tbuckley/cabot-search huggingface dataset:
S53 Studying fibre specific gene expression in COPD using laser capture micro-dissection in human skeletal muscle
Authors: D Mohan, A Lewis, MS Patel, K Curtis, R Tanner, P Kemp, MI Polkey
Journal: Thorax (2013)

<h3>Background</h3> Approximately 30% of patients with Chronic Obstructive Pulmonary Disease (COPD) exhibit peripheral skeletal muscle dysfunction and a shift towards type II glycolytic fibres in the quadriceps compared to healthy controls (Nanatek <i>et al</i>, 2013). Previous work to elucidate the molecular mechanisms underlying these changes has relied on whole biopsy samples and may have missed fibre-specific pathways; thus a method to evaluate fibre specific signalling pathways would be useful. <h3>Objective</h3> To describe a novel laser capture micro-dissection (LCM) method to examine fibre-specific signalling in quadriceps biopsies. <h3>Methods</h3> First larger Intercostal muscle biopsies were used to validate the methodology since they yielded more RNA. Fibres were classified as type-2 positive or type-2 negative based on immunoreactivity with a type-2 fibre specific anti-myosin Heavy Chain Alexa FLUOR 488 antibody. The type-2 negative fibre population was hence assumed to contain type-1 fibres, which was confirmed by the type-2 negative fibre population exhibiting a higher myhc7/2 mRNA ratio and expressing higher levels of genes associated with type-1 fibres, e.g. TNNT-1 and STARS, and lower levels of genes associated with type-2 fibres, e.g. TGF-B, myostatin, GAPDH and HDAC-4 (n = 2). We then examined OCT-embedded <i>vastus lateralis</i> muscle biopsy specimens. 10micron cryosections underwent fixation with 4% paraformaldehyde before immunostaining. LCM (PALM Microbeam, Zeiss, UK) was used to capture type I and type II fibre populations, before RNA extraction with RNAeasy FFPE kit (Qiagen, USA) and rtPCR to obtain cDNA. Sybr-II qPCR was performed on fibre populations for target genes MHC I, MHC IIa, MHC IIx, HDAC-4 and RPLPO. <h3>Results</h3> Preliminary results from three 10micron slices indicate that this technique is feasible to study fibre-specific signalling in COPD. LCM following immunostaining captures distinct fibre populations (Figure 1) confirmed by a higher MHC I content in ‘type I fibres’, with ‘type II’ fibres containing more MHC IIa, MHC IIx and HDAC-4 as would be expected. Gene expression is normalised against RPLPO. <h3>Conclusion</h3> LCM can be used to study fibre specific inflammatory signalling in the skeletal muscle of COPD patients and immunostaining with MHC antibodies is a feasible way to distinguish between fibre types when capturing composite fibre populations.
Nitrovasodilators, Low-Dose Aspirin, Other Nonsteroidal Antiinflammatory Drugs, and the Risk of Upper Gastrointestinal Bleeding
Authors: Angel Lanas, Eduardo Bajador, Pedro Serrano, Javier Fuentes, Sofía Carreño, Jesusa Guardia, Mercedes Sanz, Miguel Montoro, Ricardo Sáinz
Journal: New England Journal of Medicine (2000)

The relation between medications that release nitric oxide, such as nitroglycerin and other nitrovasodilators, and upper gastrointestinal bleeding is uncertain. In animals, these medications reduce the gastric damage induced by nonsteroidal antiinflammatory drugs. Nitric oxide, however, inhibits platelet aggregation and may contribute to bleeding from an ulcer.
LONG-TERM OUTCOMES OF AN FFRCT DIAGNOSTIC STRATEGY VERSUS USUAL CARE IN SUSPECTED CORONARY ARTERY DISEASE: RESULTS FROM THE PLATFORM (PROSPECTIVE LONGITUDINAL TRIAL OF FFRCT: OUTCOME AND RESOURCE IMPACTS) STUDY
Authors: Pamela S. Douglas, Bernard De Bruyne, Gianluca Pontone, Manesh Patel, Bjarne Norgaard, Robert Byrne, Nick Curzen, Ian Purcell, Matthias Gutberlet, Gilles Rioufol, Ulrich Hink, Herwig Schuchlenz, Gudrun Feuchtner, Martine Gilard, Karen Chiswell, Derek Cyr, Alan Wilk, Campbell Rogers, Mark Hlatky
Journal: Journal of the American College of Cardiology (2016)
Postmenopausal hormone therapy in a prospective randomized trial of termination versus long-term continuation results in greater regional brain metabolism.
Authors: DH Silverman, CL Geist, HA Kenna, NL Rasgon
Journal: Cancer Research (2009)

Abstract Abstract #5088 Objective: Beyond the potential effects of sex steroids on the risk of developing breast and other cancers, the effect of postmenopausal hormone therapy on human brain aging and cognition is also currently highly controversial. In a prospective study of women at increased risk for developing Alzheimer disease (AD), we examined the influence of exogenous and endogenous estrogen exposure on regional cerebral metabolism. Methods: Women on postmenopausal hormone therapy (HT) and at increased risk for AD were randomized to immediately terminate or continue HT. Of 81 total subjects studied to date, data from the first 25 consecutive subjects to complete the 2-yr protocol are presented. Subjects in each randomized arm were similar in average yrs of education (16.5 vs. 16.6), age at menarche (13.1 vs. 12.6), age at menopause (47.3 vs. 47.9), and age at recruitment (58.4 vs. 58.9). All subjects underwent FDG-PET imaging at baseline as well as 2 yrs after randomization, and scans were assessed for interactions of time-, exogenous therapy arm-, and endogenous hormonal covariate-based effects, with statistical parametric mapping. Results: Across all subjects, yrs of endogenous estrogen exposure (age at menopause minus age at menarche) positively correlated most significantly (t=4.23,p&amp;lt;0.0005) with metabolism of the precuneus area of the posterior medial cortex (area where perfusion is most significantly diminished in early stages of AD), which is consistent with experimental animal and human epidemiologic data supporting a neuroprotective role for estrogen. Two years after termination of HT, subjects demonstrated a highly significant negative correlation (t=-9.27,p&amp;lt;0.0005) of yrs of endogenous exposure with metabolism of anterior medial frontal cortex (area of the brain undergoing the most significant decline of perfusion and metabolism with normal aging), suggesting that the levels of frontal metabolism reached during the years of greater endogenous exposure were more rapidly lost during 2 yrs of estrogen deprivation. Moreover, those women who continued HT during the 2 yr interval of randomization, actually demonstrated a significant increase in the most anterior portion of their medial prefrontal cortex during that period (t=5.06,p&amp;lt;0.0005), while those women who discontinued HT did not, and this part of the brain was the location of the largest increase over 2 yrs (4083 contiguous voxels having signigicance of p&amp;lt;0.01) throughout the brain. Conclusion: Both exogenous and endogenous hormone exposure were associated with changes in medial cortical metabolism consistent with neuroprotective roles relevant to metabolic changes occurring in brain aging and dementia. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5088.
P12.14 * SAFETY AND DIAGNOSTIC YIELD OF FRAME-BASED STEREOTACTIC BIOPSY
Authors: A. Smolanka
Journal: Neuro-Oncology (2014)

OBJECTIVE: To determine the diagnostic yield and safety of frame-based stereotactic biopsy. METHODS: Stereotactic biopsy was performed in 65 patients with supratentorial lesions treated in Regional Centre of Neurosurgery and Neurology from January, 2009 till January, 2014. 25 (38.5%) patients were male, and 40 (61.5%) – female. Mean age of the patients was 49.8 years. Indications for stereotactic biopsy were: deep location (basal ganglia, thalamus, internal capsule, corpus callosum), multiple lesions, eloquent cortical location or poor somatic condition of the patient. In all cases frame-based CT-navigated stereotactic biopsy was performed using ELEKTA FrameG. Computed tomography was performed on first postoperative day in all cases. RESULTS: Histologic results: anaplastic glioblastoma – 28 patients (43.1%), anaplastic astrocytoma – 10 patients (15.4%), anaplastic oligodendroglioma – 4 patients (6.2%), oligodendroglioma – 4 patients (6.2%), diffuse astrocytoma – 4 patients (6.2%), primary CNS lymphoma – 4 patients (6.2%), metastasis – 4 patients (6.2%), inflammatory lesion – 3 patients (4.6%), demyelination – 2 patients (3.1%), radiation necrosis – 1 patient (1.5%), negative result – 1 patient (1.5%). None of the patients deteriorated neurologically. Hemorrhage in biopsy site was found in 2 patients (3.1%) on CT, but was asymptomatic in both. 1 patient (1.5%) had superficial wound infection. Diagnostic yield in our series was 98.5%, as we had negative result in only 1 patient. CONCLUSION: Frame-based stereotactic biopsy can be considered a safe procedure with high diagnostic yield.
Abstract 1022: PI3-kinase inhibition enhances ABT-737-induced apoptosis in colorectal cancer cell lines
Authors: Christopher J. Morrow, Jian-Mei Hou, Caroline Dive
Journal: Cancer Research (2010)

Abstract The PI3-kinase signalling pathway is widely reported to promote survival, proliferation and migration. This pathway is up-regulated in several solid tumours by a host of different mechanisms, including PTEN deletion, RAS or PIK3CA mutation and aberrant activation of receptor tyrosine kinases. As such, inhibitors of PI3-kinase and its down-stream effectors are of great interest as tractable anti-cancer agents. The effect of PI3-kinase inhibition was investigated in colorectal cancer cell lines and demonstrated that, while PI3-kinase inhibition by itself did not cause cell death, it enhanced apoptosis induced by the BH3 mimetic ABT-737 (assessed by nuclear fragmentation, caspase 3 cleavage and phosphatidylserine exposure). Furthermore, ABT-737 and PI3-kinase inhibition caused increased level of Bak activating conformational change compared to ABT-737 alone, suggesting that the effect of PI3-kinase inhibition is up-stream of cytochrome C release. PI3-kinase inhibition did not alter the expression level of Bcl-2 family members, but co-immunoprecipitation revealed that it increased the amount of Bim bound to Bcl-xL. No change was seen in the binding of other BH3 only proteins or of Bax or Bak to ABT-737 targets Bcl-2 or Bcl-xL. ABT-737-induced apoptosis was independent of AKT and mTOR signalling as it was unaffected by the inhibitors AKTi1/2 and rapamycin respectively. A model is proposed whereby ABT-737 interrupts PI-3K inhibition-induced Bim/Bcl-xL complexes to promote apoptosis via Bax/Bak activation. Function testing experiments are underway to interrogate this model. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 1022.
Use of Glycyrrhizin after Bilateral Adrenalectomy
Authors: Perry B. Hudson, Arnold Mittelman, Meir Podberezec
Journal: New England Journal of Medicine (1954)

IN 1951 Groen et al.1 , 2 described the satisfactory maintenance of several patients with Addison's disease by means of glycyrrhizinic acid. Although Addison's disease differs in many respects from the state of complete absence of the adrenal glands, the similarity of the two conditions is striking enough to warrant an evaluation of glycyrrhizinic acid in patients subjected to bilateral adrenalectomy.Clinical StudyThree patients with metastatic cancer were utilized in this study: a man with papillary carcinoma of the kidney (Case 1), another man with embryonal-cell carcinoma of the right testicle (Case 3) and a woman with adenocarcinoma of the breast . . .
Abstract 32: P190B RhoGAP overexpression drives mammary epithelial cell proliferation by altering stromal-epithelial interactions in the developing mammary gland
Authors: Melissa Gillette, Peter McHenry, Alisa Blumenthaler, Peggy Chang, Tracy Vargo-Gogola
Journal: Cancer Research (2012)

Abstract Breast cancer development and progression is enabled by alterations in the surrounding stroma originating from stromal interactions with cancerous epithelium. Rho GTPases and their regulators have been implicated as important mediators of stromal-epithelial interactions in mammary epithelial cells (MECs), and alterations in the microenvironment profoundly affect MEC morphogenesis in a Rho GTPase-dependent manner. Previously, we demonstrated that p190B Rho GTPase activating protein (RhoGAP), a major inhibitor of Rho GTPases, has pro-tumorigenic functions during MMTV-Neu induced mammary tumorigenesis. We hypothesized that p190B overexpression in the epithelium promotes mammary tumor development by altering stromal-epithelial interactions to drive MEC proliferation and disrupt tissue architecture. To investigate this hypothesis, we examined the effects of p190B overexpression in the developing mammary gland (MG) using Tet-regulatable p190B overexpressing mice. Interestingly, overexpression of p190B in the mammary epithelium during postnatal MG development causes hyperbranching and disorganization of the ductal tree. Using a combination of in vivo morphometric and immunohistochemical analyses and in vitro stromal-epithelial co-cultures, we have demonstrated that p190B overexpression in MECs activates fibroblasts in the adjacent microenvironment leading to increased extracellular matrix (ECM) deposition, elevated expression of the collagen crosslinking enzyme lysyl oxidase, and increased expression of potent regulators of branching morphogenesis, including FGF and TGFβ growth factors. These stromal alterations correlated with increased proliferation of p190B overexpressing MECs in vivo. Taken together, these data suggest that p190B overexpression may contribute to mammary tumorigenesis by creating a pro-tumorigenic stromal environment leading to increased MEC proliferation and altered tissue architecture. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 32. doi:1538-7445.AM2012-32
Abstract 5380: Prophylactic MUC1/Poly-ICLC vaccine in individuals with the history of advanced colorectal adenoma
Authors: Takashi Kimura, John R. McKolanis, Robert E. Schoen, Olivera J. Finn
Journal: Cancer Research (2012)

Abstract Background MUC1 is aberrantly expressed in a hypoglycosylated form with lack of luminal polarity in variety of human adenocarcinomas including colon cancer. Aberrant MUC1 is also highly expressed in colonic adenomas where it may promote malignant transformation by interacting withβ-catenin known to be an important pathway in colon carcinogenesis. We hypothesized that induction of an immune response against aberrant MUC1 in individuals with a recent history of adenoma may prevent adenoma recurrence and/or their progression to colon cancer. We conducted a clinical study using MUC1 peptide and Poly-ICLC adjuvant vaccine to evaluate the safety and immunogenicity in individuals who are cancer free but at high risk for developing colorectal cancer because of a recent history of advanced adenoma. Method Patients with advanced colorectal adenoma which meets at least one of following criteria: 1) ≥ 1cm in maximal diameter, 2) villous or tubulovillous histology, 3) high-grade dysplasia, were vaccinated with 100μg of 100aa MUC1 peptide (H2N-(GVTSAPDTRPAPGSTAPPAH)5-CONH2) admixed with 500μg of Poly-ICLC (TLR-3 agonist) as adjuvant, on week 0, 2, 10 and one year later. Bloods were collected two weeks after each injection for monitoring of general immunocompetence, development of anti-MUC1 antibody and safety. Results The vaccine was well tolerated without any adverse event grade 2 or higher. Among 36 evaluable patients, anti MUC1 IgG antibody was elicited in 17 patients as measured on week12 (response rate 47.2%). This response rate and the high levels of IgG have never been seen in response to MUC1 vaccines in cancer patients. Antibody titers declined over time but could be boosted to previous or higher levels at 1 year, showing development of immune memory. Vaccine responders were distributed across most HLA-DR and DQ types with similar frequency as in the general population, indicating that the MUC1 peptide could be presented by multiple Class II alleles. Immune competence of colon adenoma patients evaluated by cytokine production of lymphocyte and regulatory T cell frequency was generally equal to healthy individuals, however myeloid derived suppressor cells (MDSCs) were significantly increased in colon adenoma patients. Increase in MDSCs was especially pronounced in non-responders to the vaccine. Conclusion MUC1 poly-ICLC vaccine is highly immunogenic in this prophylactic setting and no significant adverse events have been seen. Vaccine immunogenicity is reduced in individuals with increased numbers of MDSC and this immunosuppressive population might be used as a biomarker to select patients most likely to respond. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5380. doi:1538-7445.AM2012-5380
Peginesatide in Patients with Anemia Undergoing Hemodialysis
Authors: Steven Fishbane, Brigitte Schiller, Francesco Locatelli, Adrian C. Covic, Robert Provenzano, Andrzej Wiecek, Nathan W. Levin, Mark Kaplan, Iain C. Macdougall, Carol Francisco, Martha R. Mayo, Krishna R. Polu, Anne-Marie Duliege, Anatole Besarab
Journal: New England Journal of Medicine (2013)

Peginesatide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease.We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point--death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia--with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3.In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort.Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].).
Endoscopic retrieval of a disrupted pancreatic stent using a nasopancreatic drainage tube
Authors: T. Nambu, T. Ukita, H. Shigoka, S. Omuta, I. Maetani
Journal: Endoscopy (2010)

A proximally migrated pancreatic stent is usually removed using a basket, balloon, snare or forceps [1] [2] [3]. The lasso technique [4] and its variation [5] have been described. However, no method for retrieval of a migrated pancreatic stent has been established. We retrieved a disrupted pancreatic stent using a nasopancreatic drainage tube (NPDT).
Deficiency of Pulmonary Surfactant Protein B in Congenital Alveolar Proteinosis
Authors: Lawrence M. Nogee, Daphne E. deMello, Louis P. Dehner, Harvey R. Colten
Journal: New England Journal of Medicine (1993)

Congenital pulmonary alveolar proteinosis is an uncommon cause of respiratory failure in full-term newborns1–4. Although its histopathological appearance is similar to that of the alveolar proteinosis observed in older children and adults,5 the congenital form of the illness follows a different clinical course. All reported infants with congenital alveolar proteinosis have died within the first year of life despite maximal medical therapy. The incidence and cause of congenital alveolar proteinosis are unknown. Familial cases have been reported, and it has been speculated that the cause is an inborn error of surfactant metabolism4. In this report we describe . . .
Esophageal lesions herald widely metastatic disease
Authors: M. Krier, T. Sato, R. Soetikno, T. Kaltenbach
Journal: Endoscopy (2010)

A 59-year-old man with chronic hepatitis C and chronic obstructive pulmonary disease presented with an 8-month history of progressive solid food dysphagia, voice hoarseness, and weight loss. Prior ENT evaluation had revealed left vocal cord paralysis, with referral to gastroenterology. An upper endoscopy showed multiple polypoid masses in the mid and distal esophagus ([Fig. 1], [Video 1]).
THE EFFECT OF INHIBITION OF THE NA+/H+ EXCHANGER ON THE DEVELOPMENT OF HYPERTROPHY IN HYPERTROPHIC CARDIOMYOPATHY
Authors: Wessel Brouwer, Arjan C. Houweling, Marcel GJ Nederhoff, Tjeerd Germans, Marcel MGJ van Borren, Gerard Pasterkamp, Jolanda van der Velden, Albert C. van Rossum
Journal: Journal of the American College of Cardiology (2011)
Ian Douglas-Wilson
Authors: A. Gulland
Journal: BMJ (2013)

Editor of the Lancet 



Shortly after being demobbed at the end of the second world war, Ian Douglas-Wilson was interviewed for a job at the BMJ . He was told by its editor, Hugh Clegg, that he was too radical for the then staid publication, and that he should apply for a job at the Lancet . Douglas-Wilson followed Clegg’s advice and was appointed assistant editor at the Lancet in 1946. He stayed with the journal for the next 30 years, the last 11 of which he served as editor.

Whether he could be described as a true radical or not is a moot point, but he certainly did not mind upsetting the establishment—medical or otherwise. In the 1960s, when GPs were threatening to withdraw their services over pay, he wrote an editorial criticising their stance. He also wrote in support of trainee psychiatrists, who had been given a platform in the journal to campaign for a fairer examination system.1 According to Robin Fox, one of Douglas-Wilson’s new recruits at the time, …