tbuckley/cabot-search huggingface dataset:
Rational Selection of Patients for Antibacterial Prophylaxis After Chemotherapy
Authors: Michael H. Cullen, Lucinda J. Billingham, Claire H. Gaunt, Neil M. Steven
Journal: Journal of Clinical Oncology (2007)

The SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy +/- Antibiotic in a Number of Tumours) trial reported a reduction in febrile episodes (FEs) among 1,565 patients with solid cancers and lymphomas receiving cyclical, myelosuppressive chemotherapy (causing grade 4 neutropenia) in a randomized, placebo-controlled, double-blind trial of levofloxacin (P = .01). In response to concerns that increased antibacterial prescribing selects for microbial resistance, we examined our data to explore the rationale for more limited prophylaxis.The risk of FE was calculated for control patients on first versus nonfirst cycles, with or without first-cycle FE, and within subgroups defined by cancer type, performance status (PS), age, and treatment context (adjuvant v nonadjuvant). Using the randomized trial data, the prophylactic efficacy of levofloxacin was examined for the same subgroups.The per-cycle FE incidence was much lower on nonfirst (3.3%) versus first cycles (8.0%). Prophylaxis was less effective for nonfirst (odds ratio [OR] = 0.78; P = .16) compared with first cycles (OR = 0.42; P < .001). However, FE on cycle 1 predicted a much higher risk of FE and a trend to continued prophylactic efficacy on subsequent cycles. FE rate was greatest for testicular cancer (27.9%), then small-cell lung cancer (17.3%), and lowest for breast cancer (11.5%). Prophylactic efficacy was consistent across age, sex, PS, treatment context, and disease type (except possibly non-Hodgkin's lymphoma).Under pressure to limit antibacterial use, these exploratory data support offering prophylactic levofloxacin on cycle 1 only of myelosuppressive cancer chemotherapy and on subsequent cycles after a cycle-1 fever. Prophylactic levofloxacin is effective regardless of age, PS, or tumor type.
Blockade of Transforming Growth Factor β/Smad Signaling in T Cells by Overexpression of Smad7 Enhances Antigen-Induced Airway Inflammation and Airway Reactivity
Authors: Atsuhito Nakao, Satoshi Miike, Masahiko Hatano, Ko Okumura, Takeshi Tokuhisa, Chisei Ra, Itsuo Iwamoto
Journal: The Journal of Experimental Medicine (2000)

Transforming growth factor (TGF)-β has been implicated in immunosuppression. However, it remains obscure whether regulation of T cells by TGF-β contributes to the immunosuppression in vivo. To address this issue, we developed transgenic mice expressing Smad7, an intracellular antagonist of TGF-β/Smad signaling, selectively in mature T cells using a plasmid construct coding a promoter element (the distal lck promoter) that directs high expression in peripheral T cells. Peripheral T cells were not growth inhibited by TGF-β in Smad7 transgenic mice. Although Smad7 transgenic mice did not spontaneously show a specific phenotype, antigen-induced airway inflammation and airway reactivity were enhanced in Smad7 transgenic mice associated with high production of both T helper cell type 1 (Th1) and Th2 cytokines. Thus, blockade of TGF-β/Smad signaling in mature T cells by expression of Smad7 enhanced airway inflammation and airway reactivity, suggesting that regulation of T cells by TGF-β was crucial for negative regulation of the inflammatory (immune) response. Our findings also implicated TGF-β/Smad signaling in mature T cells as a regulatory component of allergic asthma.
Influence of systolic intracavity pressure on right ventricular perfusion in the awake dog
Authors: F. L GOLD, R. J BACHE
Journal: Cardiovascular Research (1982)

This study tested the hypothesis that an acute increase in right ventricular pressure would result in selective impedance of blood flow into the right ventricular subendocardium (ENDO) similar to that seen normally in the left ventricle. Since tachycardia (reduces diastolic time) and vasomotor paralysis will reveal impedence to blood flow by a decrease in ENDO to subepicardial (EPI) myocardial blood flow (MBF) ratio, MBF was measured with microspheres in eight awake dogs during rapid pacing at 176 +/- 2 beats . min-1 (mean +/- SE) after acute pulmonary artery constriction (PAC) before and during adenosine (A) infusion (1.00 mg . kg-1 . min-1). AP was held constant by aortic constriction. During control pacing the ENDO/EPI ratios were 1.38 +/- 0.08 and 1.46 +/- 0.12 in the RV and LV, respectively. During adenosine infusion the ENDO/EPI decreased to 0.85 +/- 0.08 (P less than 0.05) in the LV but did not change in the RV (1.17 +/- 0.10). During PAC and pacing alone the RV ENDO/EPI was 1.24 +/- 0.05 (NS vs control), but during adenosine fell to 0.88 +/- 0.07 (P less than 0.05). Transmural blood flow to the interventricular septum (IVS) was also affected by increased RV pressure. During control the ratio of blood flow to the left and right side (LV/RV) of the IVS was 1.32 +/- 0.12. PAC alone caused a redistribution of MBF toward the right side and the LV/RV fell to 0.66 +/- 0.06 (P less than 0.05). During PAC and adenosine, however the LV/RV rose to 1.38 +/- 0.08. These data demonstrate that increased RV systolic pressure produces systolic impedance to blood flow to the right ventricular ENDO and the right side of the interventricular septum.
Response to Comment on “Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model”
Authors: Lee E. Goldstein, Ann C. McKee
Journal: Science Translational Medicine (2012)

