tbuckley/cabot-search huggingface dataset:
P53 inhibition exacerbates late-stage anthracycline cardiotoxicity
Authors: Wuqiang Zhu, Wenjun Zhang, Weinian Shou, Loren J. Field
Journal: Cardiovascular Research (2014)

Doxorubicin (DOX) is an effective anti-cancer therapeutic, but is associated with both acute and late-stage cardiotoxicity. Children are particularly sensitive to DOX-induced heart failure. Here, the impact of p53 inhibition on acute vs. late-stage DOX cardiotoxicity was examined in a juvenile model.Two-week-old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last DOX treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient DOX-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals.These data support a model wherein a p53-dependent cardioprotective pathway, mediated via STAT3 activation, mitigates DOX-induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced cardiotoxicity long after the cessation of drug treatment.
Mutation of<i>CEBPA</i>in Familial Acute Myeloid Leukemia
Authors: Matthew L. Smith, Jamie D. Cavenagh, T. Andrew Lister, Jude Fitzgibbon
Journal: New England Journal of Medicine (2004)

We describe a family in whom three members affected by acute myeloid leukemia (AML) had an identical, 212delC mutation in CEBPA, the gene encoding the granulocytic differentiation factor C/EBPalpha. Unaffected family members did not have this mutation. Latent periods of 10, 18, and 30 years elapsed before the onset of overt leukemia in the three patients. One of them had a second CEBPA mutation, but only at the time of diagnosis. All three patients are currently well, with no abnormalities in the bone marrow. CEBPA mutation is apparently the primary event in the development of AML in this family.
Selective antagonism of hormone-induced vasoconstriction by synthetic atrial natriuretic factor in the rat microcirculation.
Authors: K G Proctor, S L Bealer
Journal: Circulation Research (1987)

Synthetic atrial natriuretic factor (ANF) was either added to suffusate solutions (30 nM) or infused into the jugular vein (0.1 nanomol/min/100 g) of anesthetized rats. Steady-state blood flow was calculated from arteriolar diameter and red blood cell velocity measurements using video microscopy in the intestinal or skeletal muscle microcirculation. Arterioles demonstrated spontaneous vasomotor tone by dilating to topical adenosine, but topical or intravenous ANF did not cause vasodilation. Either angiotensin, norepinephrine, or vasopressin was added to the suffusates in the presence or absence of a cyclooxygenase inhibitor (30 microM, meclofenamate or indomethacin) because each agonist is known to stimulate vasoactive prostanoid synthesis. In the intestine, angiotensin (500 nM) caused 40 +/- 2% blood flow decreases during intravenous saline but only 23 +/- 6% during intravenous ANF. Angiotensin (162 nM) and a cyclooxygenase inhibitor caused 19 +/- 4% blood flow decreases but only 8 +/- 5% decreases with cyclooxygenase inhibitor and topical ANF. In contrast, norepinephrine (2-5 microM) caused vasoconstriction that was not altered by topical or intravenous ANF, either alone or in combination with cyclooxygenase inhibitors. In the spinotrapezius muscle, angiotensin (1-2 nM) plus a cyclooxygenase inhibitor caused 40-60% blood flow decreases but only 20-30% decreases during intravenous or topical ANF. Topical or intravenous ANF did not alter the vasoconstriction evoked by arginine vasopressin (0.5-1.0 nM) or by norepinephrine (40-230 nM). Thus, supraphysiologic concentrations of ANF produced no direct vasodilation in the intestinal or skeletal muscle microcirculation.(ABSTRACT TRUNCATED AT 250 WORDS)
IMMUNOLOGIC BASIS OF ANTIGEN-INDUCED AIRWAY HYPERRESPONSIVENESS
Authors: Marsha Wills-Karp
Journal: Annual Review of Immunology (1999)

▪ Abstract The incidence, morbidity, and mortality of asthma has increased worldwide over the last two decades. Asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), and airway inflammation. The inflammatory response in the asthmatic lung is characterized by infiltration of the airway wall with mast cells, lymphocytes, and eosinophils. Although asthma is multifactorial in origin, the inflammatory process in the most common form of the disease (extrinsic asthma) is believed to be a result of inappropriate immune responses to common aero-allergens in genetically susceptible individuals. As such, it has been hypothesized that CD4 + T cells that produce a Th2 pattern of cytokines play a pivotal role in the pathogenesis of this disease. Through the release of cytokines such as IL-4, IL-13, and IL-5, these cells orchestrate the recruitment and activation of the primary effector cells of the allergic response, the mast cell and the eosinophil. Activation of these cells results in the release of a plethora of inflammatory mediators that individually or in concert induce changes in airway wall geometry and produce the symptoms of the disease. The aim of this review is to discuss our current understanding of the pathophysiologic mechanisms by which Th2 cytokines induce airway disease, and the factors that predispose to the generation of these pathogenic cells in response to inhalation of ubiquitous aero-allergens. Elucidation of the exact immunological basis for allergic asthma may yield immunotherapeutic strategies to reverse the development of pathogenic Th2-mediated immune responses and reduce the morbidity and mortality associated with this disease.
Focal Transient Cerebral Ischemia in the Squirrel Monkey
Authors: THORALF M. SUNDT, JOHN D. MICHENFELDER
Journal: Circulation Research (1972)

