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1.
Clin Genet ; 103(6): 704-708, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36861389

RESUMO

Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to nonsense mediated decay (NMD). Treating the fibroblasts with an NMD inhibitor, cycloheximide, greatly improved the detection of the pseudoexon-containing transcript. Family members with the FBN1 variant had later onset aortic events and fewer MFS systemic features than typical for individuals with haploinsufficiency of FBN1. Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies.


Assuntos
Doenças da Aorta , Síndrome de Marfan , Humanos , Síndrome de Marfan/genética , Fibrilina-1/genética , Mutação , Fenótipo
2.
Sensors (Basel) ; 22(15)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35957287

RESUMO

COVID-19, the illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus belonging to the Coronaviridade family, a single-strand positive-sense RNA genome, has been spreading around the world and has been declared a pandemic by the World Health Organization. On 17 January 2022, there were more than 329 million cases, with more than 5.5 million deaths. Although COVID-19 has a low mortality rate, its high capacities for contamination, spread, and mutation worry the authorities, especially after the emergence of the Omicron variant, which has a high transmission capacity and can more easily contaminate even vaccinated people. Such outbreaks require elucidation of the taxonomic classification and origin of the virus (SARS-CoV-2) from the genomic sequence for strategic planning, containment, and treatment of the disease. Thus, this work proposes a high-accuracy technique to classify viruses and other organisms from a genome sequence using a deep learning convolutional neural network (CNN). Unlike the other literature, the proposed approach does not limit the length of the genome sequence. The results show that the novel proposal accurately distinguishes SARS-CoV-2 from the sequences of other viruses. The results were obtained from 1557 instances of SARS-CoV-2 from the National Center for Biotechnology Information (NCBI) and 14,684 different viruses from the Virus-Host DB. As a CNN has several changeable parameters, the tests were performed with forty-eight different architectures; the best of these had an accuracy of 91.94 ± 2.62% in classifying viruses into their realms correctly, in addition to 100% accuracy in classifying SARS-CoV-2 into its respective realm, Riboviria. For the subsequent classifications (family, genera, and subgenus), this accuracy increased, which shows that the proposed architecture may be viable in the classification of the virus that causes COVID-19.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Redes Neurais de Computação , Pandemias , SARS-CoV-2/genética
3.
Carcinogenesis ; 41(11): 1529-1542, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-32603404

RESUMO

K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. The absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-κB)-driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB-driven immunosuppressive response, and reduced anti-tumor cytotoxicity, whereas estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Transformação Celular Neoplásica/imunologia , Estrogênios/metabolismo , Imunomodulação , Neoplasias Pulmonares/imunologia , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Imunidade/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Mutação , NF-kappa B/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas
4.
Glob Chang Biol ; 26(1): 274-286, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31642554

RESUMO

Energy from biomass plays a large and growing role in the global energy system. Energy from biomass can make significant contributions to reducing carbon emissions, especially from difficult-to-decarbonize sectors like aviation, heavy transport, and manufacturing. But land-intensive bioenergy often entails substantial carbon emissions from land-use change as well as production, harvesting, and transportation. In addition, land-intensive bioenergy scales only with the utilization of vast amounts of land, a resource that is fundamentally limited in supply. Because of the land constraint, the intrinsically low yields of energy per unit of land area, and rapid technological progress in competing technologies, land intensive bioenergy makes the most sense as a transitional element of the global energy mix, playing an important role over the next few decades and then fading, probably after mid-century. Managing an effective trajectory for land-intensive bioenergy will require an unusual mix of policies and incentives that encourage appropriate utilization in the short term but minimize lock-in in the longer term.


Assuntos
Biocombustíveis , Carbono , Biomassa
5.
Dig Dis Sci ; 65(8): 2379-2387, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31758431

