IDH-wildtype grade diffuse glioma is the most aggressive primary brain tumor in adults, with limited survival despite standard therapy with temozolomide (TMZ). Resistance to TMZ is driven by DNA repair pathways, tumor heterogeneity, and microenvironmental adaptations, indicating the need for novel therapeutic strategies. Using a systems biology approach, a compound-protein and protein-protein interaction networks was constructed with STRING 12.0 and STITCH 5.0 databases, identifying hub-bottleneck proteins associated with TMZ resistance. Topological and gene ontology analyses revealed 5 functional modules enriched in DNA repair and apoptosis, with PARP1, PCNA, TP53, MSH2, and HSPA1a emerging as key regulators. HSPA1a modulated survival by inhibiting TP53 and caspase signaling, while also blocking mismatch repair via MSH2 and MLH1 upregulation. In vitro studies using U87MG cells exhibited greater sensitivity to demethoxycurcumin (DMC) compared to TMZ. Importantly, DMC synergized with TMZ to reduce the concentration required for growth inhibition. Comet assays data confirmed TMZ-induced DNA damage and transient base excision repair (BER) impairment, while DMC enhanced both PCNA expression and caspase-mediated apoptosis. Co-treatment with DMC and TMZ sustained PARP1 downregulation, prolonged DNA damage, and amplified apoptosis. These findings indicated that DMC functions as an effective chemosensitizer, elevating TMZ efficacy. Combining DMC with DNA repair inhibitors may represent a promising therapeutic strategy to overcome resistance and improve IDH-wildtype grade diffuse glioma treatment outcomes.

Introduction: No tumor marker is recommended in the available guidelines for prognostic evaluation, treatment monitoring, and follow-up of patients with cervical cancer. However, the squamous cell carcinoma antigen (SCC-Ag) may play a role as a prognostic factor in the disease. Objective: To carry out a survey with Brazilian gynecologic oncology specialists on their knowledge and use of SCC-Ag in clinical practice. Methods: This was a transversal epidemiological study based on the application of a questionnaire developed on the Google Forms platform, comprised of three questions about the knowledge and use of SCC-Ag in the clinical routine of gynecologic oncology specialists. Results: The questionnaire was sent to 50 gynecologic oncology specialists, and the response rate was 80%. A total of 62.5% (n=25/40) of respondents reported knowing SCC-Ag. However, when asked about the use of SCC-Ag as a prognostic marker during the management of cervical cancer, 36 (90%) specialists stated that they had never requested it. Informed about the cost of the exam, 27 (67.5%) declared that they would request biomarker analysis in their clinical routine. Conclusion: SCC-Ag is the most widely studied tumor marker as a prognostic factor in cervical cancer, but it is underutilized by Brazilian gynecologic oncology specialists, despite their knowledge of this marker and willingness to request it.

Duodenal eosinophils have been associated with functional dyspepsia, but its association with Helicobacter pylori (H. pylori) remains unclear. Our aim was to investigate the connection between eosinophils in duodenal villi and dyspeptic symptoms, as well as its association with H. pylori infection. We evaluated 100 functional dyspeptic patients, 50 H. pylori positive and 50 H. pylori negative, all meeting Rome III criteria. Participants underwent upper gastrointestinal endoscopy with gastric and duodenal biopsies. Duodenal villi eosinophil were counted in 5 random high-power fields (HPF). We evaluated the association between duodenal villi eosinophils and dyspeptic symptoms using the validated PADYQ questionnaire. Duodenal villi eosinophils were also compared between H. pylori-positive and -negative groups and analyzed according to demographic and endoscopic variables. Patients were predominantly female (88

