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1.
J Appl Clin Med Phys ; 22(9): 215-226, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34406710

RESUMO

BACKGROUND AND PURPOSE: When treating lung tumors with stereotactic body radiation therapy (SBRT), patient immobilization is of outmost importance. In this study, the intra-fractional shifts of the patient (based on bony anatomy) and the tumor (based on the visible target volume) are quantified, and the associated impact on the delivered dose is estimated for a frameless immobilization approach in combination with surface guided radiation therapy (SGRT) monitoring. METHODS: Cone beam computed tomographies (CBCT) were collected in free breathing prior and after each treatment for 25 patients with lung tumors, in total 137 fractions. The CBCT collected after each treatment was registered to the CBCT collected before each treatment with focus on bony anatomy to determine the shift of the patient, and with focus on the visible target volume to determine the shift of the tumor. Rigid registrations with 6 degrees of freedom were used. The patients were positioned in frameless immobilizations with their position and respiration continuously monitored by a commercial SGRT system. The patients were breathing freely within a preset gating window during treatment delivery. The beam was automatically interrupted if isocenter shifts >4 mm or breathing amplitudes outside the gating window were detected by the SGRT system. The time between the acquisition of the CBCTs was registered for each fraction to examine correlations between treatment time and patient shift. The impact of the observed shifts on the dose to organs at risk (OAR) and the gross tumor volume (GTV) was assessed. RESULTS: The shift of the patient in the CBCTs was ≤2 mm for 132/137 fractions in the vertical (vrt) and lateral (lat) directions, and 134/137 fractions in the longitudinal (lng) direction and ≤4 mm in 134/137 (vrt) and 137/137 (lat, lng) of the fractions. The shift of the tumor was ≤2 mm in 116/137 (vrt), 123/137 (lat) and 115/137 (lng) fractions and ≤4 mm in 136/137 (vrt), 137/137 (lat), and 135/137 (lng) fractions. The maximal observed shift in the evaluated CBCT data was 4.6 mm for the patient and 7.2 mm for the tumor. Rotations were ≤3.3ᵒ for all fractions and the mean/standard deviation were 0.2/1.0ᵒ (roll), 0.1/0.8ᵒ (yaw), and 0.3/1.0ᵒ (pitch). The SGRT system interrupted the beam due to intra-fractional isocenter shifts >4 mm for 21% of the fractions, but the patients always returned within tolerance without the need of repositioning. The maximal observed isocenter shift by the SGRT system during the beam holds was 8 mm. For the respiration monitoring, the beam was interrupted at least one time for 54% of the fractions. The visual tumor was within the planned internal target volume (ITV) for 136/137 fractions in the evaluated CBCT data collected at the end of each fraction. For the fraction where the tumor was outside the ITV, the D98% for the GTV decreased with 0.4 Gy. For the OARs, the difference between planned and estimated dose from the CBCT data (D2% or Dmean ) was ≤2.6% of the prescribed PTV dose. No correlation was found between treatment time and the magnitude of the patient shift. CONCLUSIONS: Using SGRT for motion management and respiration monitoring in combination with a frameless immobilization is a feasible approach for lung SBRT.


Assuntos
Neoplasias Pulmonares , Radiocirurgia , Radioterapia Guiada por Imagem , Tomografia Computadorizada de Feixe Cônico , Humanos , Pulmão , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Movimento , Planejamento da Radioterapia Assistida por Computador
2.
Hum Mol Genet ; 30(21): 2012-2026, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34169315

RESUMO

Deoxyguanosine kinase (DGUOK) deficiency causes mtDNA depletion and mitochondrial dysfunction. We reported long survival of DGUOK knockout (Dguok-/-) mice despite low (<5%) mtDNA content in liver tissue. However, the molecular mechanisms enabling the extended survival remain unknown. Using transcriptomics, proteomics and metabolomics followed by in vitro assays, we aimed to identify the molecular pathways involved in the extended survival of the Dguok-/- mice. At the early stage, the serine synthesis and folate cycle were activated but declined later. Increased activity of the mitochondrial citric acid cycle (TCA cycle) and the urea cycle and degradation of branched chain amino acids were hallmarks of the extended lifespan in DGUOK deficiency. Furthermore, the increased synthesis of TCA cycle intermediates was supported by coordination of two pyruvate kinase genes, PKLR and PKM, indicating a central coordinating role of pyruvate kinases to support the long-term survival in mitochondrial dysfunction.

