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Envenomation by reptile venom, particularly from lizards, poses significant health risks and can lead to physiological and cardiovascular changes. The venom of Heloderma horridum horridum, endemic to Colima, Mexico, was tested on Wistar rats. Electrocardiographic (ECG) data were collected pre-treatment and at 5-min intervals for 1 h post-envenomation. A specially designed computational linear regression algorithm (LRA) was used for the segmentation analysis of the ECG data to improve the detection of fiducial points (P, Q, R, S, and T) in ECG waves. Additionally, heart tissue was analyzed for macroscopic and microscopic changes. The results revealed significant electrocardiographic alterations, including pacemaker migration, junctional extrasystoles, and intraventricular conduction aberrations. By applying a linear regression algorithm, the study compensated for noise and anomalies in the isoelectric line in an ECG signal, improving the detection of P and T waves and the QRS complex with an efficiency of 97.5%. Cardiac enzyme evaluation indicated no statistically significant differences between the control and experimental groups. Macroscopic and microscopic examination revealed no apparent signs of damage or inflammatory responses in heart tissues. This study enhances our understanding of the cardiovascular impact of Heloderma venom, suggesting a greater influence on changes in conduction and arrhythmias than on direct cardiac damage to the myocardium.
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Algoritmos , Eletrocardiografia , Ratos Wistar , Animais , Ratos , Modelos Lineares , Coração/efeitos dos fármacos , Lagartos , Masculino , Peçonhas/toxicidade , México , Animais PeçonhentosRESUMO
We aimed to characterize the echocardiographic alterations in dogs from an endemic region that were naturally infected with T. cruzi. Dogs (n = 130) seropositive for antibodies against T. cruzi and/or with acute parasitemia were enrolled in the study. Indicators of changes in the structure and systolic and diastolic functions of the left ventricle (LV) and blood flow patterns were evaluated by echocardiography. The frequency and extent of alterations in these indicators were associated with the severity of the disease. Briefly, 15 (11.54%) dogs were diagnosed with dilated cardiomyopathy (DCM), and 115 (88.46%) dogs were diagnosed as being without DCM. Infected dogs with DCM exhibited structural features of LV dysfunction, e.g., a significant (p < 0.05) increase in the LV internal diameter at systole and diastole (LVID-s, LVID-d) and a decline in the LV posterior wall (LVPW-d) thickness at diastole. Despite an increase in stroke volume and cardiac output indicating contraction force, DCM resulted in a decreased ejection fraction, affecting systolic function. Dogs that were diagnosed as DCM-negative but were positive for T. cruzi by PCR exhibited a high frequency of an increase in the thickness of the interventricular septum in systole (IVS-s) and the LV posterior wall in diastole (LVPW-d), a decline in the LV inner diameter (LVID-d, LVID-s), and fractional shortening (FS). The thinning of the LVPW at systole was the most defining feature observed in chronically infected dogs. In summary, this is the first study reporting the echocardiographic changes occurring in dogs naturally infected with T. cruzi and developing DCM. Our data suggest that changes in LVID are a major indicator of risk of cardiac involvement, and the observation of changes in the IVS, LVPW, and FS have predictive value in determining the risk of DCM development in infected dogs.
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Purpose: Coal mining is a vital sector in Colombia, contributing significantly to the nation's economy and the development of its regions. However, despite its importance, it has led to a gradual decline in the health of mine workers and nearby residents. While the adverse health effects of open-pit coal mining on exposed individuals have been well-documented in Colombia and globally, studies investigating genetic damage in underground coal miners are lacking. Methods: The aim of our study was to evaluate chromosomal and genotoxic damage, in peripheral blood samples from a group of underground coal miners and residents of areas exposed to coal, in the town of Samacá, Boyacá-Colombia, and in a group of unexposed individuals by using banding and molecular cytogenetic techniques, as well as cytokinesis block micronucleus assays. Results: Our results suggest that occupational exposure to coal induces chromosomal and genotoxic damage in somatic cells of underground coal miners. Chromosomal and genotoxic damage is an important step in carcinogenesis and the development of many other diseases. Our findings provide valuable insights into the effects of coal dust exposure on chromosomal integrity and genetic stability. Conclusion: Our pilot study suggests that occupational exposure to coal induces chromosomal damage in underground coal miners, highlighting the importance of validating these findings with a larger sample size. Our results highlight the need to implement prevention and protection measures, as well as educational programs for underground coal miners. Characterizing and estimating exposure risks are extremely important for the safety of people exposed occupationally and environmentally to coal and its derivatives.
