tbuckley/cabot-search huggingface dataset:
Breathing and pulmonary surfactant function in mice 24 h after ozone exposure
Authors: WD Currie, S van Schaik, I Vargas, G Enhorning
Journal: European Respiratory Journal (1998)

The aim of this study was to determine whether an acute ozone exposure affects breathing, and the ability of pulmonary surfactant to maintain the patency of terminal conducting airways. BALB/c mice were exposed to ozone (1 part per million (ppm)) for 2, 4, 6, and 8 h. They were examined with plethysmography and with bronchoalveolar lavage (BAL) 24 h later. The BAL fluid was analysed for the presence of inflammatory cells and concentrations of proteins and phospholipids. Surfactant in the remaining BAL fluid was concentrated five-times and examined with a capillary surfactometer (CS). The surfactant was then washed with a large volume of saline solution which was removed following centrifugation. Already, after a 2 h ozone exposure, the respiratory frequency increased from 297+/-6 to 386+/-11 breaths x min(-1) (p&lt;0.0001). Pressure amplitude per breath diminished (p&lt;0.001), indicating a reduced tidal volume. A highly significant surfactant dysfunction was observed with the CS (p&lt;0.0001), although phospholipids increased. However, proteins also increased (p&lt;0.0001) and they or other water-soluble inhibitors apparently caused the surfactant dysfunction since, when they were removed with a washing procedure, the surfactant's normal ability to maintain patency was restored. The acute ozone exposure affected breathing and caused an airway inflammation. The inflammatory proteins or other water-soluble inhibitors reduced the surfactant's ability to secure airway patency.
DISSOCIATION OF HEMOLYTIC AND LYMPHOCYTE-TRANSFORMING ACTIVITIES OF STREPTOLYSIN S PREPARATIONS
Authors: Angelo Taranta, Girolamo Cuppari, Franco Quagliata
Journal: The Journal of Experimental Medicine (1969)

The ability of streptolysin S preparations to induce high percentages of transformation in human peripheral blood lymphocytes was confirmed in a series of apparently healthy donors. Transforming activity was not demonstrated in the two media used for streptolysin S production, nor in control preparations in which a strain each of Streptococcus viridans, Staphylococcus aureus (nonhemolytic), and Diplococcus pneumoniae was substituted for the beta hemolytic streptococcal strain used for streptolysin S production. The relation of the hemolytic activity to the lymphocyte transforming activity of streptolysin S preparations was studied by means of inactivation and fractionation experiments. Heating produced a loss in both activities, but more in the hemolytic than in the transforming activity. The transformation obtained with a heated preparation had a high degree of correlation with that obtained with the unheated preparation in a series of normal subjects and patients with various rheumatic diseases, whose lymphocytes were often less responsive to stimulation with streptolysin S preparations (both heated and unheated) than the lymphocytes of the normal subjects studied. Treatment of streptolysin S preparations with chymotrypsin, vegetable lecithin, or trypan blue (the latter in minute amounts) resulted in preparations with no detectable hemolytic activity but with undiminished lymphocyte transforming activity. Chromatographic fractionations on DEAE-Sephadex columns yielded fractions endowed with transforming but not with hemolytic activity, and other fractions endowed with hemolytic but not with transforming activity. The recovery of the hemolytic activity was not complete and quantitation of the recovery of the transforming activity was not attempted. These experiments indicate that the hemolytic and transforming activities of streptolysin S preparations are independent of each other, and specifically that they are the attributes of two different streptococcal products, one of which is streptolysin S. The other is a nonhemolytic streptococcal product present in streptolysin S preparations but previously unrecognized. Some implications of these findings are discussed.
Benefits and Safety of Tirofiban Among Acute Coronary Syndrome Patients With Mild to Moderate Renal Insufficiency
Authors: James L. Januzzi, Steven M. Snapinn, Peter M. DiBattiste, Ik-Kyung Jang, Pierre Theroux
Journal: Circulation (2002)

