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Asian Pacific Journal of Cancer... Jun 2021In this study, we aimed to detect Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB) frequency in paragangliomas and pheochromocytomas (PPGL) with...
Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB) Immunohistochemistry in Pheochromocytoma, Head and Neck Paraganglioma, Thoraco-Abdomino-Pelvic Paragangliomas: Is It a Good Idea to Use in Routine Work?
BACKGROUND
In this study, we aimed to detect Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB) frequency in paragangliomas and pheochromocytomas (PPGL) with immunohistochemistry; compare with Pheochromacytoma of the Adrenal Gland Scaled Score (PASS) classification and analyse the differences between pheochromocytoma (Pheo), head-neck paragangliomas (HNPGL) and thoraco-abdominal-pelvic paraganglioma (TAPPGL) sub-groups.
METHODS
A total 114 PPGL cases (73 HNPGL, 15 TAPPGL and 27 Pheo belonging to 112 cases) are included. Immunohistochemically, SDHB and Ki-67 are investigated and malignancy risks are determined by PASS classification. Results are assessed statistically with chi-square test and p <0,01 is considered significant.
RESULTS
SDHB mutations are observed in 20 of 114 (17.54 %) PPGL cases, 3 (11,12%) of which is Pheo, 12 (16,44) is HNPGL, and 5 (35,71%) is TAPPGL (P <0,02). While 15/82 (18,29%) cases with SDHB mutations do not have a malignancy potential according to PASS classification, 5/32 (15,63%) cases has (p=0,73). TAPPGL, HNPGL and Pheo sub-groups have a significant difference between SDHB expression (p <0,02), malignancy potential according to PASS classification (p <0,0001) and Ki-67 proliferation index (p <0,0001).
CONCLUSION
To identify patients for molecular pathological examination, routine application of SDHB immunohistochemistry to PPGL tumors are suggested especially in HNPGLs.
Topics: Head and Neck Neoplasms; Humans; Immunohistochemistry; Paraganglioma; Pheochromocytoma; Succinate Dehydrogenase; Thoracic Neoplasms
PubMed: 34181326
DOI: 10.31557/APJCP.2021.22.6.1721 -
BioMed Research International 2021Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process known as cytokine storm. Xuebijing injection (hereinafter referred to as Xuebijing) is a patent drug that was used to treat ARDS or severe pneumonia (SP) in China. However, its efficacy and mechanism of actions remain unclear. In this study, we used meta-analysis and network pharmacology to assess these traits of Xuebijing.
METHODS
We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases for randomized controlled trials (RCTs) that evaluated Xuebijing therapy for ARDS or SP. The outcomes were total mortality, intensive care unit (ICU) stay time, and TNF- and IL-6 levels. We performed a meta-analysis using RevMan 5.3 software. The putative targets, top 10 proteins, and possible pathway of Xuebinjing on ARDS were analyzed by network pharmacology. TNF- and IL-6 were further docked with the six main active components of Xuebinjing using AutoDock 4.2.6 and PyMol 1.5.0.3 software.
RESULTS
Fifteen RCTs involving 2778 patients (13 ARDS and 2 SP) were included. Compared with the control, Xuebijing treatment significantly reduced the mortality rate (risk ratio, 0.64 (95% credible interval (CrI), 0.54-0.77)), reduced the ICU stay time (mean difference (MD), -4.51 (95% CrI, -4.97--4.06)), reduced the TNF- ((MD), -1.23 (95% CrI, -1.38--1.08)) and IL-6 ((MD), -1.15 (95% CrI, -1.52--0.78)) levels. The 56 putative targets, top 10 proteins (MAPK1 (mitogen-activated protein kinase 1), MAPK8 (mitogen-activated protein kinase 8), RELA (transcription factor p65), NFKB1 (nuclear factor NF-kappa-B p105 subunit), JUN (transcription factor AP-1), SRC (proto-oncogene tyrosine-protein kinase), TNF (tumor necrosis factor), HRAS (GTPase HRas), IL6 (interleukin-6), and APP (amyloid-beta A4 protein)), and possible pathways (Ret tyrosine kinase, IL2-mediated signaling events, CD4+/CD8+ T cell-related TCR signaling, p75(NTR)-mediated signaling, CXCR4-mediated signaling events, LPA receptor-mediated events, IL12-mediated signaling events, FAS (CD95) signaling pathway, and immune system) of Xuebinjing's action on ARDS were obtained. The molecular docking results showed that all the six components of Xuebinjing docked with TNF-, and two components docked with IL-6 got the binding energies lower than -5.
