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1.
J Med Chem ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33017535

RESUMO

Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have improved affinity, are able to bind to extended protein surfaces, and otherwise have favorable properties. Macrocyclization of a known binder may stabilize its bioactive conformation and improve its metabolic stability, cell permeability, and in certain cases oral bioavailability. Herein, we present implementation and application of an approach that automatically generates, evaluates, and proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the three-dimensional (3D) conformation of the linear molecule in complex with a target protein as the starting point, this approach identifies attachment points, generates linkers, evaluates their geometric compatibility, and ranks the resulting molecules with respect to their predicted conformational stability and interactions with the target protein. As we show here with prospective and retrospective case studies, this procedure can be applied for the macrocyclization of small molecules and peptides and even PROteolysis TArgeting Chimeras (PROTACs) and proteins.

2.
Sci Rep ; 10(1): 16758, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028880

RESUMO

Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [68Ga]Ga-DO3A-Tuna-2 and [68Ga]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 ± 14.4% (SD) in N = 5 patients and a GLP1R occupancy of 49.9 ± 13.3%. Fasting Plasma Glucose levels (- 3.30 ± 1.14 mmol/L) and body weight (- 3.87 ± 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.

3.
Nat Commun ; 11(1): 5104, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037214

RESUMO

Many intestinal pathogens, including Clostridioides difficile, use mucus-derived sugars as crucial nutrients in the gut. Commensals that compete with pathogens for such nutrients are therefore ecological gatekeepers in healthy guts, and are attractive candidates for therapeutic interventions. Nevertheless, there is a poor understanding of which commensals use mucin-derived sugars in situ as well as their potential to impede pathogen colonization. Here, we identify mouse gut commensals that utilize mucus-derived monosaccharides within complex communities using single-cell stable isotope probing, Raman-activated cell sorting and mini-metagenomics. Sequencing of cell-sorted fractions reveals members of the underexplored family Muribaculaceae as major mucin monosaccharide foragers, followed by members of Lachnospiraceae, Rikenellaceae, and Bacteroidaceae families. Using this information, we assembled a five-member consortium of sialic acid and N-acetylglucosamine utilizers that impedes C. difficile's access to these mucosal sugars and impairs pathogen colonization in antibiotic-treated mice. Our findings underscore the value of targeted approaches to identify organisms utilizing key nutrients and to rationally design effective probiotic mixtures.

4.
Water Res ; 186: 116372, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916620

RESUMO

Ammonia-oxidizing bacteria (AOB) of the betaproteobacterial genera Nitrosomonas and Nitrosospira are key nitrifying microorganisms in many natural and engineered ecosystems. Since many AOB remain uncultured, fluorescence in situ hybridization (FISH) with rRNA-targeted oligonucleotide probes has been one of the most widely used approaches to study the community composition, abundance, and other features of AOB directly in environmental samples. However, the established and widely used AOB-specific 16S rRNA-targeted FISH probes were designed up to two decades ago, based on much smaller rRNA gene sequence datasets than available today. Several of these probes cover their target AOB lineages incompletely and suffer from a weak target specificity, which causes cross-hybridization of probes that should detect different AOB lineages. Here, a set of new highly specific 16S rRNA-targeted oligonucleotide probes was developed and experimentally evaluated that complements the existing probes and enables the specific detection and differentiation of the known, major phylogenetic clusters of betaproteobacterial AOB. The new probes were successfully applied to visualize and quantify AOB in activated sludge and biofilm samples from seven pilot- and full-scale wastewater treatment systems. Based on its improved target group coverage and specificity, the refined probe set will facilitate future in situ analyses of AOB.