RESUMO

BACKGROUND: Abdominal pain and opioid analgesic use are common in Crohn's disease (CD). AIMS: We sought to identify factors associated with abdominal pain in CD and evaluate the impact of opioid analgesics on pain and quality-of-life scores in this setting. METHODS: We performed a longitudinal cohort study using a prospective, consented IBD natural history registry from a single academic center between 2009 and 2013. Consecutive CD patients were followed for at least 1 year after an index visit. Data were abstracted regarding pain experience (from validated surveys), inflammatory activity (using endoscopic/histologic findings), laboratory studies, coexistent psychiatric disorders, medical therapy, opioid analgesic, and tobacco use. RESULTS: Of 542 CD patients (56.6% women), 232 (42.8%) described abdominal pain. Individuals with pain were more likely to undergo surgery and were more frequently prescribed analgesics and/or antidepressants/anxiolytics. Elevated ESR (OR 1.79; 95%CI 1.11-2.87), coexistent anxiety/depression (OR 1.87; 95%CI 1.13-3.09), smoking (OR 2.08; 95%CI 1.27-3.40), and opioid use (OR 2.46; 95%CI 1.33-4.57) were independently associated with abdominal pain. Eighty patients (14.8%) were prescribed opioids, while 31 began taking them at or after the index visit. Patients started on opioids demonstrated no improvement in abdominal pain or quality-of-life scores on follow-up compared to patients not taking opioids. CONCLUSIONS: Abdominal pain is common in CD and is associated with significant opioid analgesic utilization and increased incidence of anxiety/depression, smoking, and elevated inflammatory markers. Importantly, opioid use in CD was not associated with improvement in pain or quality-of-life scores. These findings reinforce the limitations of currently available analgesics in IBD and support exploration of alternative therapies.


Assuntos
Dor Abdominal/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Doença de Crohn/complicações , Sistema de Registros , Dor Abdominal/epidemiologia , Dor Abdominal/etiologia , Adulto , Doença de Crohn/psicologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pennsylvania/epidemiologia , Qualidade de Vida
6.
Public Health Nutr ; 22(6): 988-996, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30755286

RESUMO

OBJECTIVE: To assess the reliability and validity of body weight (BW) and body image (BI) perception reported by parents (in children) and by adolescents in a South American population. DESIGN: Cross-sectional study. BW perception was evaluated by the question, 'Do you think you/your child are/is: severely wasted, wasted, normal weight, overweight, obese?' BI perception was evaluated using the Gardner scale. To evaluate reliability, BW and BI perceptions were reported twice, two weeks apart. To evaluate validity, the BW and BI perceptions were compared with WHO BMI Z-scores. Kappa and Kendall's tau-c coefficients were obtained. SETTING: Public and private schools and high schools from six countries of South America (Argentina, Peru, Colombia, Uruguay, Chile, Brazil).ParticipantsChildren aged 3-10 years (n 635) and adolescents aged 11-17 years (n 400). RESULTS: Reliability of BW perception was fair in children's parents (κ=0·337) and substantial in adolescents (κ=0·709). Validity of BW perception was slight in children's parents (κ=0·176) and fair in adolescents (κ=0·268). When evaluating BI, most children were perceived by parents as having lower weight. Reliability of BI perception was slight in children's parents (κ=0·124) and moderate in adolescents (κ=0·599). Validity of BI perception was poor in children's parents (κ=-0·018) and slight in adolescents (κ=0·023). CONCLUSIONS: Reliability of BW and BI perceptions was higher in adolescents than in children's parents. Validity of BW perception was good among the parents of the children and adolescents with underweight and normal weight.


Assuntos
Atitude Frente a Saúde , Imagem Corporal/psicologia , Peso Corporal , Sobrepeso/psicologia , Inquéritos e Questionários/estatística & dados numéricos , Magreza/psicologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pais/psicologia , Reprodutibilidade dos Testes , América do Sul
7.
Ann Oncol ; 29(2): 472-483, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29244072

RESUMO

Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies and might also be associated with prognosis after CRC diagnosis. However, current evidence on smoking in association with CRC prognosis is limited. Patients and methods: For this individual patient data meta-analysis, sociodemographic and smoking behavior information of 12 414 incident CRC patients (median age at diagnosis: 64.3 years), recruited within 14 prospective cohort studies among previously cancer-free adults, was collected at baseline and harmonized across studies. Vital status and causes of death were collected for a mean follow-up time of 5.1 years following cancer diagnosis. Associations of smoking behavior with overall and CRC-specific survival were evaluated using Cox regression and standard meta-analysis methodology. Results: A total of 5229 participants died, 3194 from CRC. Cox regression revealed significant associations between former [hazard ratio (HR) = 1.12; 95 % confidence interval (CI) = 1.04-1.20] and current smoking (HR = 1.29; 95% CI = 1.04-1.60) and poorer overall survival compared with never smoking. Compared with current smoking, smoking cessation was associated with improved overall (HR<10 years = 0.78; 95% CI = 0.69-0.88; HR≥10 years = 0.78; 95% CI = 0.63-0.97) and CRC-specific survival (HR≥10 years = 0.76; 95% CI = 0.67-0.85). Conclusion: In this large meta-analysis including primary data of incident CRC patients from 14 prospective cohort studies on the association between smoking and CRC prognosis, former and current smoking were associated with poorer CRC prognosis compared with never smoking. Smoking cessation was associated with improved survival when compared with current smokers. Future studies should further quantify the benefits of nonsmoking, both for cancer prevention and for improving survival among CRC patients, in particular also in terms of treatment response.


