Distribuição e cronologia dos "Sepulcros de Corredor" nas Ilhas Britânicas.

62 (1-2) Jan.-Jun. 1952, p. 5-64

Rapid Breast Cancer Disease Progression Following Cyclin Dependent Kinase 4 and 6 Inhibitor Discontinuation.

Background: CDK 4 and 6 inhibitors (CDK4/6i), which arrest unregulated cancer cell proliferation, show clinical efficacy in breast cancer. Unexpectedly, a patient treated on a CDK4/6i-based trial, as first-line therapy in metastatic breast cancer, developed rapid disease progression following discontinuation of study drug while receiving standard second-line therapy off trial. We thus sought to expand this observation within a population of patients treated similarly at The University of Texas MD Anderson Cancer Center. Methods: Using an IRB-approved protocol, 4 patients previously enrolled on CDK4/6i trials were analyzed for outcomes after discontinuing study drug. These patients were treated on a randomized trial of first-line endocrine therapy +/- a CDK4/6i. Rapid disease progression was defined as progression occurring within 4 months of CDK4/6i discontinuation. Results: In total, 4 patients developed rapid disease progression and died; 2 of whom died within 6 months of CDK4/6i discontinuation. Conclusion: This case series suggests a potential for rapid disease progression following CDK4/6i discontinuation. However, the clinical course following progression must be validated in large CDK4/6i clinical trials and standard-of-care cohorts. If confirmed, such observations may alter the algorithm for subsequent therapy in patients with disease progression on CDK4/6i. Nevertheless, the need remains to define a mechanistic basis for this rapid progression and formulate alternative therapeutic strategies

Functional consequence of the MET-T1010I polymorphism in breast cancer.

Major breast cancer predisposition genes, only account for approximately 30% of high-risk breast cancer families and only explain 15% of breast cancer familial relative risk. The HGF growth factor receptor MET is potentially functionally altered due to an uncommon germline single nucleotide polymorphism (SNP), MET-T1010I, in many cancer lineages including breast cancer where the MET-T1010I SNP is present in 2% of patients with metastatic breast cancer. Expression of MET-T1010I in the context of mammary epithelium increases colony formation, cell migration and invasion in-vitro and tumor growth and invasion in-vivo. A selective effect of MET-T1010I as compared to wild type MET on cell invasion both in-vitro and in-vivo suggests that the MET-T1010I SNP may alter tumor pathophysiology and should be considered as a potential biomarker when implementing MET targeted clinical trials

The Close AGN Reference Survey (CARS) A massive multi-phase outflow impacting the edge-on galaxy HE 1353-1917

Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Open Access funding provided by Max Planck Society.Context. Galaxy-wide outflows driven by star formation and/or an active galactic nucleus (AGN) are thought to play a crucial rule in the evolution of galaxies and the metal enrichment of the inter-galactic medium. Direct measurements of these processes are still scarce and new observations are needed to reveal the nature of outflows in the majority of the galaxy population. Aims. We combine extensive, spatially-resolved, multi-wavelength observations, taken as part of the Close AGN Reference Survey (CARS), for the edge-on disc galaxy HE 1353-1917 in order to characterise the impact of the AGN on its host galaxy via outflows and radiation. Methods. Multi-color broad-band photometry was combined with spatially-resolved optical, near-infrared (NIR) and sub-mm and radio observations taken with the Multi-Unit Spectroscopy Explorer (MUSE), the Near-infrared Integral Field Spectrometer (NIFS), the Atacama Large Millimeter Array (ALMA), and the Karl G. Jansky Very Large Array (VLA) to map the physical properties and kinematics of the multi-phase interstellar medium. Results. We detect a biconical extended narrow-line region ionised by the luminous AGN orientated nearly parallel to the galaxy disc, extending out to at least 25 kpc. The extra-planar gas originates from galactic fountains initiated by star formation processes in the disc, rather than an AGN outflow, as shown by the kinematics and the metallicity of the gas. Nevertheless, a fast, multi-phase, AGN-driven outflow with speeds up to 1000 km s(-1) is detected close to the nucleus at 1 kpc distance. A radio jet, in connection with the AGN radiation field, is likely responsible for driving the outflow as confirmed by the energetics and the spatial alignment of the jet and multi-phase outflow. Evidence for negative AGN feedback suppressing the star formation rate (SFR) is mild and restricted to the central kpc. But while any SFR suppression must have happened recently, the outflow has the potential to greatly impact the future evolution of the galaxy disc due to its geometrical orientation. Conclusions.. Our observations reveal that low-power radio jets can play a major role in driving fast, multi-phase, galaxy-scale outflows even in radio-quiet AGN. Since the outflow energetics for HE 1353-1917 are consistent with literature, scaling relation of AGN-driven outflows the contribution of radio jets as the driving mechanisms still needs to be systematically explored.© B. Husemann et al. 2019We thank the referee for providing very valuable comments, which significantly improved the quality of the manuscript. MK acknowledges support from DLR grant 50OR1802. GRT acknowledges support from the NASA through Einstein Postdoctoral Fellowship Award Number PF-150128, issued by the Chandra X-ray Observatory Center, which is operated by the Smithsonian Astrophysical Observatory for and on behalf of NASA under contract NAS8-03060. MG is supported by the Lyman Spitzer Jr. Fellowship (Princeton University) and by NASA Chandra grants GO7-18121X/GO8-19104X. SMC acknowledges support from the Australian Research Council (DP190102714). We thank Alex Markowitz for helpful discussions on the RGS data in the context of warm absorbers. The work of SAB, CPO and MS was supported by a generous grant from the Natural Sciences and Engineering Research Council of Canada. Based on observations collected at the European Organization for Astronomical Research in the Southern Hemisphere under ESO programme 095. B-0015(A). Based on observations obtained at the Gemini Observatory, which is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), CONICYT (Chile), Ministerio de Ciencia, Tecnologia e Innovacion Productiva (Argentina), Ministerio da Ciencia, Tecnologia e Inovacao (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). Based on observations obtained at the Southern Astrophysical Research (SOAR) telescope, which is a joint project of the Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC) do Brasil, the U.S. National Optical Astronomy Observatory (NOAO), the University of North Carolina at Chapel Hill (UNC), and Michigan State University (MSU). Based on observations collected at the German-Spanish Astronomical Center, Calar Alto, jointly operated by the Max-Planck-Institut fur Astronomie Heidelberg and the Instituto de Astrofiica de Andaluci (CSIC). This paper makes use of the following ALMA data: ADS/JAO.ALMA#2016.1.00952. S. ALMA is a partnership of ESO (representing its member states), NSF (USA) and NINS (Japan), together with NRC (Canada), MOST and ASIAA (Taiwan), and KASI (Republic of Korea), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, AUI/NRAO and NAOJ. This work is based on observations obtained with XMM-Newton, an ESA science mission with instruments and contributions directly funded by ESA Member States and NASA. The VLA is operated by the National Radio Astronomy Observatory, a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA. This publication makes use of data products from the Wide-field Infrared Survey Explorer, which is a joint project of the University of California, Los Angeles, and the Jet Propulsion Laboratory/California Institute of Technology, funded by the National Aeronautics and Space Administration. This research has made use of the NASA/IPAC Infrared Science Archive, which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration. The Pan-STARRS1 Surveys (PS1) and the PS1 public science archive have been made possible through contributions by the Institute for Astronomy, the University of Hawaii, the Pan-STARRS Project Office, the Max-Planck Society and its participating institutes, the Max Planck Institute for Astronomy, Heidelberg and the Max Planck Institute for Extraterrestrial Physics, Garching, The Johns Hopkins University, Durham University, the University of Edinburgh, the Queen's University Belfast, the Harvard-Smithsonian Center for Astrophysics, the Las Cumbres Observatory Global Telescope Network Incorporated, the National Central University of Taiwan, the Space Telescope Science Institute, the National Aeronautics and Space Administration under Grant No. NNX08AR22G issued through the Planetary Science Division of the NASA Science Mission Directorate, the National Science Foundation Grant No. AST-1238877, the University of Maryland, Eotvos Lorand University (ELTE), the Los Alamos National Laboratory, and the Gordon and Betty Moore Foundation. This work is based in part on observations made with the Galaxy Evolution Explorer (GALEX). GALEX is a NASA Small Explorer, whose mission was developed in cooperation with the Centre National d'Etudes Spatiales (CNES) of France and the Korean Ministry of Science and Technology. GALEX is operated for NASA by the California Institute of Technology under NASA contract NAS5-98034

Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas

Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology

The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer

Current hormonal therapies have benefited millions of patients with breast cancer. Their success, however, is often temporary and limited to a subset of patients whose tumors express estrogen receptor alpha (ER). The therapies are entirely ineffective in ER-negative disease. Recent studies suggest that there are many biological pathways and alterations involved in determining whether ER is expressed and how it is regulated during breast cancer evolution. Improving hormonal therapies, in addition to perfecting current strategies, will also target these newly discovered pathways and alterations, and others yet to be found. The present commentary will briefly highlight a few important observations and unanswered questions regarding ER status and growth regulation during breast cancer evolution, which hopefully will help to stimulate new thinking and progress in this important area of medial research

