Circulating Exosomal microRNAs as Predictive Biomarkers of Neoadjuvant Chemotherapy Response in Breast Cancer

Background: Neoadjuvant chemotherapy (NACT) is an increasingly used approach for treatment of breast cancer. The pathological complete response (pCR) is considered a good predictor of disease-specific survival. This study investigated whether circulating exosomal microRNAs could predict pCR in breast cancer patients treated with NACT. Method: Plasma samples of 20 breast cancer patients treated with NACT were collected prior to and after the first cycle. RNA sequencing was used to determine microRNA profiling. The Cancer Genome Atlas (TCGA) was used to explore the expression patterns and survivability of the candidate miRNAs, and their potential targets based on the expression levels and copy number variation (CNV) data. Results: Three miRNAs before that NACT (miR-30b, miR-328 and miR-423) predicted pCR in all of the analyzed samples. Upregulation of miR-127 correlated with pCR in triple-negative breast cancer (TNBC). After the first NACT dose, pCR was predicted by exo-miR-141, while miR-34a, exo-miR182, and exo-miR-183 predicted non-pCR. A significant correlation between the candidate miRNAs and the overall survival, subtype, and metastasis in breast cancer, suggesting their potential role as predictive biomarkers of pCR. Conclusions: If the miRNAs identified in this study are validated in a large cohort of patients, they might serve as predictive non-invasive liquid biopsy biomarkers for monitoring pCR to NACT in breast cancer

Diagnostic criterion for crystallized beams

Small ion crystals in a Paul trap are stable even in the absence of laser cooling. Based on this theoretically and experimentally well-established fact we propose the following diagnostic criterion for establishing the presence of a crystallized beam: Absence of heating following the shut-down of all cooling devices. The validity of the criterion is checked with the help of detailed numerical simulations.Comment: REVTeX, 11 pages, 4 figures; submitted to PR

Development of intuitive rules: Evaluating the application of the dual-system framework to understanding children's intuitive reasoning

This is an author-created version of this article. The original source of publication is Psychon Bull Rev. 2006 Dec;13(6):935-53 The final publication is available at www.springerlink.com Published version: http://dx.doi.org/10.3758/BF0321390

Experimental constraints on a dark matter origin for the DAMA annual modulation effect

A claim for evidence of dark matter interactions in the DAMA experiment has been recently reinforced. We employ a new type of germanium detector to conclusively rule out a standard isothermal galactic halo of Weakly Interacting Massive Particles (WIMPs) as the explanation for the annual modulation effect leading to the claim. Bounds are similarly imposed on a suggestion that dark pseudoscalars mightlead to the effect. We describe the sensitivity to light dark matter particles achievable with our device, in particular to Next-to-Minimal Supersymmetric Model candidates.Comment: v4: introduces recent results from arXiv:0807.3279 and arXiv:0807.2926. Sensitivity to pseudoscalars is revised in light of the first. Discussion on the subject adde

Results from a Search for Light-Mass Dark Matter with a P-type Point Contact Germanium Detector

We report on several features present in the energy spectrum from an ultra low-noise germanium detector operated at 2,100 m.w.e. By implementing a new technique able to reject surface events, a number of cosmogenic peaks can be observed for the first time. We discuss several possible causes for an irreducible excess of bulk-like events below 3 keVee, including a dark matter candidate common to the DAMA/LIBRA annual modulation effect, the hint of a signal in CDMS, and phenomenological predictions. Improved constraints are placed on a cosmological origin for the DAMA/LIBRA effect.Comment: 4 pages, 4 figures. v2: submitted version. Minimal changes in wording, one reference adde

Impaired regulation of the TNF-alpha converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans

Aims/hypothesis: TNF-alpha levels are increased in obesity and type 2 diabetes. The regulation of TNF-alpha converting enzyme (TACE) and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), in human type 2 diabetes is unknown. Methods: We examined TACE/TIMP3 regulation: (1) in lean and obese normal glucose tolerant (NGT) individuals and in type 2 diabetes patients; (2) following 6 h of lipid/saline infusion in NGT individuals; and (3) in cultured human myotubes from lean NGT individuals incubated with palmitate. Insulin sensitivity was assessed by a euglycaemic clamp and TACE/TIMP3 was evaluated by confocal microscopy, RT-PCR, western blotting and an in vitro activity assay. Circulating TNF-alpha, TNF-alpha-receptor 1 (TNFR1), TNF-alpha-receptor 2 (TNFR2), IL-6 receptor (IL-6R), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) levels were evaluated. Results: TIMP3 levels were reduced and TACE enzymatic activity was increased in type 2 diabetes skeletal muscle. TACE expression, and TACE, TNF-alpha, TNFR1 and IL-6R levels were increased in type 2 diabetes, and positively correlated with insulin resistance. A 6 h lipid infusion into NGT individuals decreased insulin-stimulated glucose metabolism by 25% with increased TACE, decreased expression of the gene encoding TIMP3 and increased IL-6R release. Palmitate induced a dramatic reduction of TIMP3 and increased the TACE/TIMP3 ratio in cultured myotubes. Conclusions/interpretation: TACE activity was increased in skeletal muscle of obese type 2 diabetes patients and in lipid-induced insulin resistance. We propose that dysregulation of membrane proteolysis by TACE/TIMP3 of TNF-alpha and IL-6R is an important factor for the development of skeletal muscle insulin resistance in obese type 2 diabetes patients by a novel autocrine/paracrine mechanism

Dexamethasone impairs the expression of antimicrobial mediators in lipopolysaccharide-activated primary macrophages by inhibiting both expression and function of interferon β

Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which immunosuppression is one of the most common. Here we used microarrays and proteomic approaches to characterise the effect of dexamethasone (a synthetic glucocorticoid) on the responses of primary mouse macrophages to a potent pro-inflammatory agonist, lipopolysaccharide (LPS). Gene ontology analysis revealed that dexamethasone strongly impaired the lipopolysaccharide-induced antimicrobial response, which is thought to be driven by an autocrine feedback loop involving the type I interferon IFNβ. Indeed, dexamethasone strongly and dose-dependently inhibited the expression of IFNβ by LPS-activated macrophages. Unbiased proteomic data also revealed an inhibitory effect of dexamethasone on the IFNβ-dependent program of gene expression, with strong down-regulation of several interferon-induced antimicrobial factors. Surprisingly, dexamethasone also inhibited the expression of several antimicrobial genes in response to direct stimulation of macrophages with IFNβ. We tested a number of hypotheses based on previous publications, but found that no single mechanism could account for more than a small fraction of the broad suppressive impact of dexamethasone on macrophage type I interferon signaling, underlining the complexity of this pathway. Preliminary experiments indicated that dexamethasone exerted similar inhibitory effects on primary human monocyte-derived or alveolar macrophages.</p

Ancient mitochondrial DNA provides high-resolution time scale of the peopling of the Americas

The exact timing, route, and process of the initial peopling of the Americas remains uncertain despite much research. Archaeological evidence indicates the presence of humans as far as southern Chile by 14.6 thousand years ago (ka), shortly after the Pleistocene ice sheets blocking access from eastern Beringia began to retreat. Genetic estimates of the timing and route of entry have been constrained by the lack of suitable calibration points and low genetic diversity of Native Americans. We sequenced 92 whole mitochondrial genomes from pre-Columbian South American skeletons dating from 8.6 to 0.5 ka, allowing a detailed, temporally calibrated reconstruction of the peopling of the Americas in a Bayesian coalescent analysis. The data suggest that a small population entered the Americas via a coastal route around 16.0 ka, following previous isolation in eastern Beringia for ~2.4 to 9 thousand years after separation from eastern Siberian populations. Following a rapid movement throughout the Americas, limited gene flow in South America resulted in a marked phylogeographic structure of populations, which persisted through time. All of the ancient mitochondrial lineages detected in this study were absent from modern data sets, suggesting a high extinction rate. To investigate this further, we applied a novel principal components multiple logistic regression test to Bayesian serial coalescent simulations. The analysis supported a scenario in which European colonization caused a substantial loss of pre-Columbian lineages.Bastien Llamas, Lars Fehren-Schmitz, Guido Valverde, Julien Soubrier, Swapan Mallick, Nadin Rohland, Susanne Nordenfelt, Cristina Valdiosera, Stephen M. Richards, Adam Rohrlach, Maria Inés Barreto Romero, Isabel Flores Espinoza, Elsa Tomasto Cagigao, Lucía Watson Jiménez, Krzysztof Makowski, Ilán Santiago Leboreiro Reyna, Josefina Mansilla Lory, Julio Alejandro Ballivián Torrez, Mario A. Rivera, Richard L. Burger, Maria Constanza Ceruti, Johan Reinhard, R. Spencer Wells, Gustavo Politis, Calogero M. Santoro, Vivien G. Standen, Colin Smith, David Reich, Simon Y. W. Ho, Alan Cooper and Wolfgang Haa