tbuckley/cabot-search huggingface dataset:
Expression of p53 protein in malignant melanoma: clinicopathological and prognostic implications
Authors: J. WEISS, M. HEINE, B. KÖRNER, H. PILCH, E. G. JUNG
Journal: British Journal of Dermatology (2006)

In the present study, we investigated the expression of the tumour suppressor protein p53 in 113 primary and 43 metastatic malignant melanomas by immunohistochemistry, and correlated the findings with clinicopathological parameters such as histological melanoma subtype, thickness of primary melanomas (Breslow thickness) and patient outcome. In primary melanomas, the polyclonal anti-p53 antibody CM-1 detected immunoreactivity in 70% of the lesions, predominantly in the cytoplasm. Signals were observed in this cellular compartment in 57% of the melanomas, whereas in 32% nuclear p53 over-expression was detected. Immunohistochemistry, using the monoclonal antibody DO-1, revealed lower staining frequencies. However, both antibodies showed congruent results in approximately 80% of the cases. Overall, immunoreactivity was observed in 73% of superficial spreading melanomas, but only in 52% of lentigo maligna melanomas. This difference (P < 0.001) was mainly due to a lower frequency of cytoplasmic immunoreactivity (P < 0.002). There was no difference with respect to cytoplasmic and nuclear immunoreactivity between thin (< 1 mm thickness) and thicker primary melanomas. Staining frequencies detected in metastatic lesions seemed to be lower than in primary tumours. In 103 primary melanomas, follow-up data for at least 5 years were available. In 71% (54 of 76) of the primary melanomas which did not recur, and in 78% (21 of 27) of tumours with subsequent metastases, p53 over-expression was detected by CM-1. However, this difference was not statistically significant. The results of the present study indicate that immunoreactivity to anti-p53 antibodies is a common observation in malignant melanomas, with staining signals predominantly found in the cytoplasm of cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of Adrenal Steroidogenesis by the Anesthetic Etomidate
Authors: R. Lee Wagner, Paul F. White, Patricia B. Kan, Myer H. Rosenthal, David Feldman
Journal: New England Journal of Medicine (1984)

The use of the intravenous anesthetic etomidate for prolonged sedation has been associated with low levels of plasma cortisol and increased mortality. We measured the cortisol and aldosterone responses to ACTH stimulation in five patients receiving etomidate, and we also studied the direct effects of etomidate on enzymes in the rat steroidogenic pathway. One patient who was receiving a 20-hour infusion of etomidate (1.3 to 1.5 mg per kilogram of body weight per hour) had marked adrenocortical suppression that was still evident four days after etomidate was discontinued. Four surgical patients receiving etomidate during their operations were all found to have adrenal suppression four hours after the operation; mean (±S.D.) increases in cortisol and aldosterone after ACTH stimulation were only 1.8±0.5 μg per deciliter and 0.5±1.1 ng per deciliter, respectively. In rat adrenal cells, etomidate produced a concentration-dependent blockade of the two mitochondrial cytochrome P-450–dependent enzymes, cholesterol-side-chain cleavage enzyme, and 11β-hydroxylase, without evident inhibition of the microsomal enzymes in the glucocorticoid pathway. Physicians should be aware that etomidate Inhibits adrenal steroidogenesis, and they should consider treating selected patients with corticosteroids if etomidate is used. (N Engl J Med 1984; 310:1415–21.)
Anti-KJ: a new antibody associated with the syndrome of polymyositis and interstitial lung disease.
Authors: I N Targoff, F C Arnett, L Berman, C O'Brien, M Reichlin
Journal: Journal of Clinical Investigation (1989)