Brain death (BD) represents the irreversible loss of all brain functions, including the brainstem, and is equivalent to clinical death established by neurological criteria. However, clinical diagnosis, mainly based on the absence of primary reflexes post-acute brain injury, remains a challenge in hospital settings. The S100 calcium-binding protein beta (S100b) is used to monitor brain injuries, as recommended by neurotrauma care guidelines in some countries. Its levels are associated with severity and mortality, particularly after traumatic brain injury (TBI) and cerebral hemorrhage. The evaluation of S100b levels in investigating brain death is promising; however, aspects such as cutoff values remain to be elucidated. This paper reviews the literature on the use of S100b as a biomarker in diagnosing brain death. It is noteworthy that there is still no defined cutoff for S100b levels in confirming brain death. Additionally, when considering the use of S100b in emergency situations, a point-of-care methodology should be established to support clinical decision-making quickly and easily in the early identification of patients who are more likely to progress to brain death. In this context, S100b levels may assist in establishing the diagnosis of brain death, complementing existing clinical evidence. This, in turn, can optimize and qualify the organ donation process, reducing costs with ineffective therapies and minimizing the suffering of the families involved.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is also an important cause of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV has the capacity to evade immune surveillance by altering the host immune response. Moreover, variations in immune‐related genes can lead to differential susceptibility to HCV infection as well as interfere on the susceptibility to the development of hepatic fibrosis, cirrhosis and HCC. The human leucocyte antigen G ( HLA‐G ) gene codes for an immunomodulatory protein known to be expressed in the maternal–foetal interface and in immune‐privileged tissues. The HLA‐G 3′ untranslated region (3′UTR) is important for mRNA stability, and variants in this region are known to impact gene expression. Studies, mainly focusing in a 14 bp insertion/deletion polymorphism, have correlated HLA‐G 3′UTR with susceptibility to viral infections, but other polymorphic variants in the HLA‐G 3′UTR might also affect HCV infection as they are inherited as haplotypes. The present study evaluated HLA‐G 3′UTR polymorphisms and performed linkage disequilibrium test and haplotype assembly in 286 HCV infected patients who have developed fibrosis, cirrhosis or HCC, as well as in 129 healthy control subjects. Haplotypes UTR‐1, UTR‐2 and UTR‐3 were the most observed in HCV+ patients, in the frequencies of 0.276, 0.255 and 0.121, respectively. No statistically significant difference was observed between HCV+ and control subjects, even when patients were grouped according to outcome (HCC, cirrhosis or fibrosis). Despite that, some trends in the results were observed, and therefore, we cannot rule out the possibility that variants associated to high HLA‐G expression can be involved in HCV infection susceptibility.

Introduction and objectives: Chronic low back pain is the main cause of disability worldwide, generating high costs for society. To evaluate the prevalence of disability in patients with nonspecific chronic low back pain and associated factors, including the impacts of low back pain and psychosocial factors linked to kinesiophobia, catastrophism, anxiety, and depression. Patients: A cross-sectional study was carried out with 108 adult individuals who had non-specific chronic low back pain. The patients answered previously validated questionnaires, namely the Brief Pain Inventory, the Roland-Morris Disability Questionnaire, the Pain Catastrophizing Scale, the Tampa Kinesiophobia Scale, and the Hospital Anxiety and Depression Scale. Results: The prevalence of disability observed was 65.7%, with the mean disability score being 15.7 +/- 5.3 points in the Roland-Morris Disability Questionnaire. Although pain intensity and other domains of the Brief Pain Inventory, like anxiety, depression, and severe kinesiophobia were significant in the bivariate analyses, they were not associated with disability in the multivariate analysis. Only catastrophic thoughts (prevalence ratio [PR] = 1.19; 95% confidence interval [CI]: 1.07-1.32), and the 'walking' domain (PR = 1.08; 95% CI: 1.03-1.14) remained statistically associated with disability. Conclusion: Pain catastrophization and impact on gait were associated with disability in individuals with non-specific chronic low back pain. Motor control thoughts and behaviors during functional activities were considered to be relevant aspects for the better assessment and treatment of these patients. (c) 2022 Published by Elsevier Espana, a, S.L.U. on behalf of Sociedad Espanola ola de Rehabilitacion y Medicina F& imath;sica.

Objectives: Pain Neuroscience Education (PNE) shows improvement in pain and functional capacity in patients with chronic low back pain (CLBP).Therefore, the study aimed to verify if the physiotherapeutic treatment associated with PNE decreases the functional disability of patients with nonspecific CLBP.Methods: Forty patients were clinically evaluated and answered the following questionnaires: Brief pain inventory, Central Sensitization Inventory (CSI), Roland-Morris disability questionnaire, pain catastrophizing scale, Tampa scale of kinesiophobia, hospital anxiety, and depression scale, SF6D quality of life questionnaire and performed quantitative sensory tests (QSTs).Afterward, they were randomly divided into the intervention group (IG, n=20) and the control group (CG, n=20).Both performed kinesiotherapy exercises twice a week for 6 weeks.The IG received 3 individual PNE sessions and answered the pain neurophysiology questionnaire.Results: IG showed significant improvement for all variables analyzed (p<0.001).The association decreased the kinesiophobia (estimated difference between CG-IG means: 7.6-95% CI: 2.3-12.9)(p=0.006).In the lumbar paravertebral region (CG and IG), there was a statistical difference in the intensity of CLBP in the QSTs (p<0.05). Conclusion:The association showed better results compared to only therapeutic exercises to reduce kinesiophobia and change the perception of pain intensity in the lumbar region.

Objectives: To evaluate the role of Helicobacter pylori and other risk factors in recurrent aphthous stomatitis (RAS). Methods: Patients with functional dyspepsia responded to questionnaires regarding demographic and clinical data, anxiety and depression, and a specific RAS questionnaire. They underwent upper digestive endoscopy and H. pylori evaluation. Results: 476 patients were included and of the 372 evaluated for H. pylori, 65.6% were H. pylori-positive. RAS was reported by 32.6% (155/476). In the bivariate analysis of the 372 patients evaluated for gastric H. pylori status, positive subjects had a lower RAS prevalence (29.9%; 73/244) than H. pylori-negative (41.4%; 53/128) (p = .026). Smoking (p = .005) and older age (p = .034) were also associated with a lower prevalence, while female gender (p = .032) and lower income (p = .046) presented higher RAS prevalence. In the multivariate analysis, H. pylori infection (p = .017), smoking (p = .001), and older age (p = .013) were protective factors, while lower income (p = .030) and anxiety (p = .042) were risk factors. In the multivariate analysis of all patients, female gender, lower income, and more schooling years were risk factors. Conclusions: An unexpected lower prevalence of RAS was found in H. pylori-positive patients. Smoking, sex, age, income, education, and anxiety were associated with RAS.

O vírus da imunodeficiência humana do tipo 1 (HIV-1) é o agente etiológico da AIDS. As hepatites virais B (HBV) e C (HCV) são infecções comuns em indivíduos HIV-positivos. Um dos fatores genéticos humanos investigados no controle da replicação do HIV-1 e na progressão da AIDS é a enzima APOBEC3G (A3G). Pesquisas investigam sua ação na replicação do HBV e HCV. A ação da enzima resulta na perda de informação genética e produção de virions defeituosos no ciclo replicativo. Uma variante do gene APOBEC3G, o polimorfismo H186R (rs8177832), pode afetar a atividade do gene ou seus níveis de expressão. O presente estudo teve como objetivos determinar a frequência do polimorfismo H186R do gene APOBEC3G em 324 pacientes HIV-1 positivos com e sem coinfecção pelas hepatites B e C, e correlacionar os genótipos do polimorfismo com a carga viral do HIV-1. As frequências dos genótipos AA, AG e GG foram de 88,6%, 9,3% e 2,1%, respectivamente, em pacientes monoinfectados pelo HIV-1 e 85,4%, 12,4% e 2,2% em coinfectados HIV/HBV. Os pacientes coinfectados HIV/HCV apresentaram os genótipos AA e AG com frequências de 90,1% e 9,9%, respectivamente. Pacientes com genótipo AA apresentaram carga viral de 37.969 ± 68.182 cópias/ml e pacientes com genótipo AG apresentaram carga viral de 48.256 ± 54.186 cópias/ml (p=0,180). Nossos resultados demonstram que não há correlação entre os genótipos do polimorfismo H186R de APOBEC3G e a carga viral do HIV-1 na população de estudo.