Goldstein and McKee respond to points raised in two letters about their study of tau neuropathology in postmortem brain tissue samples from blast-exposed military veterans with traumatic brain injury.
Factors Determining Functional Outcomes After Radical Prostatectomy: Robot-Assisted Versus Retropubic
Authors: Seong Cheol Kim, Cheryn Song, Wansuk Kim, Taejin Kang, Jinsung Park, In Gab Jeong, Sangmi Lee, Yong Mee Cho, Hanjong Ahn
Journal: European Urology (2011)
Racial Disparities in Stage-Specific Colorectal Cancer Mortality Rates From 1985 to 2008
Authors: Anthony S. Robbins, Rebecca L. Siegel, Ahmedin Jemal
Journal: Journal of Clinical Oncology (2011)

Since the early 1980s, colorectal cancer (CRC) mortality rates for whites and blacks in the United States have been diverging as a result of earlier and larger reductions in death rates for whites. We examined whether this mortality pattern varies by stage at diagnosis.The Incidence-Based Mortality database of the Surveillance, Epidemiology, and End Results (SEER) Program was used to examine data from the nine original SEER regions. Our main outcome measures were changes in stage-specific mortality rates by race.From 1985 to 1987 to 2006 to 2008, CRC mortality rates decreased for each stage in both blacks and whites, but for every stage, the decreases were smaller for blacks, particularly for distant-stage disease. For localized stage, mortality rates decreased 30.3% in whites compared with 13.2% in blacks; for regional stage, declines were 48.5% in whites compared with 34.0% in blacks; and for distant stage, declines were 32.6% in whites compared with 4.6% in blacks. As a result, the black-white rate ratios increased from 1.17 (95% CI, 0.98 to 1.39) to 1.41 (95% CI, 1.21 to 1.63) for localized disease, from 1.03 (95% CI, 0.93 to 1.14) to 1.30 (95% CI, 1.17 to 1.44) for regional disease, and from 1.21 (95% CI, 1.10 to 1.34) to 1.72 (95% CI, 1.58 to 1.86) for distant-stage disease. In absolute terms, the disparity in distant-stage mortality rates accounted for approximately 60% of the overall black-white mortality disparity.The black-white disparities in CRC mortality increased for each stage of the disease, but the overall disparity in overall mortality was largely driven by trends for late-stage disease. Concerted efforts to prevent or detect CRC at earlier stages in blacks could improve the worsening black- white disparities.
Comparison of Ca2+, Sr2+, and Mn2+ fluxes in mitochondria of the perfused rat heart.
Authors: D R Hunter, H Komai, R A Haworth, M D Jackson, H A Berkoff
Journal: Circulation Research (1980)

The amount of readily exchangeable Ca2+ in mitochondria of an isolated working rat heart is less than 10 ng-ions/g heart. We therefore conclude that either no Ca2+ enters mitochondria or that the Ca+ which does enter is removed continuously. Using Sr2+ and Mn2+, we obtained evidence that the mitochondrial Na+-Ca2+ exchanger was indeed operational in releasing metal from mitochondria of the heart. When Ca2+ in the perfusate was replaced by Sr2+, we found that a significant amount of Sr2+ (approximately 100 ng-ions/g heart) entered mitochondria. When the heart then was returned to a Ca2+-containing perfusate, over 80% of the Sr2+ was washed out of mitochondria within 30 seconds. When low levels of Mn2+ were added to the perfusate, we found that Mn2+ accumulated in mitochondria irreversibly. This is evidence for the operation of the Na+-Ca2+ exchanger because Na+ was found to release Ca2+ and Sr2+ but not Mn2+ from isolated rat heart mitochondria. Our estimates indicate that when the Na+-Ca2+ exchanger is maximally operative, as in the Sr2+-perfused heart, the flux of Sr2+ through mitochondria is at most 10% of the total flux needed for the activation of contraction. The low level of Ca2+ in the mitochondria of Ca2+-perfused hearts suggests a much smaller flux of Ca2+ through the mitochondria in this case. We therefore conclude that mitochondria play little if any role in the beat-to-beat regulation of normal Ca2+ fluxes in the rat heart.
Cluster-Randomized Trial of a Mobile Phone Personalized Behavioral Intervention for Blood Glucose Control
Authors: Charlene C. Quinn, Michelle D. Shardell, Michael L. Terrin, Erik A. Barr, Shoshana H. Ballew, Ann L. Gruber-Baldini
Journal: Diabetes Care (2011)

OBJECTIVE To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with standard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A cluster-randomized clinical trial, the Mobile Diabetes Intervention Study, randomly assigned 26 primary care practices to one of three stepped treatment groups or a control group (usual care). A total of 163 patients were enrolled and included in analysis. The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period. Secondary outcomes were changes in patient-reported diabetes symptoms, diabetes distress, depression, and other clinical (blood pressure) and laboratory (lipid) values. Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support. Patients received automated, real-time educational and behavioral messaging in response to individually analyzed blood glucose values, diabetes medications, and lifestyle behaviors communicated by mobile phone. Providers received quarterly reports summarizing patient’s glycemic control, diabetes medication management, lifestyle behaviors, and evidence-based treatment options. RESULTS The mean declines in glycated hemoglobin were 1.9% in the maximal treatment group and 0.7% in the usual care group, a difference of 1.2% (P = 0.001) over 12 months. Appreciable differences were not observed between groups for patient-reported diabetes distress, depression, diabetes symptoms, or blood pressure and lipid levels (all P &amp;gt; 0.05). CONCLUSIONS The combination of behavioral mobile coaching with blood glucose data, lifestyle behaviors, and patient self-management data individually analyzed and presented with evidence-based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year.
Vascular Endothelial Growth Factor <sub>165</sub> Gene Transfer Augments Circulating Endothelial Progenitor Cells in Human Subjects
Authors: Christoph Kalka, Haruchika Masuda, Tomono Takahashi, Rebecca Gordon, Oren Tepper, Edwin Gravereaux, Ann Pieczek, Hideki Iwaguro, Shin-Ichiro Hayashi, Jeffrey M. Isner, Takayuki Asahara
Journal: Circulation Research (2000)

Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, alpha(v)beta(3), and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.
Decline in the Use of Anthracyclines for Breast Cancer
Authors: Sharon H. Giordano, Yu-Li Lin, Yong Fang Kuo, Gabriel N. Hortobagyi, James S. Goodwin
Journal: Journal of Clinical Oncology (2012)

To determine the patterns of use of anthracycline- and taxane-based chemotherapy for breast cancer treatment.Claims from a 5% national Medicare sample and from a nationally representative claims database (Marketscan) from 1998 to 2009 were used. Patients with International Classification of Diseases (ICD), ninth revision, codes indicating breast cancer, ICD and Common Procedural Terminology codes indicating breast surgery, and claims for chemotherapy between 3 months before and 12 months after surgery comprised the study cohort. Chemotherapy was classified as anthracycline-based or taxane-based, and the percentages of use were calculated. Piecewise regression models were used to identify the inflection points in the rates of chemotherapy use. The effect of patient characteristics on receiving different types of chemotherapy was estimated by multivariable logistic regression models.A total of 4,458 patients were included in the Medicare cohort and 30,422 in the private insurance cohort. After 2005, a sharp increase in the use of taxane-based chemotherapy and a decline in anthracycline-based chemotherapy was seen. By 2008 in the Medicare cohort, 51% of patients received taxane-based and 32% received anthracycline-based chemotherapy. By the end of 2008, the majority of patients younger than 65 years were also receiving taxane-based chemotherapy. Patients younger than 35 years were less likely to be treated with a taxane-based regimen, whereas patients who underwent 21-gene recurrence score testing and those treated with trastuzumab were more likely to receive taxane-based chemotherapy.The use of anthracycline-based chemotherapy has declined, and the majority of patients with breast cancer are instead receiving taxane-based chemotherapy. The potential impact on patient outcomes is unknown.
Abundance of Circulating Preadipocyte Factor 1 in Early Life
Authors: Francis de Zegher, Marta Díaz, Giorgia Sebastiani, Ana Martín-Ancel, David Sánchez-Infantes, Abel López-Bermejo, Lourdes Ibáñez
Journal: Diabetes Care (2012)

