tbuckley/cabot-search huggingface dataset:
Pathophysiology of Myocardial Reperfusion
Authors: K A A Fox, S R Bergmann, B E Sobel
Journal: Annual Review of Medicine (1985)

The feasibility of myocardial reperfusion induced by coronary thrombolysis stimulated marked changes in the management of patients with acute myocardial infarction. Despite the demonstrable successful recanalization achieved in many patients, effective tissue reperfusion has not necessarily been achieved. Furthermore, factors defining the risk/benefit relationships of reperfusion, the extent to which salutary effects on jeopardized myocardium can be anticipated, and the ultimate long-term benefit conferred on the patient all require further definition. Widespread implementation of interventions utilized to induce myocardial reperfusion should be based on thorough characterization of the functional and metabolic responses of the heart to reperfusion. This selective review considers reperfusion within the context of an extensive body of information pertinent to the pathophysiological mechanisms underlying ischemic injury and discusses the potential favorable and unfavorable responses to reperfusion.
Independent and Additive Impact of Blood Pressure Control and Angiotensin II Receptor Blockade on Renal Outcomes in the Irbesartan Diabetic Nephropathy Trial
Authors: Marc A. Pohl, Samuel Blumenthal, Daniel J. Cordonnier, Fernando De Alvaro, Giacomo DeFerrari, Gilbert Eisner, Enric Esmatjes, Richard E. Gilbert, Lawrence G. Hunsicker, Jose B. Lopes de Faria, Ruggero Mangili, Jack Moore, Efrain Reisin, Eberhard Ritz, Guntram Schernthaner, Samuel Spitalewitz, Hilary Tindall, Roger A. Rodby, Edmund J. Lewis
Journal: Journal of the American Society of Nephrology (2005)

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 μmol/L (3.0 mg/dl) and urine protein excretion &gt;900 mg/d. Baseline BP averaged 159/87 ± 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP &gt;149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP &lt;134 mmHg. Progressive lowering of SBP to 120 mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold, all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120 mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg, in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.
Loss of <i>HER2</i> Amplification Following Trastuzumab-Based Neoadjuvant Systemic Therapy and Survival Outcomes
Authors: Elizabeth A. Mittendorf, Yun Wu, Maurizio Scaltriti, Funda Meric-Bernstam, Kelly K. Hunt, Shaheenah Dawood, Francisco J. Esteva, Aman U. Buzdar, Huiqin Chen, Sameena Eksambi, Gabriel N. Hortobagyi, Jose Baselga, Ana M. Gonzalez-Angulo
Journal: Clinical Cancer Research (2009)

To evaluate HER2 status in residual tumor identified at the time of surgery in patients not achieving a pathologic complete response (pCR) and to determine the effect of alterations in HER2 status on recurrence-free survival (RFS).Clinicopathologic data for patients with HER2-overexpressing breast cancer receiving neoadjuvant therapy with a taxane, anthracycline, and concomitant trastuzumab between 2004 and 2007 were reviewed. Surgical specimens for patients achieving less than a pCR were assessed to determine if there was enough residual tissue to evaluate posttreatment HER2 status. RFS was determined using the Kaplan-Meier method and compared by the log-rank statistic.A pCR was achieved in 72 of the 142 (50.7%) patients. Residual tumor was sufficient to assess posttreatment HER2 status in 25 patients. Fluorescence in situ hybridization done on pretreatment specimens confirmed HER2 amplification before beginning therapy. Eight (32.0%) posttreatment tumors were found to be HER2-negative by fluorescence in situ hybridization. At a median follow-up of 37 months (range, 8-56 months), the RFS was significantly better for patients with tumors that retained HER2 amplification (87.5% versus 50%, P = 0.04).High pCR rates are achieved in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab in combination with anthracyclines and taxanes. One third of patients with significant residual disease loses HER2 amplification, and this change is associated with poor RFS. Residual tumor identified at the time of surgery should be reassessed for HER2 status, and novel adjuvant therapy strategies need to be studied in this population.
High uptake of colonoscopy in first-degree relatives of patients with colorectal cancer in a healthcare region: a population-based, prospective study
Authors: F. Armelao, P. Orlandi, E. Tasini, G. Franceschini, R. Franch, C. Paternolli, G. de Pretis
Journal: Endoscopy (2010)

Background and study aims: A screening program in first-degree relatives (FDRs) of colorectal cancer (CRC) patients (index patients) was started in Trentino, Italy, to analyze factors that influence uptake of CRC screening among invited FDRs (first objective) and to describe colorectal findings among those undergoing colonoscopy (secondary objective).
Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice
Authors: Yan Y. Sanders, James S. Hagood, Hui Liu, Wei Zhang, Namasivayam Ambalavanan, Victor J. Thannickal
Journal: European Respiratory Journal (2014)