5.
Sci Rep ; 10(1): 15319, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948795

RESUMO

Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury. Whether these species exert anti-arrhythmic effects in the acute phase of myocardial ischemia has not been investigated so far. Herein, we demonstrate that pretreatment of mice with 9- and 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA) significantly reduced the susceptibility to develop acute ventricular tachycardia (VT). Accordingly, epicardial mapping revealed a markedly enhanced homogeneity in ventricular conduction. NO2-OA treatment of isolated cardiomyocytes lowered the number of spontaneous contractions upon adrenergic isoproterenol stimulation and nearly abolished ryanodine receptor type 2 (RyR2)-dependent sarcoplasmic Ca2+ leak. NO2-OA also significantly reduced RyR2-phosphorylation by inhibition of increased CaMKII activity. Thus, NO2-OA might be a novel pharmacological option for the prevention of VT development.

6.
JAMA Oncol ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32910151

RESUMO

Importance: Anthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes. Objective: To evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas. Design, Setting, and Participants: This nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma. Interventions: Two dose levels of doxorubicin (45 and 75 mg/m2) were tested for safety in combination with pembrolizumab. Main Outcomes and Measures: Objective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines. Results: A total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank P = .03). No dose-limiting toxic effects were observed. Conclusions and Relevance: In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Trial Registration: ClinicalTrials.gov Identifier: NCT02888665.

7.
ISME J ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879458

RESUMO

Stable isotope probing (SIP) is a key tool for identifying the microorganisms catalyzing the turnover of specific substrates in the environment and to quantify their relative contributions to biogeochemical processes. However, SIP-based studies are subject to the uncertainties posed by cross-feeding, where microorganisms release isotopically labeled products, which are then used by other microorganisms, instead of incorporating the added tracer directly. Here, we introduce a SIP approach that has the potential to strongly reduce cross-feeding in complex microbial communities. In this approach, the microbial cells are exposed on a membrane filter to a continuous flow of medium containing isotopically labeled substrate. Thereby, metabolites and degradation products are constantly removed, preventing consumption of these secondary substrates. A nanoSIMS-based proof-of-concept experiment using nitrifiers in activated sludge and 13C-bicarbonate as an activity tracer showed that Flow-SIP significantly reduces cross-feeding and thus allows distinguishing primary consumers from other members of microbial food webs.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32819031

RESUMO

OBJECTIVES: Previous studies have observed protective effects of high mental demands at work on cognitive functioning and dementia risk. However, it is unclear what types of demands drive this effect and whether this effect is subject to a person's genetic risk. We investigated to what extent eight different types of mental demands at work together with the APOE e4 allele, a major risk gene for late-onset Alzheimer's disease, affect cognitive functioning in late life. METHODS/DESIGN: The population-based German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe, n = 2 154) followed cognitively healthy individuals aged 75 years and older in seven assessment waves. Cognitive functioning was assessed via the mini-mental status examination. RESULTS: Mixed-effects modeling (adjusted for education, gender, marital status, stroke, depression, and diabetes) indicated that participants who had an occupational history of working in jobs with high compared to low demands in "Language & Knowledge", "Pattern detection", "Information processing", and "Service" had a slower cognitive decline. APOE e4-allele carriers had an accelerated cognitive decline, but this decline was significantly smaller if they had a medium compared to a low level of demands in contrast to non-carriers. CONCLUSIONS: Our longitudinal observations suggest that cognitive decline could be slowed by an intellectually enriched lifestyle even in risk gene carriers. Fostering intellectual engagement throughout the life-course could be a key prevention initiative to promote better cognitive health in old age.