The evolution of hepatitis B virus genotype F (HBV-F) in Latin America is not completely understood. The aim of this study was to evaluate the molecular evolution of HBV-F in Latin America by comparing 224 whole-genome sequences. Bayesian coalescent analysis was performed to estimate the time to the most recent common ancestor. Four main clades were found, dating from between 1245 and 1730. In addition, four subclades were identified, dating to between 1705 and 1801. The overall effective population size of HBV-F grew in the 18th century and showed an initial expansion outward from Venezuela to other countries from Latin America. Although HBV-F originated thousands of years ago, circulating strains of HBV-F appear to have spread in recent centuries, particularly in the 18th and 19th centuries. The new molecular data provide valuable information for characterizing the evolution of Native American HBV-F in recent centuries.

A fibromialgia é uma desordem reumática que tem como principal sintoma a dor crônica generalizada acompanhada de um conjunto de sintomas como distúrbio do sono, depressão e fadiga crônica, entre outros. Sua fisiopatologia é complexa, de origem multifatorial, incluindo a influência de fatores genéticos. Já foi demonstrado que indivíduos com fibromialgia apresentam um padrão de agregação familiar e que a probabilidade de um indivíduo desenvolver essa condição é cerca de 50% atribuída a fatores genéticos. Neste sentido, o presente artigo tem por objetivo realizar uma revisão narrativa da literatura sobre os aspectos genéticos da fibromialgia em seu desenvolvimento e gravidade dos sintomas. Para tal foram feitas buscas nas bases de dados PubMed e Scopus, com a utilização de descritores específicos: “fibromyalgia” e “polymorphism”. Polimorfismos que influenciam na modulação da dor, como os que ocorrem em genes da via monoaminérgica ou do metabolismo das catecolaminas, são encontrados com frequência em estudos de associação com a fibromialgia. Porém, outros genes-alvo têm surgido, relacionados às vias responsáveis pelos mecanismos dos mais diversos sintomas que podem acometer esses pacientes, como neuroplasticidade, neurotransmissão, inflamação, vascularização, estresse oxidativo, ciclo celular, entre outros.

Introdução: A dor lombar crônica possui alta prevalência e carga social, mas sua fisiopatologia é incerta e o tratamento insatisfatório.Objetivo: Realizar revisão narrativa da literatura sobre dor lombar crônica inespecífica, possíveis fenômenos, mecanismos biológicos e implicações clínicas.Materiais e Métodos: Artigos publicados entre 2014 e 2020, em inglês, com palavras-chave “chronic low back pain” e “central sensitization” nas bases de dados LILACS e MEDLINE foram incluídos.Resultados: A dor lombar crônica pode apresentar alterações da neuroplasticidade cerebral por sensibilização central e dor nociplástica. O fator neurotrófico derivado do cérebro é relacionado com a hiperexcitabilidade de neurônios centrais, facilitação da nocicepção e sensibilização central. As vias biológicas envolvem a degradação dos receptores glutamato, acoplados à proteína G, por hiperatividade glial e circuitos córtico-límbicos opiordérgicos e dopaminérgicos. Essa disfunção do processamento, amplificação da percepção e modulação da dor são as características da dor nociplástica. Além da avaliação clínica para excluir red flags, dosagens sanguíneas de citocinas pró e anti-inflamatórias; testes sensoriais quantitativos; e instrumentos como Inventário de Sensibilização Central parecem relevantes para a prática clínica.Conclusão: Alterações por sensibilização central podem estar associadas à dor lombar crônica, sendo necessárias maiores investigações já que as evidências sobre este tópico ainda são incipientes.

