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Pharmacological Reviews Oct 2020RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various...
RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
Topics: Aptamers, Nucleotide; Betacoronavirus; COVID-19; Chemistry Techniques, Analytical; Clustered Regularly Interspaced Short Palindromic Repeats; Coronavirus Infections; Drug Delivery Systems; Drug Development; Drug Discovery; Humans; MicroRNAs; Oligonucleotides, Antisense; Pandemics; Pneumonia, Viral; RNA; RNA, Antisense; RNA, Messenger; RNA, Ribosomal; RNA, Small Interfering; RNA, Viral; Ribonucleases; Riboswitch; SARS-CoV-2
PubMed: 32929000
DOI: 10.1124/pr.120.019554 -
Immunity, Inflammation and Disease Jun 2016There are no reference guidelines for health care providers regarding appropriate use and interpretation of urine eosinophil protein X (u-EPX) in clinical practice.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There are no reference guidelines for health care providers regarding appropriate use and interpretation of urine eosinophil protein X (u-EPX) in clinical practice. Currently, there are no clear-cut clinical or laboratory parameters to diagnose asthma in young children.
OBJECTIVE
In this study, we (1) systematically reviewed and qualitatively appraised the epidemiological evidence to determine diagnostic u-EPX cut points for pediatric asthma, and (2) performed a meta-analysis to provide u-EPX estimates for diagnosing pediatric asthma.
METHODS
Research articles in literature were identified from PubMed/Medline and Web of Science databases from 1966 to August 2015. Children <18 years of age were included. Both serum and urine EPX were included. Twenty-seven studies met the inclusion criteria for the systematic review and nine studies for the meta-analysis. Details regarding EPX analyses, treatment efficacy, and outcomes were assessed. For meta-analyses, effect estimates were abstracted using standardized means.
RESULTS
Over 70% of studies found a significant relationship between u-EPX and childhood asthma. There was 1.94 times higher standardized means of u-EPX among acute asthmatics compared to healthy controls (confidence interval [CI]: 1.67-2.22). Similarly, the difference in standardized means between asymptomatic asthmatics and healthy controls was 1.58 times higher (CI: 1.27-1.88).
CONCLUSIONS AND CLINICAL RELEVANCE
Despite differences in sample sizes, EPX processing and measurement, and ages of children, a consistent trend of higher EPX levels with childhood asthma was revealed.
Topics: Asthma; Blood Proteins; Child; Eosinophil-Derived Neurotoxin; Humans; Ribonucleases
PubMed: 27957324
DOI: 10.1002/iid3.104 -
IScience Nov 2022The ribonuclease A (RNase A) family is one of the best-characterized vertebrate-specific proteins. In humans, eight catalytically active RNases (numbered 1-8) have been... (Review)
Review
The ribonuclease A (RNase A) family is one of the best-characterized vertebrate-specific proteins. In humans, eight catalytically active RNases (numbered 1-8) have been identified and have unique tissue distributions. Apart from the digestion of dietary RNA, a broad range of biological actions, including the regulation of intra- or extra-cellular RNA metabolism as well as antiviral, antibacterial, and antifungal activities, neurotoxicity, promotion of cell proliferation, anti-apoptosis, and immunomodulatory abilities, have been recently reported for the members of this family. Based on multiple biological roles, RNases are found to participate in the pathogenic processes of many diseases, such as infection, immune dysfunction, neurodegeneration, cancer, and cardiovascular disorders. This review summarizes the available data on the human RNase A family and illustrates the significant roles of the eight canonical RNases in health and disease, for stimulating further basic research and development of ideas on the potential solutions for disease diagnosis and treatment.
