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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 -
Acta Neuropathologica Communications Apr 2015Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia after Alzheimer's disease. A high-ranking candidate to become a diagnostic marker for a... (Review)
Review
Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia after Alzheimer's disease. A high-ranking candidate to become a diagnostic marker for a major pathological subtype of FTLD is the transactive response DNA binding protein of 43 kDa (TDP-43). The main objective is to elucidate which antibodies are specific for pathological TDP-43, with special interest in its modified isoforms. Indeed, TDP-43 has been shown to be hyperphosphorylated and truncated in disease. A secondary objective is to review existing immunoassays that quantify TDP-43 in biofluids. A systematic review of literature was performed by searching PubMed and Web of Science using predefined keywords. Of considered research papers the methods section was reviewed to select publications that enabled us to answer our learning objective. After quality assessment, antibody characteristics and related outcomes were extracted. We identified a series of well-characterized antibodies based on a scoring system that assessed the ability of each antibody to detect TDP-43 pathology. A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once. This systematic review provides an overview of antibodies that are reported to detect pathological TDP-43. These antibodies can be used in future studies of TDP-43 proteinopathies. Additionally, selected antibodies hold the potential to be used in the development of novel immunoassays for the quantification of TDP-43 in biofluids, as a possible biomarker for FTLD-TDP.
Topics: Animals; Antibodies; Biomarkers; Brain; DNA-Binding Proteins; Frontotemporal Lobar Degeneration; Humans; Immunoblotting; Immunologic Techniques
PubMed: 25853864
DOI: 10.1186/s40478-015-0195-1 -
European Journal of Drug Metabolism and... Mar 2021Cytochrome P450 (CYP) enzymes are one of the main sources of variability in drug metabolic clearance. Information on their abundance levels is therefore crucial to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cytochrome P450 (CYP) enzymes are one of the main sources of variability in drug metabolic clearance. Information on their abundance levels is therefore crucial to optimize scaling factors for in vitro-in vivo extrapolation (IVIVE) to predict metabolic clearance.
OBJECTIVE
This study aims to quantify the abundance data of hepatic drug-metabolizing CYP enzymes in East Asian subjects reported from various sources in the literature using meta-analysis.
METHOD
We conducted a meta-analysis on the abundance of drug-metabolizing CYP enzymes in the liver of East Asian adults. Eligible reports were identified based on predefined criteria-(1) individual liver microsomal samples, and (2) absolute protein abundance data from normal tissues of East Asian adult subjects. Subgroup and sensitivity analyses were also performed.
RESULTS
Among the 11 CYP isoforms analyzed in East Asian subjects, CYP3A5 and CYP3A4 had the highest protein levels. In particular, the number of studies and the liver sample used to quantify the abundance of CYP3A4 were the largest. Of the isoforms involved, CYP2J2 and CYP2B6 had the lowest abundance level, i.e., <5 pmol/ mg of microsomal protein. For enzymes with abundance values available in both Chinese and Japanese subjects (CYP1A2, CYP2C9, CYP3A4, and CYP3A5), the abundance level of each CYP isoform appeared to be higher in Chinese than in Japanese subjects. The most distinct difference was observed in CYP3A5 abundance.
CONCLUSION
The current meta-analysis shows that the abundance levels of CYP enzymes appear to vary greatly among different East Asian individuals who have similar ethnic backgrounds and food habits. The pooled data of CYP abundance can be used as preliminary reference values along with the associated variations for the projections of pharmacokinetics through physiologically based pharmacokinetic (PBPK) approaches.
Topics: Adult; Asian People; Cytochrome P-450 Enzyme System; Humans; Liver; Microsomes, Liver; Pharmaceutical Preparations
PubMed: 33368014
DOI: 10.1007/s13318-020-00667-9 -
BMJ (Clinical Research Ed.) Dec 2004To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with osteoarthritis of the knee.
DESIGN
Systematic review and meta-analysis of randomised placebo controlled trials.
STUDIES REVIEWED
23 trials including 10 845 patients, median age of 62.5 years. 7807 patients received adequate doses of NSAIDs and 3038 received placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm visual analogue scale (VAS), and average duration of symptoms was 8.2 years.
MAIN OUTCOME MEASURE
Change in overall intensity of pain.
RESULTS
Methodological quality of trials was acceptable, but 13 trials excluded patients before randomisation if they did not respond to NSAIDs. One trial provided long term data for pain that showed no significant effect of NSAIDs compared with placebo at one to four years. The pooled difference for pain on visual analogue scale in all included trials was 10.1 mm (95% confidence interval 7.4 to 12.8) or 15.6% better than placebo after 2-13 weeks. The results were heterogeneous, and the effect size for pain reduction was 0.32 (0.24 to 0.39) in a random effects model. In 10 trials that did not exclude non-responders to NSAID treatment the results were homogeneous, with an effect size for pain reduction of 0.23 (0.15 to 0.31).
