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Clinical Gastroenterology and... Aug 2018Tests to quantify fecal levels of chymotrypsin like elastase family member 3 (CELA3 or elastase-1) in feces are widely used to identify patients with exocrine pancreatic... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Tests to quantify fecal levels of chymotrypsin like elastase family member 3 (CELA3 or elastase-1) in feces are widely used to identify patients with exocrine pancreatic insufficiency (EPI). However, the diagnostic accuracy of this test, an ELISA, is not clear. We performed a systematic review and meta-analysis to determine the accuracy of measurement of fecal elastase-1 in detection of EPI.
METHODS
We searched PubMed, Embase, and reference lists for articles through November 2016 describing studies that compared fecal level of elastase-1 with results from a reference standard, direct method (secretin stimulation test), or indirect method (measurement of fecal fat) for detection of EPI. Sensitivity and specificity values were pooled statistically using bivariate diagnostic meta-analysis.
RESULTS
We included total of 428 cases of EPI and 673 individuals without EPI (controls), from 14 studies, in the meta-analysis. The assay for elastase-1, compared to secretin stimulation test, identified patients with pancreatic insufficiency with a pooled sensitivity value of 0.77 (95% CI, 0.58-0.89) and specificity value of 0.88 (95% CI, 0.78-0.93). In an analysis of 345 cases of EPI and 312 controls, from 6 studies, the fecal elastase-1 assay identified patients with EPI with a pooled sensitivity value of 0.96 (95% CI, 0.79-0.99) and specificity value of 0.88 (95% CI, 0.59-0.97), compared to quantitative fecal fat estimation. In patients with low pre-test probability of EPI (5%), the fecal elastase-1 assay would have a false-negative rate of 1.1% and a false-positive rate of 11%, indicating a high yield in ruling out EPI but not in detection of EPI. In contrast, in patients with high pre-test probability of EPI (40%), approximately 10% of patients with EPI would be missed (false negatives).
CONCLUSIONS
In a systematic review and meta-analysis of studies that compared fecal level of elastase-1 for detection of EPI, we found that normal level of elastase-1 (above 200 mcg/g) can rule out EPI in patients with a low probability of this disorder (such as those with irritable bowel syndrome with diarrhea). However, in these patients, an abnormal level of elastase-1 (below 200 mcg/g) has a high false-positive rate.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Diagnostic Tests, Routine; Exocrine Pancreatic Insufficiency; Feces; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pancreatic Elastase; Sensitivity and Specificity; Young Adult
PubMed: 29374614
DOI: 10.1016/j.cgh.2018.01.027 -
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins.Theranostics 2021Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence... (Review)
Review
Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.
Topics: Animals; Cellular Microenvironment; Drug Delivery Systems; Drug Discovery; Humans; Lysosomes; Membrane Proteins; Proteasome Endopeptidase Complex; Proteins; Proteolysis
PubMed: 34373745
DOI: 10.7150/thno.62686 -
Neurobiology of Disease Jun 2024Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has... (Meta-Analysis)
Meta-Analysis Review
Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a comprehensive review of common mechanisms, which have hitherto been discussed in separate perspectives, and to assemble and evaluate candidate loci and epigenetic modifications contributing to polygenic risk linkages between T2DM and LOAD. For the systematic review on pathophysiological mechanisms, both human and animal studies up to December 2023 are included. For the qualitative meta-analysis of genomic bases, human association studies were examined; for epigenetic mechanisms, data from human studies and animal models were accepted. Papers describing pathophysiological studies were identified in databases, and further literature gathered from cited work. For genomic and epigenomic studies, literature mining was conducted by formalised search codes using Boolean operators in search engines, and augmented by GeneRif citations in Entrez Gene, and other sources (WikiGenes, etc.). For the systematic review of pathophysiological mechanisms, 923 publications were evaluated, and 138 gene loci extracted for testing candidate risk linkages. 3 57 publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight insulin signalling, inflammation and inflammasome pathways, proteolysis, gluconeogenesis and glycolysis, glycosylation, lipoprotein metabolism and oxidation, cell cycle regulation or survival, autophagic-lysosomal pathways, and energy. Documented findings suggest interplay between brain insulin resistance, neuroinflammation, insult compensatory mechanisms, and peripheral metabolic dysregulation in T2DM and LOAD linkage. The results allow for more streamlined longitudinal studies of T2DM-LOAD risk linkages.
Topics: Humans; Diabetes Mellitus, Type 2; Alzheimer Disease; Animals; Epigenesis, Genetic
PubMed: 38643861
DOI: 10.1016/j.nbd.2024.106485 -
Brazilian Journal of Microbiology :... 2017Specific proteases capable of degrading native triple helical or denatured collagen have been required for many years and have a large spectrum of applications. There... (Meta-Analysis)
Meta-Analysis Review
Specific proteases capable of degrading native triple helical or denatured collagen have been required for many years and have a large spectrum of applications. There are few complete reports that fully uncover production, characterization and purification of fungi collagenases. In this review, authors searched through four scientific on line data bases using the following keywords (collagenolytic OR collagenase) AND (fungi OR fungus OR fungal) AND (production OR synthesis OR synthesize) AND (characterization). Scientific criteria were adopted in this review to classify found articles by score (from 0 to 10). After exclusion criteria, 21 articles were selected. None obtained the maximum of 10 points defined by the methodology, which indicates a deficiency in studies dealing simultaneously with production, characterization and purification of collagenase by fungi. Among microorganisms studied the non-pathogenic fungi Penicillium aurantiogriseum and Rhizoctonia solani stood out in volumetric and specific collagenase activity. The only article found that made sequencing of a true collagenase showed 100% homology with several metalloproteinases fungi. A clear gap in literature about collagenase production by fungi was verified, which prevents further development in the area and increases the need for further studies, particularly full characterization of fungal collagenases with high specificity to collagen.
Topics: Collagen; Collagenases; Culture Media; Enzyme Activation; Fungi; Proteolysis; Substrate Specificity
PubMed: 27756540
DOI: 10.1016/j.bjm.2016.08.001 -
Advances in Nutrition (Bethesda, Md.) Jan 2023When there is an inadequate supply of mother's milk, pasteurized donor human milk is preferred over formula to supplement feeds for preterm infants. Although providing... (Review)
Review
When there is an inadequate supply of mother's milk, pasteurized donor human milk is preferred over formula to supplement feeds for preterm infants. Although providing donor milk helps to improve feeding tolerance and reduce necrotizing enterocolitis, changes to its composition and reductions in bioactivity during processing, are thought to contribute to the slower growth often exhibited by these infants. To improve the clinical outcomes of recipient infants by maximizing the quality of donor milk, research is currently investigating strategies to optimize all aspects of processing, including pooling, pasteurization, and freezing; however, reviews of this literature typically only summarize the impact of a processing technique on composition or bioactivity. Reviews of published research investigating the impact of donor milk processing on infant digestion/absorption are lacking and thus, was the objective for this systematic scoping review, Open Science Framework (https://doi.org/10.17605/OSF.IO/PJTMW). Databases were searched for primary research studies evaluating donor milk processing for pathogen inactivation or other rationale and subsequent effect on infant digestion/absorption. Non-human milk studies or those assessing other outcomes were excluded. Overall, 24 articles from 12,985 records screened were included. Most studied thermal methods to inactivate pathogens, predominantly Holder pasteurization (HoP) (62.5°C, 30 min) and high-temperature short-time. Heating consistently decreased lipolysis and increased proteolysis of lactoferrin and caseins; however, protein hydrolysis was unaffected from in vitro studies. The abundance and diversity of released peptides remain unclear and should be further explored. Greater investigation into less-harsh methods for pasteurization, such as high-pressure processing, is warranted. Only 1 study assessed the impact of this technique and found minimal impact on digestion outcomes compared with HoP. Fat homogenization appeared to positively impact fat digestion (n = 3 studies), and only 1 eligible study investigated freeze-thawing. Identified knowledge gaps regarding optimal methods of processing should be further explored to improve the quality and nutrition of donor milk.
Topics: Infant, Newborn; Infant; Humans; Infant, Premature; Infant Nutritional Physiological Phenomena; Milk, Human; Nutritional Status; Digestion
PubMed: 36811588
DOI: 10.1016/j.advnut.2022.11.004 -
Critical Care Medicine Oct 2009To review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology. (Review)
Review
OBJECTIVE
To review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology.
MEASUREMENTS
Systematic literature review.
CONCLUSIONS
Prolonged mechanical ventilation can promote diaphragmatic atrophy and contractile dysfunction. As few as 18 hrs of mechanical ventilation results in diaphragmatic atrophy in both laboratory animals and humans. Prolonged mechanical ventilation is also associated with diaphragmatic contractile dysfunction. Studies using animal models revealed that mechanical ventilation-induced diaphragmatic atrophy is due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, and the ubiquitin-proteasome system as key proteases that contribute to mechanical ventilation-induced diaphragmatic proteolysis. The scientific challenge for the future is to delineate the mechanical ventilation-induced signaling pathways that activate these proteases and depress protein synthesis in the diaphragm. Future investigations that define the signaling mechanisms responsible for mechanical ventilation-induced diaphragmatic weakness will provide the knowledge required for the development of new medicines that can maintain diaphragmatic mass and function during prolonged mechanical ventilation.
Topics: Animals; Antioxidants; Calpain; Caspase 3; Critical Illness; Diaphragm; Enzyme Inhibitors; Humans; Muscle Contraction; Muscular Atrophy; Proteasome Endopeptidase Complex; Respiration, Artificial; Risk Factors; Ubiquitin; Ventilator Weaning
PubMed: 20046120
DOI: 10.1097/CCM.0b013e3181b6e760 -
International Journal of Molecular... Oct 2022The plant-microbe holobiont has garnered considerable attention in recent years, highlighting its importance as an ecological unit. Similarly, manipulation of the... (Review)
Review
An Insight into Microbial Inoculants for Bioconversion of Waste Biomass into Sustainable "Bio-Organic" Fertilizers: A Bibliometric Analysis and Systematic Literature Review.
The plant-microbe holobiont has garnered considerable attention in recent years, highlighting its importance as an ecological unit. Similarly, manipulation of the microbial entities involved in the rhizospheric microbiome for sustainable agriculture has also been in the limelight, generating several commercial bioformulations to enhance crop yield and pest resistance. These bioformulations were termed biofertilizers, with the consistent existence and evolution of different types. However, an emerging area of interest has recently focused on the application of these microorganisms for waste valorization and the production of "bio-organic" fertilizers as a result. In this study, we performed a bibliometric analysis and systematic review of the literature retrieved from Scopus and Web of Science to determine the type of microbial inoculants used for the bioconversion of waste into "bio-organic" fertilizers. The , species, cyanobacterial biomass species, sp. and sp. were identified to be consistently used for the recovery of nutrients and bioconversion of wastes used for the promotion of plant growth. Cyanobacterial strains were used predominantly for wastewater treatment, while and were used on a wide variety of wastes such as sawdust, agricultural waste, poultry bone meal, crustacean shell waste, food waste, and wastewater treatment plant (WWTP) sewage sludge ash. Several bioconversion strategies were observed such as submerged fermentation, solid-state fermentation, aerobic composting, granulation with microbiological activation, and biodegradation. Diverse groups of microorganisms (bacteria and fungi) with different enzymatic functionalities such as chitinolysis, lignocellulolytic, and proteolysis, in addition to their plant growth promoting properties being explored as a consortium for application as an inoculum waste bioconversion to fertilizers. Combining the efficiency of such functional and compatible microbial species for efficient bioconversion as well as higher plant growth and crop yield is an enticing opportunity for "bio-organic" fertilizer research.
Topics: Fertilizers; Biomass; Agricultural Inoculants; Food; Refuse Disposal; Sewage; Bibliometrics; Soil
PubMed: 36361844
DOI: 10.3390/ijms232113049 -
Urologic Oncology May 2022Determining meta-analysis of transcriptional profiling of muscle-invasive bladder cancer (MIBC) through Gene Expression Omnibus (GEO) datasets has not been investigated.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Determining meta-analysis of transcriptional profiling of muscle-invasive bladder cancer (MIBC) through Gene Expression Omnibus (GEO) datasets has not been investigated. This study aims to define gene expression profiles in MIBC and to identify potential candidate genes and pathways.
OBJECTIVES
To review and evaluate gene expression studies in MIBC through publicly available RNA sequencing (RNA-Seq) and microarray data in order to identify potential prognostic and therapeutic targets for MIBC.
METHODS
A systematic literature search of the Ovid MEDLINE, PubMed, and Wiley Cochrane Central Register of Controlled Trials databases was performed using the terms "gene," "gene expression," and "bladder cancer" January 1, 1990 through March 2021 focused on populations with MIBC.
RESULTS
In the final analysis, GEO datasets were included. Fixed effect model was employed in the meta-analysis. Gene networking connections and gene-set functional analyses of the identified genes as differentially expressed in MIBC were performed using ImaGEO and GeneMANIA software. A heatmap for the upregulated and downregulated genes was generated along with the correlated pathways.
CONCLUSION
A total of 9 genes were reported in this analysis. Six genes were reported as upregulated (ProTα, SPINT1, UBE2E1, RAB25, KPNB1, HDAC1) and 3 genes as downregulated (NUP188, IPO13, NUP124). Genes were found to be involved in "ubiquitin mediated proteolysis," "protein processing in endoplasmic reticulum," "transcriptional misregulation in cancer," and "RNA transport" pathways.
Topics: Female; Gene Expression Profiling; Gene Regulatory Networks; Humans; Male; Muscles; Neoplasm Invasiveness; Prognosis; Urinary Bladder Neoplasms; rab GTP-Binding Proteins
PubMed: 35039218
DOI: 10.1016/j.urolonc.2021.11.003 -
Biomolecules Jan 2024Metalloproteinases (MPs) are zinc-dependent enzymes with proteolytic activity and a variety of functions in the pathophysiology of human diseases. The main objectives of... (Review)
Review
Metalloproteinases (MPs) are zinc-dependent enzymes with proteolytic activity and a variety of functions in the pathophysiology of human diseases. The main objectives of this review are to analyze a specific family of MPs, the matrix metalloproteinases (MMPs), in the most common chronic and complex diseases that affect patients' social lives and to better understand the nature of the associations between MMPs and the psychosocial environment. In accordance with the PRISMA extension for a scoping review, an examination was carried out. A collection of 24 studies was analyzed, focusing on the molecular mechanisms of MMP and their connection to the manifestation of social aspects in human disease. The complexity of the relationship between MMP and social problems is presented via an interdisciplinary approach based on complexity paradigm as a new approach for conceptualizing knowledge in health research. Finally, two implications emerge from the study: first, the psychosocial states of individuals have a profound impact on their overall health and disease conditions, which implies the importance of adopting a holistic perspective on human well-being, encompassing both physical and psychosocial aspects. Second, the use of MPs as biomarkers may provide physicians with valuable tools for a better understanding of disease when used in conjunction with "sociomarkers" to develop mathematical predictive models.
Topics: Humans; Biomarkers; Proteolysis; Physicians; Zinc; Matrix Metalloproteinases
PubMed: 38254696
DOI: 10.3390/biom14010096 -
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