3.
Brief Bioinform ; 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971670

RESUMO

Gene-expression profiling can be used to classify human tumors into molecular subtypes or risk groups, representing potential future clinical tools for treatment prediction and prognostication. However, it is less well-known how prognostic gene signatures derived in one malignancy perform in a pan-cancer context. In this study, a gene-rule-based single sample predictor (SSP) called classifier for lung adenocarcinoma molecular subtypes (CLAMS) associated with proliferation was tested in almost 15 000 samples from 32 cancer types to classify samples into better or worse prognosis. Of the 14 malignancies that presented both CLAMS classes in sufficient numbers, survival outcomes were significantly different for breast, brain, kidney and liver cancer. Patients with samples classified as better prognosis by CLAMS were generally of lower tumor grade and disease stage, and had improved prognosis according to other type-specific classifications (e.g. PAM50 for breast cancer). In all, 99.1% of non-lung cancer cases classified as better outcome by CLAMS were comprised within the range of proliferation scores of lung adenocarcinoma cases with a predicted better prognosis by CLAMS. This finding demonstrates the potential of tuning SSPs to identify specific levels of for instance tumor proliferation or other transcriptional programs through predictor training. Together, pan-cancer studies such as this may take us one step closer to understanding how gene-expression-based SSPs act, which gene-expression programs might be important in different malignancies, and how to derive tools useful for prognostication that are efficient across organs.

4.
Commun Biol ; 4(1): 432, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785850

RESUMO

Despite being a major bacterial factor in alerting the human immune system, the role of Staphylococcus aureus (S. aureus) lipoproteins (Lpp) in skin infections remains largely unknown. Here, we demonstrated that subcutaneous injection of S. aureus Lpp led to infiltration of neutrophils and monocytes/macrophages and induced skin lesions in mice. Lipid-moiety of S. aureus Lpp and host TLR2 was responsible for such effect. Lpp-deficient S. aureus strains exhibited smaller lesion size and reduced bacterial loads than their parental strains; the altered phenotype in bacterial loads was TLR2-independent. Lpp expression in skin infections contributed to imbalanced local hemostasis toward hypercoagulable state. Depletion of leukocytes or fibrinogen abrogated the effects induced by Lpp in terms of skin lesions and bacterial burden. Our data suggest that S. aureus Lpp induce skin inflammation and promote abscess formation that protects bacteria from innate immune killing. This suggests an intriguing bacterial immune evasion mechanism.


Assuntos
Abscesso/fisiopatologia , Proteínas de Bactérias/fisiologia , Lipoproteínas/fisiologia , Infecções Estafilocócicas/fisiopatologia , Staphylococcus aureus/fisiologia , Abscesso/microbiologia , Animais , Feminino , Camundongos , Infecções Estafilocócicas/microbiologia
5.
Methods Mol Biol ; 2279: 91-107, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33683688

RESUMO

In non-small cell lung cancer (NSCLC), mutation detection and fusion gene status are treatment predictive and, hence, key factors in clinical management. Lately, alternate splicing variants of MET have gained focus as NSCLC tumors harboring a MET exon 14 skipping event have proven sensitive toward targeted therapy. Reliable methods for detection of genetic alterations in NSCLC have proven to be of increased importance. This chapter provides with hands-on experience of the NanoString gene expression platform for detection of genetic alterations in NSCLC.


