tbuckley/cabot-search huggingface dataset:
Immune biomarkers and treatment (tx) outcome in hormone receptor-positive (HR+) breast cancer (BC) patients (pts) treated with preoperative chemotherapy (preop chemo) plus bevacizumab (bev).
Authors: Adrienne Gropper Waks, William Thomas Barry, Evisa Gjini, Deborah Dillon, Scott Rodig, Jane E. Brock, Michele Baltay, Jennifer Savoie, Daniel G. Stover, Eric P. Winer, Ian E. Krop, Sara M. Tolaney
Journal: Journal of Clinical Oncology (2017)

e12134 Background: Though preliminary study of the BC immune microenvironment suggests that HR+ tumors are less immune-active than other subtypes, immune biomarkers may have important clinical implications in HR+ BC pts. Methods: 78 HR+/HER2- BC pts were enrolled on a prospective trial of preop bev followed by bev with adriamycin/cyclophosphamide/paclitaxel dose-dense chemo. Tumor samples were collected at diagnosis and surgery (pre-tx and post-tx). PD-L1 expression (by immunohistochemistry) and tumor-infiltrating lymphocytes (TILs) were scored. Whole transcriptome sequencing and Nanostring PanCancer Immune Profiling Panel were performed. Pathologic response at surgery was assessed by Miller-Payne (MP) and residual cancer burden (RCB) scores. We calculated adjusted correlations by linear/logistic regression for RCB/dichotomized MP, respectively. Results: 55 pts who received trial tx and had &gt;1 analyzable specimen are included. Pre-tx TILs and tumor PD-L1 (tPD-L1) scores (see table) were slightly positively correlated (Spearman rho 0.23, p=0.1). Large changes (&gt;5%) in TILs or tPD-L1 from pre-tx to post-tx were rare: 2 pts each had large changes in TIL or tPD-L1 score (N=38 and N=31 pairs, respectively). Higher pre-tx TILs or tPD-L1 were significantly associated with more favorable RCB and MP (all Spearman p&lt;0.01) in unadjusted analyses. After adjustment for age and tumor grade, higher pre-tx TILs and tPD-L1 were associated with more favorable RCB (p&lt;0.01 for both), and higher pre-tx tPD-L1 correlated with more favorable MP (p=0.03). Pathologic complete response occurred in 4 pts; all 4 had high pre-tx TILs, pre-tx tPD-L1, or both. Analysis of immune-related RNA signatures is ongoing. Conclusions: High levels of tumor-immune interaction were seen in only a minority of untreated HR+ breast tumors, and did not typically change after tx with chemo plus bev. Nonetheless, TILs and tPD-L1 are significantly associated with pathologic response to preop tx in HR+ disease. [Table: see text]
Abstract 350: Interaction Of Methicillin-resistant Staphylococcus Aureus With Endothelial Cells Increase Intercellular Permeability By Activating Vasopressin Receptor-2.
Authors: Ernesto Lopez, Yong Zhu, Osamu Fujiwara, Perenlei Enkhbaatar
Journal: Circulation Research (2013)

More than 700,000 people a year suffer from sepsis in the United States. From sheep studies, we reported that methicillin-resistant Staphylococcus aureus (MRSA) sepsis is associated with vascular hyperpermeability and that vasopressin receptor-2 (V2R) might be involved in this complication. Vascular hyperpermeability is associated with high mortality and new pharmacological targets are required to design new treatments. We hypothesized that in MRSA induced vascular hyperpermeability, peroxynitrite stimulates V2R to release potent angiogenic growth factor angiopoietin-2. Methods: Human lung microvascular endothelial cells (HMVECs) were incubated with MRSA plus peroxynitrite decomposition catalyst (FeTMPyP), angiopoietin-2 antibody or tie-2 antibody as well as with MRSA only. Permeability assay (FITC-Dextran quantification across the confluent cell monolayer) was then performed after the different treatments. To strengthen the hypothesis, HMVECs were then treated with MRSA, peroxynitrite or V2R selective agonist (desmopressin). Cell lysates from each treatment were screened for levels of V2R mRNA using RT-PCR. Results: 1) Permeability was significantly higher in cells treated with MRSA compared to control. 2) Permeability was significantly lower in cells treated with MRSA plus FeTMPyP, angiopoietin-2 antibody, and tie-2 antibody compared to cells treated with MRSA only. 3) Cells treated with MRSA, peroxynitrite and desmopressin had significant higher levels of V2R mRNA compared to control. Conclusion: When MRSA interacts with endothelial cells, intercellular permeability is increased suggesting disruption of tight junctions. Peroxynitrite is a player of this phenomenon by activating V2R. Angiopoietin-2 also has an important role disrupting intercellular junctions with tie-2 receptor as the mediator. Further studies have to be performed to know whether V2R activation release angiopoietin-2.
Recyclable magnetite-silver heterodimer nanocomposites with durable antibacterial performance
Authors: Chunyan Yong, Xiaoqin Chen, Qian Xiang, Qiang Li, Xiaodong Xing
Journal: Bioactive Materials (2017)