Antibodies to aminoacyl-tRNA synthetases (anti-Jo-1, anti-PL-7, anti-PL-12) have been found in the serum of some patients with polymyositis (PM). Patients with these antibodies have an unusually high rate of interstitial lung disease (ILD) in association with their PM. Two patients (K.J. and B.T.) with severe ILD and PM were found to have antibodies to a cytoplasmic antigen, but tests to determine whether the antigen was an aminoacyl-tRNA synthetase were negative, including tests of KJ serum for inhibitory effects on the 20 synthetases. KJ immunoprecipitates did not contain tRNA, in contrast to antisynthetase sera. When IgG samples were added to a reticulocyte in vitro translation system at a concentration of 0.3 mg/ml, KJ IgG inhibited globin mRNA translation by 98%, while anti-Jo-1 IgG inhibited 62% and normal IgG had little effect. Thus, both anti-KJ and the antisynthetases are directed at antigens that are involved in translation and protein synthesis, and both are associated with the syndrome of lung disease and PM. This syndrome may be associated with antibodies to translation-related proteins in general, which may have implications for the link of PM and enteroviruses, which are mRNA viruses.
GSK fights compensation claims from UK patients who took rosiglitazone
Authors: C. Dyer
Journal: BMJ (2013)

GlaxoSmithKline, the UK based multinational that makes the antidiabetes drug rosiglitazone (marketed as Avandia), is fighting compensation claims from UK patients who allege that the drug harmed them, even though the company has already paid billions of dollars to settle tens of thousands of similar claims in the United States.

Rosiglitazone, and the drug in combination with metformin (Avandamet), were withdrawn from the market in Europe in 2010 after studies showed that it could raise the risk of heart attack.1 When it was taken off the European market it is thought that around 90 000 patients in the United Kingdom …
Respiratory sensation during bronchial challenge testing with methacholine, sodium metabisulphite, and adenosine monophosphate.
Authors: G. B. Marks, D. H. Yates, M. Sist, B. Ceyhan, M. De Campos, D. M. Scott, P. J. Barnes
Journal: Thorax (1996)

BACKGROUND: There is some evidence that the perception of bronchoconstriction may very according to the nature of the provoking stimulus. The aims of this study were, firstly, to develop a method for measuring dyspnoea during induced bronchoconstriction in patients with asthma and, secondly, to apply this method to testing differences between directly and indirectly acting bronchoconstricting stimuli. METHODS: Descriptive terms suitable for quantifying respiratory discomfort due to bronchoconstriction in patients with asthma were identified in a preliminary investigation. The relation between reduction in forced expiratory volume in one second (FEV1) and respiratory discomfort, measured using a visual analogue scale (VAS), was then studied during challenges with three different inhaled stimuli: methacholine (MCH), sodium metabisulphite (MBS), and adenosine monophosphate (AMP). Three indices were calculated to describe the relation: the VAS value associated with a 20% fall in FEV1 (FEV20 VAS); the ratio of the final VAS value to the final percentage fall in FEV1 (VAS-FEV1 ratio); and the regression coefficient for predicting VAS from the percentage fall in FEV1 within each challenge (beta VAS FEV1). RESULTS: "Difficulty in breathing" and "chest tightness" were selected as suitable terms for quantifying respiratory discomfort. There were no differences between the three agonists in the qualitative aspects of the respiratory sensation. In paired challenges with the same agonist the three indices were all found to be reproducible for both sensations measured. MCH induced less intense difficulty in breathing and chest tightness for a given fall in FEV1 than did AMP. There was a trend in the same direction for the comparison between MCH and MBS. There were no differences between AMP and MBS. FEV20 VAS was less powerful in discriminating between agonists than the two slope indices. CONCLUSIONS: The relation between induced reduction in FEV1 and the intensity of respiratory discomfort can be measured reliably. The indirectly acting bronchoconstricting agonists AMP and MBS induced more intense respiratory discomfort for a given fall in FEV1 than the direct agonist MCH. This may be due to differences in unmeasured mechanical changes in the lungs or to an additional action on airway sensory nerves.
THE ROLE OF HUMORAL ANTIBODIES IN REJECTION OF SKIN HOMOGRAFTS IN RABBITS
Authors: Roberto R. Kretschmer, Ruy Pérez-Tamayo
Journal: The Journal of Experimental Medicine (1962)

Passive transfer of transplantation immunity by means of sensitized lymphoid cells enclosed within diffusion chambers has been accomplished in non-radiated and radiated rabbits. This result, together with other data available in the literature, suggests that humoral antibodies play an important role in rejection of skin homografts in the rabbit.
OUR SENSE OF HUMOR
Authors: L. J. Pankow
Journal: JAMA (1960)

