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1.
Sci Rep ; 11(1): 13805, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226613

RESUMO

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.

2.
Mol Pharm ; 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34296616

RESUMO

Halogenation can be utilized for the purposes of labeling and molecular imaging, providing a means to, e.g., follow drug distribution in an organism through positron emission tomography (PET) or study the molecular recognition events unfolding by nuclear magnetic resonance (NMR) spectroscopy. For cancer therapeutics, where often highly toxic substances are employed, it is of importance to be able to track the distribution of the drugs and their metabolites in order to ensure minimal side effects. Labeling should ideally have a negligible disruptive effect on the efficacy of a given drug. Using a combination of NMR spectroscopy and cytotoxicity assays, we identify a site susceptible to halogenation in monomethyl auristatin F (MMAF), a widely used cytotoxic agent in the antibody-drug conjugate (ADC) family of cancer drugs, and study the effects of fluorination and chlorination on the physiological solution structure of the auristatins and their cytotoxicity. We find that the cytotoxicity of the parent drug is retained, while the conformational equilibrium is shifted significantly toward the biologically active trans isomer, simultaneously decreasing the concentration of the inactive and potentially disruptive cis isomer by up to 50%. Our results may serve as a base for the future assembly of a multifunctional toolkit for the assessment of linker technologies and exploring bystander effects from the warhead perspective in auristatin-derived ADCs.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34099463

RESUMO

INTRODUCTION: Exercise is emerging as a therapy in oncology for its physical and psychosocial benefits and potential effects on chemotherapy tolerability and efficacy. However, evidence from randomised controlled trials (RCTs) supporting exercise in patients with borderline resectable or locally advanced pancreatic cancer (PanCa) undergoing neoadjuvant therapy (NAT) are lacking. METHODS AND ANALYSIS: The EXPAN trial is a dual-centre, two-armed, phase I RCT. Forty patients with borderline resectable or locally advanced PanCa undergoing NAT will be randomised equally to an exercise intervention group (individualised exercise+standard NAT) or a usual care control group (standard NAT). The exercise intervention will be supervised and consist of moderate to vigorous intensity resistance and aerobic-based training undertaken two times a week for 45-60 min per session for a maximum period of 6 months. The primary outcome is feasibility. Secondary outcomes are patient-related and treatment-related endpoints, objectively measured physical function, body composition, psychological health and quality of life. Assessments will be conducted at baseline, prior to potential alteration of treatment (~4 months postbaseline), at completion of the intervention (maximum 6 months postbaseline) and 3-month and 6-month postintervention (maximum 9 and 12 months postbaseline). ETHICS AND DISSEMINATION: The EXPAN trial has been approved by Edith Cowan University (reference no.: 2020-02011-LUO), Sir Charles Gairdner Hospital (reference no.: RGS 03956) and St John of God Subiaco Hospital (reference no.: 1726). The study results will be presented at national/international conferences and submitted for publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12620001081909.

4.
PLoS Genet ; 17(3): e1009254, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33667223

RESUMO

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

5.
Neuropsychologia ; 154: 107776, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33549585

RESUMO

Resolving interference between overlapping memories is crucial to remember the past. This study tests the novel prediction that orienting search focus benefits goal-relevant retrieval by reducing competition from unwanted memories. In a modified retrieval-practice paradigm, participants encoded word-pairs in one of two encoding tasks. Critically, to evaluate whether this retrieval orientation (RO) reduces memory interference, target and competitor memories were always related to different encoding tasks. At retrieval, instructions were provided for half of the blocks with the intention to bias remembering towards items encoded with one of the ROs. Behavioural data show that adopting an RO improved target accessibility, strengthened the testing effect, and reduced retrieval-induced forgetting (RIF) of competitors. Specifically, RIF - typically attributed to inhibitory control of memory interference - was prominent when no retrieval orientation (NRO) instruction was provided. Furthermore, a neural correlate of RO was calculated by training a linear discriminant analysis (LDA) to discriminate the electroencephalographic (EEG) spatial brain patterns correspondent to the two ROs over the time course of selective retrieval. RO was characterised by increases in the theta and decreases in the beta frequency band, evident both before and after category-cue onset. While the pre-cue RO reinstatement effect predicted both immediate retrieval-practice success and later target accessibility, the post-cue effect predicted disengagement of inhibitory control, such that participants showing a stronger RO reinstatement effect showed lower levels of RIF. These data suggest that strategically orienting search focus during retrieval both increases target memory accessibility and reduces memory interference, which consequently protects related memories from inhibition and later forgetting. Furthermore, they also highlight the roles of theta and beta oscillations in establishing and maintaining a task-relevant bias towards target memory representations during competitive memory retrieval.