Characterization and Optical Properties of the Single Crystalline SnS Nanowire Arrays

The SnS nanowire arrays have been successfully synthesized by the template-assisted pulsed electrochemical deposition in the porous anodized aluminum oxide template. The investigation results showed that the as-synthesized nanowires are single crystalline structures and they have a highly preferential orientation. The ordered SnS nanowire arrays are uniform with a diameter of 50 nm and a length up to several tens of micrometers. The synthesized SnS nanowires exhibit strong absorption in visible and near-infrared spectral region and the direct energy gapEgof SnS nanowires is 1.59 eV

Tumor-suppressor activity of RRIG1 in breast cancer

<p>Abstract</p> <p>Background</p> <p>Retinoid receptor-induced gene-1 (RRIG1) is a novel gene that has been lost in several types of human cancers. The aim of this study was to determine whether RRIG1 plays a role in breast cancer, such as in the suppression of breast cancer cell growth and invasion.</p> <p>Methods</p> <p>Immunohistochemistry was used to detect RRIG1 expression in breast tissue specimens. Gene transfection was used to restore or knock down RRIG1 expression in breast cancer cell lines for analysis of cell viability, colony formation, and migration/invasion potential. Reverse-transcription polymerase chain reaction and western blot assays were used to detect the changes in gene expression. The RhoA activation assay was used to assess RRIG1-induced inhibition of RhoA activity.</p> <p>Results</p> <p>The immunohistochemical data showed that <it>RRIG1 </it>expression was reduced in breast cancer tissues compared with normal and atypical hyperplastic breast tissues. <it>RRIG1 </it>expression was inversely correlated with lymph node metastasis of breast cancer but was not associated with the status of hormone receptors, such as estrogen receptor, progesterone receptor, or HER2. Furthermore, restoration of <it>RRIG1 </it>expression inhibited proliferation, colony formation, migration, and invasion of breast cancer cells. Expression of RRIG1 also reduced phosphorylated Erk1/2 and Akt levels; c-Jun, MMP9, and Akt expressions; and RhoA activity. In contrast, knockdown of RRIG1 expression promoted breast cancer cell proliferation, colony formation, migration, and invasion potential.</p> <p>Conclusion</p> <p>The data from the current study indicated that <it>RRIG1 </it>expression was reduced or lost in breast cancer and that restoration of RRIG1 expression suppressed breast cancer cell growth and invasion capacity. Future studies will determine the underlying molecular mechanisms and define RRIG1 as a tumor-suppressor gene in breast cancer.</p

Functional proteomics can define prognosis and predict pathologic complete response in patients with breast cancer

<p>Abstract</p> <p>Purpose</p> <p>To determine whether functional proteomics improves breast cancer classification and prognostication and can predict pathological complete response (pCR) in patients receiving neoadjuvant taxane and anthracycline-taxane-based systemic therapy (NST).</p> <p>Methods</p> <p>Reverse phase protein array (RPPA) using 146 antibodies to proteins relevant to breast cancer was applied to three independent tumor sets. Supervised clustering to identify subgroups and prognosis in surgical excision specimens from a training set (n = 712) was validated on a test set (n = 168) in two cohorts of patients with primary breast cancer. A score was constructed using ordinal logistic regression to quantify the probability of recurrence in the training set and tested in the test set. The score was then evaluated on 132 FNA biopsies of patients treated with NST to determine ability to predict pCR.</p> <p>Results</p> <p>Six breast cancer subgroups were identified by a 10-protein biomarker panel in the 712 tumor training set. They were associated with different recurrence-free survival (RFS) (log-rank p = 8.8 E-10). The structure and ability of the six subgroups to predict RFS was confirmed in the test set (log-rank p = 0.0013). A prognosis score constructed using the 10 proteins in the training set was associated with RFS in both training and test sets (p = 3.2E-13, for test set). There was a significant association between the prognostic score and likelihood of pCR to NST in the FNA set (p = 0.0021).</p> <p>Conclusion</p> <p>We developed a 10-protein biomarker panel that classifies breast cancer into prognostic groups that may have potential utility in the management of patients who receive anthracycline-taxane-based NST.</p

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA