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Movement Disorders : Official Journal... Sep 2023Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response).... (Meta-Analysis)
Meta-Analysis Review
Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response). Imaging, genetic, and biochemical biomarkers have been widely studied. In recent years, extracellular vesicles (EVs) have become a promising material for biomarker development. Proteins and molecular material from any organ, including the central nervous system, can be packed into EVs and transported to the periphery into easily obtainable biological specimens like blood, urine, and saliva. We performed a systematic review and meta-analysis of articles (published before November 15, 2022) reporting biomarker assessment in EVs in PD patients and healthy controls (HCs). Biomarkers were analyzed using random effects meta-analysis and the calculated standardized mean difference (Std.MD). Several proteins and ribonucleic acids have been identified in EVs in PD patients, but only α-synuclein (aSyn) and leucine-rich repeat kinase 2 (LRRK2) were reported in sufficient studies (n = 24 and 6, respectively) to perform a meta-analysis. EV aSyn was significantly increased in neuronal L1 cell adhesion molecule (L1CAM)-positive blood EVs in PD patients compared to HCs (Std.MD = 1.84, 95% confidence interval = 0.76-2.93, P = 0.0009). Further analysis of the biological sample and EV isolation method indicated that L1CAM-IP (immunoprecipitation) directly from plasma was the best isolation method for assessing aSyn in PD patients. Upcoming neuroprotective clinical trials immediately need peripheral biomarkers for identifying individuals at risk of developing PD. Overall, the improved sensitivity of assays means they can identify biomarkers in blood that reflect changes in the brain. CNS-derived EVs in blood will likely play a major role in biomarker development in the coming years. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; alpha-Synuclein; Biomarkers; Extracellular Vesicles; Neural Cell Adhesion Molecule L1; Parkinson Disease
PubMed: 37449706
DOI: 10.1002/mds.29497 -
Communications Medicine Oct 2023Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta...
BACKGROUND
Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.
METHODS
To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.
RESULTS
We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings.
CONCLUSIONS
While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.
PubMed: 37794169
DOI: 10.1038/s43856-023-00357-y -
Inflammation Research : Official... May 2024γδ T cells are a distinct subset of unconventional T cells, which link innate and adaptive immunity by secreting cytokines and interacting with other immune cells,... (Review)
Review
OBJECTIVE
γδ T cells are a distinct subset of unconventional T cells, which link innate and adaptive immunity by secreting cytokines and interacting with other immune cells, thereby modulating immune responses. As the first line of host defense, γδ T cells are essential for mucosal homeostasis and immune surveillance. When abnormally activated or impaired, γδ T cells can contribute to pathogenic processes. Accumulating evidence has revealed substantial impacts of γδ T cells on the pathogenesis of cancers, infections, and immune-inflammatory diseases. γδ T cells exhibit dual roles in cancers, promoting or inhibiting tumor growth, depending on their phenotypes and the clinical stage of cancers. During infections, γδ T cells exert high cytotoxic activity in infectious diseases, which is essential for combating bacterial and viral infections by recognizing foreign antigens and activating other immune cells. γδ T cells are also implicated in the onset and progression of immune-inflammatory diseases. However, the specific involvement and underlying mechanisms of γδ T cells in oral diseases have not been systematically discussed.
METHODS
We conducted a systematic literature review using the PubMed/MEDLINE databases to identify and analyze relevant literature on the roles of γδ T cells in oral diseases.
RESULTS
The literature review revealed that γδ T cells play a pivotal role in maintaining oral mucosal homeostasis and are involved in the pathogenesis of oral cancers, periodontal diseases, graft-versus-host disease (GVHD), oral lichen planus (OLP), and oral candidiasis. γδ T cells mainly influence various pathophysiological processes, such as anti-tumor activity, eradication of infection, and immune response regulation.
CONCLUSION
This review focuses on the involvement of γδ T cells in oral diseases, with a particular emphasis on the main functions and underlying mechanisms by which γδ T cells influence the pathogenesis and progression of these conditions. This review underscores the potential of γδ T cells as therapeutic targets in managing oral health issues.
Topics: Humans; Mouth Diseases; Animals; Receptors, Antigen, T-Cell, gamma-delta; Intraepithelial Lymphocytes; Graft vs Host Disease; T-Lymphocytes
PubMed: 38563967
DOI: 10.1007/s00011-024-01870-z -
Archives of Medical Research Dec 2023Predictors of first-generation somatostatin receptor ligands (fgSRLs) response in acromegaly have been studied for over 30 years, but they are still not recommended in...