Background: Host genetic factors have a major impact on susceptibility to infections. Toll-like receptors (TLRs) and their polymorphisms affect infectious diseases once they are directly involved in immune responses. The 2848 G/A variant (rs352140) of the TLR9 gene is associated with increased TLR9 expression. However, the impact of rs352140 on HIV+, HCV+, and HCV+/HIV+ individuals is still debated.Materials and Methods: This study investigated the 2848 G/A polymorphism in hepatitis C virus (HCV) infection, human immunodeficiency virus (HIV) infection, and HCV/HIV coinfection in a large sample of Brazilians (n = 1182). Groups were compared without considering stratification by ethnicity and subsequently stratifying individuals into groups of whites and nonwhites.Results: Considering nonwhite individuals, a significant difference between the HIV+/HCV+ group and controls was observed (p = 0.023; GG genotype as a protective factor). In addition, significant allele differences were observed between the HCV+ group and controls (p = 0.042), between the HIV+/HCV+ group and controls (p = 0.011), and between the HIV+/HCV+ group and HIV+ individuals (p = 0.047). However, all significant results are lost if adjustment by multiple comparisons is applied (p > 0.05).Conclusions: Although our initial results indicate a potential influence of rs352140 on altered host susceptibility to viral infections, no statistical influence of polymorphism on protection from/susceptibility to infections was observed in Brazilians if adjustment by multiple comparisons is considered.

BACKGROUND:The Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene is a potential biomarker of vulnerability to pain. Thus, the present study aimed to investigate the association of this polymorphism with clinical and biopsychosocial factors in patients with chronic low back pain (CLBP).METHODS:A total of 107 individuals with CLBP answered questionnaires that were validated and adapted for the Brazilian population, including the Brief Inventory of Pain, the Central Sensitization Inventory, the Roland Morris Disability Questionnaire, the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, the Survey of Pain Attitude-Brief, and the Hospital Anxiety and Depression Scale. All of the subjects were genotyped for the BDNF Val66Met polymorphism.RESULTS:The sample showed moderate scores of disability, central sensitization, and kinesiophobia, in addition to mild anxiety, hopelessness, and ruminant thoughts. No significant association was observed between the Val66Met polymorphism and the variables analyzed. Besides, there was no relationship between the BDNF Val66Met polymorphism with CSI, catastrophization, or disabilities that were generated by CLBP.CONCLUSION:The results showed that the Val66Met polymorphism of the BDNF gene was not associated with clinical and biopsychosocial characteristics of CLBP in the sample studied.

Hepatitis B virus genotype A (HBV-A) is disseminated in different countries around the world. It presents a high genetic diversity and is classified into seven subgenotypes (A1-A7). HBV-A1 and HBV-A2 are the most frequent and spread in almost all American countries. This study aimed to evaluate the molecular epidemiology of these two subgenotypes, with a special focus on the temporal and geographic spreading in the Americas and Brazil. Bayesian coalescent analyses with HBV-A1 and HBV-A2 whole-genome sequences were performed to study viral phylodynamic and phylogeography. HBV-A1 evolutionary history demonstrated that it was initially disseminated from Africa to other continents probably after the 1400s and mainly in the 17th-18th centuries. The whole viral population grew between the 1700s-1900s and then reached a stationary phase. In Brazil, HBV-A1 common ancestors dated back to the 1600s with successive introductions between the 17th-18th centuries. In contrast, HBV-A2 spread from Europe to other continents after the 1800s, with an increase in the viral population over decades. It was introduced in the 20th century in America and between the 1950s-1970s in Brazil, presenting a high increase in the viral population from the 1970s to the 1980s. The circulation continents for HBV-A1 are Africa and America, while for HBV-A2 are Europe and America. HBV-A is one of the predominant genotypes in America (including Brazil) because of the early introduction by human migration processes of the subgenotypes A1 and A2 between the 16th and 20th centuries and the continuous spreading inside the continent over time.