CONCLUSION
NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious adverse effects are associated with oral NSAIDs, only limited use can be recommended.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disabled Persons; Humans; Isoenzymes; Membrane Proteins; Middle Aged; Osteoarthritis, Knee; Pain; Prostaglandin-Endoperoxide Synthases; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 15561731
DOI: 10.1136/bmj.38273.626655.63 -
Prenatal Diagnosis Jun 2015This overview provides insight into the underlying genetic mechanism of the high incidence of cardiac defects in fetuses with increased nuchal translucency (NT). Nuchal... (Review)
Review
This overview provides insight into the underlying genetic mechanism of the high incidence of cardiac defects in fetuses with increased nuchal translucency (NT). Nuchal edema, the morphological equivalent of increased NT, is likely to result from abnormal lymphatic development and is strongly related to cardiac defects. The underlying genetic pathways are, however, unknown. This study aims to present a systematic overview of genes involved in both cardiac and lymphatic development in mouse embryos. A search of PubMed and the Mammalian Phenotype Browser was performed. Fifteen candidate genes involved in both cardiac and lymphatic development were identified: Adrenomedullin; Chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TFII); Cyp51; Ephrin-B2; Forkhead box protein C2 (Foxc2); Nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1); Neurofibromatosis type 1 (Nf1); Phosphoinositide 3-kinase encoding isoform p110α (Pik3ca); Podoplanin; Prospero-related homeobox 1 (Prox1); T-box 1 (Tbx1); Tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains 1 (Tie1); vascular endothelial growth factor (Vegf)-A; Vegf receptor-3 (Vegfr-3); and Vascular endothelial zinc finger 1 (Vezf1). Mutations in all but one gene (Pik3ca) resulted in both a cardiac defect and nuchal edema. Candidate genes - mainly encoding for endothelium - are involved in both cardiac and lymphatic development. Alterations in candidate genes are associated with the strong relation between increased NT and cardiac defects.
Topics: Animals; Edema; Genes, Developmental; Heart; Heart Defects, Congenital; Lymphatic System; Mice; Nuchal Translucency Measurement
PubMed: 25728762
DOI: 10.1002/pd.4586 -
Stem Cell Reviews and Reports Aug 2013Mesenchymal stem cells (MSC) from fetal-placental tissues have translational advantages over their adult counterparts, and have variably been reported to express... (Meta-Analysis)
Meta-Analysis Review
Mesenchymal stem cells (MSC) from fetal-placental tissues have translational advantages over their adult counterparts, and have variably been reported to express pluripotency markers. OCT-4 expression in fetal-placental MSC has been documented in some studies, paradoxically without tumourogenicity in vivo. It is possible that OCT-4 expression is insufficient to induce true "stemness", but this issue is important for the translational safety of fetal-derived MSC. To clarify this, we undertook a systematic literature review on OCT-4 in fetal or adnexal MSC to show that most studies report OCT-4 message or protein expression, but no study provides definitive evidence of true OCT-4A expression. Discrepant findings were attributable not to different culture conditions, tissue sources, or gestational ages but instead to techniques used. In assessing OCT-4 as a pluripotency marker, we highlight the challenges in detecting the correct OCT-4 isoform (OCT-4A) associated with pluripotency. Although specific detection of OCT-4A mRNA is achievable, it appears unlikely that any antibody can reliably distinguish between OCT-4A and the pseudogene OCT-4B. Finally, using five robust techniques we demonstrate that fetal derived-MSC do not express OCT-4A (or by default OCT-4B). Reports suggesting OCT-4 expression in fetal-derived MSC warrant reassessment, paying attention to gene and protein isoforms, pseudogenes, and antibody choice as well as primer design. Critical examination of the OCT-4 literature leads us to suggest that OCT-4 expression in fetal MSC may be a case of "The Emperor's New Clothes" with early reports of (false) positive expression amplified in subsequent studies without critical attention to emerging refinements in knowledge and methodology.
Topics: Animals; Female; Fetus; Gene Expression Regulation, Developmental; Humans; Mesenchymal Stem Cells; Octamer Transcription Factor-3; Placenta; Pluripotent Stem Cells; Pregnancy
PubMed: 22161644
DOI: 10.1007/s12015-011-9336-5 -
Intensive Care Medicine Oct 2001To investigate whether accurate prognostic rules can be derived from the combined results of studies concerning prediction of poor prognosis in anoxic-ischaemic coma... (Review)
Review
OBJECTIVE
To investigate whether accurate prognostic rules can be derived from the combined results of studies concerning prediction of poor prognosis in anoxic-ischaemic coma with biochemical markers of brain damage in cerebrospinal fluid (CSF) or serum.
DESIGN
A meta-analysis of prognostic studies in anoxic-ischaemic coma, selected from Medline and EMBASE databases, according to predefined criteria.
SUBJECTS
Twenty-eight studies, with a total of 802 unselected, consecutive patients, in which tests, sampling time and outcome measures were described unequivocally and results were described using clear cut-off values or raw data.
MAIN OUTCOME MEASURES
Poor outcome, defined as death or vegetative state, versus good outcome, defined as any other outcome state.