CONCLUSION
Our results recommended Xuebijing treatment for patients with ARDS. Xuebijing has therapeutic effects on ARDS patients partly by regulating the immune cell/cytokine pathways and thus inhibiting the cytokine storm. TNF- is the cytokine both directly and indirectly inhibited by Xuebijing, and IL-6 is the cytokine mainly indirectly inhibited by Xuebijing.
Topics: Drugs, Chinese Herbal; Gene Expression Regulation; Humans; Intensive Care Units; Proto-Oncogene Mas; Respiratory Distress Syndrome; Signal Transduction
PubMed: 34124260
DOI: 10.1155/2021/8824059 -
The Journal of International Medical... May 2021germline variants of the casein kinase 2α subunit (CK2α) gene () have been reported in individuals with the congenital neuropsychiatric disorder Okur-Chung...
Identification of novel variants and the genotype-phenotype relationship in patients with Okur-Chung neurodevelopmental syndrome: a case report and systematic literature review.
germline variants of the casein kinase 2α subunit (CK2α) gene () have been reported in individuals with the congenital neuropsychiatric disorder Okur-Chung neurodevelopmental syndrome (OCNS). Here, we report on two unrelated children with OCNS and review the literature to explore the genotype-phenotype relationship in OCNS. Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel variants: c.479A>G p.(H160R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 variants in various protein-coding regions of CK2α. By quantitatively analyzing data related to these variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2α regions appear to influence the phenotypic spectrum of OCNS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNS, but also provides a comprehensive overview to improve our understanding of the genotype-phenotype relationship in OCNS.
Topics: Casein Kinase II; Child; Genotype; Humans; Intellectual Disability; Mutation; Neurodevelopmental Disorders; Phenotype
PubMed: 34038195
DOI: 10.1177/03000605211017063 -
Orphanet Journal of Rare Diseases May 2021Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium... (Review)
Review
BACKGROUND
Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel.
MAIN BODY
A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro.
CONCLUSION
Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.
Topics: Calcium; Calcium Channels, L-Type; Channelopathies; Child; DNA Copy Number Variations; Developmental Disabilities; Humans; Intellectual Disability
PubMed: 33985586
DOI: 10.1186/s13023-021-01850-0 -
Neurogenetics May 2021Dravet syndrome (DS) is a rare and severe epileptic syndrome of childhood with prevalence between 1/22,000 and 1/49,900 of live births. Approximately 80% of patients... (Comparative Study)
Comparative Study
Dravet syndrome (DS) is a rare and severe epileptic syndrome of childhood with prevalence between 1/22,000 and 1/49,900 of live births. Approximately 80% of patients with this syndrome present SCN1A pathogenic variants, which encodes an alpha subunit of a neural voltage-dependent sodium channel. There is a correlation between PCDH19 pathogenic variants, encodes the protocadherin 19, and a similar disease to DS known as DS-like phenotype. The present review aims to clarify the differences between DS and DS-like phenotype according to the SCN1A and PCDH19 variants. A systematic review was conducted in PubMed and Virtual Health Library (VHL) databases, using "Dravet Syndrome" and "Severe Myoclonic Epilepsy in Infancy (SMEI)" search words, selecting cohort of studies published in journal with impact factor of two or greater. The systematic review was according to the Preferred Reporting Items for Systematic Review and Meta-Analysis recommendations. Nineteen studies were included in the present review, and a significant proportion of patients with DS-carrying SCN1A was greater than patients with DS-like phenotype-harboring PCDH19 variants (76.6% versus 23.4%). When clinical and genetic data were correlated, autism was predominantly observed in patients with DS-like-carrying PCDH19 variants compared to SCN1A variant carriers (62.5% versus 37.5%, respectively, P-value = 0.044, P-value corrected = 0.198). In addition, it was noticed a significant predisposition to hyperthermia during epilepsy crisis in individuals carrying PCDH19 variants (P-value = 0.003; P-value corrected = 0.027). The present review is the first to point out differences between the DS and DS-like phenotype according to the SCN1A and PCDH19 variants.
Topics: Autistic Disorder; Epilepsies, Myoclonic; Genetic Heterogeneity; Humans; Hyperthermia; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Observational Studies as Topic; Phenotype; Protocadherins; Seizures, Febrile; Syndrome
PubMed: 33937968
DOI: 10.1007/s10048-021-00644-7 -
Neurological Sciences : Official... Jul 2021Previous studies have investigated the association between rs2304016 and rs17183814 polymorphisms in sodium voltage-gated channel alpha subunit 2 (SCN2A) and epilepsy... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Previous studies have investigated the association between rs2304016 and rs17183814 polymorphisms in sodium voltage-gated channel alpha subunit 2 (SCN2A) and epilepsy risk and responsiveness to antiepileptic drugs (AEDs) but with conflicting results. Our aim was to reevaluate the relationship by performing a systematic review and meta-analysis.