Hepatitis B virus (HBV) infection is considered a major health problem in the world. HBV is classified into genotypes A to J disseminated worldwide. Genotypes A, D and F are the most frequent in the Western World, B and C are predominant in the East, and E, F, H and J are infrequent and restricted to specific regions. HBV‐G is a rare genotype, but it has been detected in different continents. This study aimed to report the temporal evolution and global spread of HBV‐G comparing whole‐genome sequences of this genotype from different regions in the world. Bayesian coalescent analysis was performed to estimate the time to the most recent common ancestor (tMRCA) and the population dynamics in the last decades. The results demonstrated that tMRCA of all HBV‐Gs dated back to 1855 (95% highest posterior density interval [HPD 95%]: 1778 ‐ 1931). This genotype has a possible origin in North America and it was disseminated to other continents (South and Central America, Europe, Asia and Africa) more than one century later (around the 1970s). The viral population demonstrated constant spreading from 1855 to the 1980s, followed by an increase in the 1990s and reached a plateau after the 2000s. Wide spreading at the beginning of the 1990s was probably associated with the dissemination by highly sexual active groups and injecting drug users. In conclusion, the present study demonstrated that HBV‐G was originated in the 19th century with main events of spread at the end of the 20th century.

Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) pandemic spread rapidly and this scenario is concerning in South America, mainly in Brazil with more than seven million cases of infection. Three major pandemic lineages/clades could be identified along with SARS‐CoV‐2 dissemination (G, GR, and GH) in the Americas. These clades differ according to their genomic characteristics, virulence, and spreading times. The present study describes the main clades and the respective temporal spreading analyses based on SARS‐CoV‐2 whole‐genome sequences (WGS) from South America, obtained in the early pandemic phase (from March 1 to May 31 in 2020). SARS‐CoV‐2 WGSs with available information from country and year of sampling were obtained from different countries and the main clades were identified and analyzed independently with a Bayesian approach. The results demonstrated the prevalence of clades GR (n = 842; 54.6%), G (n = 529; 34.3%), and GH (n = 171; 11.1%). The frequencies of the clades were significantly different between South American countries. Clade G was the most prevalent in Ecuador, Suriname, and Uruguay, clade GR in Argentina, Brazil, and Peru, and clade GH in Colombia. The phylodynamic analysis indicated that all these main lineages increased viral spreading from February to early March and after an evolutionary stationary phase was observed. The decrease observed in the virus dissemination was directly associated to the reduction of social movement after March. In conclusion, these data demonstrated the current predominance of clades G, GR, and GH in South America because of the early dissemination of them in the first pandemic phase in South America.

BACKGROUND Hepatitis C virus (HCV) infection is a public health concern worldwide. Several factors, including genetic polymorphisms, may be evolved in the progression of HCV infection to liver diseases. Interferon lambdas (IFNLs) modulate the immune response during viral infections. IFNLs induce antiviral activity, interfering in the viral replication by promoting the expression of several genes that regulate immunological functions. The interferon lambda-4 (IFNL4) rs12979860 polymorphism, which is characterized by a C to T transition in intron 1, is associated with spontaneous and treatment-induced clearance of HCV infection and may play a role in the development of HCV-associated liver diseases, including hepatocellular carcinoma (HCC). AIM To investigate the association of IFNL4 rs12979860 polymorphism with fibrosis, cirrhosis, and HCC in patients with chronic HCV infection. METHODS This study was comprised of 305 chronic HCV-infected patients (53 fibrosis, 154 cirrhosis, and 98 HCC cases). The control group was comprised of 260 HCV-negative healthy individuals. The IFNL4 rs12979860 polymorphism was genotyped using the TaqMan assay. Fibrosis was diagnosed based on liver biopsy findings, while cirrhosis was diagnosed through clinical, laboratory, anatomopathological, and/or imaging data. HCC was diagnosed through imaging tests, tumor, and/or anatomopathological markers. RESULTS The T allele was observed in the three groups of patients (fibrosis, cirrhosis, and HCC) at a significantly higher frequency when compared with the control group (P = 0.047, P < 0.001, and P = 0.01, respectively). Also, genotype frequencies presented significant differences between the control group and cirrhosis patients (P < 0.001) as well as HCC patients (P = 0.002). The risk analysis was performed using the codominant and dominant T allele models. In the codominant model, it was observed that the CT genotype showed an increased risk of developing cirrhosis in comparison with the CC genotype [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.55-4.15; P < 0.001] as well as with HCC (OR = 2.54; 95%CI: 1.44-4.56; P = 0.001). A similar result was observed in the comparison of the TT vs CC genotype between the control group and cirrhosis group (OR = 2.88; 95%CI: 1.44-5.77; P = 0.001) but not for HCC patients. In the dominant T allele model, the CT + TT genotypes were associated with an increased risk for progression to cirrhosis (OR = 2.60; 95%CI: 1.63-4.19; P < 0.001) and HCC (OR = 2.45; 95%CI: 1.42-4.31; P = 0.001). CONCLUSION These findings suggest that the T allele of IFNL4 rs12979860 polymorphism is associated with the development of cirrhosis and HCC in chronic HCV-infected patients.

Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C. Sofosbuvir and simeprevir are prescribed worldwide. However, there is a scarcity of information regarding their genotoxicity. Therefore, the present study assessed the cytotoxic and genotoxic effects of sofosbuvir and simeprevir, alone and combined with ribavirin. HepG2 cells were analyzed using the in vitro cytokinesis-block micronucleus cytome assay. Cells were treated for 24 h with sofosbuvir (0.011-1.511 mM), simeprevir (0.156-5.0 µM), and their combinations with ribavirin (0.250-4.0 mM). No significant differences were observed in the nuclear division cytotoxicity index, reflecting the absence of cytotoxic effects associated to sofosbuvir. However, the highest concentration of simeprevir showed a significant difference for the nuclear division cytotoxicity index. Moreover, significant results were observed for nuclear division cytotoxicity index in two combinations of sofosbuvir plus ribavirin and only in the highest combination of simeprevir plus ribavirin. Additionally, our results showed that sofosbuvir did not increase the frequency of chromosomal damage, but simeprevir significantly increased the frequency of micronuclei at the highest concentrations. The combination index demonstrated that both sofosbuvir and simeprevir produced antagonism to the genotoxic effects of ribavirin. In conclusion, our results showed that simeprevir, but not sofosbuvir, has genotoxic effects in HepG2 cells.

The present study aimed to evaluate the influence of the IL1B -31C/T polymorphism on gastric inflammatory response and precancerous lesions development - atrophic gastritis (AG) and intestinal metaplasia (IM) - in patients positive for Helicobacter pylori infection with functional dyspepsia (FD). The diagnosis of FD followed the Rome III criteria, and the H. pylori infection was evaluated by urease test and histological examination of gastric biopsies (corpus, antrum, and incisura). The severity of chronic inflammation and inflammatory activity, as well as the presence of precancerous lesions were evaluated accordingly to the updated Sydney System. Genotyping of the IL1B -31C/T polymorphism (rs1143627) was performed by polymerase chain reaction-restriction fragment length polymorphism. A total of 303 patients positive for H. pylori infection with FD were analyzed (81.8% women; mean age of 46.3 +/- 12.3 years). No differences were observed in overall genotype frequencies among outcomes evaluated. However, in the dominant -31C allele model (CC+CT vs. TT), the frequency of the TT genotype was significantly higher among patients with moderate/severe chronic inflammation of the antrum than the frequency of the CC+CT genotypes (80.8% vs. 65.2%; OR = 2.25; 95% CI = 1.23-4.24; P = .005). The presence of AG and IM in the gastric mucosa of patients was of 19.5% and 19.1%, respectively. No significant association was observed concerning the frequencies of the genotypes of IL1B -31C/T polymorphism with development of precancerous lesions. In conclusion, our data suggest that genetic variants of the IL1B -31C/T polymorphism play a role in chronic inflammation of the gastric mucosa in H. pylori-infected FD patients.