tbuckley/cabot-search huggingface dataset:
ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation
Authors: Chia-Jen Siao, Christina U. Lorentz, Pouneh Kermani, Tina Marinic, John Carter, Kelly McGrath, Victoria A. Padow, Willie Mark, Domenick J. Falcone, Leona Cohen-Gould, Diana C. Parrish, Beth A. Habecker, Anders Nykjaer, Lora H. Ellenson, Lino Tessarollo, Barbara L. Hempstead
Journal: The Journal of Experimental Medicine (2012)

Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro-nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75(NTR)) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75(NTR) in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up-regulation of proNGF by cardiomyocytes and p75(NTR) by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF-expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75(NTR) in proNGF-expressing mice rescues the phenotype, confirming the importance of p75(NTR)-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75(NTR) limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction.
T-Lymphocyte Clones
Authors: C. Garrison Fathman, John G. Frelinger
Journal: Annual Review of Immunology (1983)

To date, the most successful uses of T-cell clones have been in the demonstration that a single type of cell can perform multiple functions. However, their potential usefulness is enormous, and the study of cell interactions using clonal populations has just begun. The development and study of more cloned populations will surely lead to a clearer analysis of cellular interactions in the immune system. The use of T-cell clones and hybridomas to analyze T-cell receptors and/or factors is well under way, and will continue to be an area of intense investigation. Molecular biologists will undoubtedly make more extensive use of T-cell clones in the future, both as a source of cloning material and as transfection recipients. The most exciting area for development, from a medical point of view, is the potential for use of these cell lines or their products in immunotherapy and in providing a mechanism for specifically modulating the immune response.
Schizophrenia: The elusive disease
Authors: Jaak Panksepp, Joseph Moskal
Journal: Behavioral and Brain Sciences (2004)

All mammals have social brains, and there is presently no evidence that humans have relatively more genetically dictated social brain circuitry than other species. The postulation that schizophrenia arises from disruption of brains systems uniquely devoted to social traits is obviated not only by the large number of anatomical and biochemical brain differences, but also by nonsocial symptoms of schizophrenic disorders.
Indoleamine 2,3-dioxygenase–dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model
Authors: Yousef A. Taher, Benoit J.A. Piavaux, Reneé Gras, Betty C.A.M. van Esch, Gerard A. Hofman, Nanne Bloksma, Paul A.J. Henricks, Antoon J.M. van Oosterhout
Journal: Journal of Allergy and Clinical Immunology (2008)
Primary Bone Neoplasms in Beagle Dogs Exposed by Inhalation to Aerosols of Plutonium-238 Dioxide&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: F F Hahn, J A Mewhinney, B S Merickel, R A Guilmette, B B Boecker, R O McClellan
Journal: JNCI Journal of the National Cancer Institute (1981)

Primary bone neoplasms developed in beagle dogs briefly exposed by inhalation to aerosols of 238PuO2. 238PuO2 was initially deposited in the respiratory tract where it was retained with a half time greater than 100 days. A portion of the 238Pu was solubilized and translocated to the liver and skeleton. Five years after exposure, 46 osteosarcomas developed in 35 of 144 exposed dogs. The cumulative absorbed radiation doses to skeleton for these dogs ranged from 210 to 830 rad. Of the 46 bone tumors, 22 originated in the vertebrae, 12 in the humeri, 6 in the pelves, and 6 in miscellaneous long and flat bones. Most of the tumors were well-differentiated sarcomas. Only 10 of the tumors metastasized; the lung was the organ most often invaded. Bone tumors were associated with lesions of radiation osteodysplasia. The number of bone tumors found in this study indicated that inhaled 238PuO2 was an effective skeletal carcinogen. The rate of solubilization in the lung and translocation to bone may be a factor in the radiation dose pattern and type and location of bone tumors that developed after inhalation of 238PuO2.
Acute Host-Mediated Endothelial Injury After Adenoviral Gene Transfer in Normal Rabbit Arteries
Authors: Keith M. Channon, HuSheng Qian, Scot A. Youngblood, Ercument Olmez, Geetha A. Shetty, Valentina Neplioueva, Michael A. Blazing, Samuel E. George
Journal: Circulation Research (1998)