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Background and Objectives: New investigations have detected an enhanced probability for women to develop menstrual cycle alterations after anti-COVID-19 vaccination. Moreover, given that the protective immunity provided by anti-COVID-19 vaccination appears to wane quickly, booster vaccination has been recommended. Nonetheless, whether adverse events arise from such repeated immunization has not been studied. Materials and Methods: We studied the incidence of menstrual cycle alterations, the quantity of menstrual cycle alterations per subject, and of altered menstrual cycles in nonpregnant women of fertile age after anti-COVID-19 vaccination in a cohort of vaccinated female subjects by the means of a standardized questionary that was applied via telephone calls each month. Subjects that received up to four doses were studied for 6 months after each dose. We calculated the odds ratio for enhanced incidence, as well as quadratic functions for the tendencies. A sensitivity analysis excluding subjects taking hormonal birth control and those with polycystic ovary syndrome was performed. Results: Anti-COVID-19 vaccination enhanced the probability to develop menstrual cycle alterations (OR 1.52, CI at 95% 1.2-1.8, p < 0.0001) and, interestingly, such a tendency was enhanced when subjects received more doses (R2 = 0.91). Furthermore, the same trends repeated for the quantity of alterations per subject, and of altered cycles. Such an effect was further demonstrated to be independent upon the vaccine brand being applied, the birth control status, and the diagnosis of polycystic ovary syndrome. Conclusions: Vaccination is the most cost-effective measure for primary prevention and is considered to be safe. Nonetheless, in this article, we show data that suggest that repeated vaccination of adult female subjects may lead to an enhanced incidence of menstrual cycle-related adverse events, quantity of alterations per subject, and altered cycles. We therefore think that the development of new vaccine formulations that produce longer-lasting immunity is of paramount importance to reduce the potential for dose accumulation-dependent enhanced risk.
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Vacinas contra COVID-19 , COVID-19 , Ciclo Menstrual , Humanos , Feminino , Adulto , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Ciclo Menstrual/efeitos dos fármacos , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinação/métodos , Vacinação/efeitos adversos , Distúrbios Menstruais/epidemiologia , Estudos de Coortes , Imunização Secundária/métodos , Incidência , Adulto JovemRESUMO
Superparamagnetic iron oxide nanoparticles (SPIONs) have gained significant attention in biomedical research due to their potential applications. However, little is known about their impact and toxicity on testicular cells. To address this issue, we conducted an in vitro study using primary mouse testicular cells, testis fragments, and sperm to investigate the cytotoxic effects of sodium citrate-coated SPIONs (Cit_SPIONs). Herein, we synthesized and physiochemically characterized the Cit_SPIONs and observed that the sodium citrate diminished the size and improved the stability of nanoparticles in solution during the experimental time. The sodium citrate (measured by thermogravimetry) was biocompatible with testicular cells at the used concentration (3%). Despite these favorable physicochemical properties, the in vitro experiments demonstrated the cytotoxicity of Cit_SPIONs, particularly towards testicular somatic cells and sperm cells. Transmission electron microscopy analysis confirmed that Leydig cells preferentially internalized Cit_SPIONs in the organotypic culture system, which resulted in alterations in their cytoplasmic size. Additionally, we found that Cit_SPIONs exposure had detrimental effects on various parameters of sperm cells, including motility, viability, DNA integrity, mitochondrial activity, lipid peroxidation (LPO), and ROS production. Our findings suggest that testicular somatic cells and sperm cells are highly sensitive and vulnerable to Cit_SPIONs and induced oxidative stress. This study emphasizes the potential toxicity of SPIONs, indicating significant threats to the male reproductive system. Our findings highlight the need for detailed development of iron oxide nanoparticles to enhance reproductive nanosafety.
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Nanopartículas Magnéticas de Óxido de Ferro , Espermatozoides , Testículo , Masculino , Animais , Camundongos , Testículo/efeitos dos fármacos , Nanopartículas Magnéticas de Óxido de Ferro/toxicidade , Nanopartículas Magnéticas de Óxido de Ferro/química , Espermatozoides/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Citrato de Sódio , Células CultivadasRESUMO
Introduction: Gastric cancer is one of the most prevalent types of cancer worldwide. The World Health Organization (WHO), the International Agency for Research on Cancer (IARC), and the Global Cancer Statistics (GLOBOCAN) reported an age standardized global incidence rate of 9.2 per 100,000 individuals for gastric cancer in 2022, with a mortality rate of 6.1. Despite considerable progress in precision oncology through the efforts of international consortia, understanding the genomic features and their influence on the effectiveness of anti-cancer treatments across diverse ethnic groups remains essential. Methods: Our study aimed to address this need by conducting integrated in silico analyses to identify actionable genomic alterations in gastric cancer driver genes, assess their impact using deleteriousness scores, and determine allele frequencies across nine global populations: European Finnish, European non-Finnish, Latino, East Asian, South Asian, African, Middle Eastern, Ashkenazi Jewish, and Amish. Furthermore, our goal was to prioritize targeted therapeutic strategies based on pharmacogenomics clinical guidelines, in silico drug prescriptions, and clinical trial data. Results: Our comprehensive analysis examined 275,634 variants within 60 gastric cancer driver genes from 730,947 exome sequences and 76,215 whole-genome sequences from unrelated individuals, identifying 13,542 annotated and predicted oncogenic variants. We prioritized the most prevalent and deleterious oncogenic variants for subsequent pharmacogenomics testing. Additionally, we discovered actionable genomic alterations in the ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53, and CDKN2A genes that could enhance the efficacy of anti-cancer therapies, as suggested by in silico drug prescription analyses, reviews of current pharmacogenomics clinical guidelines, and evaluations of phase III and IV clinical trials targeting gastric cancer driver proteins. Discussion: These findings underline the urgency of consolidating efforts to devise effective prevention measures, invest in genomic profiling for underrepresented populations, and ensure the inclusion of ethnic minorities in future clinical trials and cancer research in developed countries.
