarkers; Autoantibodies; Heart Diseases; Predictive Value of Tests; Troponin I; Prognosis
PubMed: 38879450
DOI: 10.1161/JAHA.123.035128 -
Cellular and Molecular Life Sciences :... Jun 2024Members of the myosin superfamily of molecular motors are large mechanochemical ATPases that are implicated in an ever-expanding array of cellular functions. This review... (Review)
Review
Members of the myosin superfamily of molecular motors are large mechanochemical ATPases that are implicated in an ever-expanding array of cellular functions. This review focuses on mammalian nonmuscle myosin-2 (NM2) paralogs, ubiquitous members of the myosin-2 family of filament-forming motors. Through the conversion of chemical energy into mechanical work, NM2 paralogs remodel and shape cells and tissues. This process is tightly controlled in time and space by numerous synergetic regulation mechanisms to meet cellular demands. We review how recent advances in structural biology together with elegant biophysical and cell biological approaches have contributed to our understanding of the shared and unique mechanisms of NM2 paralogs as they relate to their kinetics, regulation, assembly, and cellular function.
Topics: Animals; Humans; Myosins; Models, Molecular
PubMed: 38878079
DOI: 10.1007/s00018-024-05264-6 -
Proceedings of the National Academy of... Jun 2024Plants rely on immune receptor complexes at the cell surface to perceive microbial molecules and transduce these signals into the cell to regulate immunity. Various...
Plants rely on immune receptor complexes at the cell surface to perceive microbial molecules and transduce these signals into the cell to regulate immunity. Various immune receptors and associated proteins are often dynamically distributed in specific nanodomains on the plasma membrane (PM). However, the exact molecular mechanism and functional relevance of this nanodomain targeting in plant immunity regulation remain largely unknown. By utilizing high spatiotemporal resolution imaging and single-particle tracking analysis, we show that myosin XIK interacts with remorin to recruit and stabilize PM-associated kinase BOTRYTIS-INDUCED KINASE 1 (BIK1) within immune receptor FLAGELLIN SENSING 2 (FLS2)-containing nanodomains. This recruitment facilitates FLS2/BIK1 complex formation, leading to the full activation of BIK1-dependent defense responses upon ligand perception. Collectively, our findings provide compelling evidence that myosin XI functions as a molecular scaffold to enable a spatially confined complex assembly within nanodomains. This ensures the presence of a sufficient quantity of preformed immune receptor complex for efficient signaling transduction from the cell surface.
Topics: Arabidopsis; Arabidopsis Proteins; Cell Membrane; Immunity, Innate; Myosins; Plant Diseases; Plant Immunity; Protein Kinases; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 38875149
DOI: 10.1073/pnas.2312415121 -
Molecular Biomedicine Jun 2024Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying...
Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying mechanisms are still unclear, and the development of targeted drugs is lagging. Here, we used mice to explore the effects of prolonged SD on cardiac structure and function. Echocardiography analysis revealed that cardiac function was significantly decreased in mice after five weeks of SD. Real-time quantitative PCR (RT-q-PCR) and Masson staining analysis showed that cardiac remodeling marker gene Anp (atrial natriuretic peptide) and fibrosis were increased, Elisa assay of serum showed that the levels of creatine kinase (CK), creatine kinase-MB (CK-MB), ANP, brain natriuretic peptide (BNP) and cardiac troponin T (cTn-T) were increased after SD, suggesting that cardiac remodeling and injury occurred. Transcript sequencing analysis indicated that genes involved in the regulation of calcium signaling pathway, dilated cardiomyopathy, and cardiac muscle contraction were changed after SD. Accordingly, Western blotting analysis demonstrated that the cardiac-contraction associated CaMKK2/AMPK/cTNI pathway was inhibited. Since our preliminary research has confirmed the vital role of Casein Kinase-2 -Interacting Protein-1 (CKIP-1, also known as PLEKHO1) in cardiac remodeling regulation. Here, we found the levels of the 3' untranslated region of Ckip-1 (Ckip-1 3'UTR) decreased, while the coding sequence of Ckip-1 (Ckip-1 CDS) remained unchanged after SD. Significantly, adenovirus-mediated overexpression of Ckip-1 3'UTR alleviated SD-induced cardiac dysfunction and remodeling by activating CaMKK2/AMPK/cTNI pathway, which proposed the therapeutic potential of Ckip-1 3'UTR in treating SD-induced heart disease.