METHODS
By searching PubMed, Medline, and CNKI, 14 studies were selected. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were computed to measure the association between rs17183814 and rs2304016 polymorphisms and the risk of epilepsy and AEDs response using the fixed-effects model or the random-effects model.
RESULTS
No significant association between the rs17183814 in SCN2A and the risk of epilepsy was observed (heterozygous comparison: OR = 0.78, 95% CI: 0.61-1.00; homozygous comparison: OR = 1.34, 95% CI: 0.63-2.86; dominant model: OR = 0.82, 95% CI: 0.64-1.04; recessive model: OR = 1.44, 95% CI: 0.68-3.05; allele comparison: OR = 0.88, 95%CI: 0.71-1.10). Moreover, neither the rs17183814 nor the rs2304016 was associated with AEDs response.
CONCLUSION
This meta-analysis suggests that the rs17183814 and rs2304016 polymorphisms in SCN2A are not associated with the risk of epilepsy and response to AEDs.
Topics: Alleles; Anticonvulsants; Epilepsy; Genetic Predisposition to Disease; Humans; NAV1.2 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide
PubMed: 33914194
DOI: 10.1007/s10072-021-05242-x -
Urologic Oncology Aug 2021The clinical relevance of telomerase subunits (human reverse transcriptase - hTERT, and human telomerase RNA - hTR) and TERT promotor mutations as biomarkers in...
The clinical relevance of telomerase subunits (human reverse transcriptase - hTERT, and human telomerase RNA - hTR) and TERT promotor mutations as biomarkers in genitourinary cancers was reviewed through the systematic analysis of the current literature. We performed a systematic literature search using 2 databases (Medline and Scopus) over the past 20 years. Primary outcomes were sensitivity and specificity of hTR, hTERT and TERT promoter mutations. Secondary outcomes were the biomarkers predictive values for tumor characteristics. Regarding bladder cancer, hTERT in urine showed high sensitivity (mean values: 55%-96%), and specificity (69%-100%): it correlated with bladder cancer grade and/or stage. hTR sensitivity ranged from 77% to 92%. With adapted cut-off, it demonstrated 72% to 89% specificity. TERT promoter mutation rate was up to 80% both in tissue and urine, resulting in 62%-92% sensitivity for primary tumors and 42% for relapse. Specificity ranged from 73% to 96%, no correlations with stage were observed. In prostate cancer, hTERT in tissue, prostate secretion and serum showed high sensitivity (97.9%, 36%, and 79.2%-97.5%, respectively) and specificity values (70%, 66%, 60%-100%). hTR showed very high sensitivity (88% in serum and 100% in tissue) although specificity values were highly variable depending on the series and techniques (0%-96.5%). In RCC, hTERT sensitivity on tissue ranged from 90 to 97%, specificity from 25 to 58%. There was an association of hTERT expression with tumor stage and grade. hTERT showed high accuracy in genitourinary cancers, while the value of hTR was more controversial. hTERT and TERT promotor mutations may have predictive value for bladder cancer and RCC staging and grading, while no such relationship was observed in CaP. Although telomerase subunits showed clinically relevant values in genitourinary cancers, developing fast and cost-effective methods is required before contemplating routine use.
Topics: Biomarkers, Tumor; Humans; Mutation; Promoter Regions, Genetic; RNA; Telomerase; Urologic Neoplasms
PubMed: 33676848
DOI: 10.1016/j.urolonc.2021.01.022 -
Medicine Feb 2021Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results.
METHODS
Searches were conducted in databases, including PubMed, EMbase, Web of Science, CNKI, and Wanfang, for case-control studies up to August 1, 2019. After retrieving eligible studies and data extraction, we calculated pooled odds ratios with 95% confidence intervals. In the meta-analysis, we included 32 publications with a total of 52,795 patients with LC and 97,493 control cases to evaluate the polymorphisms in the CHRNA5/A3/B4 gene cluster in the 15q25 region.
RESULTS
Data of the meta-analysis showed a significantly increased risk of LC in the presence of genetic polymorphisms (rs1051730, rs16969968, rs8034191). In the smoking subgroup, the CHRNA3 rs1051730 polymorphism was found to contribute to LC risk using following 5 models: the allelic model, the homozygous model, the heterozygous model, the dominant model, and the recessive model. Thus, the rs1051730 polymorphism may modify LC susceptibility under the condition of smoking. Stratification studies for CHRNA5-rs8034191 showed that Caucasian groups with the wild-type genotype (C/C) may be susceptible to LC in all 5 models. No significant relationship between CHRNA3 rs6495309 or rs3743073 and LC susceptibility was found. However, Asians with the rs3743037 B-allele showed an obviously higher risk of LC susceptibility than the Caucasian population, observed via allelic, heterozygous, and dominant models.