There is a significant need for magnetite-silver nanocomposites that exhibit durable and recyclable antimicrobial activity. In this study, magnetic iron oxide nanoparticles (Fe3O4 NPs) coated with ethylenediamine-modified chitosan/polyacrylic acid copolymeric layer (Fe3O4@ECS/PAA) were fabricated. Subsequently, directly deposited silver (Ag) NPs procedure was carried out to form the antibacterial heterodimers of Fe3O4@ECS/PAA-Ag NPs. The composition and morphology of the resultant nanostructures were confirmed by FT-IR, XRD, TEM and TGA. The overall length of the heterodimers was approximately 45 nm, in which the mean diameter of Fe3O4@ECS/PAA NPs reached up to 35 nm, and that of Ag NPs was around 15 nm. The mass fraction of silver NPs in the nanocomposites was about 63.1%. The obtained Fe3O4@ECS/PAA NPs exhibited good colloidal stability, and excellent response to additional magnetic field, making the NPs easy to recover after antibacterial tests. In particular, the Fe3O4@ECS/PAA-Ag NPs retained nearly 100% biocidal efficiency (106-107 CFU/mg nanoparticles) for both Gram-negative bacteria E. coli and Gram-positive bacteria S. aureus throughout ten cycles without washing with any solvents or water, exhibiting potent and durable antibacterial activity.
A retrospective study of 21-gene recurrence score assay compared with clinicopathological markers in node-negative, hormone receptor-positive, HER2-negative breast cancer.
Authors: Junqing Chen, Xiaojia Wang, Zhanhong Chen
Journal: Journal of Clinical Oncology (2017)

e12023 Background: The 21-gene recurrence score assay is a validated genomic predictor of cancer recurrence and the benefits of adjuvant chemotherapy in hormone receptor-positive, HER2-negative early breast cancer patients. However, the assay is rather expensive and complex, and many patients in our country can not afford it. We performed a retrospective study to evaluate the association between traditional clinicopathological features and 21-gene recurrence score in patients with node-negative, hormone receptor-positive, HER2-negative breast cancer. Methods: A total of 76 consecutive patients with node-negative, hormone receptor-positive, HER2-negative breast cancer who underwent 21-gene recurrence score testing in our hospital from 2015 to 2016 were enrolled. Data including age, tumor size, histological type, tumor grade were collected. Estrogen receptor (ER) expression, progesterone receptor (PR) expression, Ki-67 index, p53 and androgen receptor (AR) expression were detected by immunohistochemical assay. 21-gene recurrence score assay was performed by RT-PCR. The correlation between clinicopathological characteristics and 21-gene recurrence score assay was analyzed by using nonparametric tests. Results: Among the 76 patients, 43 (56.6%) had a low recurrence score of &lt; 18, 13 (17.1%) had an intermediate recurrence score of 18-31, and 20 (26.3%) had a high recurrence score of ≥31. There was a significant difference in recurrence score in patients divided by PR expression ( P=0.027). Patients with low PR expression (&lt;20%) had a higher recurrence score as compared to those with high PR expression. Tumor grade was observed to be significantly correlated with recurrence score ( P=0.004). No significant associations were found between recurrence score and age, tumor size, histological type, ER expression, Ki-67 index, p53 or AR expression in this study. Conclusions: Our study shows that low PR expression is associated with higher 21-gene recurrence score, and PR expression may be a promising predictor of 21-gene recurrence score assay in node-negative, hormone receptor-positive, HER2-negative breast cancer patients.
Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma
Authors: Mark B. Faries, John F. Thompson, Alistair J. Cochran, Robert H. Andtbacka, Nicola Mozzillo, Jonathan S. Zager, Tiina Jahkola, Tawnya L. Bowles, Alessandro Testori, Peter D. Beitsch, Harald J. Hoekstra, Marc Moncrieff, Christian Ingvar, Michel W.J.M. Wouters, Michael S. Sabel, Edward A. Levine, Doreen Agnese, Michael Henderson, Reinhard Dummer, Carlo R. Rossi, Rogerio I. Neves, Steven D. Trocha, Frances Wright, David R. Byrd, Maurice Matter, Eddy Hsueh, Alastair MacKenzie-Ross, Douglas B. Johnson, Patrick Terheyden, Adam C. Berger, Tara L. Huston, Jeffrey D. Wayne, B. Mark Smithers, Heather B. Neuman, Schlomo Schneebaum, Jeffrey E. Gershenwald, Charlotte E. Ariyan, Darius C. Desai, Lisa Jacobs, Kelly M. McMasters, Anja Gesierich, Peter Hersey, Steven D. Bines, John M. Kane, Richard J. Barth, Gregory McKinnon, Jeffrey M. Farma, Erwin Schultz, Sergi Vidal-Sicart, Richard A. Hoefer, James M. Lewis, Randall Scheri, Mark C. Kelley, Omgo E. Nieweg, R. Dirk Noyes, Dave S.B. Hoon, He-Jing Wang, David A. Elashoff, Robert M. Elashoff
Journal: New England Journal of Medicine (2017)

Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear.
Erratum: Corrigendum: Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice
Authors: Nicolas Wein, Adeline Vulin, Maria S Falzarano, Christina Al-Khalili Szigyarto, Baijayanta Maiti, Andrew Findlay, Kristin N Heller, Mathias Uhlén, Baskar Bakthavachalu, Sonia Messina, Giuseppe Vita, Chiara Passarelli, Simona Brioschi, Matteo Bovolenta, Marcella Neri, Francesca Gualandi, Steve D Wilton, Louise R Rodino-Klapac, Lin Yang, Diane M Dunn, Daniel R Schoenberg, Robert B Weiss, Michael T Howard, Alessandra Ferlini, Kevin M Flanigan
Journal: Nature Medicine (2015)
Preventable Deaths From Medical Errors
Authors: Paul Barach
Journal: JAMA (2001)

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Fecal microbiota variation across the lifespan of the healthy laboratory rat
Authors: Burkhardt Flemer, Nadia Gaci, Guillaume Borrel, Ian R. Sanderson, Prem P. Chaudhary, William Tottey, Paul W. O'Toole, Jean-François Brugère
Journal: Gut Microbes (2017)

Laboratory rats are commonly used in life science research as a model for human biology and disease, but the composition and development of their gut microbiota during life is poorly understood. We determined the fecal microbiota composition of healthy Sprague Dawley laboratory rats from 3 weeks to 2 y of age, kept under controlled environmental and dietary conditions. Additionally, we determined fecal short-chain fatty acid profiles, and we compared the rat fecal microbiota with that of mice and humans. Gut microbiota and to a lesser extent SCFAs profiles separated rats into 3 different clusters according to age: before weaning, first year of life (12- to 26-week-old animals) and second year of life (52- to 104-week-old). A core of 46 bacterial species was present in all rats but its members' relative abundance progressively decreased with age. This was accompanied by an increase of microbiota α-diversity, likely due to the acquisition of environmental microorganisms during the lifespan. Contrastingly, the functional profile of the microbiota across animal species became more similar upon aging. Lastly, the microbiota of rats and mice were most similar to each other but at the same time the microbiota profile of rats was more similar to that of humans than was the microbiota profile of mice. These data offer an explanation as to why germ-free rats are more efficient recipients and retainers of human microbiota than mice. Furthermore, experimental design should take into account dynamic changes in the microbiota of model animals considering that their changing gut microbiota interacts with their physiology.
Environmental insults: critical triggers for amyotrophic lateral sclerosis
Authors: Bing Yu, Roger Pamphlett
Journal: Translational Neurodegeneration (2017)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons. As a complex disease, the ageing process and complicated gene-environment interactions are involved in the majority of cases.Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies, while environmental insults remain a suspected but largely unexplored source of risk. Several studies applying the strategy of Mendelian randomisation have strengthened the link between environmental insults and ALS, but none so far has proved conclusive. We propose a new ALS model which links the current knowledge of genetic factors, ageing and environmental insults. This model provides a mechanism as to how ALS is initiated, with environmental insults playing a critical role.The available evidence has suggested that inherited defect(s) could cause mitochondrial dysfunction, which would establish the primary susceptibility to ALS. Further study of the underlying mechanism may shed light on ALS pathogenesis. Environmental insults are a critical trigger for ALS, particularly in the aged individuals with other toxicant susceptible genes. The identification of ALS triggers could lead to preventive strategies for those individuals at risk.
Small heterodimer partner deletion prevents hepatic steatosis and when combined with farnesoid X receptor loss protects against type 2 diabetes in mice
Authors: Oludemilade Akinrotimi, Ryan Riessen, Philip VanDuyne, Jung Eun Park, Yoon Kwang Lee, Lee‐Jun Wong, Ann M. Zavacki, Kristina Schoonjans, Sayeepriyadarshini Anakk
Journal: Hepatology (2017)

Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are important regulators of bile acid, lipid, and glucose homeostasis. Here, we show that global Fxr -/- Shp-/- double knockout (DKO) mice are refractory to weight gain, glucose intolerance, and hepatic steatosis when challenged with high-fat diet. DKO mice display an inherently increased capacity to burn fat and suppress de novo hepatic lipid synthesis. Moreover, DKO mice were also very active and that correlated well with the observed increase in phosphoenolpyruvate carboxykinase expression, type IA fibers, and mitochondrial function in skeletal muscle. Mechanistically, we demonstrate that liver-specific Shp deletion protects against fatty liver development by suppressing expression of peroxisome proliferator-activated receptor gamma 2 and lipid-droplet protein fat-specific protein 27 beta.These data suggest that Fxr and Shp inactivation may be beneficial to combat diet-induced obesity and uncover that hepatic SHP is necessary to promote fatty liver disease. (Hepatology 2017;66:1854-1865).
Morphologic and Molecular Characteristics of De Novo AML With<i>JAK2</i>V617F Mutation
Authors: Juliana E. Hidalgo-López, Rashmi Kanagal-Shamanna, L. Jeffrey Medeiros, Zeev Estrov, C. Cameron Yin, Srdan Verstovsek, Sergej Konoplev, Jeffrey L. Jorgensen, Mohammad M. Mohammad, Roberto N. Miranda, Chong Zhao, John Lee, Zhuang Zuo, Carlos E. Bueso-Ramos
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: JAK2 V617F mutation (mut) in acute myeloid leukemia (AML) is rare. We describe the clinicopathologic findings of a single-institution series of 11 de novo AML cases with JAK2 V617. Methods: We identified cases of de novo AML with JAK2 V617F over a 10-year period. We reviewed diagnostic peripheral blood and bone marrow (BM) morphologic, cytogenetic, and molecular studies, including next-generation sequencing. The control group consisted of 12 patients with JAK2 wild-type (wt) AML matched for age, sex, and diagnosis. Results: We identified 11 patients (0.5%) with JAK2 V617F, with a median age at diagnosis of 72.5 years (range, 36–90 years). Ten neoplasms were classified as AML with myelodysplasia-related changes and 1 as AML with t(8;21)(q22;q22). All JAK2mut AML cases showed at least bilineage dysplasia, 7 of 11 showed fibrosis, 8 of 11 had an abnormal karyotype, and 5 had deletions or monosomy of chromosomes 5 and 7. Using the European LeukemiaNet (ELN) classification, 9 patients (82%) with JAK2mut AML were intermediate-2 and adverse risk. Cases of JAK2mut AML did not have mutations in other activating signaling pathways (P=.013); 7 (64%) showed additional mutations in at least one gene involving DNA methylation and/or epigenetic modification. Patients with JAK2mut AML had a significantly higher median BM granulocyte percentage (12% vs 3.5%; P=.006) and a higher frequency of ELN intermediate-2 and adverse risk cytogenetics (P=.04) compared with those with JAK2wt AML. JAK2mut AML showed higher circulating blasts, but this difference was not significant (17% vs 5.5%; P=not significant). No difference was seen in the median overall survival rate of patients with JAK2mut AML versus those with JAK2wt AML (14 vs 13.5 months, respectively). Conclusions: De novo JAK2mut AML is rare and frequently found in patients with dysplasia, BM fibrosis, and abnormal karyotype with intermediate- or high-risk features; gene mutations in DNA methylation and epigenetic-modifying pathways; and absence of gene mutations in activating signaling pathways.
2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: Executive Summary
Authors: L. David Hillis, Peter K. Smith, Jeffrey L. Anderson, John A. Bittl, Charles R. Bridges, John G. Byrne, Joaquin E. Cigarroa, Verdi J. DiSesa, Loren F. Hiratzka, Adolph M. Hutter, Michael E. Jessen, Ellen C. Keeley, Stephen J. Lahey, Richard A. Lange, Martin J. London, Michael J. Mack, Manesh R. Patel, John D. Puskas, Joseph F. Sabik, Ola Selnes, David M. Shahian, Jeffrey C. Trost, Michael D. Winniford
Journal: Circulation (2011)
Clinical and cost outcomes associated with multiple open procedures following percutaneous breast biopsy in Medicare patients.
Authors: Christine Ida Nichols, Chloe C Kimball, Joshua Vose
Journal: Journal of Clinical Oncology (2017)