Topics: Animals; Male; Mice; 3' Untranslated Regions; AMP-Activated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Carrier Proteins; Mice, Inbred C57BL; Myocardium; Signal Transduction; Sleep Deprivation; Troponin I
PubMed: 38871861
DOI: 10.1186/s43556-024-00186-y -
BMJ Open Jun 2024Clinical assessment in emergency departments (EDs) for possible acute myocardial infarction (AMI) requires at least one cardiac troponin (cTn) blood test. The...
Protocol for Improving Care by FAster risk-STratification through use of high sensitivity point-of-care troponin in patients presenting with possible acute coronary syndrome in the EmeRgency department (ICare-FASTER): a stepped-wedge cluster randomised quality improvement initiative.
INTRODUCTION
Clinical assessment in emergency departments (EDs) for possible acute myocardial infarction (AMI) requires at least one cardiac troponin (cTn) blood test. The turn-around time from blood draw to posting results in the clinical portal for central laboratory analysers is ~1-2 hours. New generation, high-sensitivity, point-of-care cardiac troponin I (POC-cTnI) assays use whole blood on a bedside (or near bedside) analyser that provides a rapid (8 min) result. This may expedite clinical decision-making and reduce length of stay. Our purpose is to determine if utilisation of a POC-cTnI testing reduces ED length of stay. We also aim to establish an optimised implementation process for the amended clinical pathway.
METHODS AND ANALYSIS
This quality improvement initiative has a pragmatic multihospital stepped-wedge cross-sectional cluster randomised design. Consecutive patients presenting to the ED with symptoms suggestive of possible AMI and having a cTn test will be included. Clusters (comprising one or two hospitals each) will change from their usual-care pathway to an amended pathway using POC-cTnI-the 'intervention'. The dates of change will be randomised. Changes occur at 1 month intervals, with a minimum 2 month 'run-in' period. The intervention pathway will use a POC-cTnI measurement as an alternate to the laboratory-based cTn measurement. Clinical decision-making steps and logic will otherwise remain unchanged. The POC-cTnI is the Siemens (Erlangen Germany) Atellica VTLi high-sensitivity cTnI assay. The primary outcome is ED length of stay. The safety outcome is cardiac death or AMI within 30 days for patients discharged directly from the ED.
ETHICS AND DISSEMINATION
Ethics approval has been granted by the New Zealand Southern Health and Disability Ethics Committee, reference 21/STH/9. Results will be published in a peer-reviewed journal. Lay and academic presentations will be made. Māori-specific results will be disseminated to Māori stakeholders.
TRIAL REGISTRATION NUMBER
ACTRN12619001189112.
Topics: Humans; Emergency Service, Hospital; Quality Improvement; Acute Coronary Syndrome; Point-of-Care Systems; Cross-Sectional Studies; Risk Assessment; Troponin I; Myocardial Infarction; Length of Stay; Point-of-Care Testing; Biomarkers; Clinical Decision-Making
PubMed: 38871661
DOI: 10.1136/bmjopen-2023-083752 -
Neurology Jul 2024Prolonged compound muscle action potential (CMAP) duration and preferential loss of myosin are considered the diagnostic hallmarks of critical illness myopathy (CIM);...
BACKGROUND AND OBJECTIVES
Prolonged compound muscle action potential (CMAP) duration and preferential loss of myosin are considered the diagnostic hallmarks of critical illness myopathy (CIM); however, their correlation and prognostic values have not been studied. We aimed to investigate the correlation between CMAP duration and myosin loss and their effect on mortality by comparing between patients with CIM with and without myosin loss.
METHODS
We searched the Mayo Clinic Electromyography Laboratory databases (1986-2021) for patients diagnosed with CIM on the basis of prolonged distal CMAP durations (>15 msec in fibular motor nerve studies recording over the tibialis anterior or >8 msec in other motor nerves) and needle EMG findings compatible with myopathy. Electrodiagnostic studies were generally performed within 24 hours after weakness became noticeable. We included only patients who underwent muscle biopsy. Clinical, electrophysiologic, and myopathologic data were reviewed. We conducted myosin/actin ratio analysis when muscle tissue was available. We used the Fisher exact test for categorical data comparisons and the Mann-Whitney 2-tailed test for continuous data. We applied the Kaplan-Meier technique to analyze survival rates.