PubMed: 36304117
DOI: 10.1016/j.isci.2022.105284 -
Head and Neck Pathology Dec 2022Nasal chondromesenchymal hamartoma (NCMH) is a very rare, benign sinonasal tract tumor commonly affecting infants. In this paper, in addition to presenting a systematic... (Review)
Review
Nasal chondromesenchymal hamartoma (NCMH) is a very rare, benign sinonasal tract tumor commonly affecting infants. In this paper, in addition to presenting a systematic review of the literature on NCMH, we also report an unusual case of NCMH in an adolescent patient. A systematic review conducted following the PRISMA guidelines. PubMed, EMBASE and manual search through references of relevant publication were utilised to gather all published case-reports of NCMH. Data collected from each case-report for patient demographics, site and size of NCMH, clinical presentation, co-morbidities, diagnostic methods, treatment options and follow-up methods. The systemic review collected sixty-two case-reports of NCMH (including our case) affecting 42 men and 21 women (2:1 male to female ratio). Mean average age was 5.1 years (age range: 1 day to 70 years). The anatomical sites of the tumor were: nasal cavity (n = 17), paranasal sinuses (n = 30), orbital region (n = 17), and the base of the skull (n = 16). The reported clinical manifestations were nasal obstruction or congestion (n = 29), nasal mass (n = 27), epistaxis (n = 6), orbital symptoms (n = 14). NCMH is a very rare cause of nasal masses in infants and toddlers. Our case and previous case reports confirm that NCMH can mimic other benign and malignant tumors, therefore we should be vigilant for rare pathologies that lead to nasal masses. Recently the link between DIECR1 mutation with NCMH has been established, so NCMH should be considered in any patient with nasal or orbital symptoms with a history of DICER1-related tumor spectrum.
Topics: Female; Male; Humans; Adolescent; Child, Preschool; Infant; Neoplasms; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 35507301
DOI: 10.1007/s12105-022-01452-7 -
Frontiers in Oncology 2023Circular RNAs (circRNAs) are types of endogenous noncoding RNAs produced by selective splicing that are expressed highly specifically in various organisms and tissues...
BACKGROUND
Circular RNAs (circRNAs) are types of endogenous noncoding RNAs produced by selective splicing that are expressed highly specifically in various organisms and tissues and have numerous clinical implications in the regulation of cancer development and progression. Since circRNA is resistant to digestion by ribonucleases and has a long half-life, there is increasing evidence that circRNA can be used as an ideal candidate biomarker for the early diagnosis and prognosis of tumors. In this study, we aimed to reveal the diagnostic and prognostic value of circRNA in human pancreatic cancer (PC).
METHODS
A systematic search for publications from inception to 22 July 2022 was conducted on Embase, PubMed, Web of Science (WOS), and the Cochrane Library databases. Available studies that correlated circRNA expression in tissue or serum with the clinicopathological, diagnostic, and prognostic values of PC patients were enrolled. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to evaluate clinical pathological characteristics. Area under the curve (AUC), sensitivity, and specificity were adopted to assess diagnostic value. Hazard ratios (HRs) were utilized to assess disease-free survival (DFS) and overall survival (OS).
RESULTS
This meta-analysis enrolled 32 eligible studies, including six on diagnosis and 21 on prognosis, which accounted for 2,396 cases from 245 references. For clinical parameters, high expression of carcinogenic circRNA was significantly associated with degree of differentiation (OR = 1.85, 95% CI = 1.47-2.34), TNM stage (OR = 0.46, 95% CI = 0.35-0.62), lymph node metastasis (OR = 0.39, 95% CI = 0.32-0.48), and distant metastasis (OR = 0.26, 95% CI = 0.13-0.51). As for clinical diagnostic utility, circRNA could discriminate patients with pancreatic cancer from controls, with an AUC of 0.86 (95% CI: 0.82-0.88), a relatively high sensitivity of 84%, and a specificity of 80% in tissue. In terms of prognostic significance, carcinogenic circRNA was correlated with poor OS (HR = 2.00, 95% CI: 1.76-2.26) and DFS (HR = 1.96, 95% CI: 1.47-2.62).
CONCLUSION
In summary, this study demonstrated that circRNA may act as a significant diagnostic and prognostic biomarker for pancreatic cancer.
PubMed: 37361594
DOI: 10.3389/fonc.2023.1174577 -
Respiratory Medicine Apr 2007Eosinophil cationic protein (ECP) has been widely investigated as a potential biomarker of airway inflammation. (Review)
Review
INTRODUCTION
Eosinophil cationic protein (ECP) has been widely investigated as a potential biomarker of airway inflammation.
METHOD
A systematic review was performed using Medline with key terms eosinophil cationic protein and asthma, limiting the search to titles or abstracts. Out of 688 potential papers found, abstracts were reviewed based on the following criteria: (1) ECP was used as a biological marker, (2) asthma was the index disease studied, (3) it was a controlled clinical study and (4) ECP was assessed as a diagnostic, assessment or management tool. One hundred and sixty-nine articles satisfied the selection criteria and their full-text versions were reviewed. Only 53 papers were found to provide clinically useful information.
