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Neuroscience and Biobehavioral Reviews Oct 2021Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as... (Review)
Review
Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as schizophrenia. Rodent models of mIA have explored possible mechanisms underlying this paradigm and provide a vital tool for preclinical research. However, a comprehensive analysis of the molecular changes that occur in mIA-models is lacking, hindering identification of robust clinical targets. This systematic review assesses mIA-driven transcriptomic and epigenomic alterations in specific offspring brain regions. Across 118 studies, we focus on 88 candidate genes and show replicated changes in expression in critical functional areas, including elevated inflammatory markers, and reduced myelin and GABAergic signalling proteins. Further, disturbed epigenetic markers at nine of these genes support mIA-driven epigenetic modulation of transcription. Overall, our results demonstrate that current outcome measures have direct relevance for the hypothesised pathology of schizophrenia and emphasise the importance of mIA-models in contributing to the understanding of biological pathways impacted by mIA and the discovery of new drug targets.
Topics: Animals; Behavior, Animal; Brain; Disease Models, Animal; Epigenesis, Genetic; Epigenomics; Female; Gene Expression; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Rodentia
PubMed: 34280428
DOI: 10.1016/j.neubiorev.2021.07.015 -
Critical Reviews in Analytical Chemistry 2022Diabetes mellitus is known as an epidemic problem of public health in worldwide. According to the reports of International Diabetes Federation, the global number of... (Review)
Review
Diabetes mellitus is known as an epidemic problem of public health in worldwide. According to the reports of International Diabetes Federation, the global number of diabetic adults has been growing annually. Unfortunately, millions of diabetes cases may remain undiagnosed every year. Unfortunately, the glucose level of blood can be fluctuated by lifestyle. So, development of reliable, simple and fast response diagnostic methods is urgently required. Aptamer-based sensors have been recently developed as a sensitive and fast method for the diagnosis and detection of diabetes. We systematically checked the scientific literature including studies related to aptasensors as a diagnostic tool for diabetes. Many electronic databases such as Google Scholar, Scopus, PubMed and Science Direct were searched up to 2020. The present study obviously demonstrates important and unavoidable role of aptasensors as a potential technique for the diagnosis of diabetes. Different aptasenosrs such as optical, mass-related, microfluidic, and electrochemical aptasenors were successfully designed for diagnosis of diabetic biomarkers in desired range which is necessary for diagnosis or pre-diagnosis of diabetes. Although the introduced aptasensors were interestingly useful for detection of biomarkers in biological samples, but some defects may limit the incorporation of aptasensors, especially optical, mass-related, and microfluidic types, and lateral flow strips with point-of-care test (POCT) method which is necessary for self-controlling the diabetes. The results obviously demonstrate that electrochemical aptasensors, specially label-free types, due to the unbelievable sensitivity and easy to fabrication can be a promising methods for designing the POCT chips to diagnosis the diabetic biomarkers.
Topics: Humans; Aptamers, Nucleotide; Biomarkers; Biosensing Techniques; Diabetes Mellitus; Electrochemical Techniques
PubMed: 34254847
DOI: 10.1080/10408347.2021.1919986 -
Current Medical Research and Opinion Oct 2021Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration,... (Comparative Study)
Comparative Study
OBJECTIVE
Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up.
METHODS
In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference.
RESULTS
Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07-0.54; 99% CI: 0.05-0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09-1.32; 99% CI: 0.06-2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results.
CONCLUSIONS
Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.