CONCLUSIONS
The 3 polymorphisms of rs1051730, rs16969968 and rs8034191 in the CHRNA5/A3/B4 gene cluster in the 15q25 region were associated with LC risk, which might be influenced by ethnicity and smoking status.
Topics: Genetic Predisposition to Disease; Humans; Lung Neoplasms; Multigene Family; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Receptors, Nicotinic; Risk Factors
PubMed: 33578531
DOI: 10.1097/MD.0000000000024355 -
Reproductive Sciences (Thousand Oaks,... Feb 2022Mediator complex subunit 12 (MED12) is the most frequently mutated gene in uterine leiomyomas (ULs)-with a frequency of up to 85%-suggesting that it plays key roles in... (Meta-Analysis)
Meta-Analysis
Mediator complex subunit 12 (MED12) is the most frequently mutated gene in uterine leiomyomas (ULs)-with a frequency of up to 85%-suggesting that it plays key roles in the pathogenesis of ULs. However, there is no established relationship between genetic alteration and other risk factors of UL pathogenesis such as the patient's age, weight, and race. In this meta-analysis, we established an association between these risk factors and the frequency of MED12 mutation. We also established the relationship between MED12 mutation with the number and size of tumors in a patient. A systematic literature search was performed for studies published by May 2020 and performed a meta-analysis according to PRISMA guidelines. Twenty-five studies were included in the analysis, representing 3151 tissue samples. MED12 mutations were more common in Black (74.5%) as compared to White (65.8%) and Asian (53.2%) patients. There was no significant relationship between the patient's age and the frequency of mutations (OR 0.73, 95% CI 0.38 to 1.41). MED12 mutations were common in patients barring small-sized (OR 1.46, 95% CI 1.09 to 1.95) multiple (OR 0.39, 95% CI 0.17 to 0.92) tumors. For the patient's weight, studies were few and the outcome was not statistically significant. This meta-analysis provides valuable information on the relationship between the patient's clinical characteristics and frequency of MED12 mutation among patients barring ULs, which is relevant for understanding the pathogenesis of ULs.Protocol registration: The protocol was registered in PROSPERO with registration number CRD42019123439.
Topics: Female; Humans; Leiomyoma; Mediator Complex; Mutation; Mutation Rate; Uterine Neoplasms
PubMed: 33569750
DOI: 10.1007/s43032-021-00473-x -
Scandinavian Journal of Immunology May 2021Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signalling pathways are...
BACKGROUND
Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signalling pathways are modulated by a number of transcription factors, one of which is runt-related transcription factor 3 (RUNX3).
OBJECTIVE
To systematically review the immune roles of RUNX3 in immune regulation, with a focus on the context of IBD.
METHODS
Relevant articles and reviews were identified through a Scopus search in April 2020. Information was categorized by immune cell types, analysed and synthesized. IBD transcriptome data sets and FANTOM5 regulatory networks were processed in order to complement the literature review.
RESULTS
The available evidence on the immune roles of RUNX3 allowed for its description in twelve cell types: intraepithelial lymphocyte, Th1, Th2, Th17, Treg, double-positive T, cytotoxic T, B, dendritic, innate lymphoid, natural killer and macrophages. In the gut, the activity of RUNX3 is multifaceted and context-dependent: it may promote homeostasis or exacerbated reactions via cytokine signalling and regulation of receptor expression. RUNX3 is mostly engaged in pathways involving ThPOK, T-bet, IFN-γ, TGF-β/IL-2Rβ, GATA/CBF-β, SMAD/p300 and a number of miRNAs. RUNX3 targets relevant to IBD may include RAG1, OSM and IL-17B. Moreover, in IBD RUNX3 expression correlates positively with GZMM, and negatively with IFNAR1, whereas in controls, it strongly associates with TGFBR3.
CONCLUSIONS
Dysregulation of RUNX3, mostly in the form of deficiency, likely contributes to IBD pathogenesis. More clinical research is needed to examine RUNX3 in IBD.
Topics: B-Lymphocytes; Core Binding Factor Alpha 3 Subunit; Dendritic Cells; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Intraepithelial Lymphocytes; T-Lymphocytes
PubMed: 33528856
DOI: 10.1111/sji.13025