tbuckley/cabot-search huggingface dataset:
HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer
Authors: Hae Ryung Chang, Seungyoon Nam, Myeong-Cherl Kook, Kyung-Tae Kim, Xiuping Liu, Hui Yao, Hae Rim Jung, Robert Lemos, Hye Hyun Seo, Hee Seo Park, Youme Gim, Dongwan Hong, Iksoo Huh, Young-Woo Kim, Dongfeng Tan, Chang-Gong Liu, Garth Powis, Taesung Park, Han Liang, Yon Hui Kim
Journal: Gut (2014)

<h3>Background</h3> Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. <h3>Objective</h3> To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. <h3>Methods</h3> We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. <h3>Results</h3> Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. <h3>Conclusions</h3> Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate 'metabolic switch' characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development.
Effect of chronic circulatory volume overload on digitalis intoxication
Authors: G. D. COPE, B. E. HOPKINS, R. R. TAYLOR
Journal: Cardiovascular Research (1973)

The tolerance to acetylstrophanthidin of eight mongrel dogs was determined before and three to seven weeks after the creation of a side to side aortocaval fistula. The latter resulted in gross cardiac failure and a variable degree of left ventricular hypertrophy. For each tolerance test the dogs were sedated and given acetylstrophanthidin intravenously in a dose of 0·02 mg/kg over 2 min, followed by 0·004 mg/kg/min until toxicity was produced. Toxicity was defined as an ectopic tachycardia continuing for at least 10 consecutive beats or complete atrioventricular block. Acetylstrophanthidin tolerance was markedly reduced after fistula production, the mean toxic dose falling 0·67 ± 0·43 (SD) mg, or 37%, from 0·087 mg/kg to 0·052 mg/kg (P < 0·005). Increased cardiotoxicity to acetylstrophanthidin in these animals may be a direct or indirect consequence of volume overload or may be secondary to induced biochemical or structural myocardial changes.
A Hole in the Argument
Authors: Donald D. Hegland, Geoffrey A. Kunz, J. Kevin Harrison, Andrew Wang
Journal: New England Journal of Medicine (2005)

An 80-year-old man presented for evaluation of shortness of breath and fatigue four weeks after repair of a hiatal hernia. He reported a mild, nonproductive cough and abdominal bloating. Before the surgery, he had been very active and had had no dyspnea.
Effects of Lowering Average or Below-Average Cholesterol Levels on the Progression of Carotid Atherosclerosis
Authors: Stephen MacMahon, Norman Sharpe, Greg Gamble, Hamish Hart, John Scott, John Simes, Harvey White
Journal: Circulation (1998)

Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis and lower the risk of coronary heart disease events. However, there has been uncertainty about the effects of cholesterol lowering in patients with average or below-average cholesterol levels.In this study, 522 patients with a history of myocardial infarction or unstable angina and with baseline levels of total cholesterol between 4 and 7 mmol/L (mean, 5.7 mmol/L) were randomized to treatment with a low fat diet plus pravastatin (40 mg daily) or to a low fat diet plus placebo. Treatment with pravastatin reduced the levels of total cholesterol by 19%, LDL cholesterol by 27%, apolipoprotein B by 19%, and triglycerides by 13% (all 2P<.0001) and increased apolipoprotein A1 and HDL cholesterol levels by 4% (both 2P<.0005), in comparison with placebo. Carotid atherosclerosis was assessed from B-mode ultrasound measurements of the common carotid artery. After 4 years, mean carotid wall thickness had increased by 0.048 mm (SE=0.01) in the placebo group and declined by 0.014 mm in the pravastatin-treated group (SE=0.01) (2P for difference <.0001). The effect of treatment on wall thickness was similar in three groups classified by tertiles of total cholesterol at baseline, with mean levels of 4.8, 5.7, and 6.6 mmol/L, respectively (2P for interaction >.8).Treatment with pravastatin reduced the development of carotid atherosclerosis among patients with coronary heart disease and a wide range of pretreatment cholesterol levels. Treatment with this agent prevented any detectable increase in carotid wall thickening over 4 years of follow-up.
Effect of pre‐ and postnatal tobacco smoke exposure on specific sensitization to food and inhalant allergens during the first 3 years of life
Authors: M Kulig, W Luck, S Lau, B Niggemann, R Bergmann, U Klettke, I Guggenmoos‐Holzmann†, U Wahn
Journal: Allergy (1999)

