tbuckley/cabot-search huggingface dataset:
Abstract 3124: Platelet-derived growth factor receptor α cooperates with loss of p16/INK4a and p19/ARF to enhance tumorigenesis through the PI3K- and SHP-2-mediated signaling in the brain
Authors: Kunwei Liu, Bo Hu, Haizhong Feng, Andrius Kazlauskas, Erin Smith, Karen Symed, Robert Bachoo, Shi-Yuan Cheng
Journal: Cancer Research (2010)

Abstract Glioblastomas are the most common and lethal cancer in the central nervous system. Comprehensive genetic studies showed that in high-grade gliomas, overexpression of platelet-derived growth factor receptor alpha (PDGFRα) ranks third among top amplified genes and frequently co-occurs with loss of tumor suppressor genes, p16/INK4a and p14/ARF (p19/ARF in mice), in these high-grade glioblastomas. However, the biological consequences of PDGFRα overexpression in INK4a/ARF-deficient glial cells and glioma cells remain elusive. Here we show that activation of PDGFRα signaling by overexpressing PDGFRα and/or PDGF-A transformed Ink4a/Arf-deficient mouse astrocytes in vitro and rendered these cells highly tumorigenic in the brain of mice. Consistently, in INK4a/ARF null but not wild-type human glioma cell lines that express endogenous PDGFRα, overexpression of PDGF-A significantly enhances glioma formation in the brain. Re-introduction of p16/INK4a into Ink4a/Arf-null astrocytes suppressed PDGFRα-induced cell transformation in vitro and glioma formation in the brain. Conversely, cellular depletion of endogenous p16/INK4a by RNA interference in human glioma cells markedly enhances colony formation in vitro when compared to the controls. Mechanistically, abrogation of intrinsic tyrosine kinase activity of PDGFRα or interruptions of signaling modules at PDGFRα (Y to F mutations at specific tyrosine residues) that lost binding capacity for PI3K or Shp-2, but not PLC gamma or c-Src, significantly diminished PDGFRα-induced glioma formation in the brain. In vitro, specific YF mutations or inhibitors of PI3K or Shp-2 attenuated Akt activation and PDGFRα-induced colony formation. Furthermore, inhibition of Shp-2 by its inhibitors and siRNAs disrupts the interaction of PI3K with PDGFRα that is critical for gliomagenesis of Ink4a/Arf null cells. In summary, our data suggests that activation of PDGFRα signaling, particularly through the PI3K and Shp-2 pathways, in INK4a/ARF deficient astrocytes and glioma cells induce gliomagenesis in the brain. Our findings provide critical insights into interactions of genetic lesions frequently found in clinical glioma specimens and will be useful for identification of new therapeutic targets for treatments of patients with malignant gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3124.
Methotrexate Treatment of Idiopathic Granulomatous Hepatitis
Authors: Tamsin A. Knox
Journal: Annals of Internal Medicine (1995)

Objective: To test the efficacy and safety of low-dose oral pulse methotrexate therapy in patients with idiopathic granulomatous hepatitis who had complications of, did not respond to, or refused glucocorticoid therapy. Design: Prospective case study. Setting: Academic medical center hospital. Patients: Seven patients with biopsy-proven, idiopathic granulomatous hepatitis who could not tolerate or were unresponsive to glucocorticoid therapy. Intervention: Low-dose oral pulse methotrexate, 15 mg/wk. Measurements: Temperature, symptoms, dose of concurrent glucocorticoids, biochemical tests of liver function, side effects of methotrexate, and assessment of liver biopsy specimens. Results: All six febrile patients became afebrile within 3 months of starting methotrexate. Fatigue and anorexia improved in all patients. Glucocorticoid therapy was successfully discontinued within 6 months of starting methotrexate in four patients receiving prednisone at entry. Liver biopsy specimens were obtained again after methotrexate therapy and showed absence of granulomas in four of four patients. The minimum effective dose of methotrexate was 0.20 mg/kg body weight per week. No serious adverse effects and no failures to respond to methotrexate therapy were noted in this group of patients. In three patients, methotrexate therapy has been successfully tapered without signs or symptoms of recurrent disease. Conclusions: Low-dose oral pulse methotrexate was effective in treating patients with granulomatous hepatitis.
VEGFR2 blockade in patients with solid tumors: Mechanism of hypertension and effects on vascular function
Authors: N. Steeghs, M. M. Hovens, A. J. Rabelink, J. Op ’t Roodt, A. Matthys, O. Christensen, H. Gelderblom
Journal: Journal of Clinical Oncology (2006)