Assuntos
Neoplasias Colorretais/mortalidade , Fumar/efeitos adversos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Abandono do Hábito de Fumar
8.
Pediatr Cardiol ; 38(4): 734-745, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28214967

RESUMO

Surgeries to correct congenital heart diseases are increasing in Brazil and worldwide. However, even with the advances in surgical techniques and perfusion, some cases, especially the more complex ones, can develop heart failure and death. A retrospective study of patients who underwent surgery for correction of congenital heart diseases with cardiopulmonary bypass (CPB) in a university tertiary-care hospital that died, showed infarction in different stages of evolution and scattered microcalcifications in the myocardium, even without coronary obstruction. CPB is a process routinely used during cardiac surgery for congenital heart disease. However, CPB has been related to increased endogenous catecholamines that can lead to major injuries in cardiomyocytes. The mechanisms involved are not completely understood. The aim of this study was to evaluate the alterations induced in the ß-adrenergic receptors and GRK-2 present in atrial cardiomyocytes of infants with congenital heart disease undergoing surgical repair with CPB and correlate the alterations with functional and biochemical markers of ischemia/myocardial injury. The study consisted of right atrial biopsies of infants undergoing surgical correction in HC-FMRPUSP. Thirty-three cases were selected. Atrial biopsies were obtained at the beginning of CPB (group G1) and at the end of CPB (group G2). Real-time PCR, Western blotting, and immunofluorescence analysis were conducted to evaluate the expression of ß1, ß2-adrenergic receptors, and GRK-2 in atrial myocardium. Cardiac function was evaluated by echocardiography and biochemical analysis (N-terminal pro-brain natriuretic peptide (NT-ProBNP), lactate, and cardiac troponin I). We observed an increase in serum lactate, NT-proBNP, and troponin I at the end of CPB indicating tissue hypoxia/ischemia. Even without major clinical consequences in cardiac function, these alterations were followed by a significant increase in gene expression of ß1 and ß2 receptors and GRK-2, suggesting that this is one of the mechanisms responsible for the exacerbated response of cardiomyocytes to circulating catecholamines. These alterations could explain the irreversible myocardial damage and lipid peroxidation of membranes classically attributed to catecholamine excess, observed in some infants who develop heart failure and postoperative death. Although other factors may be involved, this study confirms that CPB acts as a potent inducer of increased gene expression of ß- adrenergic receptors and GRK-2, making the myocardium of these infants more susceptible to the effects of circulating endogenous catecholamines, which may contribute to the development of irreversible myocardial damage and death.


Assuntos
Ponte Cardiopulmonar/efeitos adversos , Quinase 2 de Receptor Acoplado a Proteína G/genética , Átrios do Coração/metabolismo , Cardiopatias Congênitas/cirurgia , Insuficiência Cardíaca/genética , Receptores Adrenérgicos beta/genética , Biomarcadores/análise , Biópsia , Catecolaminas/metabolismo , Feminino , Quinase 2 de Receptor Acoplado a Proteína G/análise , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Expressão Gênica , Átrios do Coração/química , Átrios do Coração/patologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Receptores Adrenérgicos beta/análise , Receptores Adrenérgicos beta/metabolismo , Estudos Retrospectivos
9.
Transpl Infect Dis ; 17(5): 737-43, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26224318

RESUMO

Necrotizing pulmonary aspergillosis and Aspergillus device infection are rare and have potentially fatal complications after left ventricular assist device (LVAD) implantation. To date, few cases of patients surviving Aspergillus device infection have been published, with survival reported only after device removal. We present a patient implanted with an LVAD in whom necrotizing pulmonary aspergillosis with device involvement was successfully treated by segmentectomy and prolonged antifungal treatment without device exchange or removal. Similar cases in the literature were searched for and are discussed in view of the severity of this complication.