Abstract —Acute injury after adenoviral vascular gene transfer remains incompletely characterized. Here, we describe the early response (≤days) in 52 New Zealand White rabbits undergoing gene transfer (β-galactosidase or empty vector) or sham procedures to both carotid arteries. After gene transfer, arteries were either left in vivo for 1 hour to 3 days (in vivo arteries) or were excised immediately after gene transfer and cultured (ex vivo arteries). Within 1 hour, in vivo arteries receiving infectious titers of ≥4×10 9 plaque-forming units (pfu)/mL showed endothelial activation, with an acute inflammatory infiltrate developing by 6 hours. Ex vivo arteries showed endothelial activation but no inflammatory infiltrate. There were also significant differences in transgene expression between in vivo and ex vivo arteries. Ex vivo arteries showed titer-dependent increases in β-galactosidase expression through 2×10 10 pfu/mL, whereas in in vivo arteries, titers above 4×10 9 pfu/mL merely increased acute inflammatory response, without increasing transgene expression. In vivo arteries showed significant time- and titer-dependent impairment in endothelium-dependent relaxation, with no effect on contraction or nitroprusside-induced relaxation. Interestingly, however, if rabbits were made neutropenic with vinblastine, their arteries maintained full endothelium-dependent relaxation, even after very high titer vascular infection (up to 1×10 11 pfu/mL). These findings show that recombinant adenovirus triggers an early inflammatory response, and it is the inflammatory response that in turn causes functional endothelial injury. This occurs at much lower titers than previously appreciated (though the precise threshold will undoubtedly vary between laboratories). However, titers below the inflammatory threshold produce excellent transgene expression without inflammation or vascular injury.
Human Podocytes Adhere to the KRGDS Motif of the α3α4α5 Collagen IV Network
Authors: Corina M. Borza, Dorin-Bogdan Borza, Vadim Pedchenko, Moin A. Saleem, Peter W. Mathieson, Yoshikazu Sado, Heather M. Hudson, Ambra Pozzi, Juan Saus, Dale R. Abrahamson, Roy Zent, Billy G. Hudson
Journal: Journal of the American Society of Nephrology (2008)

Podocyte adhesion to the glomerular basement membrane is required for proper function of the glomerular filtration barrier. However, the mechanism whereby podocytes adhere to collagen IV networks, a major component of the glomerular basement membrane, is poorly understood. The predominant collagen IV network is composed of triple helical protomers containing the alpha3alpha4alpha5 chains. The protomers connect via the trimeric noncollagenous (NC1) domains to form hexamers at the interface. Because the NC1 domains of this network can potentially support integrin-dependent cell adhesion, it was determined whether individual NC1 monomers or alpha3alpha4alpha5 hexamers support podocyte adhesion. It was found that, although human podocytes did not adhere to NC1 domains proper, they did adhere via integrin alphavbeta3 to a KRGDS motif located adjacent to alpha3NC1 domains. Because the KRGDS motif is a site of phosphorylation, its interactions with integrin alphavbeta3 may play a critical role in cell signaling in physiologic and pathologic states.
Movement of Tuberculosis Patients and the Failure to Complete Antituberculosis Treatment
Authors: KATE C. CUMMINGS, JANET MOHLE-BOETANI, SARAH E. ROYCE, DANIEL P. CHIN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The outcomes of tuberculosis (TB) patients who move before completing antituberculosis treatment have not been described. We studied a population-based cohort of 2,576 adult patients reported as having TB in California during 1993, including 147 patients who moved from one local health jurisdiction to another within California. We determined treatment outcomes (completed, defaulted, died, other) for 131 (89%) of these 147 patients. Patients who moved defaulted more often (relative risk [RR] = 5.5, 95% confidence interval [CI] = 4.1 to 7.4) than patients who did not move. Including these patients' treatment outcomes increased the known number of defaulters by 30%, from 141 to 183 persons. Additionally, diagnosis of TB in a state prison emerged as the strongest risk factor for defaulting from treatment. Patients who moved or defaulted were more likely to abuse drugs or alcohol, to be homeless or to be associated with congregate settings such as jails and prisons. On average, patients who defaulted after moving received less than three-quarters of their recommended treatment regimens. These patients may remain infectious or become infectious again. Our findings highlight the importance of ensuring complete treatment for TB patients who move; failure to do so will adversely affect patient health and TB control, especially in many high-risk populations and settings.
CD28-inducible transcription factor DEC1 is required for efficient autoreactive CD4+ T cell response
Authors: Marc Martínez-Llordella, Jonathan H. Esensten, Samantha L. Bailey-Bucktrout, Robert H. Lipsky, Ann Marini, Jun Chen, Mohamed Mughal, Mark P. Mattson, Dennis D. Taub, Jeffrey A. Bluestone
Journal: The Journal of Experimental Medicine (2013)