Background : The study aimed to assess the effect of pre‐ and postnatal tobacco smoke exposure on specific sensitization to food allergens and inhalant allergens during the first 3 years of life. Methods : A total of 342 children of a prospective and observational birth cohort study on atopy (MAS) were included on the basis of a complete follow‐up of specific IgE measurements at the ages of 1, 2, and 3 years with available questionnaire information about the parental smoking habit at birth, 18 months, and 3 years of age. Study children were grouped into four exposure categories representing in utero and postnatal environmental tobacco smoke (ETS) exposure, and according to the number of cigarettes smoked by the parents. The effect on the development of allergic sensitization to food, outdoor, and indoor allergens by 3 years of age was determined by multiple logistic regression analyses. Results : At the age of 3, children who were pre‐ and postnatally exposed to tobacco smoke had a significantly higher risk of sensitization to food allergens (odds ratio: 2.3, 95% C.I.: 1.1–4.6) than unexposed children. Children who were only postnatally exposed by a smoking mother also had a 2.2 times higher risk (95% C.I.: 0.9–5.9) of sensitization than unexposed children. These two categories (pre‐ and/or postnatal exposure) contribute to the significant overall effect of the tobacco smoke exposure ( P ≤0.02). No significant association between tobacco smoke exposure and specific sensitization to inhalant allergens was observed. The determining risk factors for this type of sensitization were atopic family history and mite‐ and cat‐allergen exposure levels. Conclusions : During the first 3 years of life, both prenatal and postnatal tobacco smoke exposure has an adjuvant effect on allergic sensitization which seems to be restricted to allergens to which children are mainly exposed, in combination with the peak of the ETS exposure around the first birthday.
Role of CD44 in the reaction of vascular smooth muscle cells to arterial wall injury.
Authors: M Jain, Q He, W S Lee, S Kashiki, L C Foster, J C Tsai, M E Lee, E Haber
Journal: Journal of Clinical Investigation (1996)

CD44, the principal receptor for hyaluronic acid, is a widely distributed cell surface proteoglycan involved in cellular activation, proliferation, and migration. These processes are also central to the vascular smooth muscle cell's response to arterial wall injury. We evaluated the expression of CD44 and its isoform, CD44-V6, on vascular smooth muscle cells in vitro and in vivo and assessed the role of CD44 in DNA synthesis. Cultured vascular smooth muscle cells expressed CD44 and CD44-V6 at levels equal to or higher than those of the beta 1 and beta 2 integrins. In a rat carotid artery balloon injury model, CD44 and CD44-V6 mRNAs were unregulated in vascular smooth muscle cells after injury, and CD44 protein expression was greatest at the luminal edge of the growing neointima. CD44-expressing smooth muscle cells proliferated actively, and hyaluronic acid expression increased after injury in a temporal pattern similar to that of CD44. Through binding to hyaluronic acid, CD44 augmented DNA synthesis in cultured human and rat smooth muscle cells by 48 +/- 7.8 and 100 +/- 12.5%, respectively, an effect inhibited by an anti-CD44 antibody that blocked hyaluronate binding. These observations support a role for CD44 in the reaction of vascular smooth muscle cells to arterial wall injury.
Clinical Outcomes with Perioperative Chemotherapy in Sarcomatoid Carcinomas of the Lung
Authors: Jamie E. Chaft, Camelia S. Sima, Michelle S. Ginsberg, James Huang, Mark G. Kris, William D. Travis, Christopher G. Azzoli
Journal: Journal of Thoracic Oncology (2012)