Topics: Bayes Theorem; Biological Products; Genetic Therapy; Humans; Oligonucleotides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Spinal Muscular Atrophies of Childhood
PubMed: 34236007
DOI: 10.1080/03007995.2021.1947216 -
Journal of Experimental & Clinical... Jun 2021Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological... (Review)
Review
Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological complexities surrounding glioblastoma, lymphocytes that infiltrate the brain to develop durable immunity with memory will be key. Polyinosinic:polycytidylic acid, or poly(I:C), and its derivative poly-ICLC could serve as a priming or boosting therapy to unleash lymphocytes and other factors in the (immuno)therapeutic armory against glioblastoma. Here, we present a systematic review on the effects and efficacy of poly(I:C)/poly-ICLC for glioblastoma treatment, ranging from preclinical work on cellular and murine glioblastoma models to reported and ongoing clinical studies. MEDLINE was searched until 15 May 2021 to identify preclinical (glioblastoma cells, murine models) and clinical studies that investigated poly(I:C) or poly-ICLC in glioblastoma. A systematic review approach was conducted according to PRISMA guidelines. ClinicalTrials.gov was queried for ongoing clinical studies. Direct pro-tumorigenic effects of poly(I:C) on glioblastoma cells have not been described. On the contrary, poly(I:C) changes the immunological profile of glioblastoma cells and can also kill them directly. In murine glioblastoma models, poly(I:C) has shown therapeutic relevance as an adjuvant therapy to several treatment modalities, including vaccination and immune checkpoint blockade. Clinically, mostly as an adjuvant to dendritic cell or peptide vaccines, poly-ICLC has been demonstrated to be safe and capable of eliciting immunological activity to boost therapeutic responses. Poly-ICLC could be a valuable tool to enhance immunotherapeutic approaches for glioblastoma. We conclude by proposing several promising combination strategies that might advance glioblastoma immunotherapy and discuss key pre-clinical aspects to improve clinical translation.
Topics: Animals; Brain Neoplasms; Cancer Vaccines; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Glioblastoma; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Mice; Poly I-C; Polylysine
PubMed: 34172082
DOI: 10.1186/s13046-021-02017-2 -
Medicine May 2021Pain in the tendons or ligaments is extremely common, accounting for 30% of the causes of visiting general practitioners. Polydeoxyribonucleotide (PDRN) is emerging as a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pain in the tendons or ligaments is extremely common, accounting for 30% of the causes of visiting general practitioners. Polydeoxyribonucleotide (PDRN) is emerging as a new treatment for musculoskeletal pain. However, the effects of PDRN in patients with tendon or ligament pain are unclear. Therefore, this study aimed to determine the impact of PDRN in patients with tendon or ligament pain through a meta-analysis.
METHODS
Electronic literature search of PubMed, Embase, SCOPUS, and Cochrane Library databases of all articles on PDRN treatment for patients with tendon or ligament pain published in the English language from inception until January 31, 2020. The search identified 262 citations.
RESULTS
One randomized controlled trial and 3 retrospective observational studies were included. Pain due to tendon or ligament disorders showed significant improvement after PDRN injection (standardized mean difference [SMD] = -1.43, 95% confidence interval [CI] = -1.80 to -1.06, P < .00001). In the subanalysis of patients with rotator cuff tendinopathy, rotator cuff tendinopathy-induced pain significantly improved (SMD = -2.34, 95% CI = -3.61 to -1.07, P = .0003) after PDRN injection. However, there was no difference in shoulder pain and disability index score and strength of shoulder abduction in patients with rotator cuff tendinopathy (shoulder pain and disability index score, SMD = 1.16, 95% CI = -1.20 to 3.52, P = .34; strength of shoulder abduction, SMD = 0.42, 95% CI = -0.03 to 0.88, P = .07).
CONCLUSION
Effective pain relief was achieved in patients with tendon or ligament disorders after PDRN injection. To more precisely determine this effect, a meta-analysis with a larger number of clinical trials is warranted.
Topics: Analgesics; Humans; Injections; Ligaments; Musculoskeletal Pain; Pain Measurement; Polydeoxyribonucleotides; Tendinopathy; Treatment Outcome
PubMed: 34106615
DOI: 10.1097/MD.0000000000025792 -
JAMA Network Open Apr 2021A thorough understanding of the optimal role and sequence of agents for treatment of multiple myeloma (MM) requires knowledge of the use and rate of postprotocol...
