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Frontiers in Immunology 2020Biological agents (also termed biologics or biologicals) play a growingly central role in the treatment of immunological diseases. However, the numerous studies...
Biological agents (also termed biologics or biologicals) play a growingly central role in the treatment of immunological diseases. However, the numerous studies published on biologics complicate the decision on the most appropriate biologic for a given disease. We aim to address this problem by publishing a series of systematic reviews evaluating the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. This article assesses the safety and efficacy of atacicept, a recombinant fusion protein consisting of the binding portion of transmembrane activator and CAML interactor (TACI; also known as tumor necrosis factor receptor superfamily member 13B), which is able to bind the cytokines B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL). To evaluate atacicept's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics. The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. The literature search identified 118 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, ten articles were finally included in a narrative synthesis. Atacicept failed to show an effect in multiple sclerosis, optic neuritis, rheumatoid arthritis, and systemic lupus erythematosus. In patients with systemic lupus erythematosus, atacicept led to increased infection rates, but this adverse effect was not seen in the other treated diseases.
Topics: Arthritis, Rheumatoid; B-Cell Activating Factor; Biological Products; Humans; Lupus Erythematosus, Systemic; Multiple Sclerosis; Optic Neuritis; Protein Binding; Recombinant Fusion Proteins; Transmembrane Activator and CAML Interactor Protein; Tumor Necrosis Factor Ligand Superfamily Member 13
PubMed: 32265917
DOI: 10.3389/fimmu.2020.00433 -
AJOG Global Reports Aug 2023This study evaluated the correlation between maternal hepcidin and other biomarkers of iron status, markers of inflammation, and maternal body weight during pregnancy,... (Review)
Review
Hepcidin across pregnancy and its correlation with maternal markers of iron and inflammation, maternal body weight outcomes, and offspring neurodevelopmental outcomes: a systematic review and meta-analysis.
OBJECTIVE
This study evaluated the correlation between maternal hepcidin and other biomarkers of iron status, markers of inflammation, and maternal body weight during pregnancy, as well as neurodevelopment in the offspring.
DATA SOURCES
PubMed, Web of Science, Scopus, and Embase were searched from inception until March 2022.
STUDY ELIGIBILITY CRITERIA
Studies conducted among pregnant women without apparent pregnancy complications were included. Eligible studies reported correlation coefficients between maternal hepcidin and any outcomes of maternal biomarkers of iron status or inflammatory load during pregnancy, prenatal maternal body weight, and offspring neurodevelopment. Studies without correlation data were eligible if they quantitatively reported volumes of both maternal hepcidin and any marker of iron status and/or inflammatory load during gestation.
METHODS
Pooled correlation coefficients between maternal hepcidin and outcomes of interest were calculated using the Fisher -to-Z transformation. Both fixed-effects and DerSimonian and Laird random-effects models were used to calculate pooled correlation coefficient. When meta-analysis was not feasible, results were descriptively synthesized.
RESULTS
Forty-six studies with 6624 participants were eligible. Hepcidin was significantly correlated with hemoglobin in the third trimester (=0.21; 95% confidence interval, 0.1-0.32); ferritin in the first (=0.31; 95% confidence interval, 0.01-0.61) and third trimester (=0.35; 95% confidence interval, 0.23-0.48); soluble transferrin receptor in the second trimester (=-0.27; 95% confidence interval, -0.4 to -0.14); total iron-binding capacity in the second trimester (=0.37; 95% confidence interval, 0.24-0.50); and serum iron in the third trimester (=0.11; 95% confidence interval, 0.02-0.19). Hepcidin was significantly correlated with the inflammatory marker interleukin-6 in the third trimester (=0.26; 95% confidence interval, 0.17-0.34) and C-reactive protein in the second (=0.16; 95% confidence interval, 0.03-0.30) and third trimester (=0.28; 95% confidence interval, 0.04-0.52). Four out of 5 studies reported weak-to-moderate positive correlation between hepcidin and body mass index. Hepcidin levels varied across body mass index categories. No single study reported the relationship between maternal hepcidin and neurodevelopment in offspring.
