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Prostate Cancer and Prostatic Diseases Sep 2020The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all...
BACKGROUND
The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all existing AR-directed therapies. AR-targeting agents impart therapeutic benefit, but lead to AR aberrations that underlie disease progression and therapeutic resistance. Among the AR aberrations specific to castration-resistant prostate cancer (CRPC), AR variants (AR-Vs) have emerged as important indicators of disease progression and therapeutic resistance.
METHODS
We conducted a systemic review of the literature focusing on recent laboratory studies on AR-Vs following our last review article published in 2016. Topics ranged from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We provide expert opinions and perspectives on these topics.
RESULTS
Transcript sequences for 22 AR-Vs have been reported in the literature. Different AR-Vs may arise through different mechanisms, and can be regulated by splicing factors and dictated by genomic rearrangements, but a low-androgen environment is a prerequisite for generation of AR-Vs. The unique transcript structures allowed development of in situ and in-solution measurement and detection methods, including mRNA and protein detection, in both tissue and blood specimens. AR-V7 remains the main measurement target and the most extensively characterized AR-V. Although AR-V7 coexists with AR-FL, genomic functions mediated by AR-V7 do not require the presence of AR-FL. The distinct cistromes and transcriptional programs directed by AR-V7 and their coregulators are consistent with genomic features of progressive disease in a low-androgen environment. Preclinical development of AR-V-directed agents currently focuses on suppression of mRNA expression and protein degradation as well as targeting of the amino-terminal domain.
CONCLUSIONS
Current literature continues to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. Laboratory investigations reveal both challenges and opportunities in targeting AR-Vs to overcome resistance to current AR-directed therapies.
Topics: Alternative Splicing; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Decision-Making; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genetic Testing; Humans; Male; Precision Medicine; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Proteolysis; Receptors, Androgen; Transcriptional Activation
PubMed: 32139878
DOI: 10.1038/s41391-020-0217-3 -
Frontiers in Aging Neuroscience 2022Because of high prevalence of Alzheimer's disease (AD) in low- and middle-income countries (LMICs), there is an urgent need for inexpensive and minimally invasive...
BACKGROUND
Because of high prevalence of Alzheimer's disease (AD) in low- and middle-income countries (LMICs), there is an urgent need for inexpensive and minimally invasive diagnostic tests to detect biomarkers in the earliest and asymptomatic stages of the disease. Blood-based biomarkers are predicted to have the most impact for use as a screening tool and predict the onset of AD, especially in LMICs. Furthermore, it has been suggested that panels of markers may perform better than single protein candidates.
METHODS
Medline/Pubmed was searched to identify current relevant studies published from January 2016 to December 2020. We included all full-text articles examining blood-based biomarkers as a set of protein markers or panels to aid in AD's early diagnosis, prognosis, and characterization.
RESULTS
Seventy-six articles met the inclusion criteria for systematic review. Majority of the studies reported plasma and serum as the main source for biomarker determination in blood. Protein-based biomarker panels were reported to aid in AD diagnosis and prognosis with better accuracy than individual biomarkers. Conventional (amyloid-beta and tau) and neuroinflammatory biomarkers, such as amyloid beta-42, amyloid beta-40, total tau, phosphorylated tau-181, and other tau isoforms, were the most represented. We found the combination of amyloid beta-42/amyloid beta-40 ratio and APOEε4 status to be most represented with high accuracy for predicting amyloid beta-positron emission tomography status.
CONCLUSION
Assessment of Alzheimer's disease biomarkers in blood as a non-invasive and cost-effective alternative will potentially contribute to early diagnosis and improvement of therapeutic interventions. Given the heterogeneous nature of AD, combination of markers seems to perform better in the diagnosis and prognosis of the disease than individual biomarkers.
PubMed: 35360215
DOI: 10.3389/fnagi.2022.683689 -
Frontiers in Immunology 2023The peptidyl arginine deiminase (PADI) family is a calcium ion-dependent group of isozymes with sequence similarity that catalyze the citrullination of proteins.... (Review)
Review
The peptidyl arginine deiminase (PADI) family is a calcium ion-dependent group of isozymes with sequence similarity that catalyze the citrullination of proteins. Histones can serve as the target substrate of PADI family isozymes, and therefore, the PADI family is involved in NETosis and the secretion of inflammatory cytokines. Thus, the PADI family is associated with the development of inflammatory autoimmune diseases and cancer, reproductive development, and other related diseases. In this review, we systematically discuss the role of the PADI family in the pathogenesis of various diseases based on studies from the past decade to provide a reference for future research.
Topics: Humans; Protein-Arginine Deiminases; Isoenzymes; Autoimmune Diseases; Histones; Neoplasms
PubMed: 37020554
DOI: 10.3389/fimmu.2023.1115794 -
Frontiers in Pharmacology 2022The nine membrane-delimited eukaryotic adenylyl cyclases are pseudoheterodimers with an identical domain order of seven (nine) distinct subdomains. Bioinformatics show...