BACKGROUND AND AIMS
Predictors of first-generation somatostatin receptor ligands (fgSRLs) response in acromegaly have been studied for over 30 years, but they are still not recommended in clinical guidelines. Is there not enough evidence to support their use? This systematic review aims to describe the current knowledge of the main predictors of fgSRLs response and discuss their current usefulness, as well as future research directions.
METHODS
A systematic search was performed in the Scopus and PubMed databases for functional, imaging, and molecular predictive factors.
RESULTS
A total of 282 articles were detected, of which 64 were included. Most of them are retrospective studies performed between 1990 and 2023 focused on the predictive response to fgSRLs in acromegaly. The usefulness of the predictive factors is confirmed, with good response identified by the most replicated factors, specifically low GH nadir in the acute octreotide test, T2 MRI hypointensity, high Somatostatin receptor 2 (SSTR2) and E-cadherin expression, and a densely granulated pattern. Even if these biomarkers are interrelated, the association is quite heterogeneous. With classical statistical methods, it is complex to define reliable and generalizable cut-off values worth recommending in clinical guidelines. Machine-learning models involving omics are a promising approach to achieve the highest accuracy values to date.
CONCLUSIONS
This survey confirms a sufficiently robust level of evidence to apply knowledge of predictive factors for greater efficiency in the treatment decision process. The irruption of artificial intelligence in this field is providing definitive answers to such long-standing questions that may change clinical guidelines and make personalized medicine a reality.
Topics: Humans; Acromegaly; Somatostatin; Receptors, Somatostatin; Retrospective Studies; Artificial Intelligence; Treatment Outcome
PubMed: 38042683
DOI: 10.1016/j.arcmed.2023.102924 -
Scientific Reports Sep 2023Sirtuin 1 (SIRT1) is a key physiological regulator of metabolism and a target of therapeutic interventions for cardiometabolic and ageing-related disorders. Determining... (Meta-Analysis)
Meta-Analysis
Sirtuin 1 (SIRT1) is a key physiological regulator of metabolism and a target of therapeutic interventions for cardiometabolic and ageing-related disorders. Determining the factors and possible mechanisms of acute and adaptive SIRT1 response to exercise is essential for optimising exercise interventions aligned to the prevention and onset of disease. Exercise-induced SIRT1 upregulation has been reported in animals, but, to date, data in humans have been inconsistent. This exploratory systematic review and meta-analysis aims to assess various exercise interventions measuring SIRT1 in healthy participants. A total of 34 studies were included in the meta-analysis (13 single bout exercise, 21 training interventions). Studies were grouped according to tissue sample type (blood, muscle), biomarkers (gene expression, protein content, enzyme level, enzyme activity), and exercise protocols. A single bout of high-intensity or fasted exercise per se increases skeletal muscle SIRT1 gene expression as measured by qPCR or RT-PCR, while repeated resistance training alone increases blood SIRT1 levels measured by ELISA. A limited number of studies also show a propensity for an increase in muscle SIRT1 activity as measured by fluorometric or sirtuin activity assay. In conclusion, exercise acutely upregulates muscle SIRT1 gene expression and chronically increases SIRT1 blood enzyme levels.
Topics: Animals; Humans; Sirtuin 1; Sirtuins; Biological Assay; Enzyme-Linked Immunosorbent Assay; Exercise
PubMed: 37679377
DOI: 10.1038/s41598-023-38843-x -
Nutrients Feb 2024Over the past few decades, vitamin D has been found to play a crucial role in bone homeostasis, muscle function, oncogenesis, immune response and metabolism. In the... (Meta-Analysis)
Meta-Analysis Review
Over the past few decades, vitamin D has been found to play a crucial role in bone homeostasis, muscle function, oncogenesis, immune response and metabolism. In the context of the COVID-19 pandemic, numerous researchers have tried to determine the role vitamin D might play in the immune response to the virus. The aim of this systematic review and meta-analysis is to demonstrate that preventive vitamin D supplementation can play a protective role in the incidence of COVID-19, mortality and admission to intensive care units (ICUs). A comprehensive search on the PubMed/MEDLINE, Scopus, Cochrane and Google Scholar databases was performed on 15 May 2023, and two of the authors independently screened the literature. As effect measures, we calculated the Odds Ratios with their corresponding 95% confidence intervals (ICs). The assessment of potential bias and the evaluation of study quality will be conducted independently by two researchers. Sixteen publications were selected for inclusion in the meta-analysis. Our findings indicate that vitamin D supplementation has a protective effect against the incidence of COVID-19 in RCT studies (OR 0.403, 95% IC 0.218, 0.747), in the incidence of COVID-19 in analytical studies (OR = 0.592, 95% IC 0.476-0.736) and in ICU admission (OR 0.317, 95% IC 0.147-0.680). Subsequent analyses were conducted by type of subject treated (patient/healthcare workers) and type of supplementation (vitamin D vs. placebo/no treatment or high dose vs. low dose). Our meta-analysis suggests a definitive and significant association between the protective role of vitamin D and COVID-19 incidence and ICU admission.