IMPORTANCE
A thorough understanding of the optimal role and sequence of agents for treatment of multiple myeloma (MM) requires knowledge of the use and rate of postprotocol therapies in randomized clinical trials (RCTs).
OBJECTIVES
To examine the proportion of MM RCTs that reported postprotocol therapies and, among those, the percentage of patients who received no further therapy and how treatments differed between the control and intervention arms.
EVIDENCE REVIEW
The reporting of postprotocol therapies was systematically assessed in published MM RCTs using 3 databases (PubMed, Embase, and Cochrane Registry of Controlled Trials) for MM RCTs from January 1, 2005, to December 30, 2019. All MM RCTs were included, and all other studies, such as editorials, nonrandomized studies, and review articles, were excluded.
FINDINGS
A total of 103 RCTs were identified (47 251 patients); of these, 45 (43.7%) reported subsequent treatments in that publication or in any subsequent publication. Trials funded by pharmaceutical companies (26 of 47 [55.3%]) were more likely to report subsequent treatments than cooperative group studies (19 of 56 [33.9%]) (χ21,103 = 4.8; P = .03). Differences were found in the treatments received between the intervention and control arms of RCTs. When data were reported, 5150 of 9351 patients (54.9%) in RCTs of newly diagnosed MM and 2197 of 4501 patients (48.8%) in RCTs of relapsed/refractory MM received any subsequent therapy.
CONCLUSIONS AND RELEVANCE
Postprotocol therapies in MM RCTs are often not reported and, when they are, many patients receive no further therapy. Reporting guidelines for postprotocol therapies are needed.
Topics: Aftercare; Antineoplastic Combined Chemotherapy Protocols; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Oligonucleotides; Progression-Free Survival; Randomized Controlled Trials as Topic; Research Design; Standard of Care
PubMed: 33909053
DOI: 10.1001/jamanetworkopen.2021.8084 -
Scientific Reports Apr 2021AKI has a high mortality rate, may lead to chronic kidney disease, and effective therapies are lacking. Micro-RNAs (miRNAs) regulate biologic processes by potently... (Meta-Analysis)
Meta-Analysis
AKI has a high mortality rate, may lead to chronic kidney disease, and effective therapies are lacking. Micro-RNAs (miRNAs) regulate biologic processes by potently inhibiting protein expression, and pre-clinical studies have explored their roles in AKI. We conducted a systematic review and meta-analysis of miRNAs as therapeutics in pre-clinical AKI. Study screening, data extraction, and quality assessments were performed by 2 independent reviewers. Seventy studies involving 42 miRNA species were included in the analysis. All studies demonstrated significant effects of the miRNA intervention on kidney function and/or histology, with most implicating apoptosis and phosphatase and tensin homolog (PTEN) signaling. Fourteen studies (20.0%) examined the effect of miRNA-21 in AKI, and meta-analysis demonstrated significant increases in serum creatinine and kidney injury scores with miR-21 antagonism and pre-conditioning. No studies reported on adverse effects of miRNA therapy. Limitations also included lack of model diversity (100% rodents, 61.4% ischemia-reperfusion injury), and predominance of male sex (78.6%). Most studies had an unclear risk of bias, and the majority of miRNA-21 studies were conducted by a single team of investigators. In summary, several miRNAs target kidney function and apoptosis in pre-clinical AKI models, with data suggesting that miRNA-21 may mediate protection and kidney repair.Systematic review registration ID: CRD42019128854.
Topics: Acute Kidney Injury; Animals; Antagomirs; Apoptosis; Creatinine; Drug Evaluation, Preclinical; Female; Male; Mice; MicroRNAs; Rats
PubMed: 33907298
DOI: 10.1038/s41598-021-88746-y -
Clinical Biochemistry Jul 2021Since prostate cancer (PCa) relies on limited diagnosis and therapies, more effective alternatives are needed. Aptamers are versatile tools that may be applied for...