CONCLUSION
Hepcidin weakly to moderately correlates with biomarkers of iron and inflammation in pregnancy.
PubMed: 37645642
DOI: 10.1016/j.xagr.2023.100222 -
The Cochrane Database of Systematic... Jan 2009Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). There is an understanding that an increase in L-glutamate contributes to... (Review)
Review
BACKGROUND
Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). There is an understanding that an increase in L-glutamate contributes to the pathogenesis of cerebral ischemias and AD. Memantine acts as an antagonist of N-methyl-D-aspartate (NMDA) type receptors, which is thought to reduce abnormal activation of glutamate neurotransmission. It binds with a low affinity to the NMDA receptor and so should not prevent learning and the formation of memory. Memantine can improve cognitive function and slow the decline of AD in the general population over time, and is the subject of this review. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population.
OBJECTIVES
To determine the effectiveness and safety of memantine for people with DS who develop AD.
SEARCH STRATEGY
CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of memantine, as well as experts in the field, to ask about reports of unpublished or ongoing trials.
SELECTION CRITERIA
Randomised controlled trials of participants with DS and AD in which treatment with memantine was administered compared with a placebo group.
DATA COLLECTION AND ANALYSIS
No study was identified which met the inclusion criteria for this review.
MAIN RESULTS
No study was identified which met inclusion criteria for this review, however there is an on-going randomised controlled study being conducted in the UK and data are expected in 2009.
AUTHORS' CONCLUSIONS
As there are no included trials, recommendations cannot be made about memantine for AD in DS. Well-designed, adequately powered studies are required.
Topics: Alzheimer Disease; Down Syndrome; Humans; Memantine; Receptors, N-Methyl-D-Aspartate
PubMed: 19160343
DOI: 10.1002/14651858.CD007657 -
Arthritis Care & Research Oct 2021Opioids have long been prescribed for chronic pain conditions, including osteoarthritis (OA). However, there is little information about their temporal efficacy, or... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Opioids have long been prescribed for chronic pain conditions, including osteoarthritis (OA). However, there is little information about their temporal efficacy, or differences in efficacy and safety between opioids with strong versus weak/intermediate μ opioid receptor-binding affinity. To explore these research questions, we conducted a systematic review and meta-analyses of randomized controlled trials (RCTs) conducted in patients with knee and/or hip OA.
METHODS
We searched Medline, Embase, PubMed Central, and the Cochrane Central Register of Controlled Trials from inception to December 2019 and sought unpublished data. Placebo-controlled RCTs of oral opioids in patients with knee and/or hip OA were included. Standardized mean differences (SMDs) were calculated for pain and function at 2, 4, 8, and 12 weeks. Subgroup analyses for strong and weak/intermediate opioids were conducted. Meta-regression was performed to assess the impact of dosage (morphine equivalency) on pain relief. Risk ratios were calculated for safety at the final follow-up.
RESULTS
A total of 18 RCTs (9,283 participants) were included. Opioids demonstrated small benefits on pain at each time point, with SMDs ranging from -0.28 (95% confidence interval [95% CI] -0.38, -0.17) to -0.19 (95% CI -0.29, -0.08); similar effects were observed for function. Strong opioids demonstrated consistently inferior efficacy and overall worse safety than weak/intermediate opioids. Meta-regression revealed that incremental pain relief achieved beyond 20-50-mg doses was not substantial in the context of increased safety risks.
CONCLUSION
Opioids provide minimal relief of OA symptoms within a 12-week period, and they are known to cause discomfort in a majority of patients. Clinicians and policy makers should reconsider the utility of opioids in the management of OA.