RESULTS
Twenty patients (13 female patients) were identified [median age at diagnosis of 62.5 years (range: 19-80 years)]. The median onset of weakness was 24 days (range: 1-128) from the first day of intensive care unit admission. Muscle biopsy showed myosin loss in 14 patients, 9 of whom had >50% of myofibers affected (high grade). Type 2 fiber atrophy was observed in 19 patients, 13 of whom also had myosin loss. Patients with myosin loss had higher frequency of steroid exposure (14 vs 3; = 0.004); higher median number of necrotic fibers per low-power field (2.5 vs 1, = 0.04); and longer median CMAP duration (msec) of fibular (13.4 vs 8.75, = 0.02), tibial (10 vs 7.8, = 0.01), and ulnar (11.1 vs 7.95, = 0.002) nerves compared with those without. Only patients with high-grade myosin loss had reduced myosin/actin ratios (<1.7). Ten patients died during median follow-up of 3 months. The mortality rate was similar between patients with and without myosin loss. Patients with high-grade myosin loss had a lower overall survival rate than those with low-grade or no myosin loss, but this was not statistically significant ( = 0.05).
DISCUSSION
Myosin loss occurred in 70% of the patients with CIM with prolonged CMAP duration. Longer CMAP duration predicts myosin-loss pathology. The extent of myosin loss marginally correlates with the mortality rate. Our findings highlight the potential prognostic values of CMAP duration and myosin loss severity in predicting disease outcome.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Action Potentials; Critical Illness; Electromyography; Muscle, Skeletal; Muscular Diseases; Myosins; Prognosis; Retrospective Studies; Young Adult
PubMed: 38870464
DOI: 10.1212/WNL.0000000000209496 -
BMC Urology Jun 2024To predict outcomes and identify potential therapeutic targets for cancers, it is critical to find novel specific biomarkers. The objective of this study was to search...
BACKGROUND
To predict outcomes and identify potential therapeutic targets for cancers, it is critical to find novel specific biomarkers. The objective of this study was to search for and explore novel bladder cancer-associated protein biomarkers.
METHODS
A library of monoclonal antibodies (mAbs) against the JAM-ICR cell line was first generated, and clones with high affinity were selected. Hybridomas were screened using bladder cancer (BLCA) cell lines and normal cells. The target of the selected mAb was then characterized through immunoaffinity purification, western blotting, and mass spectrometry analysis. Expression of the target antigen was assessed by flow cytometry and IHC methods. Several databases were also used to evaluate the target antigen in BLCA and other types of cancers.
RESULTS
Based on screenings, a 6D6 clone was selected that recognized an isoform of beta-actin (ACTB). Our data showed that ACTB expression on different cell lines was heterogeneous and varied significantly from low to high intensity. 6D6 bound strongly to epithelial cells while showing weak to no reactivity to stromal, endothelial, and smooth muscle cells. There was no association between ACTB intensity and related prognostic factors in BLCA. In silico evaluations revealed a significant correlation between ACTB and overexpressed genes and biomarkers in BLCA. Additionally, the differential expression of ACTB in tumor and healthy tissue as well as its correlation with survival time in a number of cancers were shown.
CONCLUSIONS
The heterogeneous expression of ACTB may suggest the potential value of this marker in the diagnosis or prognosis of cancer.
Topics: Urinary Bladder Neoplasms; Humans; Antibodies, Monoclonal; Actins; Biomarkers, Tumor; Cell Line, Tumor
PubMed: 38867273
DOI: 10.1186/s12894-024-01489-6 -
Nature Communications Jun 2024Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral...
Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associated Shank3 knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specific Shank3 conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)- mediated in vivo gene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediated Shank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion of Shank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.
Topics: Animals; Mice, Knockout; Male; Nerve Tissue Proteins; CA1 Region, Hippocampal; Autism Spectrum Disorder; Mice; Memory; Gene Editing; Social Behavior; Neurons; Dependovirus; Microfilament Proteins; Memory Disorders; Mice, Inbred C57BL
PubMed: 38866749
DOI: 10.1038/s41467-024-48430-x -
Cellular Physiology and Biochemistry :... Jun 2024Motivated by the vacuolar proton pump's importance in cancer, we investigate the effects of proton pump inhibition on breast cancer cell migration and proliferation,...
BACKGROUND/AIMS
Motivated by the vacuolar proton pump's importance in cancer, we investigate the effects of proton pump inhibition on breast cancer cell migration and proliferation, F-actin polymerization, lamin A/C, heterochromatin, and ETV7 expressions, nuclear size and shape, and AKT/mTOR signaling.