Background — The role of glycoprotein IIb/IIIa receptor antagonists for the treatment of patients with acute coronary syndrome and renal insufficiency remains undefined. Methods and Results — Patients from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial were stratified by creatinine clearance (CrCl) and assessed with respect to treatment assignment to tirofiban/heparin versus heparin alone for the risk of adverse outcomes and bleeding. Patients with severe renal insufficiency (defined as a serum creatinine ≥2.5 mg/dL) were excluded from PRISM-PLUS as a whole. Patients with the lowest CrCl (&lt;30 mL/min) were more likely to present with high-risk clinical features. Decreasing renal function was strongly associated with adverse outcome, increasing the risk for ischemic complications at all time points examined (all P &lt;0.002). Irrespective of CrCl, therapy with tirofiban reduced the odds of the composite end point of death, myocardial infarction, or refractory ischemia at 48 hours (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.46 to 1.0; P =0.05), 7 days (OR, 0.68; 95% CI, 0.52 to 0.88; P = 0.003), 30 days (OR, 0.78; 95% CI, 0.63 to 0.98; P =0.03), and 6 months (OR, 0.81; 95% CI, 0.68 to 0.98; P =0.03). The risk of myocardial infarction/death was also significantly decreased to a similar magnitude at all time points examined. There was no evidence of treatment-by-CrCl interaction. The presence of declining renal function independently increased the risk for bleeding (OR, 1.57; P &lt;0.001 for trend across categories), as did therapy with tirofiban, but no unexpected incremental risk of bleeding due to tirofiban was observed among lowest CrCl categories. Conclusions — Among patients with mild-to-moderate renal insufficiency in PRISM-PLUS, tirofiban was well tolerated and effective in reducing ischemic acute coronary syndrome complications.
Vascular Endothelial Growth Factor Induces Nephrogenesis and Vasculogenesis
Authors: ALDA TUFRO, VICTORIA F. NORWOOD, ROBERT M. CAREY, R. ARIEL GOMEZ
Journal: Journal of the American Society of Nephrology (1999)

The expression of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and Flk-1 in the rat kidney was examined during ontogeny using Northern blot analysis and immunocytochemistry. In prevascular embryonic kidneys (embryonic day 14 [E14]), immunoreactive Flt-1 and Flk-1 were observed in isolated angioblasts, whereas VEGF was not detected. Angioblasts aligned forming cords before morphologically differentiating into endothelial cells. In late fetal kidneys (E19), immunoreactive VEGF was detected in glomerular epithelial and tubular cells, whereas Flt-1 and Flk-1 were expressed in contiguous endothelial cells. To determine whether VEGF induces endothelial cell differentiation and vascular development in the kidney, the effect of recombinant human VEGF (5 ng/ml) was examined on rat metanephric organ culture, a model known to recapitulate nephrogenesis in the absence of vessels. After 6 d in culture in serum-free, defined media, metanephric kidney growth and morphology were assessed. DNA content was higher in VEGF-treated explants (1.9 +/- 0.17 microg/kidney, n = 9) than in paired control explants (1.4 +/- 0.10 microg/kidney, n = 9) (P < 0.05). VEGF induced proliferation of tubular epithelial cells, as indicated by an increased number of tubules and tubular proliferating cell nuclear antigen-containing cells. VEGF induced upregulation of Flk-1 and Flt-1 expression, as assessed by Western blot analysis. Developing endothelial cells were identified and localized using immunocytochemistry and electron microscopy. Flt-1, Flk-1, and angiotensin-converting enzyme-containing cells were detected in VEGF-treated explants, whereas control explants were negative. These studies confirmed previous reports indicating that the expression of VEGF and its receptors is temporally and spatially associated with kidney vascularization and identified angioblasts expressing Flt-1 and Flk-1 in prevascular embryonic kidneys. The data indicate that VEGF expression is downregulated in standard culture conditions and that VEGF stimulates growth of embryonic kidney explants by expanding both endothelium and epithelium, resulting in vasculogenesis and enhanced tubulogenesis. These data suggest that VEGF plays a critical role in renal development by promoting endothelial cell differentiation, capillary formation, and proliferation of tubular epithelia.
Novel Cryo-Imaging of the Glioma Tumor Microenvironment Reveals Migration and Dispersal Pathways in Vivid Three-Dimensional Detail
Authors: Susan M. Burden-Gulley, Mohammed Q. Qutaish, Kristin E. Sullivant, Hong Lu, Jing Wang, Sonya E.L. Craig, James P. Basilion, David L. Wilson, Susann M. Brady-Kalnay
Journal: Cancer Research (2011)