Assuntos
Processamento Alternativo , Carcinoma Pulmonar de Células não Pequenas , Éxons , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-met , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-met/biossíntese , Proteínas Proto-Oncogênicas c-met/genética
6.
Int J Cancer ; 148(1): 238-251, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32745259

RESUMO

Disease recurrence in surgically treated lung adenocarcinoma (AC) remains high. New approaches for risk stratification beyond tumor stage are needed. Gene expression-based AC subtypes such as the Cancer Genome Atlas Network (TCGA) terminal-respiratory unit (TRU), proximal-inflammatory (PI) and proximal-proliferative (PP) subtypes have been associated with prognosis, but show methodological limitations for robust clinical use. We aimed to derive a platform independent single sample predictor (SSP) for molecular subtype assignment and risk stratification that could function in a clinical setting. Two-class (TRU/nonTRU=SSP2) and three-class (TRU/PP/PI=SSP3) SSPs using the AIMS algorithm were trained in 1655 ACs (n = 9659 genes) from public repositories vs TCGA centroid subtypes. Validation and survival analysis were performed in 977 patients using overall survival (OS) and distant metastasis-free survival (DMFS) as endpoints. In the validation cohort, SSP2 and SSP3 showed accuracies of 0.85 and 0.81, respectively. SSPs captured relevant biology previously associated with the TCGA subtypes and were associated with prognosis. In survival analysis, OS and DMFS for cases discordantly classified between TCGA and SSP2 favored the SSP2 classification. In resected Stage I patients, SSP2 identified TRU-cases with better OS (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18-0.49) and DMFS (TRU HR = 0.52; 95% CI = 0.33-0.83) independent of age, Stage IA/IB and gender. SSP2 was transformed into a NanoString nCounter assay and tested in 44 Stage I patients using RNA from formalin-fixed tissue, providing prognostic stratification (relapse-free interval, HR = 3.2; 95% CI = 1.2-8.8). In conclusion, gene expression-based SSPs can provide molecular subtype and independent prognostic information in early-stage lung ACs. SSPs may overcome critical limitations in the applicability of gene signatures in lung cancer.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Pulmonares/diagnóstico , Pulmão/patologia , Recidiva Local de Neoplasia/epidemiologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/cirurgia , Algoritmos , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/cirurgia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Masculino , Modelos Genéticos , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Medição de Risco/métodos , Fatores de Risco
7.
Front Psychiatry ; 11: 593533, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33304287

RESUMO

Background: Gambling disorder is known to be associated with increased risk of suicidal behavior. However, relatively little is known about how the risk of suicide attempts in gambling disorder is influenced by comorbid alcohol or drug use disorders, as well as other psychiatric conditions. Methods: The present study is a nationwide, diagnostic register study assessing the risk of suicide attempts (including fatal ones) in gambling disorder in Sweden in 2005-2016. Results: In a total of 2,099 individuals (23 percent women) with gambling disorder, 417 individuals had a suicide attempt (including 10 fatal cases of suicide) during the study period. Suicidal behavior was more common in patients with substance use disorders at any time during the study period (50 percent if both alcohol and drug use disorders were present, and 10 percent if none of these were present). In logistic regression, suicidal behavior was significantly associated with female gender (OR 2.13 [1.63-2.78]), mood disorders (OR 2.65 [2.00-3.50]), anxiety disorders (OR 1.78 [1.34-2.35]), and with alcohol (OR 1.95 [1.51-2.51]) or drug use disorders (OR 3.60 [2.76-4.69]), respectively. Conclusions: Suicidal behavior in clinical gambling disorder patients is common, but markedly more common in the presence of substance use and other comorbid disorders.