<h3>To the Editor:—</h3> In my opinion, the outstanding fault with the medical profession today is that it views the world and all its (medical) problems too seriously.The Journalhas misplaced our sense of humor. Paramount, as proof of this, is the decline in the number of humorous cartoons and Tonics and Sedatives and in the quality of the few jokes that are currently published inThe Journal. Let us, for the sake of medicine and the patient, restore humor interlude to medical journals. Let us instill again the idea that all plans for legislating medicine are a joke, and all we have to do is laugh and say "All right, you guys, do it without us!" Let us return to a laughing state wherein we find humor in life and medicine. For heaven's sake, keep our sense of humor whetted by putting more humor (and not some of the
CD95-mediated murine hepatic apoptosis requires an intact glutathione status
Authors: Hannes Hentze, Gerald Künstle, Christiane Volbracht, Wolfgang Ertel, Albrecht Wendel
Journal: Hepatology (1999)

Agonistic engagement of the cytokine receptor CD95 in mice leads to activation of hepatic caspases, followed by massive hepatocyte apoptosis, acute liver failure, and death. This mechanism of cell death is thought to be associated with several human liver disorders. Because hepatic glutathione represents the major defense against toxic liver injury, we investigated its role in CD95-mediated liver failure, which represents a model for hyperinflammatory organ destruction. As a tool for modulating the liver glutathione status of mice in vivo , we used the GSH transferase substrate, phorone, which rapidly depleted hepatic glutathione in a dose-dependent manner. When GSH was depleted, CD95-initiated hepatic caspase-3-like activity and DNA fragmentation were completely blocked, and animals were protected from liver injury dose-dependently as assessed by histological examination and determination of liver enzymes in plasma. Conversely, repletion of hepatic glutathione by treatment with the permeable glutathione monoethylester restored susceptibility of GSH-depleted mice toward CD95-mediated liver injury. In contrast, the antioxidants, GSH, N -acetyl cysteine, α-tocopherol, butyl-hydroxytoluene, and catalase failed to do so. Animals treated once with phorone survived for more than 3 months after an otherwise lethal injection of the activating anti-CD95 antibody. We investigated the thiol sensitivity of recombinant caspase-3 in vitro and observed that its activity was dependent on the presence of a reducing agent such as GSH, while GSSG attenuated proteolytic activity. Based on our finding that CD95-mediated hepatocyte apoptosis requires an intact intracellular glutathione status, we propose that the activation of apoptosis-executing caspases is controlled by reduced glutathione.
Medical Education and the Social Sciences
Authors: Roger J. Bulger
Journal: JAMA (1981)

In this issue ofThe Journal, Petersdorf and Feinstein (p 943), present data relating to the breadth and depth of formal instruction in the medically related social sciences in undergraduate and some postgraduate medical curricula. Although one may not be enamored of the authors' classifications of sociology (ie, "of," "for," "in," "at," "from," and "around" medicine), their contribution is an important one because it illustrates major differences in the acceptance of the processes and products of the social sciences by academically based internists, pediatricians, and family physicians. One is left to guess where the psychiatrists, surgeons, radiologists, and others might stand. Clearly, however, one can conclude that the impact of the social sciences on medical education is still not pervasive even if their influence has increased over the past decade or two. Many medical school faculty have difficulty in understanding behavioral objectives in curriculum design. They do not realize the
A novel vascular smooth muscle chymase is upregulated in hypertensive rats
Authors: Caiying Guo, Haisong Ju, Debbie Leung, Hamid Massaeli, Mingda Shi, Marlene Rabinovitch
Journal: Journal of Clinical Investigation (2001)