RESULTS
ECP has been measured in serum, plasma, sputum, saliva and broncho-alveolar lavage fluids but serum and sputum are the most established. Levels of ECP in normal and asthmatic subjects in various body fluids were identified. ECP correlates well with airway inflammation but not airway hyper-responsiveness. It is raised in other atopic diseases and hence is not diagnostic for asthma. However, it has been shown to be useful in assessing asthma severity, compliance with anti-inflammatory asthma therapy and as a guide to tailing down inhaled corticosteroid therapy. Although there is some evidence that ECP levels are affected by age, smoking, circadian rhythm and seasonal variation, only smoking appears to be of clinical significance.
DISCUSSION
Despite its limitations, ECP remains potentially useful in asthma management. Future research on ECP should focus on using serial measurements and combining it with other markers of asthma which may increase its clinical usefulness.
Topics: Adolescent; Adult; Age Factors; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Child; Circadian Rhythm; Eosinophil Cationic Protein; Humans; Immunologic Factors; Saliva; Seasons; Smoking; Sputum
PubMed: 17034998
DOI: 10.1016/j.rmed.2006.08.012 -
International Journal of Molecular... Aug 2018Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical resection when these tumours are detected at an early stage, this cancer is usually asymptomatic, and disease only becomes apparent after metastasis. Several risk factors are associated with this disease, the most relevant being chronic pancreatitis, diabetes, tobacco and alcohol intake, cadmium, arsenic and lead exposure, certain infectious diseases, and the mutational status of some genes associated to a familial component. PDAC incidence has increased in recent decades, and there are few alternatives for chemotherapeutic treatment. Endoplasmic reticulum (ER) stress factors such as GRP78/BiP (78 kDa glucose-regulated protein), ATF6α (activating transcription factor 6 isoform α), IRE1α (inositol-requiring enzyme 1 isoform α), and PERK (protein kinase RNA-like endoplasmic reticulum kinase) activate the transcription of several genes involved in both survival and apoptosis. Some of these factors aid in inducing a non-proliferative state in cancer called dormancy. Modulation of endoplasmic reticulum stress could induce dormancy of tumour cells, thus prolonging patient survival. In this systematic review, we have compiled relevant results concerning those endoplasmic reticulum stress factors involved in PDAC, and we have analysed the mechanism of dormancy associated to endoplasmic reticulum stress and its potential use as a chemotherapeutic target against PDAC.
Topics: Activating Transcription Factor 6; Animals; Antibodies; Carcinoma, Pancreatic Ductal; Communicable Diseases; Deoxycytidine; Diabetes Complications; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Endoribonucleases; Gene Expression Regulation; Heat-Shock Proteins; Humans; Pancreatic Neoplasms; Pancreatitis, Chronic; Protein Serine-Threonine Kinases; RNA, Small Interfering; Risk Factors; Sulfones; eIF-2 Kinase; Gemcitabine
PubMed: 30134550
DOI: 10.3390/ijms19092468 -
BioMed Research International 2021Bladder cancer (BCa) is a common cancer in North America and Europe that carries considerable morbidity and mortality. A reliable biomarker for early detection of the... (Meta-Analysis)
Meta-Analysis
AIMS
Bladder cancer (BCa) is a common cancer in North America and Europe that carries considerable morbidity and mortality. A reliable biomarker for early detection of the bladder is crucial for improving the prognosis of BCA. In this meta-analysis, we examine the diagnostic role of the angiogenin (ANG) protein in patients' urine with bladder neoplasm.
METHODS
We performed a systematic literature search using ScienceDirect, Web of Science, PubMed/MEDLINE, Scopus, Google Scholar, and Embase, up to 10 October 2020 databases. Meta-Disc V.1.4 and Comprehensive Meta-Analysis V.2.2 software calculated the pooled specificity, sensitivity, area under the curve (AUC), diagnostic odds ratio (DOR), positive likelihood ratio (LR), negative likelihood ratio (LR), index, and summary receiver-operating characteristic (SROC) for the role of ANG as a urinary biomarker for BCa patients.
RESULTS
Four case-control studies were included with 656 participants (417 cases and 239 controls) in this meta-analysis. The pooled sensitivity of 0.71 (95% CI: 0.66-0.75), specificity of 0.78 (95% CI: 0.73-0.81), LR of 3.34 (95% CI: 2.02-5.53), LR of 0.37 (95% CI: 0.32-0.44), DOR of 9.99 (95% CI: 4.69-21.28), and AUC of 0.789 and index of 0.726 demonstrate acceptable diagnostic precision of ANG in identifying BCa.