METHODS
Lowly metastatic MCF7 and highly metastatic MDA-MB-231 breast cancer cells were treated with 120 nM of proton pump inhibitor Bafilomycin A1 for 24 hours. Cell migration was studied with wound- scratch assays, ATP levels with a chemiluminescent assay; cell proliferation was quantified by a cell area expansion assay. Nuclear size and shape were determined using DAPI nuclear stain and fluorescence microscopy. The levels of F-actin, lamin A/C, heterochromatin, and ETV7 were quantified using both immunocytochemistry and western blots; p-mTORC1, p-mTORC2, mTOR, p-AKT, and AKT were measured by western blots.
RESULTS
We reveal that proton pump inhibition reduces F-actin polymerization, cell migration, proliferation, and increases heterochromatin in both lowly and highly metastatic cells. Surprisingly, Bafilomycin decreases lamin A/C in both cell lines. Inhibition has different effects on ETV7 expression in lowly and highly metastatic cells, as well as nuclear area, perimeter, and circularity. Bafilomycin also significantly decreases p-mTORC1, p-MTORC2, and MTOR expression in both cell lines, whereas it significantly decreases p-AKT in lowly metastatic cells and surprisingly significantly increases p-AKT in highly metastatic cells. Our proton pump inhibition protocol reduces V-ATPase levels (~25%) within three hours. V-ATPase levels vary in time for both control and inhibited cells, and inhibition reduces cellular ATP.
CONCLUSION
Proton pumps promote F-actin polymerization and decrease heterochromatin, facilitating invasion. These pumps also upregulate both mTORC1 and mTORC2, thus highlighting the relevance of vacuolar proton pumps as metastatic cancer targets.
Topics: Humans; Actins; Breast Neoplasms; Signal Transduction; Cell Movement; Cell Line, Tumor; Female; Mechanistic Target of Rapamycin Complex 2; Macrolides; Vacuolar Proton-Translocating ATPases; Cell Proliferation; TOR Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Heterochromatin; DNA-Binding Proteins; Transcription Factors; Mechanistic Target of Rapamycin Complex 1; MCF-7 Cells
PubMed: 38865588
DOI: 10.33594/000000706 -
Revista Da Associacao Medica Brasileira... 2024Chemotherapy with doxorubicin may lead to left ventricular dysfunction. There is a controversial recommendation that biomarkers can predict ventricular dysfunction,... (Observational Study)
Observational Study
BACKGROUND
Chemotherapy with doxorubicin may lead to left ventricular dysfunction. There is a controversial recommendation that biomarkers can predict ventricular dysfunction, which is one of the most feared manifestations of anthracycline cardiotoxicity.
OBJECTIVE
The aim of this study was to evaluate the behavior of biomarkers such as Troponin I, type B natriuretic peptide, creatine phosphokinase fraction MB, and myoglobin in predicting cardiotoxicity in a cohort of women with breast cancer undergoing chemotherapy with anthracycline.
METHODS
This is an observational, prospective, longitudinal, unicentric study, which included 40 women with breast cancer, whose therapeutic proposal included treatment with doxorubicin. The protocol had a clinical follow-up of 12 months. Biomarkers such as Troponin I, type B natriuretic peptide, creatine phosphokinase fraction MB, and myoglobin were measured pre-chemotherapy and after the first, third, fourth, and sixth cycles of chemotherapy.
RESULTS
There was a progressive increase in type B natriuretic peptide and myoglobin values in all chemotherapy cycles. Although creatine phosphokinase fraction MB showed a sustained increase, this increase was not statistically significant. Troponin, type B natriuretic peptide, myoglobin, and creatine phosphokinase fraction MB were the cardiotoxicity markers with the earliest changes, with a significant increase after the first chemotherapy session. However, they were not able to predict cardiotoxicity.
CONCLUSION
Troponin I, type B natriuretic peptide, myoglobin, and creatine phosphokinase fraction MB are elevated during chemotherapy with doxorubicin, but they were not able to predict cardiotoxicity according to established clinical and echocardiographic criteria. The incidence of subclinical cardiotoxicity resulting from the administration of doxorubicin was 12.5%.
Topics: Humans; Female; Breast Neoplasms; Prospective Studies; Troponin I; Doxorubicin; Cardiotoxicity; Middle Aged; Biomarkers; Myoglobin; Adult; Antibiotics, Antineoplastic; Natriuretic Peptide, Brain; Aged; Creatine Kinase, MB Form; Longitudinal Studies; Anthracyclines; Ventricular Dysfunction, Left; Predictive Value of Tests
PubMed: 38865526
DOI: 10.1590/1806-9282.2024S106