Assuntos
Coração Auxiliar/efeitos adversos , Infecções Relacionadas à Prótese/diagnóstico , Aspergilose Pulmonar/diagnóstico , Adulto , Humanos , Masculino
10.
Pediatr Cardiol ; 36(8): 1657-61, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26036352

RESUMO

The objective of this paper was to describe the outcomes in patients submitted to arterial switch operation and to analyze the predictors of in-hospital mortality and further need of re-operation at a single-center institution. Between September 1995 and January 2014, 128 consecutive arterial switch operations were performed. Surgical mortality during this period was analyzed retrospectively, and a follow-up analysis of the survivors was conducted. Surgical era, cardiopulmonary bypass time (p = 0.001), and diagnosis category (p = 0.025) influenced in-hospital mortality. The estimated overall survival for the 91 hospital survivors was 96.8, 96.4, and 96.2 % at 5, 10, and 15 years, respectively. The median follow-up time was 67 months (range 0.71-222 months). Three patients (5 %) presented severe aortic regurgitation. Right ventricle outflow tract systolic gradient by echocardiography was above 60 mmHg in 2 %. Late re-interventions occurred in 12 (13 %) patients with mean time of 64 ± 34 months after the initial procedure. Actuarial freedom from re-interventions at 5, 10, and 15 years was 96.4, 69.7, and 61.9 %, respectively. Arterial switch operation remains the procedure of choice in patients with transposition of great arteries. It can be performed even in middle-volume institutions, leading to the same middle- and long-term outcomes of high-volume institutions. Early high mortality rate may occur due not only to learning curve, but also to cardiopulmonary bypass time and ventricular septal defect closure.


Assuntos
Insuficiência da Valva Aórtica/cirurgia , Transposição das Grandes Artérias/estatística & dados numéricos , Comunicação Interventricular/cirurgia , Transposição dos Grandes Vasos/mortalidade , Transposição dos Grandes Vasos/cirurgia , Brasil , Criança , Pré-Escolar , Ecocardiografia , Feminino , Seguimentos , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Complicações Pós-Operatórias/diagnóstico , Reoperação/mortalidade , Estudos Retrospectivos
11.
Ann Oncol ; 25(8): 1517-25, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24692581

RESUMO

Smoking is a risk factor for colorectal cancer (CRC) incidence and mortality. However, little is known on smoking and its association with survival after CRC diagnosis. We conducted a systematic review and meta-analysis to summarize current evidence. A systematic literature search was carried out in MEDLINE and ISI Web of Science. We included studies that analyzed recurrence-free survival, disease-free survival, all-cause, and CRC-specific mortality according to smoking status. Data were extracted in duplicate. Standard methods of meta-analysis were applied. Sixteen studies from 11 countries were identified, comprising a total sample size of 62 278 CRC patients. Overall, in the 16 included studies, current smoking and, to a lesser extent, former smoking were rather consistently associated with a poorer prognosis compared with never smokers. Meta-analyses yielded random-effects hazard ratio estimates (95% confidence intervals) for all-cause mortality of 1.26 (1.15-1.37) and 1.11 (0.93-1.33) for current and former smokers, compared with never smokers, respectively. In particular, 30-day mortality was found to be increased by between 49% and 100% among current compared with never smokers. Our results support the existence of detrimental effects of smoking on survival also after CRC diagnosis. Perspectives for enhancing prognosis of CRC patients by smoking abstinence deserve increased attention in further research and clinical practice.


Assuntos
Neoplasias Colorretais/mortalidade , Fumar/epidemiologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/diagnóstico , Feminino , Humanos , Masculino , Prognóstico , Fatores de Risco , Fumar/mortalidade , Abandono do Hábito de Fumar/estatística & dados numéricos
13.
Vision Res ; 205: 108184, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36720191

RESUMO

As an 'early alerting' sense, one of the primary tasks for the human visual system is to recognize distant objects. In the specific context of facial identification, this ecologically important task has received surprisingly little attention. Most studies have investigated facial recognition at short, fixed distances. Under these conditions, the photometric and configural information related to the eyes, nose and mouth are typically found to be primary determinants of facial identity. Here we characterize face recognition performance as a function of viewing distance and investigate whether the primacy of the internal features continues to hold across increasing viewing distances. We find that exploring the distance dimension reveals a qualitatively different salience distribution across a face. Observers' recognition performance significantly exceeds that obtained with the internal facial physiognomy, and also exceeds the computed union of performances with internal and external features alone, suggesting that in addition to the mutual configuration of the eyes, nose and mouth, it is the relationships between these features and external head contours that are crucial for recognition. We have also conducted computational studies with convolutional neural networks trained on the task of face recognition to examine whether this representational bias could emerge spontaneously through exposure to faces. The results provide partial support for this possibility while also highlighting important differences between the human and artificial system. These findings have implications for the nature of facial representations useful for a visual system, whether human or machine, for recognition over large and varying distances.