3037 Background: Hypertension is the most common side effect in trials with inhibitors of vascular endothelial growth factor (VEGF) signaling, although the underlying pathophysiology is unclear. As the use of anti-VEGF therapy is increasing, hypertension and related serious adverse events are likely to become more important. Methods: To better understand this pathophysiology,blood pressure and vascular function parameters were assessed in this substudy of a phase I trial in patients with advanced solid tumours treated with BAY 57–9352, an oral VEGF receptor 2 (VEGFR2) inhibitor. Blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD) and pulse-wave velocity (PWV) were measured at baseline and after 5 weeks of daily treatment in 10 patients. Patients were spread out over different cohorts, taking different dosages of study drug. Results: Mean systolic blood pressure increased from 129.0 mm Hg to 139.4 mm Hg after 5 weeks of treatment (difference 10.4 mm Hg; 95% confidence interval (CI) 5.0–15.7 mm Hg; p=0.002). Mean diastolic blood pressure increased from 80.9 to 87.4 mm Hg (difference 6.5 mm Hg; 95% CI 1.7–11.3; p=0.013). Endothelium-dependent vasodilatation (FMD) decreased from 5.6% to 3.0% (95% CI 1.1–3.9%; p=0.003). NMD, indicating endothelium-independent vasodilatation, also decreased from 12.9% to 7.7% (95% CI 2.7–7.6%; p=0.001). Arterial stiffness (PWV), increased from 9.4 m/s to 10.3 m/s (p=0.07). Conclusions: Inhibition of VEGFR2 significantly increases systolic and diastolic blood pressure. As VEGF enhances endothelial nitric oxide (NO) synthetase activity, the clear decrease in FMD could be explained by reduced bioavailability of NO. The decrease in NMD may be a direct effect of VEGFR2 inhibition on vascular smooth muscle cells. However, a more likely hypothesis for these profound vascular effects is a reduced number of microvessels (i.e. rarefaction). As the microcirculation is largely responsible for peripheral resistance, the rarefaction associated with VEGFR2 inhibition is likely to increase peripheral resistance and lead to hypertension. [Table: see text]
Bioenergetic abnormalities associated with severe left ventricular hypertrophy.
Authors: J Zhang, H Merkle, K Hendrich, M Garwood, A H From, K Ugurbil, R J Bache
Journal: Journal of Clinical Investigation (1993)

Transmurally localized 31P-nuclear magnetic resonance spectroscopy (NMR) was used to study the effect of severe pressure overload left ventricular hypertrophy (LVH) on myocardial high energy phosphate content. Studies were performed on 8 normal dogs and 12 dogs with severe left ventricular hypertrophy produced by banding the ascending aorta at 8 wk of age. Spatially localized 31P-NMR spectroscopy provided measurements of the transmural distribution of myocardial ATP, phosphocreatine (CP), and inorganic phosphate (Pi); spectra were calibrated from measurements of ATP content in myocardial biopsies using HPLC. Blood flow was measured with microspheres. In hypertrophied hearts during basal conditions, ATP was decreased by 42%, CP by 58%, and the CP/ATP ratio by 32% in comparison with normal. Increasing myocardial blood flow with adenosine did not correct these abnormalities, indicating that they were not the result of persistent hypoperfusion. Atrial pacing at 200 and 240 beats per min caused no change in high energy phosphate content in normal hearts but resulted in further CP depletion with Pi accumulation in the inner left ventricular layers of the hypertrophied hearts. These changes were correlated with redistribution of blood flow away from the subendocardium in LVH hearts. These findings demonstrate that high energy phosphate levels and the CP/ATP ratio are significantly decreased in severe LVH. These abnormalities are proportional to the degree of hypertrophy but are not the result of persistent abnormalities of myocardial perfusion. In contrast, depletion of CP and accumulation of Pi during tachycardia in LVH are closely related to the pacing-induced perfusion abnormalities and likely reflect subendocardial ischemia.
Fibrin promotion and lysis in arthritic joints.
Authors: M I Barnhart, J M Riddle, G B Bluhm, C Quintana
Journal: Annals of the Rheumatic Diseases (1967)