The nine membrane-delimited eukaryotic adenylyl cyclases are pseudoheterodimers with an identical domain order of seven (nine) distinct subdomains. Bioinformatics show that the protein evolved from a monomeric bacterial progenitor by gene duplication and fusion probably in a primordial eukaryotic cell around 1.5 billion years ago. Over a timespan of about 1 billion years, the first fusion product diverged into nine highly distinct pseudoheterodimeric isoforms. The evolutionary diversification ended approximately 0.5 billion years ago because the present isoforms are found in the living fossil coelacanth, a fish. Except for the two catalytic domains, C1 and C2, the mAC isoforms are fully diverged. Yet, within each isoform a high extent of conservation of respective subdomains is found. This applies to the C- and N-termini, a long linker region between the protein halves (C1b), two short cyclase-transducing-elements (CTE) and notably to the two hexahelical membrane domains TM1 and TM2. Except for the membrane anchor all subdomains were previously implicated in regulatory modalities. The bioinformatic results unequivocally indicate that the membrane anchors must possess an important regulatory function specifically tailored for each mAC isoform.
PubMed: 36238545
DOI: 10.3389/fphar.2022.1009797 -
Journal of Clinical Medicine Oct 2020Cardiovascular diseases (CVD) remain a global pandemic and leading cause of deaths worldwide. While several guidelines have been developed to control the development of... (Review)
Review
Cardiovascular diseases (CVD) remain a global pandemic and leading cause of deaths worldwide. While several guidelines have been developed to control the development of CVDs, its prevalence keeps on increasing until this day. Cardiovascular risk factors, such as reduced exercises and high fat or glucose diets, culminate in the development of the metabolic syndrome and eventually atherosclerosis, which is driven by high blood lipid and cholesterol levels, and by endothelial dysfunction. Late complications of atherosclerosis give rise to serious clinical cardiovascular manifestations such as myocardial infarction and hypertension. Therefore, endothelial functions and the lipid metabolism play critical roles in the pathogenesis of CVDs. Fatty acid-binding proteins are a family of intracellular proteins expressed in many cell types known mainly for their interaction with and trafficking of cellular lipids. The roles of a number of isoforms in this family have been implicated in lipid metabolic homeostasis, but their influence on endothelial function and vascular homeostasis remain largely unknown. This review's purpose is to update fundamentals about the connection between cardiovascular disease, metabolism, endothelial function, and mainly the roles of fatty acid-binding proteins.
PubMed: 33105856
DOI: 10.3390/jcm9113390 -
Glia Aug 2019Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and...
Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.
Topics: Animals; Astrocytoma; Biomarkers, Tumor; Central Nervous System Neoplasms; Glial Fibrillary Acidic Protein; Humans; Protein Isoforms
PubMed: 30667110
DOI: 10.1002/glia.23594 -
Molecular Genetics & Genomic Medicine Sep 2020Dishevelled (DVL) family members are crucial to Wnt-induced signaling transduction, and their expression is highly correlated with the progression of multiple malignant...
BACKGROUND
Dishevelled (DVL) family members are crucial to Wnt-induced signaling transduction, and their expression is highly correlated with the progression of multiple malignant cancers. However, the expression profiles and exact prognostic values of DVLs in hepatocellular carcinoma (HCC) have not been explored until now.
METHODS
The expression of DVL isoforms was assessed using the Oncomine, HCCDB and UALCAN databases. The prognostic roles of DVLs were further evaluated using the GEPIA database. The relationship between the expression of DVLs and immune infiltration of HCC was investigated using the Timer and ImmuCellAI tools. Furthermore, protein-protein interaction (PPI) networks were built and enrichment analyses were conducted.
RESULTS
We found that the expression levels of DVL2 (OMIM accession number: 602151) and DVL3 (OMIM accession number: 601368) were upregulated in HCC tissues as revealed by the Oncomine and HCCDB databases. Additionally, the expression of DVLs tended to be associated with advanced clinical features in the UALCAN database. Prognostic analysis revealed that the expression levels of DVL1 (OMIM accession number: 601365) and DVL3 were remarkably associated with a poor prognosis in HCC patients. The results also revealed that the DVL expression level was correlated with the infiltration levels of multiple immune cells. By constructing the PPI network and enrichment analyses, the DVL1-3 gene was identified to interact with 20 key genes and participate in several pathways.
CONCLUSION
In summary, DVL2 and DVL3 are highly expressed in HCC, and DVL1 and DVL3 are related to a poor prognosis, which might be used as candidate targets for targeted therapy and reliable prognostic biomarkers in HCC.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Databases, Genetic; Dishevelled Proteins; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Up-Regulation
PubMed: 32588988
DOI: 10.1002/mgg3.1384 -
Animals : An Open Access Journal From... Sep 2020Adiponectin is an abundant plasma protein that is closely related to obesity and obesity-related pathologies. The molecule can be found in three different isoforms, each...