10.
Water Res ; 185: 116182, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32763530

RESUMO

Biofilm activities and their interactions with physical, chemical and biological processes are of great importance for a variety of ecosystem functions, impacting hydrogeomorphology, water quality and aquatic ecosystem health. Effective management of water bodies requires advancing our understanding of how flow influences biofilm-bound sediment and ecosystem processes and vice-versa. However, research on this triangle of flow-biofilm-sediment is still at its infancy. In this Review, we summarize the current state of the art and methodological approaches in the flow-biofilm-sediment research with an emphasis on biostabilization and fine sediment dynamics mainly in the benthic zone of lotic and lentic environments. Example studies of this three-way interaction across a range of spatial scales from cell (nm - µm) to patch scale (mm - dm) are highlighted in view of the urgent need for interdisciplinary approaches. As a contribution to the review, we combine a literature survey with results of a pilot experiment that was conducted in the framework of a joint workshop to explore the feasibility of asking interdisciplinary questions. Further, within this workshop various observation and measuring approaches were tested and the quality of the achieved results was evaluated individually and in combination. Accordingly, the paper concludes by highlighting the following research challenges to be considered within the forthcoming years in the triangle of flow-biofilm-sediment: i) Establish a collaborative work among hydraulic and sedimentation engineers as well as ecologists to study mutual goals with appropriate methods. Perform realistic experimental studies to test hypotheses on flow-biofilm-sediment interactions as well as structural and mechanical characteristics of the bed. ii) Consider spatially varying characteristics of flow at the sediment-water interface. Utilize combinations of microsensors and non-intrusive optical methods, such as particle image velocimetry and laser scanner to elucidate the mechanism behind biofilm growth as well as mass and momentum flux exchanges between biofilm and water. Use molecular approaches (DNA, pigments, staining, microscopy) for sophisticated community analyses. Link varying flow regimes to microbial communities (and processes) and fine sediment properties to explore the role of key microbial players and functions in enhancing sediment stability (biostabilization). iii) Link laboratory-scale observations to larger scales relevant for management of water bodies. Conduct field experiments to better understand the complex effects of variable flow and sediment regimes on biostabilization. Employ scalable and informative observation techniques (e.g., hyperspectral imaging, particle tracking) that can support predictions on the functional aspects, such as metabolic activity, bed stability, nutrient fluxes under variable regimes of flow-biofilm-sediment.

11.
Qual Life Res ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32851600

RESUMO

PURPOSE: To describe health status and health state utilities measured by the EQ-5D-3L in a population-based sample of individuals aged 85 + in Germany, and to analyze associations with basic socio-demographic variables. METHODS: Cross-sectional data from follow-up wave 7 (n = 761) of the German AgeCoDe Study were used. The EQ-5D-3L questionnaire was used to record problems in five health dimensions, its visual analogue scale (EQ VAS) was used to record self-rated health status, and the German EQ-5D-3L index was used to derive health state utilities. RESULTS: Mean age of respondents was 88.9 years (SD 2.9; range 85 to 100), 67.4% were female. 81.9% reported problems in at least one of the EQ-5D dimensions, with 15.3% reporting extreme problems. Most frequent were problems with pain/discomfort (64.8%), followed by mobility (62.5%), usual activities (42.6%), self-care (28.2%), and anxiety/depression (20.5%). Mean EQ VAS score was 62.4 (SD 18.8), and mean EQ-5D index was 0.77 (SD 0.24). Multiple regression analysis showed associations of problem frequency in various EQ-5D dimensions with age, gender, living situation, marital status, and education. The EQ VAS score was negatively associated with age (ß = - 0.56; p < 0.05) and female gender (ß = - 3.49; p < 0.05). The EQ-5D index was negatively associated with not living in the community (ß = - 0.10; p < 0.001) and being single (ß = - 0.09; p < 0.05). CONCLUSIONS: The results show a substantially impaired health status of the oldest-old population. The data can be used for comparing health status of population groups as well as for health economic models.