While greater than 80% of angiotensin II (Ang II) formation in the human heart and greater than 60% in arteries appears to result from chymase activity, no cardiovascular cell-expressed chymase has been previously reported. We now describe the cloning of a full-length cDNA encoding a novel chymase from rat vascular smooth muscle cells. The cDNA encompasses 953 nucleotides, encodes 247 amino acids, and exhibits 74% and 80% homology in amino acid sequence to rat mast cell chymase I and II, respectively. Southern blot analysis indicates that the rat vascular chymase is encoded by a separate gene. This chymase was induced in hypertrophied rat pulmonary arteries, with 11-fold and 8-fold higher chymase mRNA levels in aortic and pulmonary artery smooth muscle cells from spontaneously hypertensive than in corresponding tissues from normotensive rats. We assayed the activity of the endogenous enzyme and of a recombinant, epitope-tagged chymase in transfected smooth muscle cells and showed that Ang II production from Ang I can be inhibited with chymostatin, but not EDTA or captopril. Spontaneously hypertensive rats show elevated chymase expression and increased chymostatin-inhibitable angiotensin-converting activity, suggesting a possible role for this novel enzyme in the pathophysiology of hypertension.
Alcohol intake: a risk factor for psoriasis in young and middle aged men?
Authors: K Poikolainen, T Reunala, J Karvonen, J Lauharanta, P Karkkainen
Journal: BMJ (1990)

To clarify the nature of the association between alcohol intake and psoriasis.Case-control study of men aged 19-50 with onset of skin disease in 1976 or later.Outpatient clinics of the departments of dermatology of the university central hospitals in Helsinki, Oulu, and Tampere from September 1987 to April 1989.144 Patients with psoriasis and 285 unmatched controls with other skin diseases.Results of clinical examination and self administered questionnaire assessing lifestyle and alcohol intake during two specified periods--namely, 12 months before the onset of skin disease and 12 months before the date of examination.Recalled mean alcohol intake before the onset of skin diseases was 42.9 g/day among the patients with psoriasis and 21.0 g/day among the controls. In logistic regression analysis psoriasis was associated with alcohol intake but not with coffee consumption, smoking, age, marital state, or social group. The odds ratio for psoriasis at an alcohol intake of 100 g/day compared with no intake was 2.2 (95% confidence interval 1.3 to 3.9). The controls decreased their alcohol intake after the onset of the disease but the group with psoriasis did not. Analysis of serum enzyme values showed that gamma-glutamyltransferase activity was significantly correlated with alcohol intake (r = 0.35), the mean activity being 75.0 U/l among patients with psoriasis and 41.9 U/l among controls.Alcohol is a risk factor for psoriasis in young and middle aged men, and psoriasis may sustain drinking.
Interrogating Two Schedules of the AKT Inhibitor MK-2206 in Patients with Advanced Solid Tumors Incorporating Novel Pharmacodynamic and Functional Imaging Biomarkers
Authors: Timothy A. Yap, Li Yan, Amita Patnaik, Nina Tunariu, Andrea Biondo, Ivy Fearen, Kyriakos P. Papadopoulos, David Olmos, Richard Baird, Liliana Delgado, Ernestina Tetteh, Robert A. Beckman, Lisa Lupinacci, Ruth Riisnaes, Shaun Decordova, Simon P. Heaton, Karen Swales, Nandita M. deSouza, Martin O. Leach, Michelle D. Garrett, Daniel M. Sullivan, Johann S. de Bono, Anthony W. Tolcher
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60–80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Experimental Design: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic–pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. Results: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Conclusions: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). Clin Cancer Res; 20(22); 5672–85. ©2014 AACR.
Sulfobromphthalein Test Increasingly Unnecessary
Authors: Carl Wierum
Journal: JAMA (1969)

To the Editor:—  A recent survey in our teaching community hospital indicated that about one half the sulfobromphthalein (SBP) tests ordered need not have been done. Increased use of automatic chemical analyzers now permits inexpensive screening of  function without the risk or inconvenience of the SBP test.  In a study conducted at the Englewood (NJ) Hospital, a test  was used to determine values of alkaline phosphatase, serum glutamic oxaloacetic (SGOT) (done by automatic chemical analyzer), thymol turbidity, and direct bilirubin ( done easily by hand). Of 27 patients with abnormal SBP tests, who had such a liver panel done, 16 had either (1) a direct bilirubin value greater than 0.25 (in the absence of hemolytic disease) or (2) elevated alkaline phosphatase level (in association with a normal skeletal survey or an elevated SGOT level). In the same study, 19 patients were observed with entirely normal values for direct bilirubin,
Importance of endothelial NF-κB signalling in vascular remodelling and aortic aneurysm formation
Authors: Tokuo Saito, Yutaka Hasegawa, Yasushi Ishigaki, Tetsuya Yamada, Junhong Gao, Junta Imai, Kenji Uno, Keizo Kaneko, Takehide Ogihara, Tatsuo Shimosawa, Tomoichiro Asano, Toshiro Fujita, Yoshitomo Oka, Hideki Katagiri
Journal: Cardiovascular Research (2012)