Assuntos
Memória , Rememoração Mental , Encéfalo , Eletroencefalografia , Humanos , Inibição Psicológica
6.
Cancer Res ; 81(13): 3738-3748, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33574093

RESUMO

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/ß-catenin pathway. Overall, this study identifies lung cancer-related dysregulation of CDCP1 expression years before diagnosis. SIGNIFICANCE: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms.See related commentary by Itzstein et al., p. 3441.

7.
Mol Pharm ; 18(1): 285-304, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33390018

RESUMO

Boron neutron capture therapy (BNCT) is a noninvasive binary therapeutic modality applicable to the treatment of cancers. While BNCT offers a tumor-targeting selectivity that is difficult to match by other means, the last obstacles preventing the full harness of this potential come in the form of the suboptimal boron delivery strategies presently used in the clinics. To address these challenges, we have developed delivery agents that target the glucose transporter GLUT1. Here, we present the chemical synthesis of a number of ortho-carboranylmethyl-substituted glucoconjugates and the biological assessment of all positional isomers. Altogether, the study provides protocols for the synthesis and structural characterization of such glucoconjugates and insights into their essential properties, for example, cytotoxicity, GLUT1-affinity, metabolism, and boron delivery capacity. In addition to solidifying the biochemical foundations of a successful GLUT1-targeting approach to BNCT, we identify the most promising modification sites in d-glucose, which are critical in order to further develop this strategy toward clinical use.

8.
Int J Cancer ; 148(5): 1077-1086, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32914876

RESUMO

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.

9.
Front Med ; 15(2): 275-291, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32889700

RESUMO

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Heterogeneidade Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único
10.
J Sleep Res ; 30(3): e13128, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32557911

RESUMO

It has been proposed that sleep readies the brain for novel learning, and previous work has shown that sleep loss impairs the ability to encode new memories. In the present study, we examined if a daytime nap would increase mnemonic discrimination (MD) performance. MD is the ability to differentiate between memories that are similar but not identical. Participants performed the Mnemonic Similarity Task (MST) twice, once in the morning and once in the afternoon. The goal of this task is to distinguish stimuli that have been seen before from novel stimuli that are similar but not identical. After the morning MST, participants were randomly allocated into either a sleep or a wake group. The sleep group had a 2-hr nap opportunity, whereas the wake group spent a similar amount of time passively resting. All participants then performed a second MST in the afternoon with a novel set of images. Results did not show any support for increased MD ability after a nap. There was, however, a correlation showing that an increase in sleepiness between sessions predicted a decrease in MD performance. Future work must systematically examine how strong sleep manipulations that are needed for sleep to have an effect on encoding ability, as well as which kind of memory tasks that are sensitive to sleep manipulations. More knowledge about the relationship between sleep and the ability to differentiate similar memories from each other is important because impaired MD ability has previously been reported in various groups in which sleep disturbances are also common.