CONCLUSION
This meta-analysis showed that ANG could be a fair biomarker for the diagnosis of BCa patients.
Topics: Biomarkers, Tumor; Humans; Ribonuclease, Pancreatic; Sensitivity and Specificity; Urinary Bladder Neoplasms
PubMed: 33997007
DOI: 10.1155/2021/5557309 -
Journal of B.U.ON. : Official Journal... 2020PIWIL2, one of the PIWI gene subfamily, is now thought to be closely related to poor clinical outcomes in various cancers. The aim of this research was to... (Meta-Analysis)
Meta-Analysis
PURPOSE
PIWIL2, one of the PIWI gene subfamily, is now thought to be closely related to poor clinical outcomes in various cancers. The aim of this research was to comprehensively estimate its predictive value in the prognosis of cancer patients.
METHODS
We thoroughly searched PubMed, Web of Science and Embase databases for eligible articles published until April 4th 2019, in which the association between cancer prognosis and PIWIL2 expression level was studied. Study qualities were assessed using NOS criteria. We performed analyses by Stata SE 12.0 and RevMan 5.3. The primary endpoints contained overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS), recurrence-free survival (RFS) and disease-free survival (DFS).
RESULTS
Ten studies containing 2116 patients with 8 various solid cancers were finally included. The outcomes indicated that cancer patients with higher PIWIL2 expression level had significant shorter OS (HR:2.20, 95%CI:1.25-3.88, p=0.006), DFS/RFS/MFS (HR:2.96, 95%CI:1.68-5.23, p<0.001), CSS (HR: 2.12, 95%CI: 1.40-3.23, p<0.001) than cancer patients with lower PIWIL2 expression level. What's more, PIWIL2 over-expression was significantly correlated to more lymph node metastasis (LNM) (OR:1.61, 95%CI:1.28-2.02, p<0.001). And PIWIL2 expression was not significantly correlated with age, gender, differentiation, tumor invasion, tumor size, TNM stage and distant metastasis (DM).
CONCLUSIONS
A higher expression level of PIWIL2 may predict a poorer prognosis of cancer patients. And its prognostic values are not significantly influenced by clinicopathological characters. Therefore, PIWIL2 could serve as a personalized prognostic predictor in cancers in the future.
Topics: Argonaute Proteins; Biomarkers, Tumor; Humans; Prognosis
PubMed: 33455119
DOI: No ID Found -
Oncotarget Nov 2016The role of Dicer in the prognosis of cancer patients remains controversial. This systematic review is attempted to assess the influence of Dicer as a prognostic... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The role of Dicer in the prognosis of cancer patients remains controversial. This systematic review is attempted to assess the influence of Dicer as a prognostic predictor for survival in diverse types of cancers.
METHODS
Studies were selected as candidates if they published an independent evaluation of Dicer expression level together with the correlation with prognosis in cancers. Random-effect model was applied in this meta-analysis. Heterogeneity between studies was assessed by Q-statistic with P < 0.10 to be statistically significant. Publication bias was investigated using funnel plot and test with Begg's and Egger's test. P < 0.05 was regarded as statistically significant.
RESULTS
24 of 44 articles revealed low Dicer status as a predictor of poor prognosis. The aggregate result of overall survival (OS) indicated that low Dicer expression level resulted in poor clinical outcomes, and subgroup of IHC and RT-PCR method both revealed the same result. Overall analysis of progression-free survival (PFS) showed the same result as OS, and both the two subgroups divided by laboratory method revealed positive results. Subgroup analysis by tumor types showed low dicer levels were associated with poor prognosis in ovarian cancer (HR = 1.93, 95% CI: 1.19-3.15), otorhinolaryngological tumors (HR = 2.39, 95% CI: 1.70-3.36), hematological malignancies (HR = 2.45, 95% CI: 1.69-3.56) and neuroblastoma (HR = 4.03, 95% CI: 1.91-8.50).
CONCLUSION
Low Dicer status was associated with poor prognosis in ovarian cancer, otorhinolaryngological tumors and ematological malignancies. More homogeneous studies with high quality are needed to further confirm our conclusion and make Dicer a useful parameter in clinical application.
Topics: Biomarkers, Tumor; DEAD-box RNA Helicases; Gene Expression; Humans; Neoplasms; Prognosis; Proportional Hazards Models; Publication Bias; Ribonuclease III
PubMed: 27682871
DOI: 10.18632/oncotarget.12183