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1.
Eur J Neurol ; 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34965002

RESUMO

BACKGROUND: Erenumab (ERE) is the first anti-calcitonin gene related peptide (CGRP) receptor monoclonal antibody approved for migraine prevention. A proportion of patients does not adequately respond to ERE. METHODS: Prospective, multicenter study involving 110 migraine patients starting ERE 70 mg monthly. Baseline socio-demographics and migraine characteristics including mean monthly migraine days (MMDs), migraine-related burden (MIDAS and HIT-6 scales) and use of abortive medications during 3 months before and after ERE start were collected. Real-time PCR was used to determine polymorphic variants of calcitonin receptor-like receptor and receptor activity-modifying protein-1 genes. Logistic regression models were used to identify independent predictors for 50% (50-RESP) and 75% (75-RESP) responder patients. RESULTS: At month 3, MMDs decreased from 17.2 to 9.2 (p<0.0001), 59/110 (53.6%) patients were 50-RESP, and 30/110 (27.3%) were 75-RESP. Age at migraine onset [OR (95%CI):1.062(1.008-1.120), p=0.024], number of failed preventive medications [0.753(0.600-0.946) p=0.015], and MIDAS score [1.011(1.002-1.020) p=0.017] were associated with 75-RESP. Among the genetic variants investigated, RAMP1 rs7590387 was found associated to a lower probability of being 75-RESP [per G allele OR (95%CI): 0.53(0.29-0.99), p=0.048], but this association did not survive adjustment for confounding clinical variables [per G allele, 0.55 (0.28-1.10), p=0.09]. CONCLUSIONS: In this real word study treatment with ERE significant reduced MMDs. Number of failed preventive medications, migraine burden, and age at migraine onset predicted response to ERE. Larger studies are required to confirm a possible role of RAMP1 rs7590387 as genetic predictor of ERE efficacy.

2.
Clin Transl Sci ; 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34719115

RESUMO

On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08-3.29), bradycardia (aOR: 2.09, 95% CI: 1.24-3.53), and hypotension (aOR: 1.67, 95% CI: 1.03-2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin.

3.
J Pers Med ; 11(10)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34683108

RESUMO

Normal tissue radiosensitivity is thought to be influenced by an individual's genetic background. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2-3 subcutaneous fibrosis and/or grade 2-3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance (p < 0.05). In the replication study, which consisted of an additional 45 cases and 192 controls, none of the SNVs identified by targeted NGS achieved nominal replication. Nevertheless, TP53 rs1042522 (G > C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82-2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51-14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06-3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients; however, large replication studies are warranted for conclusive evidence.

4.
Headache ; 61(7): 1060-1076, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34309832

RESUMO

BACKGROUND: A plethora of studies have attempted to identify genetic determinants of disease susceptibility and treatment response of patients with cluster headache (CH), but results are often conflicting, and no comprehensive overview with a quantitative summary of the evidence in this field is available. METHODS: A systematic search of relevant publications was performed without any language restrictions on PubMed, Web of Knowledge, Cochrane Library, and OpenGrey, up to December 2020. A standardized data extraction form was used to collect relevant data from each included study. Meta-analyses were conducted for gene polymorphisms investigated in at least two studies and the Bayesian false discovery probability (BFDP) test was applied to the pooled odds ratios (ORs) to assess the credibility of the observed associations. RESULTS: Among the 27 articles identified by the systematic review, 17 studies evaluating 12 single nucleotide polymorphisms (SNPs) were included in the quantitative data analysis. The pooled results showed no significant association with CH risk of 10 SNPs, including five SNPs of HCRTR2 (rs2653349, rs2653342, rs3122156, rs10498801, and rs3800539), two SNPs of ADH4 (rs1800759 and rs1126671), CLOCK rs1801260, and two SNPs (rs1006417 and ADCYAP1R1 rs12668955) previously identified by a genome-wide association study (GWAS). Conversely, the pooled results revealed the association of the HCRTR2 rs9357855 A allele with a higher risk of CH (A vs. G, OR: 1.33, 95% CI: 1.04-1.72, p = 0.026), and of GNB3 rs5443 with a higher response rate of patients with CH to triptan drugs (CT+TT vs. CC, OR: 1.96, 95% CI: 1.04-3.72, p = 0.038). However, assuming a prior probability of 0.001, the respective BFDP values being higher than 0.8 (BFDPrs9357855  = 0.998; BFDPrs5443  = 0.998) revealed lack of noteworthy results. CONCLUSIONS: Well-designed GWASs and large replication studies are still needed to identify reliable genetic variants of disease susceptibility and treatment response of patients with CH.