The significance of extravascular coagulation and fibrinolysis is poorly understood and little appre- ciated.A unique opportunity for studying these events is provided in arthritis where the joint fluids may reflect the presence and extent of inflammation.This report on 144 pathological fluids expands our knowledge of the biochemistry of inflammation.Further, it may provide a more instructive base than currently available for comprehending the mechan- isms operative in arthritis.Fibrin deposition must be considered seriously as a contributor to permanent joint damage.Synovial fluid is a complex mixture of substances largely derived from the plasma but also the product and recipient of both cells in the synovial membrane and extravascular leucocytes (Ropes and Bauer, 1953).Protein comprises 1 *4 to 5 *6 per cent. of the synovial fluid and is mainly known in terms of electrophoretic properties (Decker, McKenzie,
Endothelial nitric oxide synthase activity in aorta of normocholesterolemic rabbits: regional variation and the effect of estrogen
Authors: M Andersen
Journal: Cardiovascular Research (2000)

Several animal studies suggest that nitric oxide (NO) produced by the endothelium attenuates arterial cholesterol accumulation. In the present study we have asked the following questions: (1) is the regional variation in aortic cholesterol accumulation in hypercholesterolemic rabbits preceded by a regional variation in endothelial NO synthase (eNOS) activity in normocholesterolemic rabbits, and (2) is the antiatherogenic effect of estrogen in hypercholesterolemic rabbits preceded by a higher eNOS activity in normocholesterolemic rabbits.The eNOS activity was determined by conversion of 14C-L-arginine to 14C-L-citrulline in freshly isolated endothelial cells of aorta in normocholesterolemic rabbits. In the regional variation study, 16 male and eight female rabbits were used. In the estrogen study, ovariectomized female rabbits were subcutaneously injected three times weekly with either 17beta-estradiol (n=7) or vehicle (n=7) for 18 weeks.In the regional variation study, the atherosclerosis prone aortic arch showed a significant lower eNOS activity than the more resistant abdominal aorta in both male (P<0.0001) and female (P<0.05) rabbits. In the estrogen study, the eNOS activity in the aortic arch and upper thoracic aorta was significantly higher in the estrogen than in the vehicle rabbits (P<0.05). In the lower thoracic aorta, however, the eNOS activity was the same.The findings suggest that a high NO production in the luminal endothelium of the arterial wall precedes a low cholesterol accumulation during a subsequent period of hypercholesterolemia.
Neonatal Relapsing Fever Due to Transplacental Transmission of Borrelia
Authors: Peter C. Fuchs
Journal: JAMA (1969)

Transplacental transmission of relapsing fever occured; spirochetes of the genus Borrelia were demonstrated in the blood of the mother and infant and in the cerebrospinal fluid (CSF) of the infant. Autopsy of the baby, who died 39 hours after birth, showed meningitis and typical splenic lesions with numerous spirochetes. Some unusual aspects of this case are the transplacental transmission, fatal outcome in the infant, and the demonstration of spirochetes in the CSF on direct smear.
Mechanisms whereby extracellular adenosine 3',5'-monophosphate inhibits phosphate transport in cultured opossum kidney cells and in rat kidney. Physiological implication.
Authors: G Friedlander, S Couette, C Coureau, C Amiel
Journal: Journal of Clinical Investigation (1992)

The mechanism of phosphaturia induced by cAMP infusion and the physiological role of extracellular cAMP in modulation of renal phosphate transport were examined. In cultured opossum kidney cells, extracellular cAMP (10-1,000 microM) inhibited Na-dependent phosphate uptake in a time- and concentration-dependent manner. The effect of cAMP was reproduced by ATP, AMP, and adenosine, and was blunted by phosphodiesterase inhibitors or by dipyridamole which inhibits adenosine uptake. [3H]cAMP was degraded extracellularly into AMP and adenosine, and radioactivity accumulated in the cells as labeled adenosine and, subsequently, as adenine nucleotides including cAMP. Radioactivity accumulation was decreased by dipyridamole and by inhibitors of phosphodiesterases and ecto-5'-nucleotidase, assessing the existence of stepwise hydrolysis of extracellular cAMP and intracellular processing of taken up adenosine. In vivo, dipyridamole abolished the phosphaturia induced by exogenous cAMP infusion in acutely parathyroidectomized (APTX) rats, decreased phosphate excretion in intact rats, and blunted phosphaturia induced by PTH infusion in APTX rats. These results indicate that luminal degradation of cAMP into adenosine, followed by cellular uptake of the nucleoside by tubular cells, is a key event which accounts for the phosphaturic effect of exogenous cAMP and for the part of the phosphaturic effect of PTH which is mediated by cAMP added to the tubular lumen under the influence of the hormone.
SARCOMA OF THE PONS AND GLIO-SARCOMA OF THE CEREBELLUM.Read before the January, 1893, Meeting of the Chicago Academy of Medicine.
Authors: LUDWIG HEKTOEN
Journal: JAMA (1893)

age to get there), and then remember the conse¬ quences, when the real life of the soldier began to dawn upon them ; when they stood fast and firm through the dreadful carnage, and saw one by by one of their comrades in arms (or even their childhood's playmates) drop out-then when the battle was won or lost, or stopped by the welcome shades of night, only to be renewed at dawn, can we fail to realize the shock to the young heart.Then perhaps, after a hurried dipper of coffee \vith the hard-tack, the inevitable detail for picket falls to the lot of the poor wearied fellow ; is it to be won¬ dered at that an artificial stimulant was necessary before he was able to take another step forward?No ; and then the habit was formed, the appetite created which to many thousands was worse than the crack of doom itself.General Sherman said, " War is hell "-and it was.The deadly minie bul¬ let was not the worst part of that hell.Let Uncle Sam continue to be grateful to his defenders, and take the best care possible of them in their old age.There is only a very narrow line between prosperity and adversity, between success and defeat; and they saved to the freest and best of Governments ; a government for the people, and by the people, and money cannot pay for the boon.
Autosomal dominant ichthyosis exfoliativa
Authors: F. VAKILZADEH, G. KOLDE
Journal: British Journal of Dermatology (1991)

An unusual ichthyosiform dermatosis with circumscribed areas of blistering hyperkeratoses as well as scaly areas was observed in five consecutive generations of a German family. Light and electron microscopical studies revealed oedema of the keratinocytes in the upper epidermis but no defects of tonofilaments and keratohyalin granules. We suggest that this type of ichthyosis exfoliativa inherited as an autosomal dominant trait represents a new and distinct entity.
Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man.
Authors: P De Feo, V Gallai, G Mazzotta, G Crispino, E Torlone, G Perriello, M M Ventura, F Santeusanio, P Brunetti, G B Bolli
Journal: Journal of Clinical Investigation (1988)

To establish the glycemic threshold for onset of neuroglycopenia (impaired cognitive function, measured by the latency of the P300 wave), activation of hormonal counterregulation and hypoglycemic symptoms, 12 normal subjects were studied either under conditions of insulin-induced, glucose-controlled plasma glucose decrements, or during maintenance of euglycemia. A decrement in plasma glucose concentration from 88 +/- 3 to 80 +/- 1 mg/dl for 150 min did not result in changes in the latency of the P300 wave nor in an activation of counterregulatory hormonal response. In contrast, a greater decrement in plasma glucose concentration from 87 +/- 3 to 72 +/- 1 mg/dl for 120 min caused an increase in the latency of the P300 wave (from 301 +/- 12 to 348 +/- 20 ms, P less than 0.01), a subsequent increase in all counterregulatory hormones but no hypoglycemic symptoms. Finally, when plasma glucose concentration was decreased in a stepwise manner from 88 +/- 2 to 50 +/- 1 mg/dl within 75 min, the increase in the latency of the P300 wave was correlated with the corresponding plasma glucose concentration (r = -0.76, P less than 0.001). The glycemic threshold for hypoglycemic symptoms was 49 +/- 2 mg/dl. Thus, in normal man the glycemic threshold for neuroglycopenia (72 +/- 1 mg/dl) is greater than currently thought; the hormonal counterregulation follows the onset of neuroglycopenia; the hypoglycemic symptoms are a late indicator of advanced neuroglycopenia.
1055 SIGNATURE OF THREE NOVEL SURROGATE MARKERS PREDICTS LIVER STIFFNESS AND FIBROSIS STAGES IN A COHORT OF PATIENTS WITH CHRONIC LIVER DISEASE
Authors: M. Krawczyk, A. Hoblinger, G. Hess, T. Sauerbruch, F. Lammert, F. Grünhage
Journal: Journal of Hepatology (2012)
Value of Three-dimensional Surface Display of Brain Perfusion Imaging
Authors: NORINARI HONDA, KIKUO MACHIDA, TOSHIO MAMIYA, TAKU TAKAHASII, TERUO TAKISHIMA, TSUYOSHI KAMANO, SATOSHI TAMAKI, MASAYUKI MURAMATSU, RYUICHI BAN
Journal: Clinical Nuclear Medicine (1992)

The diagnostic ability of a three-dimensional surface display of 1-123 IMP brain scintigrams and tomographic images was compared in 12 patients who underwent 1-123 brain tomography for cerebral cortical hypoperfusion. Foci of decreased accumulation were independently diagnosed by four radiologists, first with transaxial images, second with three-dimensional images, and finally with both images subjectively compared for the purpose of diagnosing the existence, localization, and extent of lesions. Six different lesions (0 to 3 lesions/radiologist) were found only on the transaxial images, but 30 different lesions (1 to 14 lesions/radiologist) were found on the three-dimensional images. In 9 out of 12 cases, the threedimensional images were regarded as superior for evaluating the extension of the lesion and for lesion existence and lesion localization in 5 out of 12 (P < 0.05). In conclusion, a three-dimensional display of an 1-123 IMP brain tomogram is superior to tomographic images in diagnosing the extent of cerebral cortical hypoperfusion. However, the display is not superior to tomographic images for diagnosing the existence and localization of hypoperfusion.
Endoscopic detection of colonic tuberculosis in an asymptomatic patient
Authors: C. Yang, C. Chen, S. Yan
Journal: Endoscopy (2007)

There has been a resurgence of intestinal tuberculosis during the last decade following the increase of immigrants to Western countries [1] [2]. The abdominal symptoms of intestinal tuberculosis are nonspecific, consisting mainly of abdominal pain, weight loss, anorexia, and fever [2] [3]. The characteristic endoscopic features of colonic tuberculosis include transversely oriented ulcer, nodules, deformed ileocecal valve, stricture, erosions, and aphthous ulcers [1] [2] [3]. However, in patients without abdominal symptoms or pulmonary infection, endoscopists face the challenge of distinguishing between intestinal tuberculosis and malignancy or Crohn's disease. We report here a case of colonic tuberculosis found incidentally during a health check-up, and which was diagnosed by typical endoscopic features and histological and microbiological evidence.
Gynecology: Principles and Practice
Authors: Dave E. David
Journal: JAMA (1987)

<i>Gynecology Principles and Practice</i>, fourth edition, by Robert W. Kistner, MD, is a well executed textbook, which affords the reader with a nicely balanced overview of the basic science of gynecology coupled with information on clinical diagnosis and management. The first half of the book is laid out by organ system, with each chapter containing subchapters on that particular organ's pathological entities, after covering the basics with the normal anatomy, embryology, and physiology of that organ. The second half of the book deals mainly with more systemic or nonorgan-oriented gynecologic disease, and these chapters go into much more depth on each pathological entity. The book is somewhat reminiscent of<i>The Textbook of Gynecology</i>by Novak in both its format and its emphasis on histological pathology. This book gives an up-to-date and concise overview of gynecology that can be appreciated in many forms: the third- and fourth-year medical student will find
ELECTRON MICROSCOPIC OBSERVATIONS ON ALLERGIC ENCEPHALOMYELITIS IN THE RABBIT
Authors: Sarah A. Luse, David B. McDougal
Journal: The Journal of Experimental Medicine (1960)

Allergic encephalomyelitis was produced in rabbits by injection of white matter from bovine brain plus adjuvants. Electron microscopy revealed focal demyelinization in both the spinal roots and cord. The peripheral lesions were characterized by vacuolization of Schwann cytoplasm, destruction of the myelin sheath, and by some appearances suggesting remyelinization. In the cord there was a marked perivascular inflammatory infiltration with focal destruction of the blood-brain barrier as demonstrated by formation of an abnormal interstitial space about capillaries. Mitochondria of oligodendroglia were strikingly swollen whereas those of other cells were morphologically normal. Axons were denuded of their myelin sheaths and the myelin detritus sequestered within gitter cells. Fibrous astrocytic gliosis occurred to some degree. Focal evidences of myelin reformation were noted centrally as well as peripherally. Allergic encephalomyelitis, as a primary demyelinating lesion, is contrasted with Wallerian degeneration in which myelin degeneration is secondary to destruction of the axon.
Etiology of Primary Atypical Pneumonia in a Military Population
Authors: Ben R. Forsyth
Journal: JAMA (1965)

An investigation of patients with primary atypical pneumonia (PAP) was undertaken at a large military base, Camp Lejeune, NC, to determine the cause. Serologic and isolation methods were used to detect viral and<i>Mycoplasma</i>infections. Recovery of virus was the most precise index of adenovirus infection under epidemic conditions. Serologic conversion was the most efficient method for detecting<i>Mycoplasma pneumoniae</i>infection. These studies revealed that adenovirus and<i>M pneumoniae</i>infections were individually associated with PAP simultaneously. Together, these agents were responsible for over 70% of the PAP seen in a three-month period of intensive study. A 30-month survey of pneumonia patients revealed infection with each agent to be associated with about 20% of the PAP sampled.<i>M pneumoniae</i>infection did not exhibit a seasonal predilection while pneumonia associated with adenovirus infection occurred predominantly during the winter months. The finding that more than one agent may be an important cause of PAP in the same population during the same period of time must be considered in future studies of PAP.