Since prostate cancer (PCa) relies on limited diagnosis and therapies, more effective alternatives are needed. Aptamers are versatile tools that may be applied for better clinical management of PCa patients. This review shows the trends on aptamer-based applications for PCa to understand their future development. We searched articles reporting aptamers applied in PCa on the Pubmed, Scopus and Web of Science databases over the last decade. Almost 80% of the articles used previously selected aptamers in novel approaches. However, cell-SELEX was the most applied technique for the selection of new aptamers allowing their binding to targets in their native configuration. ssDNA aptamers were 24% more common than RNA aptamers. The most studied PCa-specific aptamers were the DNA PSA-specific aptamer PSap4#5 and the PSMA-specific RNA aptamers A10 and A9, being PSA and PSMA the most reported targets. Thus, researchers still prefer the ease of use of DNA aptamers. Blood-based liquid biopsies represented 24% of all samples, being the most promising clinical samples. Especially noteworthy, electro-analytical methods accounted for more than 40% of the diagnostic techniques and treatment approaches with drug delivery systems or transcriptional modifiers were reported in 70% of the articles. Although all these articles showed clinically relevant aptamers for PCa and there are good prospects for their use, the development of all these strategies was in its early stages. Thus, the aptamers are not completely validated and we foresee that the completion of clinical studies will allow the implementation of these aptamer-based technologies in the clinical practice of PCa.
Topics: Animals; Antigens, Surface; Aptamers, Nucleotide; Glutamate Carboxypeptidase II; Humans; Male; Precision Medicine; Prostate-Specific Antigen; Prostatic Neoplasms
PubMed: 33794195
DOI: 10.1016/j.clinbiochem.2021.03.014 -
Clinical Pharmacology and Therapeutics Dec 2021Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA...
Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years of age. Individuals with types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of types 1, 2, and 3 SMA. In untreated infants with type 1 SMA, absence of symptoms at birth, a later symptom onset, and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation, and, to a lesser extent, baseline function were identified as potential treatment-modifying factors for survival, emphasizing that early treatment with disease-modifying therapies (DMT) is essential in type 1 SMA. In patients with types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age, and ambulatory status. Individuals aged 6-15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment-effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching, or summarizing results from different studies on the treatments for SMA.
Topics: Cholestenones; Humans; Muscular Atrophy, Spinal; Observational Studies as Topic; Oligonucleotides; Prognosis; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 33792051
DOI: 10.1002/cpt.2247 -
AJNR. American Journal of Neuroradiology May 2021Spinal muscular atrophy is a progressive neurodegenerative disorder that can be treated with intrathecal antisense oligonucleotide therapy (nusinersen). However,...
BACKGROUND
Spinal muscular atrophy is a progressive neurodegenerative disorder that can be treated with intrathecal antisense oligonucleotide therapy (nusinersen). However, administration is often complicated by posterior spinal fusion and neuromuscular scoliosis, necessitating a transforaminal approach.
PURPOSE
To assess the safety profile of the transforaminal approach for intrathecal access.
DATA SOURCES
Searches of the PubMed, Web of Science, and SCOPUS databases.
STUDY SELECTION
Thirteen articles were selected based on inclusion of transforaminal access and appropriate clinical information about the procedure.
DATA ANALYSIS
Complications were taken from the included articles and aggregated based on Cardiovascular and Interventional Radiological Society of Europe scale adverse event grading.
DATA SYNTHESIS
Total number of complications and grade of complications were analyzed, by year and in total.
LIMITATIONS
Selection bias in publication, small patient population size, and variability of the procedure limits the available data.
CONCLUSIONS
Transforaminal approach is a safe alternative for intrathecal access in patients with spinal muscular atrophy and may be applicable to a larger patient population.
Topics: Europe; Humans; Injections, Spinal; Male; Muscular Atrophy, Spinal; Oligonucleotides; Postoperative Complications
PubMed: 33632735
DOI: 10.3174/ajnr.A7009