11.
Genet Epidemiol ; 45(1): 99-114, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32924180

RESUMO

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

12.
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
13.
J Phys Chem C Nanomater Interfaces ; 124(44): 24441-24450, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33193943

RESUMO

Spontaneous growth of complexes consisted of a number of individual nanoparticles in a controlled manner, particularly in demanding environments of gas-phase synthesis, is a fascinating opportunity for numerous potential applications. Here, we report the formation of such core-satellite gold nanoparticle structures grown by magnetron sputtering inert gas condensation. Combining high-resolution scanning transmission electron microscopy and computational simulations, we reveal the adhesive and screening role of H2O molecules in formation of stable complexes consisted of one nanoparticle surrounded by smaller satellites. A single layer of H2O molecules, condensed between large and small gold nanoparticles, stabilizes positioning of nanoparticles with respect to one another during milliseconds of the synthesis time. The lack of isolated small gold nanoparticles on the substrate is explained by Brownian motion that is significantly broader for small-size particles. It is inferred that H2O as an admixture in the inert gas condensation opens up possibilities of controlling the final configuration of the different noble metal nanoparticles.

14.
Mol Pharm ; 17(10): 3885-3899, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32787269

RESUMO

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.

15.
Sci Rep ; 10(1): 12603, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724158

RESUMO

Memory allows us to draw on past experiences to inform behaviour in the present. However, memories rarely match the situation at hand exactly, and new situations regularly trigger multiple related memories where only some are relevant to act upon. The flexibility of human memory systems is largely attributed to the ability to disregard irrelevant, but salient, memories in favour of relevant ones. This is considered an expression of an executive function responsible for suppressing irrelevant memories, associated with the prefrontal cortex. It is unclear to what extent animals have access to this ability. Here, we demonstrate, in a series of tool-use tasks designed to evoke conflicting memories, that chimpanzees and an orangutan suffer from this conflict but overcome it in favour of a more relevant memory. Such mnemonic flexibility is among the most advanced expressions of executive function shown in animals to date and might explain several behaviours related to tool-use, innovation, planning and more.


Assuntos
Memória/fisiologia , Rememoração Mental/fisiologia , Pan troglodytes/fisiologia , Pongo/fisiologia , Animais , Feminino , Masculino , Percepção/fisiologia , Fatores de Tempo
16.
Acta Neurochir (Wien) ; 162(12): 3043-3053, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32666378

RESUMO

PURPOSE: This study evaluates the application of a microdialysis technique for interstitial chemotherapy using cisplatin in high-grade glioma. METHOD: An in vitro study demonstrated that cisplatin can be administered through retrograde microdialysis and defined the recovery for cisplatin. In a subsequent phase I study, 1-4 microdialysis catheters were implanted in tumor tissue, brain adjacent to tumor (BAT) tissue, and subcutaneous tissue in 10 patients with recurrent high-grade glioma. Cisplatin was administered continuously in daily doses between 0.3 and 3.9 mg for 4 to12 days. Microdialysis samples were continuously collected and analyzed for glucose metabolites, glutamate, glycerol, and cisplatin concentrations. Treatment tolerability was evaluated through clinical monitoring. Quality of life was assessed using the EORTC-QLQ-C30 questionnaire for up to 3 months after treatment. RESULTS: This in vitro study showed that cisplatin could be administrated with a recovery of 41-97%, depending on flowrate, type of catheter, and cisplatin concentration. During the treatment, patients were exposed to a total dose of 1.2-36.8 mg cisplatin. The concentration of cisplatin in BAT, serum, and subcutaneous tissue was close to detection level in all but two patients. A transient neurologic deterioration due to edema was commonly observed, but no systemic side effects were recorded. After onset of treatment, concentrations of glutamate and glycerol were significantly increased in tumor tissue but not in BAT, with a peak after 3 days, and consistent for the rest of the treatment. Five of the patients survived between 153 and 492 days after treatment. CONCLUSION: This phase I study demonstrates that retrograde microdialysis can be used to administer cisplatin interstitially into high-grade glioma tissue. A high cytotoxicity was detected in tumor tissue, but not in the surrounding brain. Retrograde microdialysis appears to be a clinically useful method for intratumoral drug administration in high-grade glioma.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Cisplatino/uso terapêutico , Glioma/tratamento farmacológico , Microdiálise/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Cisplatino/administração & dosagem , Feminino , Glioma/patologia , Glucose/metabolismo , Ácido Glutâmico/metabolismo , Glicerol/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Qualidade de Vida , Resultado do Tratamento
17.
Neurobiol Learn Mem ; 173: 107268, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32534019