Topics: Humans; Vitamin D; Pandemics; COVID-19; Vitamins; Dietary Supplements
PubMed: 38474807
DOI: 10.3390/nu16050679 -
BMC Cancer Nov 2023RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial.
METHODS
We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.
RESULTS
Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (P < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (P for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (P = 0.01) and OS (P = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.
CONCLUSIONS
In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
Topics: Humans; Prognosis; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); ErbB Receptors; Antibodies, Monoclonal; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; Class I Phosphatidylinositol 3-Kinases; Mutation; MicroRNAs; Biomarkers, Tumor
PubMed: 37974093
DOI: 10.1186/s12885-023-11600-z -
Brain and Behavior Nov 2023Obstructive sleep apnea (OSA) is a common sleep disorder that causes intermittent hypoxia and sleep fragmentation, leading to attention impairment and other cognitive... (Review)
Review
BACKGROUND AND OBJECTIVE
Obstructive sleep apnea (OSA) is a common sleep disorder that causes intermittent hypoxia and sleep fragmentation, leading to attention impairment and other cognitive deficits. Magnetic resonance imaging (MRI) is a powerful modality that can reveal the structural and functional brain alterations associated with attention impairment in OSA patients. The objective of this systematic review is to identify and synthesize the evidence on MRI biomarkers and neuropsychological assessments of attention deficits in OSA patients.
METHODS
We searched the Scopus and PubMed databases for studies that used MRI to measure biomarkers related to attention alteration in OSA patients and reported qualitative and quantitative data on the association between MRI biomarkers and attention outcomes. We also included studies that found an association between neuropsychological assessments and MRI findings in OSA patients with attention deficits.
RESULTS
We included 19 studies that met our inclusion criteria and extracted the relevant data from each study. We categorized the studies into three groups based on the MRI modality and the cognitive domain they used: structural and diffusion tensor imaging MRI findings, functional, perfusion, and metabolic MRI findings, and neuropsychological assessment findings.
CONCLUSIONS
We found that OSA is associated with structural, functional, and metabolic brain alterations in multiple regions and networks that are involved in attention processing. Treatment with continuous positive airway pressure can partially reverse some of the brain changes and improve cognitive function in some domains and in some studies. This review suggests that MRI techniques and neuropsychological assessments can be useful tools for monitoring the progression and response to treatment of OSA patients.
Topics: Humans; Diffusion Tensor Imaging; Sleep Apnea, Obstructive; Brain; Magnetic Resonance Imaging; Biomarkers; Neuropsychological Tests
PubMed: 37743582
DOI: 10.1002/brb3.3262 -
Behavioural Brain Research Oct 2023SARS-CoV-2 infection produces a wide range of symptoms. Some of the structural changes caused by the virus in the nervous system are found in the medial temporal lobe,... (Review)
Review
SARS-CoV-2 infection produces a wide range of symptoms. Some of the structural changes caused by the virus in the nervous system are found in the medial temporal lobe, and several neuropsychological sequelae of COVID-19 are related to the function of the hippocampus. The main objective of the systematic review is to update and further analyze the existing evidence of hippocampal and related cortices' structural and functional alterations due to SARS-CoV-2 infection. Both clinical and preclinical studies that used different methodologies to explore the effects of this disease at different stages and grades of severity were considered, besides exploring related cognitive and emotional symptomatology. A total of 24 studies were identified by searching in SCOPUS, Web Of Science (WOS), PubMed, and PsycInfo databases up to October 3rd, 2022. Thirteen studies were performed in clinical human samples, 9 included preclinical animal models, 3 were performed post-mortem, and 1 included both post-mortem and preclinical samples. Alterations in the hippocampus were detected in the acute stage and after several months of infection. Clinical studies revealed alterations in hippocampal connectivity and metabolism. Memory alterations correlated with altered metabolic profiles or changes in grey matter volumes. Hippocampal human postmortem and animal studies observed alterations in neurogenesis, dendrites, and immune response, besides high apoptosis and neuroinflammation. Preclinical studies reported the viral load in the hippocampus. Olfactory dysfunction was associated with alterations in brain functionality. Several clinical studies revealed cognitive complaints, neuropsychological alterations, and depressive and anxious symptomatology.