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BACKGROUND: In prostate cancer (PCa), well-established biomarkers such as MSI status, TMB high, and PDL1 expression serve as reliable indicators for favorable responses to immunotherapy. Recent studies have suggested a potential association between CDK12 mutations and immunotherapy response; however, the precise mechanisms through which CDK12 mutation may influence immune response remain unclear. A plausible explanation for immune evasion in this subset of CDK12-mutated PCa may be reduced MHC expression. RESULTS: Using genomic data of CDK12-mutated PCa from 48 primary and 10 metastatic public domain samples and a retrospective cohort of 53 low-intermediate risk primary PCa, we investigated how variation in the expression of the MHC genes affected associated downstream pathways. We classified the patients based on gene expression quartiles of MHC-related genes and categorized the tumors into "High" and "Low" expression levels. CDK12-mutated tumors with higher MHC-expressed pathways were associated with the immune system and elevated PD-L1, IDO1, and TIM3 expression. Consistent with an inflamed tumor microenvironment (TME) phenotype, digital cytometric analyses identified increased CD8 + T cells, B cells, γδ T cells, and M1 Macrophages in this group. In contrast, CDK12-mutated tumors with lower MHC expression exhibited features consistent with an immune cold TME phenotype and immunoediting. Significantly, low MHC expression was also associated with chromosome 6 loss of heterozygosity (LOH) affecting the entire HLA gene cluster. These LOH events were observed in both major clonal and minor subclonal populations of tumor cells. In our retrospective study of 53 primary PCa cases from this Institute, we found a 4% (2/53) prevalence of CDK12 mutations, with the confirmation of this defect in one tumor through Sanger sequencing. In keeping with our analysis of public domain data this tumor exhibited low MHC expression at the RNA level. More extensive studies will be required to determine whether reduced HLA expression is generally associated with primary tumors or is a specific feature of CDK12 mutated PCa. CONCLUSIONS: These data show that analysis of CDK12 alteration, in the context of MHC expression levels, and LOH status may offer improved predictive value for outcomes in this potentially actionable genomic subgroup of PCa. In addition, these findings highlight the need to explore novel therapeutic strategies to enhance MHC expression in CDK12-defective PCa to improve immunotherapy responses.
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This study delves into the eco-endocrinological dynamics concerning the impact of dexamethasone (DXE) on the interrenal axis in juvenile carp, Cyprinus carpio. Through a comprehensive analysis, we investigated the effects of DXE exposure on oxidative stress, biochemical biomarkers, gene expression, and bioaccumulation within the interrenal axis. Results revealed a concentration-dependent escalation of cellular oxidation biomarkers, including 1) hydroperoxides content (HPC), 2) lipid peroxidation level (LPX), and 3) protein carbonyl content (PCC), indicative of heightened oxidative stress. Concurrently, the activity of critical antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT), significantly increased, underscoring the organism's response to oxidative insult. Notable alterations were observed in biochemical biomarkers, particularly Gamma-glutamyl-transpeptidase (GGT) and alkaline phosphatase (ALP) activity, with GGT displaying a significant decrease with increasing DXE concentrations. Gene expression analysis revealed a significant upregulation of stress and inflammation response genes, as well as those associated with sensitivity to superoxide ion presence and calcium signaling, in response to DXE exposure. Furthermore, DXE demonstrated a concentration-dependent presence in interrenal tissue, with consistent bioconcentration factors observed across all concentrations tested. These findings shed light on the physiological and molecular responses of juvenile carp to DXE exposure, emphasizing the potential ecological implications of DXE contamination in aquatic environments. Understanding these dynamics is crucial for assessing the environmental impact of glucocorticoid pollutants and developing effective management strategies to mitigate their adverse effects on aquatic ecosystems.