Traditional methods of imaging cell migration in the tumor microenvironment include serial sections of xenografts and standard histologic stains. Current molecular imaging techniques suffer from low resolution and difficulty in imaging through the skull. Here we show how computer algorithms can be used to reconstruct images from tissue sections obtained from mouse xenograft models of human glioma and can be rendered into three-dimensional images offering exquisite anatomic detail of tumor cell dispersal. Our findings identify human LN-229 and rodent CNS-1 glioma cells as valid systems to study the highly dispersive nature of glioma tumor cells along blood vessels and white matter tracts in vivo. This novel cryo-imaging technique provides a valuable tool to evaluate therapeutic interventions targeted at limiting tumor cell invasion and dispersal.
Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell
Authors: Shiro Yui, Tetsuya Nakamura, Toshiro Sato, Yasuhiro Nemoto, Tomohiro Mizutani, Xiu Zheng, Shizuko Ichinose, Takashi Nagaishi, Ryuichi Okamoto, Kiichiro Tsuchiya, Hans Clevers, Mamoru Watanabe
Journal: Nature Medicine (2012)
Second-degree atrioventricular block.
Authors: D P Zipes
Journal: Circulation (1979)

1) While it is possible only one type of second-degree AV block exists electrophysiologically, the available data do not justify such a conclusion and it would seem more appropriate to remain a "splitter," and advocate separation and definition of multiple mechanisms, than to be a "lumper," and embrace a unitary concept. 2) The clinical classification of type I and type II AV block, based on present scalar electrocardiographic criteria, for the most part accurately differentiates clinically important categories of patients. Such a classification is descriptive, but serves a useful function and should be preserved, taking into account the caveats mentioned above. The site of block generally determines the clinical course for the patient. For most examples of AV block, the type I and type II classification in present use is based on the site of block. Because block in the His-Purkinje system is preceded by small or nonmeasurable increments, it is called type II AV block; but the very fact that it is preceded by small increments is because it occurs in the His-Purkinje system. Similar logic can be applied to type I AV block in the AV node. Exceptions do occur. If the site of AV block cannot be distinguished with certainity from the scalar ECG, an electrophysiologic study will generally reveal the answer.
Probable Transmission of HIV from an Orthopedic Surgeon to a Patient in France
Authors: Florence Lot
Journal: Annals of Internal Medicine (1999)

Background: Transmission of HIV from infected health care workers to patients has been documented in only one cluster involving 6 patients of a dentist in Florida. In October 1995, the French Ministry of Health offered HIV testing to patients who had been operated on by an orthopedic surgeon in whom AIDS was recently diagnosed. Objective: To determine whether the surgeon transmitted HIV to patients during operations. Design: Epidemiologic investigation. Setting: The practice of an orthopedic surgeon in a French public hospital. Participants: 1 surgeon and 983 of his former patients. Measurements: 3004 patients who had undergone invasive procedures were contacted by mail for counseling and HIV testing. One HIV-positive patient was interviewed, and DNA sequence analysis was performed to compare the genetic relation of the patient's and the surgeon's viruses. Infection-control precautions and the surgeon's practices were assessed. Results: Of 983 patients in whom serologic status was ascertained, 982 were HIV negative and 1 was HIV positive. The HIV-positive patient, a woman born in 1925, tested negative for HIV before placement of a total hip prosthesis with bone graft (a prolonged operation) performed by the surgeon in 1992. She had no identified risk for HIV exposure. Molecular analysis indicated that the viral sequences obtained from the surgeon and the HIV-infected woman were closely related. Infection-control precautions were in accordance with recommendations, but blood contact between the surgeon and his patients occurred commonly during surgical procedures. Conclusions: An HIV-infected surgeon may have transmitted HIV to one of his patients during surgery.
Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease
Authors: Anne M. Landau, Kelvin C. Luk, Michelle-Lee Jones, Rosmarie Siegrist-Johnstone, Yoon Kow Young, Edouard Kouassi, Vladimir V. Rymar, Alain Dagher, Abbas F. Sadikot, Julie Desbarats
Journal: The Journal of Experimental Medicine (2005)

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo.
Real Time Dynamic Imaging and Current Targeted Therapies in the War on Cancer: A New Paradigm
Authors: Ramasamy Paulmurugan, Bryan Oronsky, Chad F Brouse, Tony Reid, Susan Knox, Jan Scicinski
Journal: Theranostics (2013)