12.
Europace ; 2020 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-32830233

RESUMO

AIMS: Atrial fibrillation (AF) and heart failure (HF) often coexist. Catheter ablation has been reported to restore left ventricular (LV) function but patients benefit differently. This study investigated the correlation between left atrial (LA) fibrosis extent and LV ejection fraction (LVEF) recovery after AF ablation. METHODS AND RESULTS: In this study, 103 patients [64 years, 69% men, 79% persistent AF, LVEF 33% interquartile range (IQR) (25-38)] undergoing first time AF ablation were investigated. Identification of LA fibrosis and selection of ablation strategy were based on sinus rhythm voltage mapping. Continuous rhythm monitoring was used to assess ablation success. Improvement in post-ablation LVEF was measured as primary study endpoint. An absolute increase in post-ablation LVEF ≥10% was defined as 'Super Response'. Left atrial fibrosis was present in 38% of patients. After ablation LVEF increased by absolute 15% (IQR 6-25) (P < 0.001). Left ventricular ejection fraction improvement was higher in patients without LA fibrosis [15% (IQR 10-25) vs. 10% (IQR 0-20), P < 0.001]. An inverse correlation between LVEF improvement and the extent of LA fibrosis was found (R2 = 0.931). In multivariate analysis, the presence of LA fibrosis was the only independent predictor for failing LVEF improvement [odds ratio 7.2 (95% confidence interval 2.2-23.4), P < 0.001]. Echocardiographic 'Super Response' was observed in 55/64 (86%) patients without and 21/39 (54%) patients with LA fibrosis, respectively (P < 0.001). CONCLUSION: Presence and extent of LA fibrosis predict LVEF response in HF patients undergoing AF ablation. The assessment of LA fibrosis may impact prognostic stratification and clinical management in HF patients with AF.

13.
ISME J ; 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770119

RESUMO

Nitrification is a fundamental process in terrestrial nitrogen cycling. However, detailed information on how climate change affects the structure of nitrifier communities is lacking, specifically from experiments in which multiple climate change factors are manipulated simultaneously. Consequently, our ability to predict how soil nitrogen (N) cycling will change in a future climate is limited. We conducted a field experiment in a managed grassland and simultaneously tested the effects of elevated atmospheric CO2, temperature, and drought on the abundance of active ammonia-oxidizing bacteria (AOB) and archaea (AOA), comammox (CMX) Nitrospira, and nitrite-oxidizing bacteria (NOB), and on gross mineralization and nitrification rates. We found that N transformation processes, as well as gene and transcript abundances, and nitrifier community composition were remarkably resistant to individual and interactive effects of elevated CO2 and temperature. During drought however, process rates were increased or at least maintained. At the same time, the abundance of active AOB increased probably due to higher NH4+ availability. Both, AOA and comammox Nitrospira decreased in response to drought and the active community composition of AOA and NOB was also significantly affected. In summary, our findings suggest that warming and elevated CO2 have only minor effects on nitrifier communities and soil biogeochemical variables in managed grasslands, whereas drought favors AOB and increases nitrification rates. This highlights the overriding importance of drought as a global change driver impacting on soil microbial community structure and its consequences for N cycling.

15.
Basic Res Cardiol ; 115(5): 53, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32748289

RESUMO

In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H2O2 by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H2O2 elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in skeletal muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control H2O2 emission in cardiac mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H2O2 emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases H2O2 emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting H2O2-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H2O2 emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H2O2-eliminating capacity increases H2O2 emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H2O2 emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for H2O2 elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32856598

RESUMO

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMCS) is a rare tumor that typically has an indolent course but high rate of recurrence. We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess factors associated with metastasis, treatment, and survival. METHODS: We queried the SEER 1973-2016 database for patients with myxoid chondrosarcoma (ICD-O-3: 9231/3). Kaplan-Meier analyses and Cox proportional hazard models assessed effects on overall survival (OS) of demographics and clinical characteristics. Logistic regression assessed associations between tumor location and distant disease. Primary analysis was a complete case analysis; multiple imputation (MI) was used in a sensitivity analysis. RESULTS: Locoregional disease (LRD) was found in 373 (85%) of patients. In univariate analysis with LRD, surgery correlated with superior OS [HR = 0.27; 95% confidence interval (CI), 0.16-0.47]; chemotherapy and radiotherapy associated with inferior OS (HR = 1.90; 95% CI, 1.11-3.27 and HR = 1.45; 95% CI, 1.03-2.06, respectively). No treatment modality associated with OS in the adjusted, complete case model. In the adjusted sensitivity analysis, surgery associated with superior outcomes (HR = 0.36; 95% CI, 0.19-0.69). There was no OS difference by primary tumor site. 10-year OS with distant disease was 10% (95% CI, 2%-25%). CONCLUSIONS: Surgery in LRD associated with improved OS in univariate analysis and adjusted models correcting for missing data. There was no OS benefit with chemotherapy or radiotherapy. IMPACT: This represents the largest report of EMCS with long-term follow-up. Despite the reputedly indolent nature of EMCS, outcomes with metastatic disease are poor. We provide OS benchmarks and guidance for stratification in future prospective trials.

17.
ISME J ; 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709974

RESUMO

Nitrite-oxidizing bacteria of the genus Nitrospira are key players of the biogeochemical nitrogen cycle. However, little is known about their occurrence and survival strategies in extreme pH environments. Here, we report on the discovery of physiologically versatile, haloalkalitolerant Nitrospira that drive nitrite oxidation at exceptionally high pH. Nitrospira distribution, diversity, and ecophysiology were studied in hypo- and subsaline (1.3-12.8 g salt/l), highly alkaline (pH 8.9-10.3) lakes by amplicon sequencing, metagenomics, and cultivation-based approaches. Surprisingly, not only were Nitrospira populations detected, but they were also considerably diverse with presence of members from  Nitrospira lineages I, II and IV. Furthermore, the ability of Nitrospira enrichment cultures to oxidize nitrite at neutral to highly alkaline pH of 10.5 was demonstrated. Metagenomic analysis of a newly enriched Nitrospira lineage IV species, "Candidatus Nitrospira alkalitolerans", revealed numerous adaptive features of this organism to its extreme environment. Among them were a sodium-dependent N-type ATPase and NADH:quinone oxidoreductase next to the proton-driven forms usually found in Nitrospira. Other functions aid in pH and cation homeostasis and osmotic stress defense. "Ca. Nitrospira alkalitolerans" also possesses group 2a and 3b [NiFe] hydrogenases, suggesting it can use hydrogen as alternative energy source. These results reveal how Nitrospira cope with strongly fluctuating pH and salinity conditions and expand our knowledge of nitrogen cycling in extreme habitats.

18.
ISME J ; 14(9): 2366, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32651453

RESUMO

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

19.
Neurology ; 95(9): e1134-e1143, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32636322

RESUMO

OBJECTIVE: To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with CSF biomarkers of Alzheimer disease (AD). METHOD: We analyzed data from n = 449 cognitively normal participants (n = 209 healthy controls, n = 240 patients with SCD) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, 5 cognitive domain factor structure comprising learning and memory, executive functions, language abilities, working memory, and visuospatial functions. We compared groups in terms of global and domain-specific performance and correlated performance with different CSF markers of AD pathology. RESULTS: We observed worse performance (Cohen d = ≈0.25-0.5, adjusted for age, sex differences with analysis of covariance) in global performance, memory, executive functions, and language abilities for the SCD group compared to healthy controls. In addition, worse performance in these domains was moderately (r = ≈0.3) associated with lower CSF ß-amyloid42/40 and CSF ß-amyloid42/phosphorylated tau181 in the whole sample and specifically in the SCD subgroup. CONCLUSIONS: Within the spectrum of clinically unimpaired (i.e., before mild cognitive impairment) cognitive performance, SCD is associated with minor deficits in memory, executive function, and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD.

20.
Genome Med ; 12(1): 61, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32646514

RESUMO

BACKGROUND: Angiosarcoma is an aggressive tumor. Recent case series describe exceptional responses to checkpoint blockade in this disease. METHODS: Herein, we explored the genomic correlates of 48 angiosarcomas from the Angiosarcoma Project (12,499 variants analyzed in 6603 genes; whole-exome sequencing) versus 10,106 pan-cancer tumors in The Cancer Genome Atlas including 235 sarcomas but no angiosarcoma. RESULTS: At the molecular level, angiosarcomas were heterogeneous. Those located in the face and scalp presented high tumor mutation burden, missense amino acid variations biased towards more hydrophobic (and therefore more immunogenic) peptides, and ultra-violet mutational signature. CONCLUSIONS: Angiosarcoma molecular features are similar to those observed in melanoma and other skin tumors and may explain comparable immunotherapy sensitivity of these tumor types.

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