5.
Int J Biol Sci ; 17(8): 2112-2123, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34131410

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that mainly affects young people. IBD is associated with various gastrointestinal symptoms, and thus, affects the quality of life of patients. Currently, the pathogenesis of IBD is poorly understood. Although intestinal bacteria and host immune response are thought to be major factors in its pathogenesis, a sufficient explanation of their role in its pathophysiologic mechanism has not been presented. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have gained attention as they are known to participate in the molecular interactions of IBD. Recent studies have confirmed the important role of miRNAs in targeting certain molecules in signaling pathways that regulate the homeostasis of the intestinal barrier, inflammatory reactions, and autophagy of the intestinal epithelium. Several studies have identified the specific miRNAs associated with IBD from colon tissues or serum samples of IBD patients and have attempted to use them as useful diagnostic biomarkers. Furthermore, some studies have attempted to treat IBD through intracolonic administration of specific miRNAs in the form of nanoparticle. This review summarizes the latest findings on the role of miRNAs in the pathogenesis, diagnosis, and treatment of IBD.

6.
Semin Arthritis Rheum ; 51(3): 513-522, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33866147

RESUMO

The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Animais , Doenças Autoimunes/genética , Autoimunidade , Linfócitos B , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética
7.
Cephalalgia ; 41(2): 197-202, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32955929

RESUMO

BACKGROUND: Triptans, specific symptomatic medications for migraine, are not effective in a proportion of patients, or in all attacks, hence the importance of identifying predictors of response. Our aim was to investigate the association between the efficacy of oral frovatriptan 2.5 mg and clinical characteristics of migraine attacks. METHODS: We enrolled 29 consecutive patients affected by migraine without aura at the Headache Center of "Mondino" Institute of Pavia. Each patient was given a diary and asked to record prospectively the features of three consecutive migraine attacks while using frovatriptan. A generalized estimating equations approach was used to determine phenotypic features associated with the pain free response at 2 hours. RESULTS: Participants provided complete data for 85 attacks. Thirty of these (34%) patients reported being pain free 2 hours after taking frovatriptan 2.5 mg intake. Unilateral pain, presence of phonophobia, presence of one or more cranial autonomic symptoms and presence of one or more premonitory symptom were each associated with being pain free at 2 hours. CONCLUSIONS: The response to frovatriptan was associated with particular features of the migraine attack, either before or during the pain phase of attacks. The data support larger studies to explore detailed attack phenotyping, with particular attention to early signs, to enable individualized treatment in migraine.

8.
J Exp Clin Cancer Res ; 39(1): 227, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33115526

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases.The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Terapia de Alvo Molecular , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Patologia Molecular , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
9.
Brain Sci ; 10(10)2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33007889

RESUMO

This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.

10.
Int J Mol Sci ; 21(19)2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33008138

RESUMO

Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. Clinically, it is characterized by dysphagia, food impaction, and reflux-like symptoms. Multiple genome-wide association studies (GWAS) have been conducted to identify genetic loci associated with EoE. The integration of numerous studies investigating the genetic polymorphisms in EoE and the Mendelian diseases associated with EoE are discussed to provide insights into the genetic risk of EoE, notably focusing on CCL26 and CAPN14. We focus on the genetic loci investigated thus far, and their classification according to whether the function near the loci is known. The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-ß1, and interleukin (IL)-13. This review aims to provide detailed descriptions of the genetics and the comprehensive pathophysiology of EoE.


Assuntos
Calpaína/genética , Quimiocina CCL26/genética , Esofagite Eosinofílica/genética , Predisposição Genética para Doença , Citocinas/genética , Esofagite Eosinofílica/patologia , Esôfago/patologia , Estudo de Associação Genômica Ampla , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/genética , Interleucina-13/genética , Células Th2/metabolismo , Fator de Crescimento Transformador beta1/genética
11.
Cancer Chemother Pharmacol ; 86(5): 577-588, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33005979