Cerebral adenosine triphosphate and lactate concentrations were measured in the squirrel monkey ( Saimiri sciureus ) before, during, and at selected times after various periods of middle cerebral artery occlusion. The gradual decrease in ATP to 55, 35, and 20%, of normal and the increase in lactate to 7, 8, and 10 times normal after 2, 3, and 4 hours of occlusion, respectively, were reversible with restoration of flow. Electrocorticograms recorded in acute preparations indicated potential for recovery. The correlation of lactate levels with previous determinations of blood flow in this preparation supports the theory that loss of autoregulation and "luxury perfusion" in cerebral ischemia results from localized metabolic acidosis due to accumulation of lactic acid. In a separate group of monkeys, the ischemic lesions were found to be largely reversible after 2 or 3 hours and irreversible after 4 hours of middle cerebral artery occlusion; the cause of death in the monkeys subjected to 4 hours of occlusion was edema, which progressed even after restoration of flow.
Tissue Engineering: Orthopedic Applications
Authors: C. T. Laurencin, A. M. A. Ambrosio, M. D. Borden, J. A. Cooper
Journal: Annual Review of Biomedical Engineering (1999)

▪ Abstract Because of an aging population and increased occurrence of sports-related injuries, musculoskeletal disorders have become one of the major health concerns in the United States. Current treatments, although fairly successful, do not provide the optimum therapy. These treatments typically rely on donor tissues obtained either from the patient or from another source. The former raises the issue of supply, whereas the latter poses the risk of rejection and disease transfer. This has prompted orthopedic surgeons and scientists to look for viable alternatives. In recent years, tissue engineering has gained increasing support as a method to treat orthopedic disorders. Because it uses principles of engineering, biology, and chemistry, tissue engineering may provide a more effective approach to the treatment of musculoskeletal disorders than traditional methods. This chapter presents a review of current methods and new tissue-engineering techniques for the treatment of disorders affecting bone, ligament, and cartilage.
Effects of Subcutaneous Administration of 3-Methylcholanthrene and 7,12-Dimethylbenz[a]anthracene on Spontaneous Reticulum Cell Neoplasms in SJL/J Mice2
Authors: Carrie E. Whitmire
Journal: JNCI Journal of the National Cancer Institute (1979)

Inbred 4-week-old and 16-week-old SJL/J mice were treated sc with either 150 or 450 µg 3-methylcholanthrene (MCA). No difference was noted in their subcutaneous tumor response related to age. Although the incidences of reticulum cell neoplasms (RCN's) were the same in the controls for the 2 age groups, more 16-week-old animals developed RCN's after carcinogen treatment than did 4-week-old SJL/J mice. More 16-week-old mice developed both subcutaneous tumors at the site of MCA injection and systemic RCN's than did mice treated at 4 weeks of age. This incidence was related to the coinciding of the chronologie age of the mice for RCN development with the latency for chemical carcinogen-induced subcutaneous tumor development. Mice treated with 7,12-dimethylbenz[a]anthracene at 16 weeks of age responded in the same way as did those treated with MCA.
Clinical features of photodamaged human skin are associated with a reduction in collagen VII
Authors: N.M. CRAVEN, R.E.B. WATSON, C.J.P. JONES, C.A. SHUTTLEWORTH, C.M. KIELTY, C.E.M. GRIFFITHS
Journal: British Journal of Dermatology (1997)