Adiponectin is an abundant plasma protein that is closely related to obesity and obesity-related pathologies. The molecule can be found in three different isoforms, each with different biological activities. Studies on canine obesity have suggested that adiponectin concentrations are decreased in obesity; however, no canine meta-analyses have been performed that feature all the required data. The aim of this study is to perform a systematic review and meta-analysis of studies that pertain to total and high molecular weight (HMW) adiponectin in relation to canine obesity. From 20 different studies, a total of 366 dogs with obesity and 349 normal weight dogs are included in the meta-analysis. Client-owned dogs were most represented, accounting for 54.3% of the dogs used, while experimental dogs enrolled in the studies made up the remaining 45.7%. The concentrations of total adiponectin in dogs with obesity were significantly lower compared with normal weight dogs. Additionally, adiponectin concentrations were significantly higher in dogs after a successful weight loss protocol compared to the start of the protocol and were significantly lower in dogs after gaining weight. In conclusion, although caution should be taken due to the relatively low number of studies that exist and the high heterogeneity between them, this meta-analysis indicates that adiponectin is decreased in obese dogs.
PubMed: 32937899
DOI: 10.3390/ani10091650 -
Cancer Medicine Feb 2020A meta-analysis was formulated to appraise the diagnostic accuracy of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC). (Meta-Analysis)
Meta-Analysis
PURPOSE
A meta-analysis was formulated to appraise the diagnostic accuracy of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
We enrolled all relevant studies published until September 2019. Four primary subgroups were investigated: the subgroup of quantitative or qualitative analysis of ctDNA, the subgroup of Ras association domain family 1 isoform A (RASSF1A) methylation in ctDNA and the subgroup of the combined alpha-fetoprotein (AFP) and ctDNA assay. We analyzed the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) as well as the area under the curve (AUC).
RESULTS
A total of 33 qualified articles with 4113 subjects were incorporated into our meta-analysis. The combined SEN, SPE, and DOR in quantitative studies were 0.722 (95% confidence interval (95% CI): 0.686-0.756), 0.823 (95% CI: 0.789-0.854), 18.532 (95% CI: 8.245-41.657), respectively, yielding an AUC of 0.880. For qualitative studies, the corresponding value was 0.568 (95% CI: 0.548-0.587), 0.882 (95% CI: 0.867-0.897), 10.457 (95% CI: 7.270-15.040) and 0.787, respectively. Detection of RASSF1A methylation yielded an AUC of 0.841, with a SEN of 0.644 (95% CI: 0.608-0.678) and a SPE of 0.875 (95% CI: 0.847-0.900). AFP combined with ctDNA assay achieved an AUC of 0.944, with a SEN of 0.760 (95% CI: 0.728-00.790) and a SPE of 0.920 (95% CI: 0.893-00.942).
CONCLUSION
Circulating tumor DNA displays a promising diagnostic potential in HCC. However, it is not independently sufficient and can serve as an assistant tool combined with AFP for HCC screening and detection.
Topics: Carcinoma, Hepatocellular; Circulating Tumor DNA; DNA Methylation; Humans; Liver Neoplasms; Mass Screening; Predictive Value of Tests; ROC Curve; Tumor Suppressor Proteins; alpha-Fetoproteins
PubMed: 31876977
DOI: 10.1002/cam4.2799 -
International Journal of Molecular... Mar 2024Cluster of differentiation 44 (CD44), a cell surface adhesion molecule overexpressed in cancer stem cells, has been implicated in chemoresistance. This scoping review,... (Review)
Review
Cluster of differentiation 44 (CD44), a cell surface adhesion molecule overexpressed in cancer stem cells, has been implicated in chemoresistance. This scoping review, following PRISMA-ScR guidelines, systematically identified and evaluated clinical studies on the impact of CD44 expression on chemotherapy treatment outcomes across various cancer types. The search encompassed PubMed (1985-2023) and SCOPUS (1936-2023) databases, yielding a total of 12,659 articles, of which 40 met the inclusion criteria and were included in the qualitative synthesis using a predefined data extraction table. Data collected included the cancer type, sample size, interventions, control, treatment outcome, study type, expression of CD44 variants and isoforms, and effect of CD44 on chemotherapy outcome. Most of the studies demonstrated an association between increased CD44 expression and negative chemotherapeutic outcomes such as shorter overall survival, increased tumor recurrence, and resistance to chemotherapy, indicating a potential role of CD44 upregulation in chemoresistance in cancer patients. However, a subset of studies also reported non-significant relationships or conflicting results. In summary, this scoping review highlighted the breadth of the available literature investigating the clinical association between CD44 and chemotherapeutic outcomes. Further research is required to elucidate this relationship to aid clinicians in managing CD44-positive cancer patients.
Topics: Humans; Drug Resistance, Neoplasm; Hyaluronan Receptors; Treatment Outcome
PubMed: 38542115
DOI: 10.3390/ijms25063141