8.
Neuropsychologia ; 148: 107658, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33069792

RESUMO

Our episodic memories vary in their specificity, ranging from a mere sense of familiarity to detailed recollection of the initial experience. Recent work suggests that alpha/beta desynchronization promotes information flow through the cortex, tracking the richness in detail of recovered memory representations. At the same time, as we age, memories become less vivid and detailed, which may be reflected in age-related reductions in alpha/beta desynchronization during retrieval. To understand age differences in the specificity of episodic memories, we investigated differences in alpha/beta desynchronization between younger (18-26 years, n = 31) and older (65-76 years, n = 27) adults during item recognition and lure discrimination. Alpha/beta desynchronization increased linearly with the demand for memory specificity, i.e., the requirement to retrieve details for an accurate response, across retrieval situations (correct rejections < item recognition < lure discrimination). Stronger alpha/beta desynchronization was related to memory success, as indicated by reliable activation differences between correct and incorrect memory responses. In line with the assumption of a loss of mnemonic detail in older age, older adults had more difficulties than younger adults to discriminate lures from targets. Importantly, they also showed a reduced modulation of alpha/beta desynchronization across retrieval demands. Together, these results extend previous findings by demonstrating that alpha/beta desynchronization dissociates between item recognition and the retrieval of highly detailed memories as required in lure discrimination, and that age-related impairments in episodic retrieval are accompanied by attenuated modulations in the alpha/beta band. Thus, we provide novel findings suggesting that alpha/beta desynchronization tracks mnemonic specificity and that changes in these oscillatory mechanisms may underlie age-related declines in episodic memory.


Assuntos
Memória Episódica , Reconhecimento Psicológico , Adolescente , Adulto , Idoso , Envelhecimento , Córtex Cerebral , Humanos , Rememoração Mental , Adulto Jovem
9.
Cancers (Basel) ; 12(8)2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32707835

RESUMO

Lung cancer is the worldwide leading cause of death from cancer. Epigenetic modifications such as methylation and changes in chromatin accessibility are major gene regulatory mechanisms involved in tumorigenesis and cellular lineage commitment. We aimed to characterize these processes in the context of neuroendocrine (NE) lung cancer. Illumina 450K DNA methylation data were collected for 1407 lung cancers including 27 NE tumors. NE differentially methylated regions (NE-DMRs) were identified and correlated with gene expression data for 151 lung cancers and 31 human tissue entities from the Genotype-Tissue Expression (GTEx) consortium. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed on eight lung cancer cell lines, including three NE cell lines, to identify neuroendocrine specific gene regulatory elements. We identified DMRs with methylation patterns associated with differential gene expression and an NE tumor phenotype. DMR-associated genes could further be split into six functional modules, including one highly specific gene module for NE lung cancer showing high expression in both normal and malignant brain tissue. The regulatory potential of NE-DMRs was further validated in vitro using paired ATAC- and RNA-seq and revealed both proximal and distal regulatory elements of canonical NE-marker genes such as CHGA, NCAM1, INSM1, as well as a number of novel candidate markers of NE lung cancer. Using multilevel genomic analyses of both tumor bulk tissue and lung cancer cell lines, we identified a large catalogue of gene regulatory elements related to the NE phenotype of lung cancer.

10.
Nat Commun ; 11(1): 3747, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719340

RESUMO

Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.


Assuntos
Proteína BRCA1/genética , Mutação/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proteína BRCA1/deficiência , Estudos de Coortes , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Regiões Promotoras Genéticas , Transcrição Genética , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/terapia
11.
Aging (Albany NY) ; 12(11): 10642-10662, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32511103