Idiopathic pulmonary fibrosis (IPF) is a fatal disease, and therapeutic agents have shown only modest efficacy. Epigenetic alterations contribute to the pathogenesis of IPF. The histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), has been approved for clinical use in cancer; however, its potential efficacy in modulating fibroblast survival and lung fibrosis has not been extensively investigated. We investigated the effects of SAHA on apoptosis of primary IPF myofibroblasts and on injury-induced lung fibrosis in a murine model. SAHA-induced apoptosis of IPF myofibroblasts, an effect that was mediated, at least in part, by upregulation of the pro-apoptotic gene Bak and downregulation of the anti-apoptotic gene Bcl-xL . Alterations in the expression of these apoptosis-related genes were associated with histone modifications and changes in DNA methylation. In addition to the expected higher levels of histone acetylation in treated cells, we also detected changes in other histone modifications, such as histone methylation. In a murine model of bleomycin-induced pulmonary fibrosis, SAHA-treated mice displayed decreased lung fibrosis and improved lung function compared to the bleomycin only group. These results suggest that histone deacetylase inhibitors may offer a new therapeutic strategy in IPF by modulating myofibroblast susceptibility to apoptosis.
Stimulation of lung epithelial liquid clearance by endogenous release of catecholamines in septic shock in anesthetized rats.
Authors: J F Pittet, J P Wiener-Kronish, M C McElroy, H G Folkesson, M A Matthay
Journal: Journal of Clinical Investigation (1994)

Exogenous administration of beta-adrenergic agonists has previously been reported to increase lung liquid clearance by stimulation of active sodium transport across the alveolar epithelium. We hypothesized for this study that endogenous release of epinephrine in septic shock would stimulate liquid clearance from the airspaces in rats. Liquid clearance from the air spaces was measured by the concentration of protein over 4 h in a test solution of 5% albumin instilled into one lung. Bacteremic rats developed severe systemic hypotension and metabolic acidosis that was associated with a 100-fold rise in plasma epinephrine levels. There was a 100% increase in liquid clearance from the airspaces of the lung in the bacteremic compared with control rats. To determine the mechanisms responsible for this accelerated lung liquid clearance, amiloride (10(-3) M), a sodium transport inhibitor, was added to the air spaces. Amiloride prevented the increase in liquid clearance from the airspaces, indicating that this effect depended on increased uptake of sodium across the lung epithelium. The addition of propranolol (10(-4) or 10(-5) M) to the instillate also prevented the acceleration in alveolar liquid clearance in the bacteremic rats. We conclude that the release of endogenous catecholamines associated with septic shock markedly stimulates fluid clearance from the distal airspaces of the lung by a beta-adrenergic mediated stimulation of active sodium transport across the epithelial barrier. This data provides evidence for a previously unrecognized mechanism that can protect against or hasten the resolution of alveolar edema in pathological conditions, such as septic shock, that are associated with the endogenous release of catecholamines.
The performance of a hydrogel nucleus pulposus prosthesis in an ex vivo canine model
Authors: Niklas Bergknut, Lucas A. Smolders, Leo H. Koole, George Voorhout, Ragnvi E. Hagman, Anne-Sofie Lagerstedt, Ketie Saralidze, Herman A.W. Hazewinkel, Albert J. van der Veen, Björn P. Meij
Journal: Biomaterials (2010)
Exposure to fatty acid increases human low density lipoprotein transfer across cultured endothelial monolayers.
Authors: B Hennig, D M Shasby, A A Spector
Journal: Circulation Research (1985)

Human low density lipoproteins radiolabeled with 125I transfer across confluent monolayers of cultured porcine pulmonary artery endothelial cells. The amount transferred was dependent on the low density lipoprotein concentration and was not saturable at concentrations up to 300 micrograms protein per 0.5 ml medium. Gel filtration showed that more than 90% of the 125I which crossed the endothelial monolayer remained associated with low density lipoproteins, indicating that appreciable amounts of lipoprotein were not degraded during the transfer process. When the endothelial monolayer was exposed for 24 hours to culture media supplemented with 100-300 microM fatty acid complexed with 100 microM albumin, the amount of low density lipoprotein subsequently transferred increased by 65% to 150%. The extent of the increase was dependent on the type of fatty acid added and its concentration. At 200 microM, albumin-bound oleic and linoleic acids increased low density lipoprotein transfer, whereas palmitic, linolenic, arachidonic, and eicosapentaenoic acids did not. These results are consistent with the hypothesis that exposure of the endothelium to elevated concentrations of fatty acid may allow excessive amounts of cholesterol-rich lipoproteins to enter the arterial intima.
Disparate interaction of peptide ligand with nascent versus mature class I major histocompatibility complex molecules: comparisons of peptide binding to alternative forms of Ld in cell lysates and the cell surface.
Authors: J D Smith, W R Lie, J Gorka, C S Kindle, N B Myers, T H Hansen
Journal: The Journal of Experimental Medicine (1992)