RESUMO

PURPOSE: To assess efficacy and safety of trastuzumab biosimilars in comparison to the reference drug through a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: A comprehensive search was conducted using PubMed, Web of Science, Cochrane library, Open Grey and ClinicalTrials.gov databases. Dichotomous data for efficacy and safety outcomes were pooled to obtain the relative risk (RR) and 95% confidence intervals (CIs). Meta-analysis was performed with the Mantel-Haenszel method using Revman 5.3 software. RESULTS: Eight phase III RCTs including a total of 3913 patients with HER2 + breast cancer were identified that met the inclusion criteria. The pooled results for the comparison of trastuzumab biosimilars to the reference drug showed no differences of objective response rate (ORR) (RR 1.05, 95% CI 0.98-1.12, P = 0.20) or overall survival (RR 0.82, 95% CI 0.61-1.09, P = 0.17) in the intention-to-treat population, as well as no difference of ORR (RR 1.03, 95% CI 0.97-1.10, P = 0.30) in the per-protocol population. Similarly, no significant difference was detected in any type of adverse event reported in at least three RCTs, including any serious treatment-emergent adverse effects (RR 0.97, 95% CI 0.76-1.25, P = 0.83), heart failure (RR 1.47, 95% CI 0.69-3.14, P = 0.32), neutropenia (RR 1.05, 95% CI 0.96-1.15, P = 0.26), and infusion-related reaction (RR 1.10, 95% CI 0.89-1.36, P = 0.38). CONCLUSION: This meta-analysis provides compelling evidence of clinical comparability between trastuzumab biosimilars and the originator product in terms of both efficacy and safety for the treatment of HER2 + breast cancer.


Assuntos
Medicamentos Biossimilares/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Neutropenia/epidemiologia , Trastuzumab/administração & dosagem , Medicamentos Biossimilares/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Estudos de Equivalência como Asunto , Feminino , Insuficiência Cardíaca/induzido quimicamente , Humanos , Infusões Intravenosas/efeitos adversos , Reação no Local da Injeção , Análise de Intenção de Tratamento , Neutropenia/induzido quimicamente , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Taxa de Sobrevida , Trastuzumab/efeitos adversos , Resultado do Tratamento
12.
Sci Rep ; 10(1): 12850, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732985

RESUMO

Contrasting results exist on the association between CTLA-4 rs231775 and acute rejection in kidney transplant recipients. We herein conducted an updated systematic review with meta-analysis and trial sequential analysis (TSA) to clarify this relationship and to establish whether the current evidence is sufficient to draw firm conclusions. In addition, noteworthiness of significant pooled odds ratios (ORs) was estimated by false positive report probability (FPRP). A comprehensive search was performed through PubMed, Web of Knowledge, Cochrane Library and Open Grey up to October 2019. Fifteen independent cohorts, including a total of 5,401 kidney transplant recipients, were identified through the systematic review. Overall, no association was detected with the allelic (OR 1.07, 95% CI 0.88-1.30, P = 0.49), dominant (OR 0.94, 95% CI 0.73-1.22, P = 0.66) or the recessive (OR 1.18, 95% CI 0.97-1.43, P = 0.096) model of CTLA-4 rs231775. In each genetic model, the cumulative Z-curve in TSA crossed the futility boundary and entered the futility area. In addition, none of the significant genetic comparisons detected in the subsequent and sensitivity analyses or in previously reported meta-analyses were found to be noteworthy by FPRP. In conclusion, this study provides strong evidence that CTLA-4 rs231775 is not a clinically-relevant genetic risk determinant of acute rejection after renal transplantation.


Assuntos
Antígeno CTLA-4/genética , Estudos de Associação Genética , Rejeição de Enxerto/genética , Transplante de Rim , Resultados Negativos , Doença Aguda , Estudos de Coortes , Humanos , Razão de Chances , Risco
13.
Int J Mol Sci ; 21(16)2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32784808

RESUMO

Sarcopenia refers to a decrease in skeletal muscle mass and function. Because sarcopenia affects mortality, and causes significant disability, the clinical importance of sarcopenia is emerging. At first, sarcopenia was recognized as an age-related disease but, recently, it has been reported to be prevalent also in younger patients with autoimmune diseases. Specifically, the association of sarcopenia and autoimmune diseases such as rheumatoid arthritis has been studied in detail. Although the pathogenesis of sarcopenia in autoimmune diseases has not been elucidated, chronic inflammation is believed to contribute to sarcopenia, and moreover the pathogenesis seems to be different depending on the respective underlying disease. The definition of sarcopenia differs among studies, which limits direct comparisons. Therefore, in this review, we cover various definitions of sarcopenia used in previous studies and highlight the prevalence of sarcopenia in diverse autoimmune diseases including rheumatoid arthritis, spondyloarthritis, systemic sclerosis, inflammatory bowel disease, and autoimmune diabetes. In addition, we cover the pathogenesis and treatment of sarcopenia in autoimmune and rheumatic diseases. This review provides a comprehensive understanding of sarcopenia in various autoimmune diseases and highlights the need for a consistent definition of sarcopenia.