During the initial hours after activation, CD4+ T cells experience profound changes in gene expression. Co-stimulation via the CD28 receptor is required for efficient activation of naive T cells. However, the transcriptional consequences of CD28 co-stimulation are not completely understood. We performed expression microarray analysis to elucidate the effects of CD28 signals on the transcriptome of activated T cells. We show that the transcription factor DEC1 is highly induced in a CD28-dependent manner upon T cell activation, is involved in essential CD4+ effector T cell functions, and participates in the transcriptional regulation of several T cell activation pathways, including a large group of CD28-regulated genes. Antigen-specific, DEC1-deficient CD4+ T cells have cell-intrinsic defects in survival and proliferation. Furthermore, we found that DEC1 is required for the development of experimental autoimmune encephalomyelitis because of its critical role in the production of the proinflammatory cytokines GM-CSF, IFN-γ, and IL-2. Thus, we identify DEC1 as a critical transcriptional mediator in the activation of naive CD4+ T cells that is required for the development of a T cell–mediated autoimmune disease.
Laboratory assessment of fitness to fly in patients with lung disease: a practical approach
Authors: A.G. Robson, T.K. Hartung, J.A Innes
Journal: European Respiratory Journal (2000)

To identify patients with respiratory disease, who may be at risk of developing respiratory distress during commercial air travel, a hypoxia inhalation test (HIT) can be performed. This paper reports our experience of using such a test combined with an interpretation algorithm in a routine respiratory function laboratory. Twenty-eight patients were studied. Baseline oxygen saturation (Sa,O2) was measured using a pulse oximeter. If Sa,O2 was &lt; 90% no HIT was performed and the patient was assessed as unfit for air travel. If baseline Sa,O2 was &gt; or = 90% an HIT was performed by the patient breathing through a 35% Venturi mask supplied with 100% nitrogen which reduced inspiratory oxygen fraction to 15.1+/-0.2%. Results were interpreted using a locally derived algorithm, and validation was attempted using a questionnaire to investigate subsequent symptoms during travel. All patients tolerated the assessment well. Twenty-two patients were assessed as "fit to fly" with a further two patients "fit to fly with supplemental O2". Four patients were considered unfit to fly. Hypoxic response could not be predicted from either forced expiratory volume in one second, or pretest saturation. Validation of such protocols is difficult, but the hypoxia inhalation test may be a useful tool for predicting hypoxia during air travel in patients with chronic respiratory disease.
Deoxyuridine suppression studies in bone marrow in primary refractory sideroblastic anemia
Authors: Anita Goodman, Bruce Bacon, John D. Hines
Journal: American Journal of Hematology (1978)

Abstract Because unexplained megaloblastic erythroid maturation occurs in patients with primary refractory sideroblastic anemia (PRSA), deoxyuridine (dU) suppression tests using 125 I‐UdR were performed on bone marrow from five patients with PRSA. All patients had megaloblastic alterations in the marrow erythroid precursors (with normal serum folate and B 12 levels) and numerous ringed sideroblasts, and most had marrow iron overload. Results of the dU suppression tests were normal in all five, both with and without incubation with pharmacologic amounts of folate, B 12 , and pyridoxal phosphate with or without 1‐serine. Despite occasional hematologic improvement subsequent to folate, pyridoxine, or pyridoxal phosphate (PLP) administration in some patients with PRSA, normal dU suppression implies that in our group the availability of B 12 and folate (and possibly PLP) was not limiting in the utilization of folate for DNA‐thymine synthesis. The marrow erythroid maturation defect remains unexplained.
Studies of neutrophil production and turnover in grey collie dogs with cyclic neutropenia
Authors: D. C. Dale, S. B. Ward, H. R. Kimball, S. M. Wolff
Journal: Journal of Clinical Investigation (1972)

12 grey collie dogs had cyclic neutropenia with the neutropenia recurring at 11.8+/-0.1-day intervals. The recovery from neutropenia was accompanied by a single wave of myeloid proliferation, an increase in marrow myeloid-labeling indices, and an increase in serum muramidase levels. After recovery from neutropenia during the period when blood neutrophils (PMN) were normal or increased, marrow myeloid precursors became scarce. The decline in marrow precursors and marrow PMN reserves heralded the recurrence of neutropenia. Neither diisopropyl fluorophosphate (DF(32)P) leukokinetic studies nor the rate of development of neutropenia suggested shortened PMN survival as a mechanism for the neutropenia. These studies indicate that the cyclic neutropenia is due to a regularly recurring failure in PMN production.
Spinal cord trauma and the molecular point of no return
Authors: Ping K Yip, Andrea Malaspina
Journal: Molecular Neurodegeneration (2012)

A mechanical trauma to the spinal cord can be followed by the development of irreversible and progressive neurodegeneration, as opposed to a temporary or partially reversible neurological damage. An increasing body of experimental and clinical evidence from humans and animal models indicates that spinal cord injury may set in motion the development of disabling and at times fatal neuromuscular disorders, whose occurrence is not normally associated with any major environmental event. This outcome appears to be dependent on the co-occurrence of a particular form of mechanical stress and of a genetically-determined vulnerability. This increased vulnerability to spinal cord injury may depend on a change of the nature and of the timing of activation of a number of neuroprotective and neurodestructive molecular signals in the injured cord. Among the main determinants, we could mention an altered homeostasis of lipids and neurofilaments, an earlier inflammatory response and the failure of the damaged tissue to rein in oxidative damage and apoptotic cell death. These changes could force injured tissue beyond a point of no return and precipitate an irreversible neurodegenerative process. A better knowledge of the molecular signals activated in a state of increased vulnerability to trauma can inform future treatment strategies and the prediction of the neurological outcome after spinal cord injury.
Defining Key Signaling Nodes and Therapeutic Biomarkers in <i>NF1</i>-Mutant Cancers
Authors: Clare F. Malone, Jody A. Fromm, Ophélia Maertens, Thomas DeRaedt, Rachel Ingraham, Karen Cichowski
Journal: Cancer Discovery (2014)

Abstract NF1 encodes a RAS GTPase-activating protein. Accordingly, aberrant RAS activation underlies the pathogenesis of NF1-mutant cancers. Nevertheless, it is unclear which RAS pathway components represent optimal therapeutic targets. Here, we identify mTORC1 as the key PI3K effector in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. However, we find that tumor regression requires sustained inhibition of both mTORC1 and MEK. Transcriptional profiling studies were therefore used to establish a signature of effective mTORC1–MEK inhibition in vivo. We unexpectedly found that the glucose transporter GLUT1 was potently suppressed, but only when both pathways were inhibited. Moreover, unlike VHL- and LKB1-mutant cancers, reduction of 18F-FDG uptake required the suppression of both mTORC1 and MEK. Together, these studies identify optimal and suboptimal therapeutic targets in NF1-mutant malignancies and define a noninvasive means of measuring combined mTORC1–MEK inhibition in vivo, which can be readily incorporated into clinical trials. Significance: This work demonstrates that mTORC1 and MEK are key therapeutic targets in NF1-mutant cancers and establishes a noninvasive biomarker of effective, combined target inhibition that can be evaluated in clinical trials. Cancer Discov; 4(9); 1062–73. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 973
Cell Cycle Checkpoints, DNA Damage/Repair, and Lung Cancer Risk
Authors: Xifeng Wu, Jack A. Roth, Hua Zhao, Sherry Luo, Yun-Ling Zheng, Silvia Chiang, Margaret R. Spitz
Journal: Cancer Research (2005)