In biology, as every science student is made to learn, ontology recapitulates phylogeny. In medicine, however, oncology recapitulates polemology, the science of warfare: The medical establishment is transitioning from highly toxic poisons that kill rapidly dividing normal and malignant cells with little specificity to tailored therapies that target the tumors with the lethality of the therapeutic warhead. From the advent of the information age with the incorporation of high-tech intelligence, reconnaissance, and surveillance has resulted in "data fusion" where a wide range of information collected in near real-time can be used to redesign most of the treatment strategies currently used in the clinic. The medical community has begun to transition from the 'black box' of tumor therapy based solely on the clinical response to the 'glass box' of dynamic imaging designed to bring transparency to the clinical battlefield during treatment, thereby informing the therapeutic decision to 'retreat or repeat'. The tumor microenvironment is dynamic, constantly changing in response to therapeutic intervention, and therefore the therapeutic assessment must map to this variable and ever-changing landscape with dynamic and non-static imaging capabilities. The path to personalized medicine will require incorporation and integration of dynamic imaging at the bedside into clinical practice for real-time, interactive assessment of response to targeted therapies. The application of advanced real time imaging techniques along with current molecularly targeted anticancer therapies which alter cellular homeostasis and microenvironment can enhance therapeutic interventions in cancer patients and further improve the current status in clinical management of patients with advanced cancers.
Zoledronic Acid Prevents Cancer Treatment–Induced Bone Loss in Premenopausal Women Receiving Adjuvant Endocrine Therapy for Hormone-Responsive Breast Cancer: A Report From the Austrian Breast and Colorectal Cancer Study Group
Authors: Michael F.X. Gnant, Brigitte Mlineritsch, Gero Luschin-Ebengreuth, Stephan Grampp, Helmut Kaessmann, Marianne Schmid, Christian Menzel, Jutta Claudia Piswanger-Soelkner, Arik Galid, Martina Mittlboeck, Hubert Hausmaninger, Raimund Jakesz
Journal: Journal of Clinical Oncology (2006)

Adjuvant therapy for breast cancer can be associated with decreased bone mineral density (BMD) that may lead to skeletal morbidity. This study examined whether zoledronic acid can prevent bone loss associated with adjuvant endocrine therapy in premenopausal patients.This study is a randomized, open-label, phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and goserelin (3.6 mg every 28 days subcutaneously) +/- zoledronic acid (4 mg intravenously every 6 months) versus anastrozole (1 mg/d orally) and goserelin +/- zoledronic acid for 3 years in premenopausal women with hormone-responsive breast cancer. In a BMD subprotocol at three trial centers, patients underwent serial BMD measurements at 0, 6, 12, 24, and 36 months.Four hundred one patients were included in the BMD subprotocol. Endocrine treatment without zoledronic acid led to significant (P < .001) overall bone loss after 3 years of treatment (BMD, -14.4% after 36 months; mean T score reduction, -1.4). Overall bone loss was significantly more severe in patients receiving anastrozole/goserelin (BMD, -17.3%; mean T score reduction, -2.6) compared with patients receiving tamoxifen/goserelin (BMD, -11.6%; mean T score reduction, -1.1). In contrast, BMD remained stable in zoledronic acid-treated patients (P < .0001 compared with endocrine therapy alone). No interactions with age or other risk factors were noted.Endocrine therapy caused significant bone loss that increased with treatment duration in premenopausal women with breast cancer. Zoledronic acid 4 mg every 6 months effectively inhibited bone loss. Regular BMD measurements and initiation of concomitant bisphosphonate therapy on evidence of bone loss should be considered for patients undergoing endocrine therapy.
Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury
Authors: Axelle Caudrillier, Kai Kessenbrock, Brian M. Gilliss, John X. Nguyen, Marisa B. Marques, Marc Monestier, Pearl Toy, Zena Werb, Mark R. Looney
Journal: Journal of Clinical Investigation (2012)

There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.
Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening
Authors: Matthew A. Held, Casey G. Langdon, James T. Platt, Tisheeka Graham-Steed, Zongzhi Liu, Ashok Chakraborty, Antonella Bacchiocchi, Andrew Koo, Jonathan W. Haskins, Marcus W. Bosenberg, David F. Stern
Journal: Cancer Discovery (2012)

Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small-molecule inhibitors on early-passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGF receptor and AKT sensitized treatment-resistant BRAF mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results show the use of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF- and RAS-driven melanomas.We have used drug combinatorial screening to identify effective combinations for mutant BRAF melanomas, including those resistant to vemurafenib, and mutant RAS melanomas that are resistant to many therapies. Mechanisms governing the interactions of the drug combinations are proposed, and in vivo xenografts show the enhanced benefit and tolerability of a mutant RAS -selective combination, which is currently lacking in the clinic.
Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall
Authors: A. Gronchi, P. Verderio, A. De Paoli, A. Ferraro, O. Tendero, J. Majò, J. Martin, A. Comandone, G. Grignani, S. Pizzamiglio, V. Quagliuolo, P. Picci, S. Frustaci, A.P. Dei Tos, E. Palassini, S. Stacchiotti, S. Ferrari, M. Fiore, P.G. Casali
Journal: Annals of Oncology (2012)