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Carpas , Dexametasona , Estresse Oxidativo , Poluentes Químicos da Água , Animais , Carpas/metabolismo , Carpas/fisiologia , Poluentes Químicos da Água/toxicidade , Biomarcadores/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Rim/metabolismo , Rim/efeitos dos fármacosRESUMO
A cavidade oral é afetada pelo caráter multissistêmico das consequências da Doença Renal Crônica (DRC) e estima-se que cerca de 90% destes pacientes têm sintomas orais. Alterações laboratoriais sanguíneas e salivares são frequentemente observadas e por isso, investigações sobre correlações clínico-laboratoriais são fundamentais para o manejo e tratamento dos pacientes. Neste estudo foi realizada uma revisão sistemática para identificar e avaliar as principais alterações laboratoriais no sangue e na saliva de pacientes portadores de DRC que apresentam manifestações orais. A busca bibliográfica incluiu artigos das bases de dados eletrônicas PubMed, Scopus, Biblioteca Virtual em Saúde, Web of Science, Embase e literatura cinzenta, incluindo estudos caso-controle, transversais e de coorte. A análise do risco de viés seguiu a abordagem QUADAS-2. PROSPERO CRD42022250533 é o registro dessa revisão. As principais alterações laboratoriais encontradas foram o aumento das concentrações sanguíneas e salivares de ureia, creatinina, fosfato e diminuição das concentrações de cálcio e da taxa de fluxo salivar. As concentrações dessas substâncias no sangue e na saliva e a TGF estavam diretamente correlacionadas. Foi observada existência da correlação entre o aparecimento das manifestações orais e as alterações laboratoriais, principalmente xerostomia, disgeusia e hálito urêmico. Em conclusão, a literatura tem revelado que as principais alterações laboratoriais encontradas são aquelas descritas comumente na rotina laboratorial, que as concentrações dessas substâncias no sangue e na saliva estão diretamente correlacionadas com a TFG, e existe correlação entre o aparecimento das manifestações orais e as alterações laboratoriais. Grandes oportunidades estão abertas para a investigação sobre de novos marcadores.
The oral cavity is affected by the multisystemic nature of the consequences of Chronic Kidney Disease (CKD) and it is estimated that around 90% of these patients present oral symptoms. Blood and salivary laboratory changes are frequently observed and, therefore, investigations of clinical-laboratory correlations are essential for the management and treatment of these patients. This study was carried out as a systematic review to identify and evaluate the main laboratory changes in the blood and saliva of patients with CKD who present oral manifestations. The bibliographic search included articles from the electronic databases PubMed, Scopus, Virtual Health Library, Web of Science, Embase and gray literature, including case-control, cross-sectional and cohort studies. The risk of bias analysis advanced the QUADAS-2 approach. PROSPERO CRD42022250533 is the record of this review. The main laboratory changes found were an increase in blood and salivary concentrations of urea, creatinine, phosphate and a decrease in calcium concentrations and salivary flow. The concentrations of substances in blood and saliva and TGF were directly correlated. The existence of the manifestation was observed between the appearance of oral manifestations and laboratory changes, mainly xerostomia, dysgeusia and uremic breath. In conclusion, the literature revealed that the main laboratory changes found are those commonly described in laboratory routine, that the concentrations of these problems in blood and saliva are directly correlated with GFR, and there is a manifestation between the appearance of oral manifestations and laboratory changes. . Great opportunities are open for the investigation of new markers.
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Manifestações Bucais , Pesquisa , Saliva , Sangue , Insuficiência Renal Crônica , LaboratóriosRESUMO
BACKGROUND: Mesenchymal epithelial transition factor (MET) is a rare oncologic driver gene, and information on immunotherapy for non-small cell lung cancer (NSCLC) patients with this driver gene is limited. Here we evaluate the efficacy and safety of immune checkpoint inhibitors (ICI) under different therapeutic regimen for NSCLC patients with MET alterations. METHODS: From June 2019 to December 2023, we assessed the efficacy and toxicity of ICIs in 42 NSCLC patients with MET alterations. Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazards model applied for univariate and multivariate analyses. We assessed the size of target lesion according to RECIST v1.1, and objective response rate (ORR) was defined as the sum of complete response (CR) and partial response (PR), disease control rate (DCR) as the sum of CR, PR, and disease stable. RESULTS: A total of 42 NSCLC patients with MET alterations were included in this retrospective study, 10 was MET 14 skipping mutation and 32 was MET amplification. The ORR for ICI treatment was 30.95% and the DCR was 71.43%. Median progression-free survival (mPFS) and median overall survival (OS) were 4.40 and 13.97 months, respectively. There exists statistical differences between the mPFS of ICI monotherapy and combine ICI therapy (2.8 vs 7.8 months, p = 0.022). The incidence of drug-related adverse reactions was 47.62%, mainly bone marrow suppression (14.28%), immune-related pneumonia (7.14%), and liver function impairment (7.14%), and six patients (14.28%) experiencing grade 3 or above adverse events. CONCLUSION: NSCLC patients with MET alterations can benefit from immunotherapy, especially the patients treated by combined ICI therapy. However, special attention should be paid to the occurrence of grade 3/4 adverse reactions while using the combined ICI therapy.