ANALYSES
The overall prognostic accuracy of these variables was expressed as the 95% CIs of the pooled false-positive test rate and the pooled positive-likelihood ratios.
RESULTS
Only markers in CSF (creatine kinase isoenzyme (CKBB) >204 U/l, neuron specific enolase (NSE) >33 ng/ml, lactate dehydrogenase (LDH) >82 U/l and glutamate oxaloacetate (GOT) >62 U/l) reached a 0% false-positive rate. However, due to small sample sizes, the confidence limits were wide. The accuracy of prediction of poor outcome seemed acceptably high for CSF-CKBB (pooled false-positive rate 0% [95% CI 0-2.3%]; pooled positive-likelihood ratio 33.2 [95% CI 4.8-230.2]), but this result was based on two retrospective studies without blinding of the treating physicians for the test result.
CONCLUSIONS
Because of small numbers of patients studied and methodological limitations the combined results are not sufficiently accurate to provide a solid basis for non-treatment decisions.
Topics: Aspartate Aminotransferases; Biomarkers; Brain Ischemia; Coma; Creatine Kinase; Creatine Kinase, BB Form; False Positive Reactions; Humans; Hypoxia, Brain; Isoenzymes; L-Lactate Dehydrogenase; Likelihood Functions; Phosphopyruvate Hydratase; Predictive Value of Tests; Prognosis; Reproducibility of Results; Research Design; Sample Size; Time Factors
PubMed: 11685309
DOI: 10.1007/s001340101076 -
Human Reproduction Update Jun 2020Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.
BACKGROUND
Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.
OBJECTIVE AND RATIONALE
We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments.
SEARCH METHODS
We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment.
OUTCOMES
Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response.
WIDER IMPLICATIONS
Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.
Topics: Endometriosis; Endometrium; Female; Fertility Agents, Female; Humans; Ligands; Peritoneal Diseases; Progesterone; Progestins; Receptors, Progesterone; Treatment Outcome; Uterine Diseases
PubMed: 32412587
DOI: 10.1093/humupd/dmaa009 -
Nutrition and Cancer 2022The term vitamin E describes tocopherols and tocotrienols, whose chemical variations result in different biological activities including antioxidants. Neuroprotective...
The term vitamin E describes tocopherols and tocotrienols, whose chemical variations result in different biological activities including antioxidants. Neuroprotective effects of alpha-tocopherol against different toxins are assumed, therefore, it is discussed as a possible protective factor for adverse effects in cancer treatment. In July 2020, a systematic search was conducted searching five databases (Embase, Cochrane, PsychInfo, Cinahl, Medline) to find studies concerning the impact of α-tocopherol application and its potential harm on cancer patients. From 7546 search results, 22 publications referring to 20 studies with 1941 patients were included. Included patients were diagnosed with various cancer types and stages. Outcome variables were overall survival of cancer, symptom management of mucositis and chemotherapy-induced peripheral neuropathy (CIPN). The studies had different methodological qualities (mainly acceptable) and reported heterogeneous results: some reported significant improvement of mucositis and CIPN while others did not find changes concerning these endpoints. Due to heterogeneous results and methodical limitations of the included studies, a clear statement regarding the effectiveness of α-tocopherol as complementary treatment for cancer patients is not possible. Despite findings regarding reduction of oral side effects, usage of α-tocopherol during therapy must be discouraged because of potential negative influence on survival rates.
Topics: Antioxidants; Humans; Mucositis; Neoplasms; Protein Isoforms; Tocotrienols; Vitamin E; alpha-Tocopherol
PubMed: 34918607
DOI: 10.1080/01635581.2021.2014905 -
Journal of Pharmacy & Pharmaceutical... 2022This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD)...
PURPOSE
This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD) patients on hemodialysis. This medication's new phosphate lowering mechanism of action reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux by inhibition of the sodium/hydrogen exporter isoform 3 (NHE3). Tenapanor additionally prevents active transcellular phosphate absorption compensation by decreasing the expression of sodium phosphorus 2b transport protein (NaPi2b).
METHODS
A comprehensive search of the literature was conducted using PubMed and ClinicalTrials.gov search engines. The search term "tenapanor hyperphosphatemia" was used for study retrieval. Results were limited to studies published in the English language and excluded review articles. Human, animal, and in vitro studies were included. No date range was specified.
RESULTS
A total of 11 primary studies were identified and included in this review, the largest human study of which enrolled 236 patients. Each study is presented in table format along with measured end points.
CONCLUSIONS
Tenapanor is the first drug in its class that lowers hyperphosphatemia in ESKD patients through a novel mechanism of action involving paracellular inactive transport. Although more studies are needed, early results indicate that tenapanor may have a place in managing hyperphosphatemia in ESKD patients both as monotherapy and as an adjunct to existing phosphate binder therapy.
Topics: Animals; Biological Transport, Active; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Humans; Hyperphosphatemia; Intestinal Absorption; Isoquinolines; Kidney Failure, Chronic; Phosphates; Rats; Sodium-Hydrogen Exchanger 3; Sulfonamides
PubMed: 35041802
DOI: 10.18433/jpps32284