Assuntos
Doenças Autoimunes/complicações , Doenças Reumáticas/complicações , Sarcopenia/complicações , Humanos , Modelos Biológicos , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia
14.
J Clin Med ; 9(8)2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32726951

RESUMO

(1) Background: The use of corticosteroids in critical coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS), or Coronavirus disease 2019 (COVID-19), has been controversial. However, a meta-analysis on the efficacy of steroids in treating these coronavirus infections is lacking. (2) Purpose: We assessed a methodological criticism on the quality of previous published meta-analyses and the risk of misleading conclusions with important therapeutic consequences. We also examined the evidence of the efficacy of corticosteroids in reducing mortality in SARS, MERS and COVID-19. (3) Methods: PubMed, MEDLINE, Embase, and Web of Science were used to identify studies published until 25 April 2020, that reported associations between steroid use and mortality in treating SARS/MERS/COVID-19. Two investigators screened and extracted data independently. Searches were restricted to studies on humans, and articles that did not report the exact number of patients in each group or data on mortality were excluded. We calculated odds ratios (ORs) or hazard ratios (HRs) under the fixed- and random-effect model. (4) Results: Eight articles (4051 patients) were eligible for inclusion. Among these selected studies, 3416 patients were diagnosed with SARS, 360 patients with MERS, and 275 with COVID-19; 60.3% patients were administered steroids. The meta-analyses including all studies showed no differences overall in terms of mortality (OR 1.152, 95% CI 0.631-2.101 in the random effects model, p = 0.645). However, this conclusion might be biased, because, in some studies, the patients in the steroid group had more severe symptoms than those in the control group. In contrast, when the meta-analysis was performed restricting only to studies that used appropriate adjustment (e.g., time, disease severity), there was a significant difference between the two groups (HR 0.378, 95% CI 0.221-0.646 in the random effects model, p < 0.0001). Although there was no difference in mortality when steroids were used in severe cases, there was a difference among the group with more underlying diseases (OR 3.133, 95% CI 1.670-5.877, p < 0.001). (5) Conclusions: To our knowledge, this study is the first comprehensive systematic review and meta-analysis providing the most accurate evidence on the effect of steroids in coronavirus infections. If not contraindicated, and in the absence of side effects, the use of steroids should be considered in coronavirus infection including COVID-19.

15.
Transplant Rev (Orlando) ; 34(3): 100548, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32498977

RESUMO

In the present study we systematically re-analyzed results from meta-analyses and genome-wide association studies (GWASs) to assess the credibility of genetic associations with acute rejection risk in renal transplantation. A comprehensive literature search was performed on PubMed, Web of Knowledge, Cochrane library, and Open Grey up to July 2019. Methodological quality of systematic meta-analyses was assessed by the AMSTAR tool. Credibility of genetic associations was assessed by employing the Venice criteria and two Bayesian statistical approaches, the false positive report probability (FPRP) and the Bayesian false discovery probability (BFDP). Sixteen systematic meta-analyses, with a moderate-high quality score (median AMSTAR score: 9, range: 6-11) and 1 GWAS fulfilled the inclusion criteria. Overall, our systematic re-analysis has identified 9 polymorphic variants in 8 genes (ACE, CD28, CTLA-4, CYP3A5, IFNG, TNF-α, PTPRO and CCDC67) as potential risk factors for acute renal graft rejection. At the pre-specified prior probability of 0.001, the 2 SNPs identified by the GWAS (rs7976329 and rs10765602) showed no evidence of noteworthiness under FPRP or BFDP, indicating the possibility of false-positive associations. After applying the Venice criteria in combination with FPRP and BFDP to results from systematic meta-analyses, TT/AT vs AA of IFNG +874 T/A reached moderate epidemiological credibility, while weak evidence of association was found for all the other genetic comparisons. Well-designed GWASs and large replication studies with updated meta-analyses are still needed to identify reliable genetic predictors of acute renal graft rejection.


Assuntos
Rejeição de Enxerto/genética , Transplante de Rim , Doença Aguda , Antígenos CD28/genética , Antígeno CTLA-4/genética , Estudo de Associação Genômica Ampla , Humanos , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Risco
16.
PLoS One ; 14(11): e0225685, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31756226

RESUMO

The relationship between the ataxia-telangiectasia mutated (ATM) rs1801516 gene polymorphism and risk of radiation-induced late skin side effects remains a highly debated issue. In the present study, we assessed the role of ATM rs1801516 as risk factor for radiation-induced fibrosis and telangiectasia, using the LENT-SOMA scoring scale in 285 breast cancer patients who received radiotherapy after breast conserving surgery. A systematic review with meta-analysis and trial sequential analysis (TSA) was then conducted to assess reliability of the accumulated evidence in breast cancer patients. In our cohort study, no association was found between ATM rs1801516 and grade ≥ 2 telangiectasia (GA+AA vs GG, HRadjusted: 0.699; 95%CI: 0.273-1.792, P = 0.459) or grade ≥ 2 fibrosis (GA+AA vs GG, HRadjusted: 1.175; 95%CI: 0.641-2.154, P = 0.604). Twelve independent cohorts of breast cancer patients were identified through the systematic review, of which 11 and 9 cohorts focused respectively on the association with radiation-induced fibrosis and radiation-induced telangiectasia. Pooled analyses of 10 (n = 2928 patients) and 12 (n = 2783) cohorts revealed, respectively, no association of ATM rs1801516 with radiation-induced telangiectasia (OR: 1.14; 95%CI: 0.88-1.48, P = 0.316) and a significant correlation with radiation-induced fibrosis (OR: 1.23; 95%CI: 1.00-1.51, P = 0.049), which however did not remain significant after TSA adjustment (TSA-adjusted 95%CI: 0.85-1.78). These results do not support an impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer, nevertheless further large studies are still required for conclusive evidences.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Raios gama/efeitos adversos , Dermatopatias/etiologia , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Feminino , Raios gama/uso terapêutico , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Dermatopatias/diagnóstico , Telangiectasia/diagnóstico , Telangiectasia/etiologia
17.
Eur J Med Chem ; 181: 111576, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400709

RESUMO

The enzyme nicotinamide phosphoribosyltransferase is both a key intracellular enzyme for NAD biosynthesis (iNAMPT) and an extracellular cytokine (eNAMPT). The relationship between this latter role and the catalytic activity of the enzyme is at present unknown. With the intent of discovering inhibitors specifically able to target eNAMPT, we increased the polarity of MV78 (EC50 = 5.8 nM; IC50 = 3.1 nM), a NAMPT inhibitor previously discovered by us. The replacement of a phenyl ring with a 1,2,3-triazole bearing a protonable N,N-dialkyl methanamine group gave a series of molecules which maintained the inhibition of the enzymatic activity but were unable to cross the plasma membrane and affect cell viability in vitro. Compounds 30b and 30f can therefore be considered as the first experimental/pharmacological tools for scientists that wish to understand the role of the catalytic activity of eNAMPT. Serendipitously, we also discovered a compound (25) which, notwithstanding its high polarity, was able to cross the plasma membrane being cytotoxic, a potent NAMPT inhibitor and effective in reducing growth of triple negative mammary carcinoma in mice. In our hands, 25 lacked retinal and cardiac toxicity, although we observed a lesser toxicity of NAMPT inhibitors in general compared to other reports.


Assuntos
Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Animais , Linhagem Celular Tumoral , Química Click , Citocinas/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/metabolismo , Triazóis/farmacocinética
18.
Cancers (Basel) ; 11(7)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336701