RESUMO

DNA methylation changes during aging, but it remains unclear whether the effect of DNA methylation on lung cancer survival varies with age. Such an effect could decrease prediction accuracy and treatment efficacy. We performed a methylation-age interaction analysis using 1,230 early-stage lung adenocarcinoma patients from five cohorts. A Cox proportional hazards model was used to investigate lung adenocarcinoma and squamous cell carcinoma patients for methylation-age interactions, which were further confirmed in a validation phase. We identified one adenocarcinoma-specific CpG probe, cg14326354PRODH, with effects significantly modified by age (HRinteraction = 0.989; 95% CI: 0.986-0.994; P = 9.18×10-7). The effect of low methylation was reversed for young and elderly patients categorized by the boundary of 95% CI standard (HRyoung = 2.44; 95% CI: 1.26-4.72; P = 8.34×10-3; HRelderly = 0.58; 95% CI: 0.42-0.82; P = 1.67×10-3). Moreover, there was an antagonistic interaction between low cg14326354PRODH methylation and elderly age (HRinteraction = 0.21; 95% CI: 0.11-0.40; P = 2.20×10-6). In summary, low methylation of cg14326354PRODH might benefit survival of elderly lung adenocarcinoma patients, providing new insight to age-specific prediction and potential drug targeting.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Metilação de DNA , Neoplasias Pulmonares/mortalidade , Prolina Oxidase/genética , Fatores Etários , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Ilhas de CpG/genética , Epigenômica , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Medição de Risco/métodos
12.
Plast Reconstr Surg Glob Open ; 8(4): e2740, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32440410

RESUMO

Background: Ulnar nerve entrapment at the elbow (UNE) is overrepresented in patients with diabetes, but the outcome of surgery is unknown. We aimed to evaluate patient-reported outcome in patients with and without diabetes, and to assess potential sex differences and compare surgical treatment methods. Methods: Data on patients operated for UNE (2010-2016, n = 1354) from the Swedish National Registry for Hand Surgery were linked to the Swedish National Diabetes Register. Symptoms were assessed preoperatively (n = 389), and 3 (n = 283), and at 12 months postoperatively (n = 267) by QuickDASH and HQ-8 (specific hand surgery questionnaire-8 questions). Only simple decompressions were included when comparing groups. Results: Men with diabetes reported higher postoperative QuickDASH scores than men without diabetes. Women scored their disability higher than men on all time-points in QuickDASH, but showed larger improvement between preoperative and 12 months postoperative values. Patients operated with transposition scored 10.8 points higher on QuickDASH than patients who had simple decompression at 12 months (95% confidence interval 1.98-19.6). Conclusions: Women with diabetes benefit from simple decompression for UNE to the same extent as women without diabetes. Men with diabetes risk not to benefit from simple decompression as much as women do. Ulnar nerve transposition had a higher risk of residual symptoms compared to simple decompression.

13.
Sci Rep ; 10(1): 7936, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404866

RESUMO

Permanent joint dysfunction is a devastating complication in patients with septic arthritis. Staphylococcus aureus (S. aureus) lipoproteins (Lpp), the predominant ligands for TLR2, are known to be arthritogenic and induce bone destruction when introduced directly into the joint. Here, we aim to investigate the importance of S. aureus Lpp and TLR2 in a hematogenous septic arthritis model, which is the most common route of infection in humans. C57BL/6 wild-type and TLR2 deficient mice were intravenously inoculated with S. aureus Newman parental strain or its lipoprotein-deficient Δlgt mutant strain. The clinical course of septic arthritis, radiological changes, and serum levels of cytokines and chemokines, were assessed. Newman strain induced more severe and frequent clinical septic polyarthritis compared to its Δlgt mutant in TLR2 deficient mice, but not in wild-type controls. Bone destruction, however, did not differ between groups. Lpp expression was associated with higher mortality, weight loss as well as impaired bacterial clearance in mouse kidneys independent of TLR2. Furthermore, Lpp expression induced increased systemic pro-inflammatory cytokine and neutrophil chemokine release. Staphylococcal Lpp are potent virulence factors in S. aureus systemic infection independent of host TLR2 signalling. However, they have a limited impact on bone erosion in hematogenous staphylococcal septic arthritis.