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Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Feminino , Proteínas Proto-Oncogênicas c-met/genética , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Adulto , Intervalo Livre de Progressão , Imunoterapia/efeitos adversos , Idoso de 80 Anos ou mais , Estimativa de Kaplan-Meier , Modelos de Riscos ProporcionaisRESUMO
INTRODUCTION: the analysis of spinopelvic imbalance in patients undergoing total hip arthroplasty has gained significance in recent years, being recognized as a risk factor for instability. Few reports exist regarding the prevalence of spinopelvic alterations in Latin American literature. The aim of this study is to determine the frequency of spinopelvic imbalance in our patients and to associate them with functional outcomes. MATERIAL AND METHODS: 29 patients who underwent total hip arthroplasty using a lateral approach (32 arthroplasties) were included. All patients completed clinical outcome questionnaires preoperatively. Twelve months after surgery, they underwent anteroposterior pelvic and lateral pelvic X-rays, both standing and sitting, and clinical outcome questionnaires were completed. The radiographic parameters examined were: pelvic incidence, lumbar lordosis, sacral slope, anterior pelvic plane and pelvic femoral angle. Functional outcome was assessed with the Harris Hip Score and WOMAC scales. Patients were classified according to their spinopelvic alteration and statistical analysis was performed to identify significant differences between the groups and the correlation with functional outcomes. RESULTS: there was a high frequency of spinopelvic balance alterations (46.8%); 6.2% (n = 2/32) presented isolated spinal stiffness (group 1B), 37.5% (n = 12/29) spinal deformity without spinal stiffness (group 2A) and 3.1% (n = 1/29) spinal deformity associated with stiffness (group 2B). We found no improvement in HHS and WOMAC scores in the groups with spinal stiffness (1B and 2B) (p = 0.98 y 0.15). There is association between spinal stiffness (SS < 10°) and poor functional outcomes (p = 0.02). CONCLUSIONS: the frequency of spinopelvic balance alterations was high. While there was no observed rise in prosthetic dislocations, the existence of spinal stiffness, defined by a SS of less than 10°, was associated to poor outcomes on functional scales.
INTRODUCCIÓN: el análisis de las alteraciones del balance espinopélvico en pacientes sometidos a artroplastía total de cadera ha adquirido importancia en años recientes, siendo reconocido como un factor de riesgo para inestabilidad. Existen pocos reportes de la prevalencia de alteraciones espinopélvicas en literatura latinoamericana. El objetivo de esta investigación es determinar la frecuencia de alteraciones del balance espinopélvico en nuestros pacientes y su asociación con los resultados funcionales. MATERIAL Y MÉTODOS: se incluyeron 29 pacientes intervenidos de artroplastía total de cadera mediante abordaje lateral (32 artroplastías). Todos los pacientes completaron escalas funcionales preoperatoriamente. A los 12 meses de la intervención, se valoró el balance espinopélvico mediante radiografías anteroposterior de pelvis y laterales de pelvis tanto de pie como en sedestación y completaron escalas funcionales. Los parámetros radiográficos valorados fueron: incidencia pélvica, lordosis lumbar, inclinación del sacro (sacral slope), plano pélvico anterior y ángulo pélvico femoral. El estado funcional se valoró con las escalas Harris Hip Score (HHS) y WOMAC. Se clasificó a los pacientes de acuerdo a su alteración espinopélvica y se realizó análisis estadístico para identificar diferencias significativas entre los grupos y la asociación con resultados funcionales. RESULTADOS: encontramos una elevada frecuencia de alteraciones del balance espinopélvico (46.8%); 6.3% (n = 2/32) presentaron rigidez espinal aislada (grupo 1B), 37.5% (n = 12/29) deformidad espinal sin rigidez espinal (grupo 2A) y 3.1% (n = 1/29) deformidad espinal asociada a rigidez (grupo 2B). En los grupos con rigidez espinal (1B y 2B) no hubo mejoría significativa en HHS y WOMAC (p = 0.98 y 0.15). Encontramos asociación entre la presencia de rigidez espinal (SS < 10°) y resultados funcionales subóptimos con valor de p = 0.02. CONCLUSIONES: la frecuencia de alteraciones en el balance espinopélvico fue elevada. A pesar de no verse reflejado en un aumento en la incidencia de luxaciones protésicas, la presencia de rigidez espinal caracterizada por un SS menor a 10° se asoció con resultados subóptimos en las escalas funcionales.