Topics: Aged; Analgesics, Opioid; Arthralgia; Chronic Pain; Female; Humans; Male; Middle Aged; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain Management; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome
PubMed: 32583972
DOI: 10.1002/acr.24363 -
Hematology/oncology and Stem Cell... Mar 2021Vitamin D is a steroid hormone that exerts its actions through ligation of the vitamin D receptor (VDR), a transcription factor of the nuclear receptor family. VDR has... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Vitamin D is a steroid hormone that exerts its actions through ligation of the vitamin D receptor (VDR), a transcription factor of the nuclear receptor family. VDR has not only physiologic actions in calcium metabolism but also several other cellular effects through extensive binding to the DNA and modification of genome expression. In cancer, it has neoplasia-suppressive effects and various mechanisms of action mediating cancer cell inhibition have been described. Vitamin D deficiency has been linked to increased risk of breast cancer. A role of the vitamin once the disease has been diagnosed is also probable.
METHODS
A systematic review and meta-analysis of studies that report on vitamin D levels (in the form of its main circulating metabolite, 25-hydroxyvitamin D [25-OHD]) in patients with newly diagnosed breast cancer was performed. Outcomes of interest included the levels of serum 25-OHD in patients with breast cancer, those of matched controlled, in studies that included controls, as well as respective percentages of patients and controls with deficient and insufficient 25-OHD levels.
RESULTS
A total of 25 studies (10 with controls and 15 without controls) provided data on the outcomes of interest. Populations from all continents, besides Australia, were represented in the studies. The mean level of 25-OHD in patients with breast cancer was 26.88 ng/mL (95% CI 22.8-30.96 ng/mL) and the mean level of 25-OHD in control patients was 31.41 ng/mL (95% CI 19.31-43.5 ng/mL). In the patients with breast cancer group, 45.28% (95% CI 24.37%-53.51%) had levels of 25-OHD below 20 ng/mL, whereas this percentage was 33.71% (95% CI 21.61%-45.82%) in controls. Similarly, 67.44% (95% CI 48.32%-86.55%) of patients with breast cancer had a baseline level of 25-OHD below 30 ng/mL, whereas this percentage was 33.71% (95% CI 21.61%-45.82%) in controls.
CONCLUSION
A high prevalence of vitamin D insufficiency is observed in patients with newly diagnosed breast cancer and may be linked pathophysiologically with breast cancer development or progression. Therapeutic benefits may be provided by manipulation of the vitamin D pathway in breast cancer.
Topics: Breast Neoplasms; Female; Humans; Vitamin D; Vitamin D Deficiency
PubMed: 33002425
DOI: 10.1016/j.hemonc.2020.08.005 -
Microbiology Spectrum Aug 2022SARS-CoV-2 Omicron variants contain many mutations in its spike receptor-binding domain, the target of all authorized monoclonal antibodies (MAbs). Determining the... (Meta-Analysis)
Meta-Analysis
SARS-CoV-2 Omicron variants contain many mutations in its spike receptor-binding domain, the target of all authorized monoclonal antibodies (MAbs). Determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We systematically reviewed PubMed and three preprint servers, last updated 11 April 2022, for the activity of authorized MAbs against the Omicron variants. Fifty-one studies were eligible, including 50 containing Omicron BA.1 susceptibility data and 17 containing Omicron BA.2 susceptibility data. The first two authorized MAb combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, were largely inactive against the Omicron BA.1 and BA.2 variants. In 34 studies, sotrovimab displayed a median 4.0-fold (interquartile range [IQR]: 2.6 to 6.9) reduction in activity against Omicron BA.1, and in 12 studies, it displayed a median 17-fold (IQR: 13 to 30) reduction in activity against Omicron BA.2. In 15 studies, the combination cilgavimab/tixagevimab displayed a median 86-fold (IQR: 27 to 151) reduction in activity against Omicron BA.1, and in six studies, it displayed a median 5.4-fold (IQR: 3.7 to 6.9) reduction in activity against Omicron BA.2. In eight studies against Omicron BA.1 and six studies against Omicron BA.2, bebtelovimab displayed no reduction in activity. Disparate results between assays were common. For authorized MAbs, 51/268 (19.0%) results for wild-type control variants and 78/348 (22.4%) results for Omicron BA.1 and BA.2 variants were more than 4-fold below or 4-fold above the median result for that MAb. Highly disparate results between published assays indicate a need for improved MAb susceptibility test standardization or interassay calibration. Monoclonal antibodies (MAbs) targeting the SARS-CoV-2 spike protein are among the most effective measures for preventing and treating COVID-19. However, SARS-CoV-2 Omicron variants contain many mutations in their spike receptor-binding domains, the target of all authorized MAbs. Therefore, determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We identified 51 studies that reported the susceptibility of the two main Omicron variants BA.1 and BA.2 to therapeutic MAbs in advanced clinical development, including eight authorized individual MAbs and three authorized MAb combinations. We estimated the degree to which different MAbs displayed reduced activity against Omicron variants. The marked loss of activity of many MAbs against Omicron variants underscores the importance of developing MAbs that target conserved regions of spike. Highly disparate results between assays indicate the need for improved MAb susceptibility test standardization.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Antibodies, Viral; Humans; Neutralization Tests; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Viral Envelope Proteins; COVID-19 Drug Treatment
PubMed: 35700134
DOI: 10.1128/spectrum.00926-22 -
Clinical and Experimental Immunology Jun 2022Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this...
Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this report, we systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. We assessed 286 patients (44.5% female) with IL10 and/or IL10R deficiencies who were predominantly from China (40.7%), Italy (13.9%), and South Korea (8.5%). The median age of onset was 1.0 (0.3-4.0) months with a median age of genetic diagnosis at 16.0 (7.4-81.0) months. Consanguinity was reported in all evaluable patients with IL10 deficiency and in 38.2% of patients with IL10R deficiency (22.9% of patients with IL10RA, and 79.4% of patients with IL10RB deficiency). The most prevalent mutations in IL10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Auto-inflammation and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (17.8%), and colitis (15.5%). Patients with IL10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60.5%), while IL10-deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30.7% underwent hemopoietic stem cell transplantation, 57.5% surgery, and 86.6% immunosuppressive treatment. The 10-year survival rate was higher in patients with IL10 deficiency than in patients with IL10R deficiency. In conclusion, IL10/IL10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. We detected no clear correlation between the phenotype of patients carrying the same variant. The high prevalence of distinct clinical manifestations reported in IL10RA- and IL10RB-deficient patients might be attributable to the interactions between the target tissue and cytokines other than IL10 capable of binding to IL10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcomes.
Topics: Diarrhea; Female; Humans; Inflammatory Bowel Diseases; Interleukin-10; Male; Phenotype; Receptors, Interleukin-10
PubMed: 35481870
DOI: 10.1093/cei/uxac040 -
Signal Transduction and Targeted Therapy Oct 2020Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that is highly pathogenic and has caused the recent worldwide pandemic officially named...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that is highly pathogenic and has caused the recent worldwide pandemic officially named coronavirus disease (COVID-19). Currently, considerable efforts have been put into developing effective and safe drugs and vaccines against SARS-CoV-2. Vaccines, such as inactivated vaccines, nucleic acid-based vaccines, and vector vaccines, have already entered clinical trials. In this review, we provide an overview of the experimental and clinical data obtained from recent SARS-CoV-2 vaccines trials, and highlight certain potential safety issues that require consideration when developing vaccines. Furthermore, we summarize several strategies utilized in the development of vaccines against other infectious viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), with the aim of aiding in the design of effective therapeutic approaches against SARS-CoV-2.