Vascular remodelling and aortic aneurysm formation are induced mainly by inflammatory responses in the adventitia and media. However, relatively little is known about the mechanistic significance of endothelium in the pathogenesis of these vascular disorders. The transcription factor nuclear factor-kappa B (NF-κB) regulates the expressions of numerous genes, including those related to pro-inflammatory responses. Therefore, to investigate the roles of endothelial pro-inflammatory responses, we examined the impact of blocking endothelial NF-κB signalling on intimal hyperplasia and aneurysm formation. To block endothelial NF-κB signalling, we used transgenic mice expressing dominant-negative IκBα selectively in endothelial cells (E-DNIκB mice). E-DNIκB mice were protected from the development of cuff injury-induced neointimal formation, in association with suppressed arterial expressions of cellular adhesion molecules, a macrophage marker, and inflammatory factors. In addition, the blockade of endothelial NF-κB signalling prevented abdominal aortic aneurysm formation in an experimental model, hypercholesterolaemic apolipoprotein E-deficient mice with angiotensin II infusion. In this aneurysm model as well, aortic expressions of an adhesion molecule, a macrophage marker, and inflammatory factors were suppressed with the inhibited expression and activity of matrix metalloproteinases in the aorta. Endothelial NF-κB activation up-regulates adhesion molecule expression, which may trigger macrophage infiltration and inflammation in the adventitia and media. Thus, the endothelium plays important roles in vascular remodelling and aneurysm formation through its intracellular NF-κB signalling.
TCTAP C-189 Successful Endovascular Treatment for Type 2 Endoleak After Endovascular Abdominal Aortic Repair: Usefulness of N-Butyl Cyanoacrylate Embolization
Authors: Kiyonori Nanto, Osamu Iida, Shin Okamoto, Takayuki Ishihara, Tatsuya Shiraki, Koji Yanaka, Shota Okuno, Masaaki Uematsu
Journal: Journal of the American College of Cardiology (2015)
Distinct FAK Activities Determine Progenitor and Mammary Stem Cell Characteristics
Authors: Ming Luo, Xiaofeng Zhao, Song Chen, Suling Liu, Max S. Wicha, Jun-Lin Guan
Journal: Cancer Research (2013)

Mammary stem cells (MaSC) and progenitor cells are important for mammary gland development and maintenance and may give rise to mammary cancer stem cells (MaCSC). Yet, there remains limited understanding of how these cells contribute to tumorigenesis. Here, we show that conditional deletion of focal adhesion kinase (FAK) in embryonic mammary epithelial cells (MaEC) decreases luminal progenitors and basal MaSCs, reducing their colony-forming and regenerative potentials in a cell-autonomous manner. Loss of FAK kinase activity in MaECs specifically impaired luminal progenitor proliferation and alveologenesis, whereas a kinase-independent activity of FAK supported ductal invasion and basal MaSC activity. Deficiency in luminal progenitors suppressed tumorigenesis and MaCSC formation in a mouse model of breast cancer. In contrast with the general inhibitory effect of FAK attenuation, inhibitors of FAK kinase preferentially inhibited proliferation and tumorsphere formation of luminal progenitor-like, but not MaSC-like, human breast cancer cells. Our findings establish distinct kinase-dependent and -independent activities of FAK that differentially regulate luminal progenitors and basal MaSCs. We suggest that targeting these distinct functions may tailor therapeutic strategies to address breast cancer heterogeneity more effectively.
Visual hallucinations, attention, and neural circuitry: Perspectives from schizophrenia research
Authors: Kevin M. Spencer, Robert W. McCarley
Journal: Behavioral and Brain Sciences (2005)

We tested Collerton et al.'s model of visual hallucinations by re-examining a data set for correlations between visual hallucinations and measures of attentional function in schizophrenia patients. These data did not support their model. We suggest that cortical hyperexcitability plays an important role in hallucinations, and propose an alternative model that links evidence for cortical hyperexcitability with abnormal neural dynamics.