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Artroplastia de Quadril , Complicações Pós-Operatórias , Humanos , Artroplastia de Quadril/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Pelve , Coluna Vertebral/cirurgiaRESUMO
Precision medicine has helped identify several tumor molecular aberrations to be treated with targeted therapies. These therapies showed substantial improvement in efficacy without excessive toxicity in patients with specific oncogenic drivers with advanced cancers. In metastatic lung cancers, the implementation of broad platforms for molecular tumor sequencing has helped oncology providers identify oncogenic drivers linked with better outcomes when treated upfront with targeted therapies. Mesenchymal-epithelial transition factor (MET) alterations are present in up to 60% of non-small cell lung cancer and are associated with a poor prognosis. Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Several agents are being developed to tackle an unmet need in patients with MET alterations. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidoresRESUMO
Cannabis is the most used illicit substance for recreational purposes around the world. However, it has become increasingly common to witness the use of approved cannabis preparations for symptoms management in various diseases. The aim of this study was to investigate the effects of cannabis nano emulsion in the liver of Wistar rats, with different proportions of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). For this, a total of 40 male Wistar rats were distributed into 5 groups, as follows (n = 8 per group): Control: G1, Experimental group (G2): treated with cannabis nano emulsion (THC and CBD) at a dose of 2.5 mg/kg, Experimental group (G3): treated with cannabis nano emulsion (THC and CBD) at a dose of 5 mg/kg, Experimental group (G4): treated with cannabis nano emulsion (CBD) at a dose of 2.5 mg/kg; Experimental group (G5): treated with cannabis nano emulsion (CBD) at a dose of 5 mg/kg. Exposure to the nano emulsion was carried out for 21 days, once a day, orally (gavage). Our results showed that cannabis nano emulsions at higher doses (5 mg/kg), regardless of the composition, induced histopathologic changes in the liver (G3 and G5) in comparison with the control group. In line with that, placental glutathione S-transferase (GST-P) positive foci increased in both G3 and G5 (p < 0.05), as well as the immune expression of Ki-67, vascular endothelial growth factor (VEGF) and p53 (p < 0.05). Also, the nano emulsion intake induced an increase in the number of micronucleated hepatocytes in G5 (p < 0.05) whereas G3 showed an increase in binucleated cells (p < 0.05). As for metanuclear alterations, karyolysis and pyknosis had an increased frequency in G3 (p < 0.05). Taken together, the results show that intake of cannabis nano emulsion may induce degenerative changes and genotoxicity in the liver in higher doses, demonstrating a clear dose-response relationship.
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Canabidiol , Cannabis , Relação Dose-Resposta a Droga , Emulsões , Fígado , Ratos Wistar , Animais , Masculino , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Canabidiol/toxicidade , Canabidiol/administração & dosagem , Cannabis/química , Dronabinol/toxicidade , Dronabinol/administração & dosagem , Ratos , Nanopartículas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/etiologiaRESUMO
BACKGROUND: Programmed death ligand-1 (PD-L1) expression is a well-known predictive biomarker of response to immune checkpoint blockade in non-small cell lung cancer (NSCLC). However, there is limited evidence of the relationship between PD-L1 expression, clinicopathological features, and their association with major driver mutations in NSCLC patients in Latin America. METHODS: This retrospective study included patients from Argentina with advanced NSCLC, and centralized evaluation of PD-L1 expression concurrently with genomic alterations in the driver genes EGFR, ALK, ROS1, BRAF, and/or KRAS G12C in FFPE tissue samples. RESULTS: A total of 10 441 patients with advanced NSCLC were analyzed. Adenocarcinoma was the most frequent histological subtype (71.1%). PD-L1 expression was categorized as PD-L1 negative (45.1%), PD-L1 positive low-expression 1%-49% (32.3%), and PD-L1 positive high-expression ≥50% (22.6%). Notably, current smokers and males were more likely to have tumors with PD-L1 tumor proportion score (TPS) ≥50% and ≥ 80% expression, respectively (p < 0.001 and p = 0.013). Tumors with non-adenocarcinoma histology had a significantly higher median PD-L1 expression (p < 0.001). Additionally, PD-L1 in distant nodes was more likely ≥50% (OR 1.60 [95% CI: 1.14-2.25, p < 0.01]). In the multivariate analysis, EGFR-positive tumors were more commonly associated with PD-L1 low expression (OR 0.62 [95% CI: 0.51-0.75], p < 0.01), while ALK-positive tumors had a significant risk of being PD-L1 positive (OR 1.81 [95% CI: 1.30-2.52], p < 0.01). CONCLUSIONS: PD-L1 expression was associated with well-defined clinicopathological and genomic features. These findings provide a comprehensive view of the expression of PD-L1 in patients with advanced NSCLC in a large Latin American cohort.
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Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Masculino , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proteínas Tirosina Quinases/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Estudos Retrospectivos , Quinase do Linfoma Anaplásico/genética , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma/genética , Mutação , Receptores ErbB/genéticaRESUMO
The COVID-19 pandemic continues to cause severe global disruption, resulting in significant excess mortality, overwhelming healthcare systems, and imposing substantial social and economic burdens on nations. While most of the attention and therapeutic efforts have concentrated on the acute phase of the disease, a notable proportion of survivors experience persistent symptoms post-infection clearance. This diverse set of symptoms, loosely categorized as long COVID, presents a potential additional public health crisis. It is estimated that 1 in 5 COVID-19 survivors exhibit clinical manifestations consistent with long COVID. Despite this prevalence, the mechanisms and pathophysiology of long COVID remain poorly understood. Alarmingly, evidence suggests that a significant proportion of cases within this clinical condition develop debilitating or disabling symptoms. Hence, urgent priority should be given to further studies on this condition to equip global public health systems for its management. This review provides an overview of available information on this emerging clinical condition, focusing on the affected individuals' epidemiology, pathophysiological mechanisms, and immunological and inflammatory profiles.
Assuntos
COVID-19 , Síndrome de COVID-19 Pós-Aguda , Humanos , Pandemias , Cinética , Infecção PersistenteRESUMO
OBJECTIVE: To evaluate the effects of magnifying the damage caused by obesity induced by monosodium glutamate, using a model of maternal periodontitis, on the structure of the anterior tibialis muscle of the offspring. MATERIALS AND METHODS: Twenty-four female Wistar rats were divided into four experimental groups: control (n = 6), obese (n = 6), control with periodontitis (n = 6) and obese with periodontitis (n = 6). At 78 days of life, the rats were mated with males without any experimental intervention. The offspring of these rats (n = 1/L), at 120 days of life, were weighed and measured, then euthanized. Plasma was collected for analysis of cytokines IL-6, IL-10, IL-17 and TNF-α. Adipose tissues were collected and weighed, and the anterior tibial muscle was designated for histomorphological analyses (n = 6/group). RESULTS: Monosodium glutamate offspring showed significant muscle changes, such as a reduction in the size of fibres and neuromuscular junctions, and an increase in the nucleus and capillaries. However, all these changes were more expressed in monosodium glutamate-obese with periodontitis offspring. CONCLUSION: This leads us to suggest a magnifying effect promoted by periodontitis to the damage already well described by monosodium glutamate-obesity, determined by low-intensity inflammation, causing greater muscle damage.
Assuntos
Músculo Esquelético , Obesidade , Periodontite , Ratos Wistar , Glutamato de Sódio , Animais , Glutamato de Sódio/efeitos adversos , Feminino , Ratos , Músculo Esquelético/patologia , Gravidez , Obesidade/complicações , Obesidade/metabolismo , Periodontite/patologia , Periodontite/metabolismo , Periodontite/complicações , Masculino , Efeitos Tardios da Exposição Pré-Natal , Fator de Necrose Tumoral alfa/metabolismo , Citocinas/metabolismoRESUMO
Polycystic ovary syndrome (PCOS) is a multifactorial disorder and obesity occurs in 38% to 88% of these women. Although hyperandrogenism may contribute to telomere lengthening, increased body mass index (BMI) is associated with telomere erosion. We sought to compare leukocyte telomere length (LTL) in PCOS women with normal, overweight, and obese BMI. We evaluated the relationship between LTL and clinical variables of PCOS and inflammatory biomarkers independent of BMI. A total of 348 women (243 PCOS and 105 non-PCOS) were evaluated for anthropometric measures, total testosterone, androstenedione, estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), free androgen index (FAI), fasting insulin and glycemia, lipid profile, homocysteine, C-reactive protein (CRP) and homeostatic model of insulin resistance (HOMA-IR). LTL was measured by qPCR. The PCOS group presented higher weight, waist circumference, BMI, testosterone, LH, fasting insulin, FAI, and HOMA-IR, and lower E2, SHBG, and fasting glycemia measures compared with the non-PCOS. When stratified by BMI, LTL was increased in all subgroups in PCOS compared to non-PCOS. However, in the PCOS group, LTL was lower in overweight (P = 0.0187) and obese (P = 0.0018) compared to normal-weight women. The generalized linear model showed that BMI, androstenedione, homocysteine, and CRP were associated with telomere biology. Women with PCOS had longer LTL, however, overweight or obesity progressively contributes to telomere shortening and may affect reproductive outcomes of PCOS, while androstenedione may increase LTL.