Topics: Angiotensin-Converting Enzyme 2; Antibodies, Viral; Betacoronavirus; COVID-19; COVID-19 Vaccines; Clinical Trials as Topic; Coronavirus Infections; Gene Expression Regulation; Humans; Immunity, Innate; Immunization Schedule; Immunogenicity, Vaccine; Middle East Respiratory Syndrome Coronavirus; Pandemics; Patient Safety; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Receptors, Virus; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; Severe Acute Respiratory Syndrome; Spike Glycoprotein, Coronavirus; Vaccines, Attenuated; Vaccines, DNA; Vaccines, Subunit; Vaccines, Virus-Like Particle; Viral Vaccines
PubMed: 33051445
DOI: 10.1038/s41392-020-00352-y -
Heliyon Mar 2022The brain maintains homeostasis of neural excitation in part through the receptor-mediated signaling of Glutamate (Glu) and Gamma Amino Butyric Acid (GABA), but... (Review)
Review
Interactions of Glutamate and Gamma Amino Butyric Acid with the insulin-like growth factor system in traumatic brain injury (TBI) and/or cardiovascular accidents (CVA or stroke): A systematic review.
The brain maintains homeostasis of neural excitation in part through the receptor-mediated signaling of Glutamate (Glu) and Gamma Amino Butyric Acid (GABA), but localized injuries cause cellular release of excess Glu leading to neurotoxicity. The literature strongly supports the role of Insulin-like growth factor-1 (IGF-1) in adult brain neuroprotection and repair, and research supporting the existence of molecular interactions between Glu, GABA, and IGF-1 and in normal animals raises the question of whether and/or how the Glu/GABA system interacts with IGF-1 post-injury. This systematic review was undertaken to explore works addressing this question among adults with a history of traumatic brain injury (TBI) and/or cerebrovascular accident (CVA; stroke). The literature was searched for human and animal studies and only four animal papers met inclusion criteria. The SYRCLE criteria was used to evaluate risk of bias; results varied between categories and papers. All the included studies, one on TBI and three on stroke, supported the molecular relationship between the excitatory and IGF-1 systems; two studies provided direct, detailed molecular evidence. The results point to the importance of research on the role of this protective system in pathological brain injury; a hypothetical proposal for future studies is presented.
PubMed: 35309405
DOI: 10.1016/j.heliyon.2022.e09037 -
International Journal of Molecular... Nov 2017The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central regulator in the development of several cancer types. In recent years,... (Review)
Review
The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central regulator in the development of several cancer types. In recent years, intriguing information has become available regarding the role of S1P in the progression of Glioblastoma multiforme (GBM), the most aggressive and common brain tumor in adults. S1P modulates numerous cellular processes in GBM, such as oncogenesis, proliferation and survival, invasion, migration, metastasis and stem cell behavior. These processes are regulated via a family of five G-protein-coupled S1P receptors (S1PR1-5) and may involve mainly unknown intracellular targets. Distinct expression patterns and multiple intracellular signaling pathways of each S1PR subtype enable S1P to exert its pleiotropic cellular actions. Several studies have demonstrated alterations in S1P levels, the involvement of S1PRs and S1P metabolizing enzymes in GBM pathophysiology. While the tumorigenic actions of S1P involve the activation of several kinases and transcription factors, the specific G-protein (Gi, Gq, and G12/13)-coupled signaling pathways and downstream mediated effects in GBM remain to be elucidated in detail. This review summarizes the recent findings concerning the role of S1P and its receptors in GBM. We further highlight the current insights into the signaling pathways considered fundamental for regulating the cellular processes in GMB and ultimately patient prognosis.
Topics: Adult; Brain Neoplasms; Cell Movement; Disease Progression; GTP-Binding Proteins; Glioblastoma; Humans; Lysophospholipids; Neoplasm Invasiveness; Neoplasm Metastasis; Prognosis; Receptors, Lysosphingolipid; Sphingosine
PubMed: 29149079
DOI: 10.3390/ijms18112448