Chronically sun-exposed or photodamaged human skin is characterized by a number of clinical features, including wrinkles. However, little is known about the molecular mechanisms that underlie these features. We investigated the hypothesis that the mechanism of wrinkle formation may involve loss of anchoring fibrils, composed mainly of collagen VII, which are important in maintaining dermal-epidermal junction integrity. Ten volunteers with moderate to severe photodamage of dorsal forearm skin were recruited to the study. Using immunohistochemistry, transmission electron microscopy and in situ hybridization, we compared collagen VII protein and mRNA content of photodamaged forearm skin with that of sun-protected hip and upper inner arm skin from the same subjects. Numbers of anchoring fibrils per linear microns of basement membrane (mean +/- SEM) were significantly lower in photodamaged skin (1.79 +/- 0.10) as compared with sun-protected hip (2.28 +/- 0.11) and upper inner arm skin (2.21 +/- 0.10) (P < 0.01), and similarly keratinocyte expression of collagen VII mRNA, quantitated as number of positively stained keratinocytes per high power field, was significantly reduced in photodamaged skin (6.3 +/- 2.5) as compared with sun-protected hip (20.0 +/- 5.6) and upper inner arm skin (17.7 +/- 4.9) (P < 0.001). Semiquantitative assessment of immunohistochemical staining for collagen VII showed a non-significant reduction in photodamaged skin as compared with sun-protected skin. We propose that reduced content of collagen VII in photodamaged skin contributes to wrinkle formation by weakening the bond between the dermis and epidermis.
Characteristics of the Delayed Rectifier Current (I <sub>Kr</sub> and I <sub>Ks</sub> ) in Canine Ventricular Epicardial, Midmyocardial, and Endocardial Myocytes
Authors: Da-Wei Liu, Charles Antzelevitch
Journal: Circulation Research (1995)

Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine, feline, rat, guinea pig, and human hearts. In this study, we use standard microelectrode and whole-cell patch-clamp techniques to examine the characteristics of the action potential and the delayed rectifier K+ current (IK) in epicardial, M region (deep subepicardial to midmyocardial), and endocardial cells isolated from the canine left ventricle. Cells from the M region displayed much longer action potential durations (APDs) at slow rates. At a basic cycle length of 4 s, APD measured at 90% repolarization was 358 +/- 16 (mean +/- SEM), 262 +/- 12, and 287 +/- 11 ms in cells from the M region, epicardium, and endocardium, respectively. Steady state APD-rate relations were steeper in cells from the M region. In complete Tyrode's solution, IK was smaller in myocytes from the M region when compared with those isolated from the epicardium or endocardium. Further characterization of IK was conducted in a Na(+)-, K(+)-, and Ca(2+)-free bath solution to isolate the slowly activating component of the delayed rectifier (IKs) from the rapidly activating component (IKr). IKs was significantly smaller in M cells than in epicardial and endocardial cells. With repolarization to -20 mV, IKs tail current density was 1.99 +/- 0.30 pA/pF (mean +/- SEM) in epicardial cells, 1.83 +/- 0.18 pA/pF in endocardial cells, and 0.92 +/- 0.14 pA/pF in M cells. Voltage dependence and time course of activation and deactivation of IKs were similar in the three cell types. The relative contribution of IKr and IKs among the three cell types was examined by using 6 mmol/L [K+]o Tyrode's solution with and without E-4031, a highly selective blocker of IKr. An E-4031-sensitive current was observed in the presence but not in the absence of extracellular K+. This rapidly activating component showed characteristics similar to those of IKr as described in rabbit and cat ventricular cells. Deactivation of IKr was significantly slower than that of IKs. IKr (E-4031-sensitive component) tail current density was similar in the three cell types, whereas IKs (E-4031-insensitive component) tail current density was significantly smaller in the M cells. Our results suggest that the distinctive phase-3 repolarization features of M cells are due in part to a lesser contribution of IKs and that this distinction may also explain why M cells are the main targets for agents that prolong APD in ventricular myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)
Tau, S-100 Calcium-Binding Protein B, and Neuron-Specific Enolase as Biomarkers of Concussion
Authors: Jeffrey J. Bazarian, Kian Merchant-Borna
Journal: JAMA Neurology (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Vascular cell-derived heparan sulfate shows coupled inhibition of basic fibroblast growth factor binding and mitogenesis in vascular smooth muscle cells.
Authors: M A Nugent, M J Karnovsky, E R Edelman
Journal: Circulation Research (1993)

Basic fibroblast growth factor (bFGF) has been previously shown to be mitogenic for vascular smooth muscle cells (VSMCs) in vivo, but only after vascular injury. We show in the present study that the regulation of bFGF-stimulated VSMC proliferation, by vascular cell-secreted heparin-like compounds, correlates with inhibition of bFGF binding to cell-associated heparin sulfate proteoglycans. The stimulation of cultured VSMC proliferation by bFGF was markedly reduced when these cells were cocultured with confluent endothelial cells or confluent VSMCs (100.8 +/- 8.4% and 55.6 +/- 2.3% inhibition, respectively) or with conditioned media from these two cell types. Balb/c3T3 fibroblasts had no statistically significant effect on bFGF-stimulated VSMC proliferation. Vascular cell-conditioned media also inhibited bFGF binding to heparan sulfate proteoglycans on VSMCs, and the inhibition of binding correlated linearly with the inhibition of proliferation after a critical amount of binding was inhibited (44%) (r = .952, P &lt; .0001). Heparinase or heparitinase treatment of conditioned media removed the bFGF-inhibitory effects, presumably by degrading heparin-like compounds. Indeed, heparin itself mimicked the inhibitory effects of conditioned media on bFGF-mediated proliferation and binding to heparin sulfate proteoglycans. These results suggest a bFGF regulatory role for vascular cell-produced heparin-like compounds, linking the mitogenic effects with binding to heparan sulfate proteoglycans for this heparin-binding growth factor.
Contribution of Toll‐like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration†
Authors: Ekihiro Seki, Hiroko Tsutsui, Yuji Iimuro, Tetsuji Naka, Gakuhei Son, Shizuo Akira, Tadamitsu Kishimoto, Kenji Nakanishi, Jiro Fujimoto
Journal: Hepatology (2005)