RESUMO

Background: A wealth of evidence has shown that microRNAs (miRNAs) can modulate specific genes, increasing our knowledge on the fine-tuning regulation of protein expression. miR-221 and miR-222 have been frequently identified as deregulated across different cancer types; however, their prognostic significance in cancer remains controversial. In view of these considerations, we performed an updated systematic review and meta-analysis of published data investigating the effects of miR-221/222 on overall survival (OS) and other secondary outcomes among cancer patients. A systematic search of PubMed, Web of Knowledge, and Cochrane Library databases was performed. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Results: Fifty studies, analyzing 6086 patients, were included in the systematic review. Twenty-five studies for miR-221 and 17 studies for miR-222 which assessed OS were included in the meta-analysis. High expression of miR-221 and miR-222 significantly predicted poor OS (HR: 1.48, 95% CI: 1.14-1.93, p = 0.003 and HR: 1.90, 95% CI: 1.43-2.54, p < 0.001, respectively). Subgroup analysis revealed that the finding on miR-221 was not as robust as the one on miR-222. Furthermore, high miR-222 expression was also associated with worse progression-free survival and disease-free survival pooled with recurrence-free survival. Conclusions: The meta-analysis demonstrated that high expression of miR-222 is associated with poor prognosis in cancer patients, whereas the significance of miR-221 remains unclear. More work is required to fully elucidate the role of miR-221 and miR-222 in cancer prognosis, particularly in view of the limitations of existing results, including the significant heterogeneity and limited number of studies for some cancers.

19.
J Clin Pharmacol ; 59(2): 288-294, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30256423

RESUMO

A large meta-analysis of genome-wide association studies has recently identified a number of risk loci for migraine without aura (MwoA). In this study, we tested the hypothesis that a genetic risk score based on single-nucleotide polymorphisms (SNPs), previously reported to be associated with MwoA at genome-wide significance, may influence headache response to triptans in patients with migraine without aura. Genotyping of rs9349379, rs2078371, rs6478241, rs11172113, rs1024905, and rs6724624 was conducted with a real-time PCR allelic discrimination assay in 172 MwoA patients, of whom 36.6% were inconsistent responders to triptans. Each genetic risk score model was constructed as an unweighted score, calculated by adding the number of risk alleles for MwoA across each SNP at selected loci. The association with headache response to triptans was evaluated by logistic regression analysis adjusted for triptan, and the P values were corrected for the false discovery rate. The genetic risk score including susceptibility risk alleles at TRPM8 rs6724624 and FGF6 rs1024905 was found to be inversely associated with risk of inconsistent response to triptans (OR, 0.62; 95%CI, 0.43-0.89; false discovery rate q value, 0.045). In addition, adding this genetic risk score to the triptan-adjusted logistic regression model significantly improved (P = .037) the discrimination accuracy, from 0.57 (95%CI, 0.50-0.65) to 0.64 (95%CI, 0.57-0.72). A modest but significant effect on risk of inconsistent response to triptans was identified for a genetic risk score model composed of 2 known risk alleles for MwoA, suggesting its potential utility in predicting headache response to triptan therapy.


Assuntos
Cefaleia/diagnóstico , Cefaleia/genética , Enxaqueca sem Aura/tratamento farmacológico , Enxaqueca sem Aura/genética , Triptaminas/uso terapêutico , Adulto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
20.
Pharmacol Res ; 135: 102-111, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30048756

RESUMO

We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review. Among these, 16 studies were available for the meta-analysis of rs116855232, 6 studies for rs186364861 and 5 studies for rs554405994 of NUDT15. A higher DOR was found for rs116855232 (8.44, 95% CI: 5.46-13.03), as compared to rs554405994 (4.336, 95% CI 2.924-6.429) or rs186364861 (2.742, 95% CI 1.453-5.175). Results of meta-regression analysis showed that incidence of leukopenia (relative DOR: 0.96; 95%CI: 0.93-1.00, p = 0.037) and leukopenia onset (late vs early leukopenia, relative DOR: 0.41, 95% CI 0.20-0.85, p = 0.0189) significantly influenced diagnostic accuracy of rs116855232. Subgroup analysis for rs186364861 and rs554405994 revealed a significant DOR for early-onset leukopenia (rs186364861: 4.04, 95% CI 1.78-9.20; rs554405994: 2.94, 95% CI 1.74-4.95), but not for late-onset leukopenia (rs186364861: 1.52, 95% CI 0.52-4.43; rs554405994: 2.02, 95% CI 0.93-4.40). The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. Nevertheless, prospective studies of genotype-guided dosing of thiopurines are warranted to prove clinical benefit and cost-effectiveness of pretreatment NUDT15 gene testing across different populations.


Assuntos
Antineoplásicos/efeitos adversos , Azatioprina/efeitos adversos , Leucopenia/induzido quimicamente , Leucopenia/genética , Mercaptopurina/efeitos adversos , Pirofosfatases/genética , Tioguanina/efeitos adversos , Humanos , Leucopenia/diagnóstico , Polimorfismo Genético
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