Topics: Animals; Humans; COVID-19; SARS-CoV-2; Hippocampus; Temporal Lobe
PubMed: 37703951
DOI: 10.1016/j.bbr.2023.114662 -
Frontiers in Immunology 2024Clinicians and healthcare policymakers have been drenched with a deluge of overlapping meta-analyses (MAs), and the necessity for comprehensive and clearly defined...
BACKGROUND
Clinicians and healthcare policymakers have been drenched with a deluge of overlapping meta-analyses (MAs), and the necessity for comprehensive and clearly defined evidence of Janus kinase inhibitors (JKIs) in atopic dermatitis (AD) is urgent.
METHODS
Six databases were searched for MAs published until October 2023. Qualitative description of MAs was mainly used, and Investigator's Global Assessment response (IGA response), the 75% improvement in Eczema Area and Severity Index (the EASI75), peak pruritus Numerical rating score (PP-NRS), and adverse effects were cited to describe the efficacy and safety of JKIs. The methodological quality of the included MAs was assessed by A Measurement Tool to Assess Systematic Reviews II (AMSTAR II), and the quality of evidence was evaluated by the grading of recommendations, assessment, development, and evaluation (GRADE).
RESULTS
Sixteen MAs were pooled in this review, of which five studies appraised JKIs, five appraised systemic JKIs, five papers assessed abrocitinib only, and one assessed baricitinib. Two studies were of "high" methodological quality and 14 MAs were of "moderate" quality. Eleven MAs integrated the results of JKIs and reported that JKIs provide faster onset of IGA response (RR=2.83, 95% CI [2.25, 3.56], high-quality evidence). Similarly, 10 MAs showed that JAK inhibitors were more effective in improving the EASI75 (RR=2.84, 95% CI [2.2, 3.67], high-quality evidence). Results from 12 MAs showed JKIs were active in reducing the PP-NRS (SMD=-0.49, 95% CI [-0.67, -0.32]). All MAs affirmed JKIs added no adverse effects leading to discontinuation and serious adverse events (P<0.05). However, 200mg of abrocitinib had a higher risk of acne (RR=4.34, 95% CI [1.61, 11.71), herpes zoster (RR=1.64, 95% CI [0.42, 6.39]), headache (RR=1.76, 95% CI [1.03, 3]), and nausea (RR=7.81, 95% CI [3.84, 15.87]). Upadacitinib was known to increase acne (RR=6.23, 95% CI [4.08, 9.49]), nasopharyngitis (RR=1.36, 95% CI [1.03, 1.8]) and blood creatine phosphokinase (blood CPK) (RR=2.41, 95% CI [1.47, 3.95]). Baricitinib at 2mg was associated with increased blood CPK (RR=2.25, 95% CI [1.1, 2.97]).
CONCLUSION
Compared to placebo or dupilumab, the administration of JKIs can ameliorate IGA response more effectively, improve the EASI75, and relieve pruritus without severe adverse effect, while accompanied by more acne, nasopharyngitis, headache, and digestive disturbances. The curative effect of 200 mg of abrocitinib is significant and more caution should be given in patients with gastrointestinal dysfunction, herpes zoster, and those who are acne-prone. Baricitinib and upadacitinib should be avoided in populations at high risk for cardiovascular events.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=369369, PROSPERO (CRD42022369369).
Topics: Humans; Dermatitis, Atopic; Janus Kinase Inhibitors; Nasopharyngitis; Pruritus; Acne Vulgaris; Headache; Herpes Zoster; Immunoglobulin A; Purines; Sulfonamides; Pyrazoles; Pyrimidines; Azetidines
PubMed: 38464512
DOI: 10.3389/fimmu.2024.1342810