Assuntos
Artrite Infecciosa/etiologia , Artrite Infecciosa/patologia , Proteínas de Bactérias/metabolismo , Hemartrose/etiologia , Hemartrose/patologia , Lipoproteínas/metabolismo , Infecções Estafilocócicas/etiologia , Infecções Estafilocócicas/patologia , Animais , Artrite Infecciosa/mortalidade , Proteínas de Bactérias/imunologia , Citocinas/biossíntese , Modelos Animais de Doenças , Suscetibilidade a Doenças , Hemartrose/mortalidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Lipoproteínas/imunologia , Camundongos , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Prognóstico , Índice de Gravidade de Doença , Infecções Estafilocócicas/mortalidade , Receptor 2 Toll-Like/deficiência
14.
Alzheimers Res Ther ; 12(1): 63, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32456694

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of Aß peptides, especially Aß42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. Aß peptides are produced by sequential proteolytic processing of APP, with ß-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inhibitors have been tested in clinical trials, but so far, all have had negative outcomes or even led to worsening of cognitive function. AD can be triggered by Aß years before the first symptoms appear and one reason for the failures could be that the clinical trials were initiated too late in the disease process. Another possible explanation could be that BACE inhibition alters physiological APP processing in a manner that impairs synaptic function, causing cognitive deterioration. METHODS: The aim of this study was to investigate if partial BACE inhibition, mimicking the putative protective effect of the Icelandic mutation in the APP gene, could reduce Aß generation without affecting synaptic transmission. To investigate this, we used an optical electrophysiology platform, in which effects of compounds on synaptic transmission in cultured neurons can be monitored. We employed this method on primary cortical rat neuronal cultures treated with three different BACE inhibitors (BACE inhibitor IV, LY2886721, and lanabecestat) and monitored Aß secretion into the cell media. RESULTS: We found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced Aß secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in Aß secretion, did not affect synaptic transmission for any of the inhibitors tested. CONCLUSION: Our results indicate that Aß production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of Aß build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide , Animais , Ácido Aspártico Endopeptidases/metabolismo , Ratos , Transmissão Sináptica
15.
Int J Mol Sci ; 21(11)2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32466567

RESUMO

Genetic up-regulation of mitochondrial 2-oxoglutarate dehydrogenase is known to increase reactive oxygen species, being detrimental for cancer cells. Thiamine diphosphate (ThDP, cocarboxylase) is an essential activator of the enzyme and inhibits p53-DNA binding in cancer cells. We hypothesize that the pleiotropic regulator ThDP may be of importance for anticancer therapies. The hypothesis is tested in the present work on lung adenocarcinoma cells A549 possessing the p53-p21 pathway as fully functional or perturbed by p21 knockdown. Molecular mechanisms of ThDP action on cellular viability and their interplay with the cisplatin and p53-p21 pathways are characterized. Despite the well-known antioxidant properties of thiamine, A549 cells exhibit decreases in their reducing power and glutathione level after incubation with 5 mM ThDP, not observed in non-cancer epithelial cells Vero. Moreover, thiamine deficiency elevates glutathione in A549 cells. Viability of the thiamine deficient A549 cells is increased at a low (0.05 mM) ThDP. However, the increase is attenuated by 5 mM ThDP, p21 knockdown, specific inhibitor of the 2-oxoglutarate dehydrogenase complex (OGDHC), or cisplatin. Cellular levels of the catalytically competent ThDP·OGDHC holoenzyme are dysregulated by p21 knockdown and correlate negatively with the A549 viability. The inverse relationship between cellular glutathione and holo-OGDHC is corroborated by their comparison in the A549 and Vero cells. The similarity, non-additivity, and p21 dependence of the dual actions of ThDP and cisplatin on A549 cells manifest a common OGDHC-mediated mechanism of the viability decrease. High ThDP saturation of OGDHC compromises the redox state of A549 cells under the control of p53-p21 axes.


Assuntos
Adenocarcinoma/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Complexo Cetoglutarato Desidrogenase/metabolismo , Neoplasias Pulmonares/metabolismo , Tiamina Pirofosfato/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Animais , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cisplatino/farmacologia , Glutationa/metabolismo , Humanos , Oxirredução , Tiamina/metabolismo , Células Vero
16.
Environ Sci Pollut Res Int ; 27(19): 24218-24230, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32306266

RESUMO

Microplastics (MP) are transported from land-based sources from rivers to marine waters. However, there is currently little knowledge about MP fate from land sources to marine waters. Traffic is estimated to be one of the largest sources of MP; hence, stormwater is expected to be an important transportation route of MP to marine waters. The aim of this study was to investigate the effect of the size and density of tyre wear particles in road run-off on their fate in the Göta River in Sweden using hydrodynamic modelling. The model of the stretch of Göta River, Sweden's largest river, passing through Gothenburg (Sweden's second largest city) and out to the sea, was set up using MIKE 3 FM software. Literature data were used to define the MP characteristics: concentrations in stormwater, prevalent particle sizes, density of MP commonly occurring in road run-off and settling velocities. Results show that higher concentrations of MP are found on the south side of the river, compared with the north side, due to higher annual average daily traffic loads along the south side of the river. The mixing processes in the river and the MP concentrations were generally influenced by the vertical water density gradient caused by saline water from the Kattegat strait. While most MP with higher density and larger size settle in the river, smaller MP with density close to 1.0 g/cm3 do not settle in the river and therefore reach the Kattegat strait and the marine environments. Further research is needed to describe the fate and transport of microplastics in the stormwater system, including treatment facilities, i.e. biofouling, aggregation, degradation and/or further fragmentation and settling.


Assuntos
Rios , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Hidrodinâmica , Microplásticos , Plásticos , Suécia
17.
Chest ; 158(2): 808-819, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32113923

RESUMO

BACKGROUND: DNA methylation and gene expression are promising biomarkers of various cancers, including non-small cell lung cancer (NSCLC). Besides the main effects of biomarkers, the progression of complex diseases is also influenced by gene-gene (G×G) interactions. RESEARCH QUESTION: Would screening the functional capacity of biomarkers on the basis of main effects or interactions, using multiomics data, improve the accuracy of cancer prognosis? STUDY DESIGN AND METHODS: Biomarker screening and model validation were used to construct and validate a prognostic prediction model. NSCLC prognosis-associated biomarkers were identified on the basis of either their main effects or interactions with two types of omics data. A prognostic score incorporating epigenetic and transcriptional biomarkers, as well as clinical information, was independently validated. RESULTS: Twenty-six pairs of biomarkers with G×G interactions and two biomarkers with main effects were significantly associated with NSCLC survival. Compared with a model using clinical information only, the accuracy of the epigenetic and transcriptional biomarker-based prognostic model, measured by area under the receiver operating characteristic curve (AUC), increased by 35.38% (95% CI, 27.09%-42.17%; P = 5.10 × 10-17) and 34.85% (95% CI, 26.33%-41.87%; P = 2.52 × 10-18) for 3- and 5-year survival, respectively, which exhibited a superior predictive ability for NSCLC survival (AUC3 year, 0.88 [95% CI, 0.83-0.93]; and AUC5 year, 0.89 [95% CI, 0.83-0.93]) in an independent Cancer Genome Atlas population. G×G interactions contributed a 65.2% and 91.3% increase in prediction accuracy for 3- and 5-year survival, respectively. INTERPRETATION: The integration of epigenetic and transcriptional biomarkers with main effects and G×G interactions significantly improves the accuracy of prognostic prediction of early-stage NSCLC survival.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Epigênese Genética , Epistasia Genética , Neoplasias Pulmonares/genética , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Metilação de DNA , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
18.
Sci Total Environ ; 700: 134382, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31698270

RESUMO

The use of contaminated biomass and waste fuels is essential for waste management, waste to energy (WtE) and mitigating carbon emissions. The contamination of heavy metals and metalloids is specially concerned by environmental regulation and waste to energy processes. In this study, comparative characterisation is performed for three typical contaminated biomass and waste fuels. i.e. recycled woods, combustible municipal solid waste, and industrial and commercial wastes. The contamination characteristics are further analysed using statistical methods (e.g. significance, correlation, profile, and principal component analyses) to identify specific contamination features, relations among the contaminants and potential contamination sources. Contamination trend is estimated based on the continuously monitoring fuel qualities, the driving forces for regulating and reduction of the contaminations, and potential changes in major contamination sources. The comparative characterisation combined with statistical analyses provides a better way to understand the contamination mechanisms. The approach can also relate the fuel contamination with the contamination sources and their changes for trend estimation. Generally, the toxic heavy metals and metalloids are expected to be significantly reduced due to stricter regulations, but there is no general trend for the reduction of other metals and metalloids because of the complicated changes in contamination sources and waste recycling streams in the near future.


Assuntos
Poluentes Ambientais/análise , Metaloides/análise , Metais Pesados/análise , Biomassa , Monitoramento Ambiental , Resíduos Sólidos/análise , Gerenciamento de Resíduos , Madeira/química
19.
Mol Oncol ; 14(11): 2759-2774, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33448640

RESUMO

Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 × 10-5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407TRIM27 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking (37.49LUAD vs 54.79LUSC, P = 1.03 × 10-19) and included a higher proportion of current smokers than LUAD patients (28.24%LUAD vs 34.09%LUSC, P = 0.037). cg05293407TRIM27 was significantly associated with overall survival only in NSCLC patients with medium-high pack-year of smoking (HR = 1.58, 95% CI: 1.26-1.96, P = 5.25 × 10-5). We conclude that cg05293407TRIM27 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Nucleares/genética , Fumar/genética , Idoso , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Proteínas Nucleares/metabolismo , Análise de Sobrevida
20.
Biotechnol Biofuels ; 12: 259, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31700542

RESUMO

Background: Waste lipids are attractive substrates for co-digestion with primary and activated sewage sludge (PASS) to improve biogas production at wastewater treatment plants. However, slow conversion rates of long-chain fatty acids (LCFA), produced during anaerobic digestion (AD), limit the applicability of waste lipids as co-substrates for PASS. Previous observations indicate that the sulfide level in PASS digesters affects the capacity of microbial communities to convert LCFA to biogas. This study assessed the microbial community response to LCFA loads in relation to sulfide level during AD of PASS by investigating process performance and microbial community dynamics upon addition of oleate (C18:1) and stearate (C18:0) to PASS digesters at ambient and elevated sulfide levels. Results: Conversion of LCFA to biogas was limited (30% of theoretical biogas potential) during continuous co-digestion with PASS, which resulted in further LCFA accumulation. However, the accumulated LCFA were converted to biogas (up to 66% of theoretical biogas potential) during subsequent batch-mode digestion, performed without additional substrate load. Elevated sulfide level stimulated oleate (but not stearate) conversion to acetate, but oleate and sulfide imposed a synergistic limiting effect on acetoclastic methanogenesis and biogas formation. Next-generation sequencing of 16S rRNA gene amplicons of bacteria and archaea showed that differences in sulfide level and LCFA type resulted in microbial community alterations with distinctly different patterns. Taxonomic profiling of the sequencing data revealed that the phylum Cloacimonetes is likely a key group during LCFA degradation in PASS digesters, where different members take part in degradation of saturated and unsaturated LCFA; genus W5 (family Cloacimonadaceae) and family W27 (order Cloacimonadales), respectively. In addition, LCFA-degrading Syntrophomonas, which is commonly present in lipid-fed digesters, increased in relative abundance after addition of oleate at elevated sulfide level, but not without sulfide or after stearate addition. Stearate conversion to biogas was instead associated with increasing abundance of hydrogen-producing Smithella and hydrogenotrophic Methanobacterium. Conclusions: Long-chain fatty acid chain saturation and sulfide level are selective drivers for establishment of LCFA-degrading microbial communities in municipal sludge digesters.

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