e12083 Background: Percutaneous core-needle biopsy (PCNB) is the standard of care to diagnose suspicious lesions of the breast. Dependent upon histology, many women require additional open procedures for definitive diagnosis and excision. However, there remains little nationally-representative research on the proportion of women undergoing multiple open biopsy or lumpectomy procedures and the associated incremental burden to the health system. Methods: This study used Medicare 100% Standard Analytic Files (2010–2014) to identify patients undergoing PCNB in an outpatient setting. Patients included females aged ≥65; continuous Medicare enrollment; no history of cancer, chemotherapy, radiation or breast cancer surgery in the prior year. Open procedures were defined as an open biopsy or lumpectomy. Study follow-up was defined as 90 days from initial PCNB or until the day prior to chemotherapy, radiation, or mastectomy—to limit analysis to diagnosis-related payments. Payments were defined as Medicare payments. Results: 110,944 patients were identified; the mean age was 73.5; 74.1% underwent only PCNB, 23.8% had one open procedure and 2.1% had multiple open procedures. Among the PCNB-only cohort, 2.7% had multiple PCNBs; among those with subsequent open procedures, 4.1-4.4% had multiple PCNBs (P &lt; .001). Incidence of all-cause complications was significantly lower among those with no open procedure (8%) versus those with one (11%) or more (20%, P &lt; .001). Mean incremental breast-related payments were $3003 greater among those with one open procedure versus none ($4526 v $1523, P &lt; .001), and $1978 greater among those with multiple open procedures ($6504 v $4526, P &lt; .001). Prior receipt of multiple PCNBs and diagnosis of breast cancer were significantly positively correlated in logistic regression with having multiple open procedures, while age ≥ 80 was a negative predictor. Conclusions: There continues to be a percentage of women that require multiple open procedures following initial biopsy. These results suggest that incomplete excision at the first open procedure remains a meaningful concern, and merits further investigation into methods to ensure excisional completeness.
A comparison of genomic assays in determining risk of late recurrence and benefit of extended endocrine therapy (EET).
Authors: Kathleen Raque, Lina Marie Rico, Eddy Yu, W. Bradford Carter, Thomas G. Frazier
Journal: Journal of Clinical Oncology (2017)

e12045 Background: Breast cancer patients who are ER positive, lymph node negative have the best overall prognosis. However 50% of recurrences occur after 5 years. The Breast Cancer Index (BCI) is a gene expression-based biomarker that provides an individual risk of distant recurrence and benefit of EET based on a continuous risk model. (1) The BCI may help with clinical decisions regarding EET since prolonged therapy may have an increase in side effects including uterine cancer, DVT, myalgias and bone loss. The OncotypeDX is a 21 gene assay that predicts recurrence with a recurrence score. A recent study by Wolmark et al. evaluated the use of quantitative Estrogen Receptor Index (ESRI) combined with RS and found that RS was prognostic in patients with higher quantitative ESRI, suggesting EET be used for patients with intermediate and high RS with ESR1 expression &gt; 9.1. (2) Methods: 20 patients, ER positive, node negative who had the BCI and ONC-DX performed were evaluated in this retrospective IRB approved review. Results: Using ESRI alone 85% of patients would be recommended to continue an additional 5 years of EET. Using BCI this number was reduced to 35%. Conclusions: Comparing both the risk of recurrence and benefit of ETT, ESRI and BCI were concordant only 37.5% of the time. The cost of extended adjuvant therapy with Anastrazole ($190/mos x 60 mos = $11,400) or Tamoxifen ($50/mos x 60 mos = $ 3,000) would have resulted in a cost savings of $79,800 (Anastrazole) or $21,000 (Tamoxifen) for this small group of patients. Utilization of the BCI (cost $ 3416.00) may be a cost effective and accurate genomic approach in determining the use of EET and avoiding concomitant side effects.