To determine the mechanism and structural consequences of peptide binding to class I molecules, we have studied the Ld molecule of the mouse. Previous studies have shown that a significant proportion of surface and intracellular Ld molecules can be detected in an alternative conformation designated Ldalt. Ldalt molecules are non-ligand associated and show weak if any beta 2-microglobulin (beta 2m) association. We report here that Ld molecules have a relatively rapid surface turnover compared with other class I molecules and that exogenous peptide dramatically prolongs Ld surface half-life. By contrast, Ldalt molecules are stably expressed on the surface and their half-life is unaffected by exogenous peptide. To study the surface interaction of peptide with Ld, live cells were incubated with iodinated peptides and Ld molecules were precipitated from cells precoated with monoclonal antibody before lysis. Using this assay, peptide binding to surface Ld molecules was found not to depend upon exchange with exogenous beta 2m, but did correlate with the level of beta 2m association. To study the intracellular interaction of peptide with Ld, cell lysates were used. In cell lysates, peptide was found to convert Ldalt molecules to properly folded Ld. This peptide-induced folding was almost complete at earlier but not later time points in pulse-chase analyses. Furthermore, conversion of Ldalt to Ld was found to affect almost exclusively immature (Endo Hs) class I molecules. Thus intrinsic properties of immature Ldalt molecules or their associated chaperonins are maintained in cell lysates that allow them to undergo de novo folding in vitro. These combined results demonstrate that immature Ldalt molecules are precursors awaiting constituents such as peptide and beta 2m that influence folding, whereas surface Ldalt molecules appear refractory to association with peptide, beta 2m, and consequent folding.
Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia
Authors: Xiao-Jing Yan, Jie Xu, Zhao-Hui Gu, Chun-Ming Pan, Gang Lu, Yang Shen, Jing-Yi Shi, Yong-Mei Zhu, Lin Tang, Xiao-Wei Zhang, Wen-Xue Liang, Jian-Qing Mi, Huai-Dong Song, Ke-Qin Li, Zhu Chen, Sai-Juan Chen
Journal: Nature Genetics (2011)
Evidence for the existence of an acetone soluble renin inhibiting factor in normal human plasma.
Authors: T A Kotchen, R T Talwalkar, J M Kotchen, M C Miller, W J Welch
Journal: Circulation Research (1975)

After addition of exogenous human renin, the in vitro rate of angiotensin I generation is faster in plasma of patients with chronic renal insufficiency and, to a lesser extent, in plasma of patients with essential hypertension than in plasma from normotensive control subjects. The increased reactivity of renin in hypertensive and uremic plasma is not related to differences of endogenous renin activity, angiotensinase activity, renin substrate concentration, or substrate reactivity. Addition of normal, hypertensive, and uremic plasma to a human renin-sheep renin substrate system inhibited the rate of angiotensin generation, although significantly less inhibition was observed with uremic plasma. The reactivity of renin increased in normal plasma but not in uremic plasma after treatment with 95% acetone. After acetone extraction renin reactivity in normal and plasma inhibited the rate of angiotensin generation in a renin-renin substrate system. Less inhibition occurred with the acetone extract from a pool of uremic plasma. These results provide evidence for the existence of a naturally occurring acetone soluble renin inhibiting factor in normal and uremic plasma. The increased reactivity of renin in uremic plasma may be related to a deficiency of this factor.
A Preclinical Assay for Chemosensitivity in Multiple Myeloma
Authors: Zayar P. Khin, Maria L.C. Ribeiro, Timothy Jacobson, Lori Hazlehurst, Lia Perez, Rachid Baz, Kenneth Shain, Ariosto S. Silva
Journal: Cancer Research (2013)

Abstract Accurate preclinical predictions of the clinical efficacy of experimental cancer drugs are highly desired but often haphazard. Such predictions might be improved by incorporating elements of the tumor microenvironment in preclinical models by providing a more physiological setting. In generating improved xenograft models, it is generally accepted that the use of primary tumors from patients are preferable to clonal tumor cell lines. Here we describe an interdisciplinary platform to study drug response in multiple myeloma, an incurable cancer of the bone marrow. This platform uses microfluidic technology to minimize the number of cells per experiment, while incorporating three-dimensional extracellular matrix and mesenchymal cells derived from the tumor microenvironment. We used sequential imaging and a novel digital imaging analysis algorithm to quantify changes in cell viability. Computational models were used to convert experimental data into dose-exposure–response “surfaces,” which offered predictive utility. Using this platform, we predicted chemosensitivity to bortezomib and melphalan, two clinical multiple myeloma treatments, in three multiple myeloma cell lines and seven patient-derived primary multiple myeloma cell populations. We also demonstrated how this system could be used to investigate environment-mediated drug resistance and drug combinations that target it. This interdisciplinary preclinical assay is capable of generating quantitative data that can be used in computational models of clinical response, demonstrating its utility as a tool to contribute to personalized oncology. Cancer Res; 74(1); 56–67. ©2013 AACR.
Bacterial cell wall-induced immunosuppression. Role of transforming growth factor beta.
Authors: S M Wahl, D A Hunt, G Bansal, N McCartney-Francis, L Ellingsworth, J B Allen
Journal: The Journal of Experimental Medicine (1988)

Group A streptococcal cell wall (SCW)-injected rats exhibit a profound immunosuppression that persists for months after the initial intraperitoneal injection of SCW. The goal of this study was to determine the mechanisms for the suppressed T lymphocyte proliferative responses in this experimental model of chronic inflammation. When spleen cell preparations were depleted of adherent cells, restoration of T cell proliferative responses to Con A and PHA occurred, implicating adherent macrophages in the regulation of immunosuppression. Furthermore, macrophages from SCW-treated animals, when cocultured with normal spleen cells in the presence of Con A or PHA, effectively inhibited the proliferative response. Supernatants from suppressed spleen cell cultures were found to inhibit normal T cell mitogenesis. Taken together, these results implicated a soluble macrophage-derived suppressor factor in the down regulation of T cell proliferation after exposure to SCW in vivo. Subsequent in vitro studies to identify this suppressor molecule(s) revealed the activity to be indistinguishable from the polypeptide transforming growth factor beta (TGF-beta). Furthermore, TGF-beta was identified by immunolocalization within the spleens of SCW-injected animals. The cells within the spleen that stained positively for TGF-beta were phagocytic cells that had ingested, and were presumably activated by, the SCW. These studies document that TGF-beta, previously shown to be a potent immunosuppressive agent in vitro, also effectively inhibits immune function in chronic inflammatory lesions in vivo.
On the Significance of Virus-Like Particles in Mammary Tissues of C3Hf Mice2
Authors: Dorothy R. Pitelka, Howard A. Bern, Satyabrata Nandi, Kenneth B. DeOme
Journal: JNCI Journal of the National Cancer Institute (1964)

Experiments were designed to determine whether the virus-like particles in mammary hyperplasias and neoplasias of low-cancer C3Hf mice represent a transmissible factor with demonstrable biologic properties. Virgin test m ice (agent-free BALB/c, BALB/c foster-nursed on C3H, BALB/c foster-nursed on C3Hf, and offspring of reciprocal matings of BALB/c and C3Hf) were given hormone treatments to promote or accelerate the appearance of hyperplastic alveolar nodules and tumors. Mammary hyperplasias appearing in the test mice were sampled for electron microscopy and/or transplanted into gland-free inguinal fat pads to test their tumorigenic potential. C3H-fostered BALB/c mice behaved in all respects as expected of animals infected with the mammary tumor virus (MTV): They had many tumors, nodules with high tumorigenic potential, and abundant virus-like particles. BALB/c mice foster-nursed on C3Hf mothers resembled BALB/c in having very few nodules and tumors and in lacking detectable virus-like particles. All hybrids had the characteristics of C3Hf: low tumor incidence, many nodules with poor tumorigenic potential, and abundant virus-like particles. These observations are discussed in the light of current theories of mammary tumorigenesis in mice. It is suggested that the C3Hf particle may represent a second agent (morphologically indistinguishable but biologically distinct from MTV) normally transmitted to offspring by either parent at conception but not ordinarily passed through milk.
Studies on collagenase from rheumatoid synovium in tissue culture
Authors: John M. Evanson, John J. Jeffrey, Stephen M. Krane
Journal: Journal of Clinical Investigation (1968)

Fragments of synovium from patients with rheumatoid arthritis survive in defined tissue culture medium in the absence of added serum and, after 3-4 days, release into the medium enzyme capable of degrading undenatured collagen. Maximal activity is observed at pH 7-9 but the enzyme is inactive at pH 5. At temperatures of 20 degrees and 27 degrees C, collagen molecules in solution are cleaved into 3/4 and 1/4 length fragments with minimal loss of negative optical rotation, but with loss in specific viscosity of approximately 60%. Above 30 degrees C the fragments begin to denature and denaturation is complete at 37 degrees C. If the enzyme is not inhibited at this stage the large fragments are broken down further to polypeptides of low molecular weight. Reconstituted collagen fibrils and native fibers at 37 degrees C are cleaved to the low molecular weight fragments, although the fibrils are resistant to breakdown at lower temperatures (20 degrees -27 degrees C). It is proposed that the production of such an enzyme by inflamed and proliferating rheumatoid synovium may be responsible for some of the destruction of collagenous structures that accompanies rheumatoid arthritis.