Assuntos
Face , Reconhecimento Facial , Humanos , Olho , Reconhecimento Psicológico , Redes Neurais de Computação , Reconhecimento Visual de Modelos
14.
Artigo em Inglês | MEDLINE | ID: mdl-36833604

RESUMO

During medical training, students are exposed to stressors that deteriorate mental health. This study determined depression and anxiety prevalence and their associated factors in students from four medical schools in northern Peru. A cross-sectional study was conducted among medical students from Lambayeque, Peru. The Goldberg Anxiety and Zung Depression tests were applied. The dependent variables were depression and anxiety, and their association with covariates (age, sex, type of university, socioeconomic level, experience, family problem, and physical activity) was evaluated. Prevalence ratios were calculated using generalized linear models. Of 482 students, the prevalence of anxiety was 61.8% and depression was 22.0%. A severe level of anxiety was observed in 6.2% in the group between 16 and 20 years old. It was observed that private university students had higher frequencies of having depression (PR = 2.01) and anxiety (PR = 1.35); males had a lower risk of anxiety (PR = 0.82), but higher risk of depression compared to females (PR = 1.45). Performing physical activity decreased the prevalence of depression (PR = 0.53); however, it increased the frequency of anxiety (PR = 1.26). Having family problems increased the prevalence of anxiety (PR = 1.26). Medical students from private universities experienced higher rates of depression and anxiety. Depression and anxiety were associated with gender and physical activity. These findings highlight the importance of mental health promotion due to its link with quality of life and academic performance.


Assuntos
Estudantes de Medicina , Masculino , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Estudantes de Medicina/psicologia , Peru , Prevalência , Estudos Transversais , Depressão/epidemiologia , Qualidade de Vida , Ansiedade/epidemiologia , Universidades
15.
Front Immunol ; 14: 1118721, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37283745

RESUMO

Introduction: Toll-like receptors (TLRs) are an extensive group of proteins involved in host defense processes that express themselves upon the increased production of endogenous damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) due to the constant contact that airway epithelium may have with pathogenic foreign antigens. We have previously shown that COPD-like airway inflammation induced by exposure to an aerosolized lysate of nontypeable Haemophilus influenzae (NTHi) promotes tumorigenesis in a K-ras mutant mouse model of lung cancer, CCSPCre/LSL-K-rasG12D (CC-LR) mouse. Methods: In the present study, we have dissected the role of TLRs in this process by knocking out TLR2, 4, and 9 and analyzing how these deletions affect the promoting effect of COPD-like airway inflammation on K-ras-driven lung adenocarcinoma. Results: We found that knockout of TLR 2, 4, or 9 results in a lower tumor burden, reduced angiogenesis, and tumor cell proliferation, accompanied by increased tumor cell apoptosis and reprogramming of the tumor microenvironment to one that is antitumorigenic. Additionally, knocking out of downstream signaling pathways, MyD88/NF-κB in the airway epithelial cells further recapitulated this initial finding. Discussion: Our study expands the current knowledge of the roles that TLR signaling plays in lung cancer, which we hope, can pave the way for more reliable and efficacious prevention and treatment modalities for lung cancer.


Assuntos
Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Camundongos , Animais , NF-kappa B/metabolismo , Receptor 2 Toll-Like/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Neoplasias Pulmonares/patologia , Inflamação/complicações , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Receptores Toll-Like/metabolismo , Epitélio/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Microambiente Tumoral
16.
J Chem Phys ; 137(12): 124502, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-23020338

RESUMO

First principles molecular dynamics simulations have been carried out at various temperatures and pressures starting with either Ca(2+) or CaO in a reactive volume of 63 H(2)O molecules. In the case of aqueous Ca(2+), the ion is surrounded by six H(2)O molecules in the first hydration shell at 300 K/0.3 GPa, with rare exchange between first and second hydrations shells. At 900 K/0.9 GPa, the coordination number in the first hydration shell fluctuates between six and eight, the average being 7.0. CaO immediately reacts with the surrounding H(2)O molecules to form Ca(2+) + 2OH(-). The hydroxyl ions form transient Ca(OH)(+) and Ca(OH)(2) complexes and have a mean residence time in the first coordination shell of Ca(2+) of 6 ± 4 ps at 500 K and 3 ± 3 ps at 900 K, respectively. At 500 K/0.5 GPa, the time-averaged relative concentrations of the transient Ca(2+), Ca(OH)(+), and Ca(OH)(2) species are 14%, 55%, and 29%, while at 900 K/0.9 GPa, they are 2%, 34%, and 63%.


Assuntos
Cálcio/química , Simulação de Dinâmica Molecular , Temperatura , Concentração de Íons de Hidrogênio , Hidróxidos/química , Pressão , Solubilidade , Água/química
17.
Proc Natl Acad Sci U S A ; 106(5): 1305-12, 2009 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-19179280

RESUMO

The Millennium Ecosystem Assessment (MA) introduced a new framework for analyzing social-ecological systems that has had wide influence in the policy and scientific communities. Studies after the MA are taking up new challenges in the basic science needed to assess, project, and manage flows of ecosystem services and effects on human well-being. Yet, our ability to draw general conclusions remains limited by focus on discipline-bound sectors of the full social-ecological system. At the same time, some polices and practices intended to improve ecosystem services and human well-being are based on untested assumptions and sparse information. The people who are affected and those who provide resources are increasingly asking for evidence that interventions improve ecosystem services and human well-being. New research is needed that considers the full ensemble of processes and feedbacks, for a range of biophysical and social systems, to better understand and manage the dynamics of the relationship between humans and the ecosystems on which they rely. Such research will expand the capacity to address fundamental questions about complex social-ecological systems while evaluating assumptions of policies and practices intended to advance human well-being through improved ecosystem services.


Assuntos
Ecossistema , Meio Ambiente , Conservação dos Recursos Naturais , Humanos , Modelos Teóricos , Probabilidade , Especificidade da Espécie
19.
J Comp Pathol ; 193: 9-19, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35487623

RESUMO

Cutaneous hyperkeratosis is one of the many clinicopathological manifestations of canine distemper and is characterized by thickening and hardening of the skin, predominantly in nasodigital areas. Although this lesion may rarely affect other regions, this has been poorly characterized. Twelve dogs with canine distemper and cutaneous hyperkeratosis, necropsied at an anatomical pathology service, were investigated. Twenty-two cutaneous hyperkeratotic foci were observed on footpads (11/22), nasal planum (3/22), haired skin on the snout (2/22), periocular region (2/22), ventral abdomen (2/22), scrotum (1/22) and vulva (1/22). The dogs had one (5/12), two (4/12) or three (3/12) regions concomitantly affected. Orthokeratotic hyperkeratosis was a predominant histopathological feature in 17 dogs, occasionally accompanied by other lesions, including inclusion bodies (14/17), epidermal hyperplasia (9/17) and keratinocyte hydropic degeneration (6/17). Canine distemper virus antigen was expressed in at least one skin lesion in 10 dogs. Fourteen (14/17) hyperkeratotic foci were immunopositive while three (3/17) were immunonegative. Viral antigen expression was most common in the sweat glands (13/17), epidermis (11/17) and vascular endothelial cells or pericytes (8/17). Histological findings and antigen detection were similar among nasodigital and other regions. We emphasize the importance of clinicopathological recognition of these lesions for the initial suspicion of canine distemper, thereby facilitating early treatment.


Assuntos
Vírus da Cinomose Canina , Cinomose , Doenças do Cão , Dermatopatias , Animais , Antígenos Virais , Doenças do Cão/patologia , Cães , Células Endoteliais/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Dermatopatias/veterinária
20.
JCI Insight ; 7(11)2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35471938

RESUMO

K-ras-mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1ß, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1ß in the lungs of mice with K-rasG12D-mutant tumors (CC-LR mice). Here, we blocked IL-1ß using an anti-IL-1ß mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1ß blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1ß blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.


Assuntos
Adenocarcinoma de Pulmão , Anticorpos Monoclonais Humanizados , Interleucina-1beta , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Citocinas/biossíntese , Citocinas/imunologia , Genes ras , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Camundongos , Terapia de Alvo Molecular , Mutação , Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente Tumoral
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