Toll-like receptors (TLRs) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLRs. When the receptors are activated, cells bearing TLRs produce various proinflammatory cytokines in a MyD88-dependent manner. Liver regeneration following partial hepatectomy (PH) requires innate immune responses, particularly interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) production by Kupffer cells, although the recognition and activation processes are still unknown. We investigated whether TLR/MyD88 signaling is critical for induction of innate immune responses after PH. In Myd88−/− mice after PH, induction of expression of immediate early genes involved in hepatocyte replication and phosphorylation of STAT3 in the liver, and production of TNF-α/IL-6 by and activation of NF-κB in the Kupffer cells were grossly subnormal and were associated with impaired liver regeneration. However, TLR2, 4 and 9, which recognize gram-negative and -positive bacterial products, are not essential for NF-κB activation and IL-6 production after PH, which excludes a possible contribution of TLR2/TLR4 or TLR9 to MyD88-mediated pathways. In conclusion, the TLR/MyD88 pathway is essential for incidental liver restoration, particularly its early phase. (HEPATOLOGY 2005;41:443–450.)
Combination Chemotherapy in Advanced Pancreatic Cancer: Time to Raise the White Flag?
Authors: Stephen A. Welch, Malcolm J. Moore
Journal: Journal of Clinical Oncology (2007)

Gemcitabine has been the standard palliative chemotherapy in advanced pancreatic cancer since 1997; this standard was established by a phase III trial that randomly assigned 126 symptomatic patients with advanced pancreatic cancer to either gemcitabine or fluorouracil (FU). 1 Treatment with gemcitabine versus FU was associated with improvements in 1-year survival (18% v 2%, respectively) and clinical benefit response (24% v 5%, respectively). Subsequently, thousands of patients have participated in large phaseIIItrialscomparinggemcitabinealonewithgemcitabineplus a second cytotoxic agent. 2-5 In the current issue, Herrmann et al 6 present another such study, comparing gemcitabine plus capecitabine with gemcitabine alone in advanced disease. The trial by Herrmann et al 6 is of high quality and was based on evidence from earlier phase studies that suggested the combination had sufficient activity to warrant further testing. 7,8 Similar to all prior studies
What's Needed Is a Health Care System That Learns
Authors: Mark Smith, George Halvorson, Gary Kaplan
Journal: JAMA (2012)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS
Authors: Christopher Kornfeld, Mickaël J.-Y. Ploquin, Ivona Pandrea, Abdourahmane Faye, Richard Onanga, Cristian Apetrei, Virginie Poaty-Mavoungou, Pierre Rouquet, Jérôme Estaquier, Lorenzo Mortara, Jean-François Desoutter, Cécile Butor, Roger Le Grand, Pierre Roques, François Simon, Françoise Barré-Sinoussi, Ousmane M. Diop, Michaela C. Müller-Trutwin
Journal: Journal of Clinical Investigation (2005)

T cell activation levels in HIV infection are predictive of AIDS progression. We searched for the immunological correlates of protection against disease progression by studying the early stages of nonpathogenic SIV infection in African green monkeys (SIVagm). The African green monkeys (AGMs) displayed high peak viremias and a transient decline in levels of blood CD4+ and CD8+ T cells between days 5 and 17 after infection. A concomitant increase in levels of CD4+DR+, CD8+DR+, and CD8+CD28– cells was detected. After the third week, T cell activation returned to baseline levels, which suggested a protective downregulation of T cell activation. A very early (24 hours after infection) and strong induction of TGF-β1 and FoxP3 expression was detected and correlated with increases in levels of CD4+CD25+ and CD8+CD25+ T cells. This was followed by a significant increase in levels of IL-10, whereas IFN-γ gene upregulation was more transient, and levels of TNF-α and MIP-1α/β transcripts did not increase in either blood or tissues. The profiles were significantly different during primary SIV infection in macaques (SIVmac); that is, there was a delayed increase in IL-10 levels accompanied by moderate and persistent increases in TGF-β levels. Together, our data show that SIVagm infection is associated with an immediate antiinflammatory environment and suggest that TGF-β may participate in the generation of Tregs, which may prevent an aberrant chronic T cell hyperactivation.