Assuntos
Índice de Massa Corporal , Obesidade , Síndrome do Ovário Policístico , Encurtamento do Telômero , Humanos , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , Feminino , Obesidade/genética , Obesidade/sangue , Adulto , Adulto Jovem , Resistência à Insulina , Telômero/metabolismo , Leucócitos/metabolismo , Biomarcadores/sangueRESUMO
BACKGROUND: Food-grade titanium dioxide (E171), a white colourant widely used in ultra-processed food products, has been banned in the European Union. However, its usage is still permitted in medicines, and in several other countries. The estimated intake of E171 in children is higher than in adults, which led us to hypothesise that E171 induces differential effects depending on age, with adult mice being the most susceptible due to age, despite the lower dose. AIM: To evaluate the effects of oral administration of E171 on intestinal permeability, ileum, and colon histology, and how these effects impact anxious and depressive behaviour in young and adult mice of both sexes. METHODS: Young and adult mice of both sexes C57BL/6 mice received 10 mg/kgbw E171/3 times per week for 3 months. E171 was administered orally in water by pipetting, while control groups only received drinking water, then intestinal permeability, histology and animal behaviour were analysed. RESULTS: E171 showed an amorphous shape, primary particles sized below 1 µm and anatase crystalline structure. Oral administration of E171 disrupted the intestinal permeability in adult male and female mice, but no effects were observed in young mice of both sexes. E171 promoted ileal adenoma formation in half of the adult female population, moreover hyperplastic crypts, and hyperplastic goblet cells at histological level in adult mice of both sexes. The colon presented hyperplastic goblet cells, hyperchromatic nuclei, increased proliferation and DNA damage in adult mice of both sexes. The anxiety and depressive behaviour were only altered in adult mice treated with E171, but no changes were detected in young animals of both sexes. CONCLUSIONS: Adult mice displayed higher susceptibility in all parameters analysed in this study compared to young mice of both sexes.
Assuntos
Aditivos Alimentares , Nanopartículas , Humanos , Criança , Masculino , Feminino , Animais , Camundongos , Aditivos Alimentares/química , Aditivos Alimentares/farmacologia , Camundongos Endogâmicos C57BL , Alimentos , Intestinos , Titânio/química , Nanopartículas/químicaRESUMO
INTRODUCTION: ALK tyrosine kinase inhibitors have exhibited promising activity against advanced ALK-rearranged NSCLC. However, co-occurring genetic alterations, such as CDKN2A/B or TP53, may negatively affect the efficacy of targeted therapies. METHODS: From December 2017 to December 2022, this study cohort analyzed next-generation sequencing data of 116 patients with metastatic ALK-rearranged NSCLC from five Latin American cancer centers. Clinicopathologic and molecular features were associated with clinical outcomes and risk of brain metastasis (BrM) in patients with and without concurrent somatic alterations. RESULTS: All patients (N = 116) received a second-generation ALK tyrosine kinase inhibitor, and alectinib was selected in 87.2% of cases. Coalterations occurred in 62% of the cases; the most frequent were TP53 mutations (27%) and CDKN2A/B loss (18%). The loss of CDKN2A/B was associated with an increased risk of BrM, with a cumulative incidence of 33.3% versus 7.4% in the non-coaltered subgroup. Compared with patients without coalterations, patients with concurrent CDKN2A/B loss (n = 21) had a shorter median progression-free survival (10.2 versus 34.2 mo, p < 0.001) and overall survival (26.2 versus 80.7 mo, p < 0.001). In the multivariate analysis, co-occurring CDKN2A/B loss was associated with poorer progression-free survival and OS despite the presence of other somatic coalterations, TP53 mutations, BrM, and Eastern Cooperative Oncology Group Performance Status. CONCLUSIONS: This study confirmed the worse prognostic value, which depicted co-occurring alterations in patients with ALK rearrangement. CDKN2A/B loss was substantially associated with worse outcomes and a higher risk of brain metastases. The evidence presented in our study may help select patients with ALK-positive tumors suitable for treatment escalation and closer brain follow-up.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , GenômicaRESUMO
BACKGROUND AND AIMS: Patients with obesity and type 2 diabetes (T2D) have shown alterations in the affinity of IgG anti-leptin antibodies which are possibly related to metabolic alterations. In the present exploratory study, we analyzed serum samples from adults with T2D classified by body mass index (BMI) and evaluated the relationship of IgG anti-leptin antibodies with body composition, metabolic and cardiovascular risk parameters. METHODS: Serum IgG anti-leptin antibodies (total, free and immune complexes fractions) were measured by in-house ELISA. Body composition, metabolic biomarkers (glucose, glycated hemoglobin, lipid profile, insulin, leptin) and cardiometabolic risk indexes (AIP, HOMA-IR, HOMA-ß) were evaluated in one hundred T2D patients. RESULTS: Patients with T2D and obesity presented a decrease in the percentage of IgG anti-leptin immune complexes compared to patients with T2D and overweight (p < 0.0053). Negative correlations of IgG anti-leptin immune complexes with triglycerides (TG) (r=-0.412, p = 0.023) and VLDL-C (r=-0.611, p = 0.017) were found in normal weight T2D patients. Free IgG anti-leptin antibodies correlated positively with TC (r = 0.390, p = 0.032) and LDL-C (r = 0.458, p = 0.011) in overweight individuals with T2D. Finally, total IgG anti-leptin antibodies correlated positively with leptin hormone levels (r = 0.409, p = 0.024) and negatively with HOMA-IR (r =-0.459, p = 0.012) in T2D patients with obesity. CONCLUSIONS: The decrease of IgG anti-leptin immune complexes observed in patients with T2D and obesity suggests a reduction in antibody affinity to the hormone that may impact its transport and signaling, lipid, lipoprotein and insulin metabolism.