Abstract Given that defects in cell cycle control and DNA repair capacity may contribute to tumorigenesis, we hypothesized that patients with lung cancer would be more likely than healthy controls to exhibit deficiencies in cell cycle checkpoints and/or DNA repair capacity as gauged by cellular response to in vitro carcinogen exposure. In an ongoing case-control study of 155 patients with newly diagnosed lung cancer and 153 healthy controls, we used the comet assay to investigate the roles of cell cycle checkpoints and DNA damage/repair capability in lung tumorigenesis. The median γ-radiation-induced and benzo(a)pyrene diol epoxide–induced Olive tail moments, the comet assay parameter for measuring DNA damage, were significantly higher in the case group (5.31 and 4.22, respectively) than in the control group (4.42 and 2.83, respectively; P &amp;lt; 0.001). Higher tail moments of γ-radiation and benzo(a)pyrene diol epoxide–induced comets were significantly associated with 2.32- and 4.49-fold elevated risks, respectively, of lung cancer. The median γ-radiation-induced increases of cells in the S and G2 phases were significantly lower in cases (22.2% and 12.2%, respectively) than in controls (31.1% and 14.9%, respectively; P &amp;lt; 0.001). Shorter durations of the S and G2 phases resulted in 4.54- and 1.85-fold increased risks, respectively, of lung cancer. Also observed were joint effects between γ-radiation-induced increases of S and G2 phase frequencies and mutagen-induced comets. In addition, we found that in controls, the S phase decreased as tail moment increased. This study is significant because it provides the first molecular epidemiologic evidence linking defects in cell cycle checkpoints and DNA damage/repair capacity to elevated lung cancer risk.
The Mechanism of Suppression of Proximal Tubular Reabsorption by Saline Infusions*
Authors: Floyd C. Rector, Jack C. Sellman, Manuel Martinez-Maldonado, Donald W. Seldin
Journal: Journal of Clinical Investigation (1967)

The mechanism by which expansion of extracellular fluid volume with isotonic saline suppresses reabsorption in the proximal tubule was studied in rats by examining the relations among glomerular filtration rate (GFR), absolute and fractional reabsorption of filtrate, intrinsic reabsorptive capacity (rate of reabsorption per unit tubular volume), transit time, and tubular volume. Saline infusions reduced the per cent of the glomerular filtrate reabsorbed in the proximal tubule from 50% during antidiuresis to 25% during saline diuresis. The suppression of proximal reabsorption was the result of two factors: 1) a 30% reduction of intrinsic reabsorptive capacity, and 2) a 26% reduction of tubular volume per unit GFR.GFR invariably rose during saline diuresis. However, prevention of the rise in GFR by aortic clamping had no effect on either the inhibition of intrinsic reabsorptive capacity or the reduction in tubular volume per unit GFR produced by saline infusions. Expansion of extracellular fluid volume with isotonic saline, therefore, depressed intrinsic reabsorptive capacity and tubular volume per unit GFR by some mechanism completely independent of GFR. The effects of furosemide administration were contrasted with those of saline infusions. Furosemide inhibited intrinsic reabsorptive capacity by 40% but had no significant effect on proximal fractional reabsorption. The failure to suppress fractional reabsorption was the consequence of a disproportionate rise in tubular volume (relative to GFR) that was sufficient to completely overcome the inhibition of intrinsic reabsorptive capacity. Inhibition of intrinsic reabsorptive capacity alone, therefore, will not result in a net suppression of reabsorption of filtrate in the proximal tubule. We concluded that, although intrinsic reabsorptive capacity was inhibited during saline diuresis, the critical factor responsible for translating this inhibition into effective net suppression of proximal reabsorption was the observed reduction in tubular volume per unit GFR.