RESUMO

Episodic memories are formed by hippocampal binding of the "what" and "where" features of everyday events. The hippocampus minimizes interference between related similar episodic memories by pattern separation. Stress and psychopathology are associated with lowered pattern separation. While current behavioral paradigms typically use correct rejections of single object or context lures rather than composite stimuli, it is not known if object and context pattern separation differentially associate with mental health. We reasoned that an object-in-context paradigm would be more sensitive to mental health state than current implementations, given increased task demands. We found that non-clinical depression and anxiety symptom severity were associated with reduced lure rejection for both object and context and that only the object domain was associated with a concomitant increase in lure overgeneralization. Therefore, we argue that reduced lure rejection and increased overgeneralization must not be conflated. Although our object-in-context paradigm was not more sensitive to variation in mental health, we show that lure rejection and overgeneralization rate in one domain (e.g. object) was affected by the status of the other domain (e.g. context target versus lure). Finally, as several metrics of pattern separation exist in the literature, we evaluated the association of different metrics with mental health.

18.
Cancer Epidemiol Biomarkers Prev ; 29(7): 1423-1429, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32277007

RESUMO

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.

19.
J Neurosci ; 40(11): 2343-2356, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32019830

RESUMO

Goal-directed behavior can benefit from proactive adjustments of cognitive control that occur in anticipation of forthcoming cognitive control demands (CCD). Predictions of forthcoming CCD are thought to depend on learning and memory in two ways: First, through direct experience, associative encoding may link previously experienced CCD to its triggering item, such that subsequent encounters with the item serve to cue retrieval of (i.e., predict) the associated CCD. Second, in the absence of direct experience, pattern completion and mnemonic integration mechanisms may allow CCD to be generalized from its associated item to other items related in memory. While extant behavioral evidence documents both types of CCD prediction, the neurocognitive mechanisms giving rise to these predictions remain largely unexplored. Here, we tested two hypotheses: (1) memory-guided predictions about CCD precede control adjustments due to the actual CCD required; and (2) generalization of CCD can be accomplished through integration mechanisms that link partially overlapping CCD-item and item-item associations in memory. Supporting these hypotheses, the temporal dynamics of theta and alpha power in human electroencephalography data (n = 43, 26 females) revealed that an associative CCD effect emerges earlier than interaction effects involving actual CCD. Furthermore, generalization of CCD from one item (X) to another item (Y) was predicted by a decrease in alpha power following the presentation of the X-Y pair. These findings advance understanding of the mechanisms underlying memory-guided adjustments of cognitive control.SIGNIFICANCE STATEMENT Cognitive control adaptively regulates information processing to align with task goals. Experience-based expectations enable adjustments of control, leading to improved performance when expectations match the actual control demand required. Using EEG, we demonstrate that memory for past cognitive control demand proactively guides the allocation of cognitive control, preceding adjustments of control triggered by the demands of the present environment. Furthermore, we demonstrate that learned cognitive control demands can be generalized through mnemonic integration processes, enabling the spread of expectations about cognitive control demands to items associated in memory. We reveal that this generalization is linked to decreased alpha oscillation in medial frontal channels. Collectively, these findings provide new insights into how memory-control interactions facilitate goal-directed behavior.


Assuntos
Aprendizagem por Associação/fisiologia , Cognição/fisiologia , Memória/fisiologia , Adaptação Psicológica , Adolescente , Adulto , Ritmo alfa/fisiologia , Mapeamento Encefálico , Sinais (Psicologia) , Eletroencefalografia , Feminino , Objetivos , Humanos , Masculino , Desempenho Psicomotor/fisiologia , Tempo de Reação , Teste de Stroop , Ritmo Teta/fisiologia , Fatores de Tempo , Adulto Jovem
20.
Sci Rep ; 10(1): 317, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924804

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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