OBJECTIVE Soluble preadipocyte factor 1 (Pref-1) inhibits adipocyte differentiation. We tested whether circulating levels of soluble Pref-1 are higher in smaller fetuses. RESEARCH DESIGN AND METHODS We performed longitudinal assessments of circulating Pref-1 in infants born appropriate for gestational age (AGA) or small for gestational age (SGA) and also in late-gestational women and in newborns on days 2 and 3. RESULTS At birth, Pref-1 levels were ~100-fold higher than in adults, being in SGA fetuses ~50% higher than in AGA fetuses. By age 4 months, Pref-1 had reached near-adult levels and the original AGA versus SGA difference had disappeared. Pref-1 levels were low in late-gestational women and were still elevated in newborns. CONCLUSIONS Pref-1 is abundantly present in the fetus, is higher in SGA than in AGA fetuses, and is likely to be of fetal origin. We speculate that Pref-1 in early life contributes to variation in postnatal adipocyte numbers, in the subsequent expandability of adipose tissue, and thus in the susceptibility to diabetes in later life.
Mucosal inflammation in severe glucocorticoid-dependent asthma
Authors: B Vrugt, S Wilson, J Underwood, A Bron, R de Bruyn, P Bradding, ST Holgate, R Djukanovic, R Aalbers
Journal: European Respiratory Journal (1999)

To improve our understanding of the inflammatory mechanisms underlying severe disease, a biopsy study was performed comparing 15 clinically unstable glucocorticoid-dependent asthmatics, 10 mild asthmatics, and 10 control subjects. Compared with mild asthma, severe asthma was characterized by reduced mucosal eosinophilia. Whilst no significant differences were found in the numbers of mast cells, neutrophils, CD3+ and CD4+ T-cells between the three groups, up to a 4-fold increase In the numbers of activated T-lymphocytes bearing the interleukin (IL)-2 receptor (IL-2R) was found in the mucosa in severe asthma compared to mild asthma (p = 0.03) and control subjects (p = 0.003). Compared to control subjects, the mucosa of severe asthmatics contained significantly (p = 0.02) higher numbers of IL-5+ cells, with no differences between mild and severe disease. In contrast, staining for the anti-IL-4 monoclonal antibody 3H4 revealed that biopsies from mild asthmatics contained more IL4+ cells than biopsies from severe asthmatics and control subjects (p = 0.0008). In the severe asthmatics, a close correlation (r(s) = 0.76, p = 0.005) was found between the numbers of IL-2R-bearing cells and the variability in peak expiratory flow. In conclusion, persistent T-cell activation is a prominent feature of severe asthma. These results also indicate that interleukin-5, and not interleukin-4, is upregulated in severe disease.
Inactivation of Serum Response Factor Contributes To Decrease Vascular Muscular Tone and Arterial Stiffness in Mice
Authors: Guillaume Galmiche, Carlos Labat, Mathias Mericskay, Karima Ait Aissa, Jocelyne Blanc, Kevin Retailleau, Mustapha Bourhim, Dario Coletti, Laurent Loufrani, Jacqueline Gao-Li, Robert Feil, Pascal Challande, Daniel Henrion, Jean-François Decaux, Véronique Regnault, Patrick Lacolley, Zhenlin Li
Journal: Circulation Research (2013)

Vascular smooth muscle (SM) cell phenotypic modulation plays an important role in arterial stiffening associated with aging. Serum response factor (SRF) is a major transcription factor regulating SM genes involved in maintenance of the contractile state of vascular SM cells.We investigated whether SRF and its target genes regulate intrinsic SM tone and thereby arterial stiffness.The SRF gene was inactivated SM-specific knockout of SRF (SRF(SMKO)) specifically in vascular SM cells by injection of tamoxifen into adult transgenic mice. Fifteen days later, arterial pressure and carotid thickness were lower in SRF(SMKO) than in control mice. The carotid distensibility/pressure and elastic modulus/wall stress curves showed a greater arterial elasticity in SRF(SMKO) without modification in collagen/elastin ratio. In SRF(SMKO), vasodilation was decreased in aorta and carotid arteries, whereas a decrease in contractile response was found in mesenteric arteries. By contrast, in mice with inducible SRF overexpression, the in vitro contractile response was significantly increased in all arteries. Without endothelium, the contraction was reduced in SRF(SMKO) compared with control aortic rings owing to impairment of the NO pathway. Contractile components (SM-actin and myosin light chain), regulators of the contractile response (myosin light chain kinase, myosin phosphatase target subunit 1, and protein kinase C-potentiated myosin phosphatase inhibitor) and integrins were reduced in SRF(SMKO).SRF controls vasoconstriction in mesenteric arteries via vascular SM cell phenotypic modulation linked to changes in contractile protein gene expression. SRF-related decreases in vasomotor tone and cell-matrix attachment increase arterial elasticity in large arteries.
Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease
Authors: Michael T. Falta, Clemencia Pinilla, Douglas G. Mack, Alex N. Tinega, Frances Crawford, Marc Giulianotti, Radleigh Santos, Gina M. Clayton, Yuxiao Wang, Xuewu Zhang, Lisa A. Maier, Philippa Marrack, John W. Kappler, Andrew P. Fontenot
Journal: The Journal of Experimental Medicine (2013)

Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4+ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4+ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4+ T cells specific for these ligands in all HLA-DP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4+ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD.