Relation between smoking history and gene expression profiles in lung adenocarcinomas

Background: Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers' lung carcinomas remain to a large extent unclear. Methods: Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets. Results: Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking. Conclusions: Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history

Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy

BACKGROUND: Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. t(15;19), has been recognized as a distinct clinical entity for over a decade. This tumor affects young individuals, shows a rapidly fatal clinical course despite intensive therapy. The t(15;19) results in the fusion oncogene BRD4-NUT. Information concerning treatment of this rare disorder is scarce. CASE PRESENTATION: A 30-year-old woman was admitted with a rapidly progressing tumor in the mediastinum, cervical lymph nodes, vertebral column and the epidural space. Pathological, cytogenetic, FISH and PCR analysis revealed a glycogenated carcinoma rarely expressing cytokeratins and showing t(15;19) and BRD4-NUT gene rearrangement. The patient was initially treated with a Ewing sarcoma chemotherapy regimen, but had rapid progression after two cycles. She then received docetaxel and radiotherapy, which resulted in almost complete disappearance of the tumor. CONCLUSION: Docetaxel may be considered for initial chemotherapy in young patients presenting with a midline carcinoma with bone marrow involvement and cytogenetic and molecular genetic finding of a t(15;19)/BRD4-NUT-rearrangement. We herein describe, in detail, the laboratory methods by which the BRD4-NUT -rearrangement can be detected

Biden e o fim do comércio livre

Este Brief analisa os mais recentes documentos estratégicos divulgados a nível oficial pelos EUA,designadamente nas implicações para a estratégia global americana e seus aliados. Para o efeito, publicamos as reflexões de alguns assessores do IDN e conhecidos especialistas nacionais.info:eu-repo/semantics/publishedVersio

Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice

Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain-of-activity mouse model presents with a premature aging-like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75-week-old) female C57BL/6 mice with a Cdc42 activity-specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan. Moreover, aged CASIN-treated animals displayed a youthful level of the aging-associated cytokines IL-1β, IL-1α, and INFγ in serum and a significantly younger epigenetic clock as based on DNA methylation levels in blood cells. Overall, our data show that systemic administration of CASIN to reduce Cdc42 activity in aged mice extends murine lifespan

Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs

SummaryWhether aged hematopoietic stem and progenitor cells (HSPCs) have impaired DNA damage repair is controversial. Using a combination of DNA mutation indicator assays, we observe a 2- to 3-fold increase in the number of DNA mutations in the hematopoietic system upon aging. Young and aged hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) do not show an increase in mutation upon irradiation-induced DNA damage repair, and young and aged HSPCs respond very similarly to DNA damage with respect to cell-cycle checkpoint activation and apoptosis. Both young and aged HSPCs show impaired activation of the DNA-damage-induced G1-S checkpoint. Induction of chronic DNA double-strand breaks by zinc-finger nucleases suggests that HSPCs undergo apoptosis rather than faulty repair. These data reveal a protective mechanism in both the young and aged hematopoietic system against accumulation of mutations in response to DNA damage

Respiratory chain complex III deficiency due to mutated BCS1L : a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model

Background: Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide. Results: A case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient's platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency. Conclusions: We describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations.Peer reviewe

Depressão em idosos de uma instituição de longa permanência

Objective: to determine the prevalence of depression in elderly residents of a Long Stay Institution for Aged. Method: this is a descriptive study transverse, of quantitative approach. The population consisted of 48 subjects. To assess the mental state was used Mini Mental State Examination and collection of data to the Geriatric Depression Scale (GDS-15). Were ethical principles contained in Resolution 196/96 of the National Health. Results: results showed that 25% of the elderly showed no signs of depression, 43.75% showed signs of depression, mild/moderate and 31.25% showed signs of severe depression. The prevalence of depression was higher in women (55.5%) than men (44.5%). Conclusion: high levels of depression in the sample report identified the need for psychological support planning can provide a better quality of life for residents in institution studied as well as warn of similar prevalence in the general ILPIsObjetivo: determinar la prevalencia de depresión en los ancianos residentes de una institución a largo plazo para los Ancianos (ILPI). Metodología: se realizó un estudio descriptivo, transverso, de enfoque cuantitativo. La población estuvo conformada por 48 sujetos. Para evaluar el estado mental se utilizó Mini Mental State Examination y la depresión con la Escala de Depresión Geriátrica (GDS-15). Resultados: los resultados mostraron que el 25% de los ancianos no mostró signos de depresión, 43,75% mostraron señales de depresión, leve/moderada y 31,25% mostraron signos de la depresión severa. La prevalencia de depresión fue mayor en mujeres (55,5%) que hombres (44,5%). Conclusión: los niveles altos de depresión en el informe de la muestra identificó la necesidad de planificar el apoyo psicológico puede proporcionar una mejor calidad de vida de los residentes en la institución estudiada, así como advertir de prevalencia similares en los ILPI generales.Objetivo: determinar a prevalência de depressão em idosos residentes em uma Instituição de Longa Permanência para Idosos (ILPI). Metodologia: trata-se de um estudo descritivo de abordagem quantitativa. A amostra foi constituída de 48 sujeitos. Para a avaliação do estado mental foi aplicado o Mini Mental State Examination e para a depressão a Escala de Depressão Geriátrica (EDG-15). Foram seguidos os princípios éticos da Resolução 196/96 do Conselho Nacional da Saúde. Resultados: os resultados demonstraram que 25% dos idosos não apresentaram sinais de depressão; 43,75% apresentaram sinais de depressão leve/moderada e 31,25% apresentaram sinais de depressão severa. A prevalência de depressão foi maior em mulheres (55,5%) do que em homens (44,5%). Conclusão: os altos níveis de depressão identificados na amostra reportam para a necessidade de planejamento de apoio psicológico capaz de proporcionar melhor qualidade de vida aos residentes na ILPI estudada, como também alertam para semelhante prevalência nas ILPIs em geral

Factor's that impact on women's decision-making around prenatal genomic tests: An international discrete choice survey

OBJECTIVE: We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. METHODS: Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. RESULTS: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. CONCLUSION: Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable

Zeitenwende : a mudança na política de defesa da Alemanha

A Guerra na Ucrânia constitui um colossal desafio à ordem de segurança europeia. Preparado enquanto decorrem as operações militares, este número especial do IDN Brief reúne um conjunto de especialistas que avaliam as consequências da guerra para a Europa e para a relação transatlântica.info:eu-repo/semantics/publishedVersio