In patients with resected lung cancer, sarcomatoid carcinomas are reputed to carry a worse prognosis. Although generally felt to be chemo-refractory, little data are available about chemotherapy in these patients. We sought to determine the effect of perioperative chemotherapy in patients with completely resected sarcomatoid carcinomas of the lung.We reviewed the pathology reports of 4675 patients consecutively resected at Memorial Sloan-Kettering between 2000 and 2010. Charts and images were reviewed for patients with a histologic diagnosis of sarcomatoid carcinoma. Response to neoadjuvant chemotherapy was assessed radiographically. Kaplan-Meier disease-free probability (DFP) curves were compared for patients who did and did not receive perioperative chemotherapy, stratified by pathological stage.Of the 4675 patients who underwent an R0 lung cancer resection, 56 (1%) were diagnosed with sarcomatoid carcinomas. Twenty received neoadjuvant and/or adjuvant chemotherapy. Overall radiographic response rate (minor + major) to neoadjuvant chemotherapy was 73% (95% confidence interval 48-90%) in the 15 evaluable patients. The median DFP of patients who received chemotherapy was 34 months versus 12 months in those who did not (p = 0.37). Subset analysis did not reveal a benefit to perioperative chemotherapy in patients with stage Ib-IIa, whereas a benefit was seen in patients with IIb-IIIa disease (p = 0.02).Although sarcomatoid carcinomas are felt to be chemo-refractory, our results demonstrate radiographic responses to neoadjuvant chemotherapy and an improvement in DFP in patients with stage IIb-IIIa disease. The use of pathological stage in this analysis may underestimate this benefit. Perioperative chemotherapy should be considered in these patients.
Secretion of an articular cartilage proteoglycan-degrading enzyme activity by murine T lymphocytes in vitro.
Authors: G M Kammer, A I Sapolsky, C J Malemud
Journal: Journal of Clinical Investigation (1985)

Destruction of articular cartilage is the hallmark of inflammatory arthritides. Enzymes elaborated by mononuclear cells infiltrating the synovium mediate, in part, the degradation of the cartilage extracellular matrix. Since mononuclear cells are the dominant cell type found in chronic inflammatory synovitis, we investigated whether interaction of immune mononuclear cells with antigen initiated the synthesis and secretion of a proteoglycan-degrading enzyme activity. Proteoglycan-degrading enzyme activity was monitored by the capacity of murine spleen cell conditioned medium to release [3H]serine/35SO4 incorporated into rabbit cartilage proteoglycan monomer fraction (A1D1), and by the relative change in specific viscosity of bovine nasal cartilage proteoglycan monomer. The results demonstrated that both virgin and immune mononuclear cells spontaneously generated proteoglycan-degrading enzyme activity and that cellular activation and proliferation induced by the antigen keyhole limpet hemocyanin or the mitogen phytohemagglutinin was not required. Kinetic studies demonstrated stable release of the enzyme activity over 72 h. Cell separation studies showed that T lymphocytes, a thymoma line, and macrophages separately produced proteoglycan-degrading enzyme activity. The enzyme activity has been partially characterized and appears to belong to a class of neutral pH metal-dependent proteinases. These observations, the first to demonstrate that T lymphocytes secrete an enzyme capable of degrading cartilage proteoglycan, raise the possibility that this enzyme activity contributes to cartilage extracellular matrix destruction in vivo. Moreover, these data support the conclusion that production of this enzyme by T lymphocytes is independent of an antigen-specific stimulus.
The Reaction of Medical Students to Drug Advertising
Authors: Solomon Garb
Journal: New England Journal of Medicine (1958)

THE problems of drug advertising have increased enormously in the past decade and have resulted in many thoughtful discussions of the best ways of solution. Most writers agree that the volume of drug advertising is excessive, that the claims are often exaggerated, and that the approach is often undignified. The physician is urged to be cautious, conservative and critical in his use of advertised drugs, but apparently such advice is not followed widely enough, as judged by the success of many pharmaceutical items of dubious value.On the other hand, the practicing physician who must make the final decision is . . .
Ukraine must loosen drugs policy to allow patients access to oral morphine, says report
Authors: A. Osborn
Journal: BMJ (2011)

Tens of thousands of people with cancer in Ukraine are being condemned to live their final months in excruciating pain because oral morphine is not available, a report has concluded.

The report, from New York based Human Rights Watch, estimates that up to 80 000 cancer patients in Ukraine had severe pain every year as a result of the country’s controversial public health policy. 

“There is no reason people have to live out their last months in torment,” said Diederik Lohman, a senior health researcher at Human Rights Watch. “Ukraine needs to fix its …
A6.43 Neutrophil extracellular traps are not only targets for ACPA but also directly trigger pro- and anti-inflammatory effects partly mediated by the C1Q complement protein
Authors: M Ribon, K Matyja, M Sebbag, C Clavel, J Mussard, G Serre, MC Boissier, P Decker
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Upon activation, neutrophils (PMN) form neutrophil extracellular traps (NET). Those structures are expelled chromatin fibres composed of DNA and associated proteins. The process, NETosis, is dependent on citrullination, a post-translational modification of proteins. NETosis has been suggested to be pathogenic in certain autoimmune diseases, particularly in rheumatoid arthritis (RA), characterised by the production of anti-citrullinated protein autoantibodies (ACPA) which are specific for the disease. Although RA PMN show enhanced NETosis and RA autoantibodies recognise NET, the pathogenic mechanisms triggered by NET are not elucidated. Therefore, we have analysed the antigenic and immunogenic properties of NET in RA. <h3>Materials and methods</h3> PMN and monocytes were freshly isolated by dextran sedimentation or purified by magnetic bead sorting, respectively, from the blood of healthy donors and RA patients. IgG were purified from healthy donors, from ACPA-positive RA patients and from ACPA-negative patients with rheumatic diseases. Monocytes were differentiated into macrophages by culturing in the presence of M-CSF. Cell purity and IgG binding were estimated by flow cytometry. NETosis was induced <i>in vitro</i> on poly-L-lysine-adherent PMN and was analysed by fluorescence microscopy, together with IgG binding. NET were detached from plastic by mild nuclease digestion to produce soluble NET which were enriched, quantified by fluorescence (PicoGreen) and by spectrophotometry (NanoDrop) and characterised by SDS-PAGE and agarose gel. Macrophages and PMN were cultured with soluble NET in the presence/absence of LPS or C1q. Cell activation was estimated by measuring cytokine secretion by ELISA. <h3>Results</h3> Only low binding of IgG was observed by flow cytometry on untreated freshly isolated PMN. Upon NETosis, a strong binding of ACPA+ IgG was observed, specifically on the NET structures, as demonstrated by the co-staining of DNA by fluorescence microscopy. Soluble NET activated both macrophages and PMN, leading to IL-8 secretion, independently of ACPA+ IgG. The stimulatory activity of soluble NET was increased in the presence of C1q. Soluble NET from both healthy donors and RA patients induced cell activation. Likewise, both PMN and macrophages from healthy donors and RA patients responded to soluble NET. On the contrary, soluble NET specifically inhibited LPS-induced IL-6 secretion by macrophages, and to a lower extent TNF secretion, but not IL-8 secretion. <h3>Conclusions</h3> ACPA+ IgG from RA patients strongly and specifically recognise NET and not untreated PMN. NET are immunogenic and possess both pro- and anti-inflammatory properties depending on the cell type, the activation status and the presence of co-factors like C1q.
Redistribution of Myocardial Blood Flow With Topical Nitroglycerin in Patients With Coronary Artery Disease
Authors: Ernest L. Fallen, Claude Nahmias, Anita Scheffel, Geoff Coates, Rob Beanlands, E. Stephen Garnett
Journal: Circulation (1995)

Background Unlike nonselective coronary vasodilators, nitroglycerin (GTN) is said to exert its primary vasodilatory effect on epicardial conductance vessels. Thus, in experimental models of coronary occlusion GTN appears to preferentially direct blood flow to poststenotic zones of ischemia. This phenomenon has, to date, not been tested in humans. Using positron emission tomography we examined the effect of transdermal GTN on global and regional myocardial perfusion in patients with angiographically proven coronary artery disease. Methods and Results Myocardial perfusion with [ 13 N]ammonia was estimated from dynamic time-activity curves at baseline and 3 hours following application of either a 0.4 mg/h GTN skin patch (n=10) or a placebo patch (n=10) in a double-blind parallel design. From resliced cross-sectional images, regional flow, expressed as [ 13 N]ammonia retention, was estimated from 216 myocardial sectors. Ischemia was defined as a significant reduction (&gt;2 SDs from average counts/pixel in maximally perfused zones) in [ 13 N]ammonia retention within 10 contiguous myocardial sectors coupled with an increase or no change in counts derived from [ 18 F]fluorodeoxyglucose. There was no change in global myocardial blood flow as expressed by [ 13 N]ammonia retention following either placebo (0.61±0.14 to 0.62±0.12 min −1 ) or GTN (0.75±0.22 to 0.74±0.19 min −1 ). Conversely, there was a significant increase in the proportion of blood flow to the ischemic zones with GTN (73.9±12.6% to 94.9±17.8%; P &lt;.05). No change in the distribution of blood flow to either ischemic or nonischemic zones was observed with placebo. A slight but insignificant decrease in [ 13 N]ammonia retention in nonischemic zones was observed with GTN (1.01±0.31 to 0.93±0.26 min −1 ). Conclusions This study suggests that under resting conditions topical GTN alters myocardial perfusion by preferentially increasing flow to areas of reduced perfusion with little or no change in global myocardial perfusion in patients whose angina is responsive to GTN.
Formulations of morphine sulphate are easily confused
Authors: G. F Cavell
Journal: BMJ (1996)

women using hormone replacement therapy for up to five years but was not significantly increased in women using it for longer.5Neither of these obser- vations is consistent with a causal relation between sex steroid hormones and cancer, such as that so clearly shown between unopposed oestrogens and endometrial cancer.Price and Little also com- pletely ignore a recent population based case- control study that showed no increase in the risk of breast cancer even when hormone replacement therapy was taken for 20 years and more.6While relying uncritically on the report on use of hormone replacement therapy and breast can- cer from the nurses' health study, the authors perfunctorily dismiss the finding from the same cohort of a 50% reduction in the risk of myocar- dial infarction among women using the therapy.We recognise that epidemiology has provided no easy answer to the question of whether use of hormone replacement therapy has an effect on the risk of breast cancer, but we object to the promulgation of any attitude towards hormone replacement therapy, whether positive or nega- tive, that is based on prejudice and a personal agenda.Making an announcement of a new organisation is no excuse for such abuse of the literature.Sadly, it is all too easy for those with no clinical responsibility for hormone replace- ment therapy to present a distorted view, to the detriment of women seeking a balanced assessment of the benefits and risks.
Surgical correction of pectus excavatum and carinatum.
Authors: S V Singh
Journal: Thorax (1980)

This paper contains an analysis of the long-term results in 85 patients who had pectus excavatum or carinatum deformities repaired at the North Middlesex Hospital between 1951 and 1977. Seventy-seven patients had operations for correction of pectus excavatum and eight for pectus carinatum. A variety of surgical techniques was used. In the excavatum deformities the best results were obtained by the extensive resection of all deformed cartilages, the correction of the sternal deformity by a simple transverse wedge osteotomy, and by stabilising the chest with a stainless steel plate. For pectus carinatum, the involved cartilages were resected and an osteotomy of the sternum was performed. We preferred in most cases to stabilise the chest wall with a metal strut in this deformity as well. The best cosmetic results were achieved by the use of a stainless steel plate passed beneath the sternum and left for not more than six months.
How we are born
Authors: Sudhansu K. Dey
Journal: Journal of Clinical Investigation (2010)

Human reproduction is relatively inefficient. Nearly 30% of pregnancies result in spontaneous losses, which are both a clinical problem and a psychological stress to the families involved. Furthermore, although the human population is growing rapidly and is predicted to reach 9 billion by 2050, 15% of couples worldwide are childless because of infertility. Many underlying causes of infertility have been overcome by assisted reproductive technologies such as in vitro fertilization, yet pregnancy success rates using such approaches remain disappointingly low. Since mechanistic approaches to study human reproductive processes are ethically restricted, future advances in fertility treatment and the development of new contraceptives rely predominantly on the study of the factors influencing reproduction in model systems. The articles in this Reproductive Biology Review series present updates on the current understanding of various reproductive processes in model systems and raise questions that need to be addressed if we are to improve human reproductive health.
Endoscopic Papillotomy on the Guide of a Transhepatic Anterograde Biliary Drainage
Authors: D. Oselladore, R. Rossoni, G. Bedogni, E. Ricci
Journal: Endoscopy (1987)

See also: Endoscopic Sphincterotomy in Patients with Difficult Cannulation: Use of an Antegrade GuideEndoscopy 1986; 18(03): 87-89DOI: 10.1055/s-2007-1013013