tbuckley/cabot-search huggingface dataset:
Regulation of Angiotensin II Receptor Subtypes During Atrial Fibrillation in Humans
Authors: Andreas Goette, Marco Arndt, Christoph Röcken, Antje Spiess, Thorsten Staack, J. Christoph Geller, Christof Huth, Siegfried Ansorge, Helmut U. Klein, Uwe Lendeckel
Journal: Circulation (2000)

Background —Previous studies have suggested that atrial fibrillation (AF) is associated with the activation of the atrial angiotensin system. However, it is not known whether the expression of angiotensin II receptors changes during AF. The purpose of this study was to determine the atrial expression of angiotensin II type 1 and type 2 receptors (AT 1 -R and AT 2 -R) in patients with AF. Methods and Results —Atrial tissue samples from 30 patients undergoing open heart surgery were examined. Eleven patients had chronic persistent AF (≥6 months; cAF), 8 patients had paroxysmal AF (pAF), and 11 patients were in sinus rhythm. AT 1 -R and AT 2 -R were localized in the atrial tissue by immunohistochemistry and quantified at the protein and mRNA level by Western blotting and quantitative polymerase chain reaction. Both types of AT-R were predominantly expressed in atrial myocytes in all groups. The amount of AT 1 -R was reduced to 34.9% during cAF ( P &lt;0.01) and to 51.7% during pAF ( P &lt;0.05) compared with patients in sinus rhythm. In contrast, AT 2 -R was increased during cAF (246%; P =NS) and pAF (505%; P &lt;0.01). AT 1 -R/AT 2 -R mRNA content was similar in all groups. Conclusions —AF is associated with the down-regulation of atrial AT 1 -R and the up-regulation of AT 2 -R proteins. These findings may help define the pathophysiological role of the angiotensin system in the structural remodeling of the fibrillating atria.
Gustave Dore's Ogre
Authors: T. A McLoughlin
Journal: Journal of the Royal Society of Medicine (2006)

In an article published in the JRSM, Volume 99, Ferner and McDowell adopted a literature review of doctors charged with manslaughter since 1795.From a reading of their article it is possible to determine that they arrived at the following conclusions.First, that there had been a significant increase in the prosecution of doctors for gross negligence manslaughter since 1990; second, that the majority of these doctors should not have been prosecuted; third, that the Crown Prosecution Service (CPS) has failed to abide by its own prosecution Code; and fourth, that we have charged doctors as 'an emotionally satisfying way to exact retribution . . .'We question the methodology, analysis and conclusions reached by the authors.They relied for the most part on newspaper reports, a notoriously unreliable source, for an accurate account of the allegations.In every case all the evidence is considered by experienced doctors before any prosecution is commenced.We apply the criminal law on gross negligence manslaughter as we are required to do, yet Ferner and McDowell criticise us for not using the criteria of 'mistakes, slips (or lapses) and violations', tests that are unknown to the criminal law.Ferner and McDowell have failed to understand the CPS 'realistic prospect of conviction' test and have applied a simplistic numerical test against all the cases they could identify.The test is whether in this particular case there is a realistic prospect of conviction, not whether half of all defendants are convicted.The suggestion that, by charging doctors with manslaughter, the CPS is somehow seeking some emotional satisfaction in retribution is self-evidently bizarre and entirely unsupported by any evidence.
Relation Between the Tumor-Specific Antigen and Cytological Characteristics in Mouse Mammary Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Reiko Furuse Irie, Kotaro Koyama, Shigeo Hino
Journal: JNCI Journal of the National Cancer Institute (1970)

The modal chromosome number of FM3A/B, a cultured cell line of mouse mammary tumor, is hyperdiploid. Its karyotype changed spontaneously into hypotetraploidy (FM3A/BR) during serial culture. FM3A/B and FM3A/BR were converted into ascites form (FM3A and FM3A/R, respectively). Transplantation of FM3A and FM3A/R was successful in all syngeneic C3H/He mice, with a mean survival of 26 and 23 days, respectively. Judged from cell numbers in the peritoneal cavity, growth rate of FM3A/R was more rapid than that of FM3A. Cytotoxic sensitivity of these cells was tested with syngeneic antiserum against the tumor-specific antigen of the mouse mammary tumor and with complement. FM3A/R was far more sensitive to the antibody than FM3A. The concentration of the antigens on the cell surface of FM3A/R was demonstrated by absorption tests to be 35 times higher than that of FM3A. Cytotoxic sensitivity of other mouse mammary tumors, MM102, MM2, and MM12, was also higher than that of FM3A. The chromosomal population of FM3A was 90% hyperdiploid and 10% hypertetraploid, whereas that of all other tumors was hypotetraploid.
A phase I study of oral rucaparib in combination with carboplatin.
Authors: L Rhoda Molife, Patricia Roxburgh, Richard H. Wilson, Avinash Gupta, Mark R. Middleton, T. R. Jeffry Evans, Caroline Ogilvie Michie, Joaquin Mateo, Donna Crawford, Martin McKinlay Eatock, Wasir Saka, Nicola Cresti, Yvette Drew, Heidi Giordano, Darrin Despain, Dayna Simpson, Andrew R. Allen, Sarah S. Jaw-Tsai, Ruth Plummer
Journal: Journal of Clinical Oncology (2013)

2586 Background: Targeting poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA damage repair, may increase efficacy of DNA-damaging agents. This study evaluated the tolerability of oral rucaparib, a potent and selective PARP1/2 inhibitor, in combination with carboplatin (CP). Methods: Patients (pts) aged ≥18 with advanced solid tumors were included. Pts received lead-in doses of IV and oral rucaparib on Days -10 and -5, respectively, followed by CP on Day 1 and oral rucaparib on Days 1-14 q21 days. Treatment continued until disease progression. Pts with benefit could continue on rucaparib monotherapy once CP dosing was completed. Dose escalation was based on toxicities observed in Cycle 1 in cohorts of n=3-6. PK was assessed during Cycle 1. Results: 23 pts (median age 62 yrs [range 20 – 76]; 16 female; 9 ECOG PS=0; 6 ovarian/peritoneal cancer (OC), 5 breast cancer (BC), 2 NSCLC, 10 other tumor) were enrolled. Rucaparib doses of 80, 120, 180, 240, and 360 mg were administered with AUC3 CP, followed by 360 mg rucaparib with AUC4 CP, and currently with AUC5 CP. No DLTs have been reported. Median treatment cycles is 3 (range 1 – 15+). Treatment-related adverse events in ≥4 pts, all grades, include anemia (n=10), fatigue (n=9), nausea (n=7), thrombocytopenia (n=6), constipation (n=5), lethargy (n=5), neutropenia (n=5), and anorexia (n=4). One pt (OC, BRCA wt , AUC3 CP/180 mg rucaparib) had a PR of 5.1 mo duration. Two patients (both with OC; 1 BRCA unk , 1BRCA wt ) discontinued CP (after 4 &amp; 8 cycles) and continued on rucaparib monotherapy (additional 5 and 7+ cycles, respectively). An additional 4 pts (all BRCA unk ) had stable disease (SD) &gt;12 wks. Overall disease control rate (CR+PR+SD&gt;12 wks) in OC pts across all dose levels was 50% (3/6). Dose-proportional increase in rucaparib exposure was observed with steady state achieved by Day 14 and mean t 1/2 of 15 h. Oral bioavailability was 38% and dose-independent. Rucaparib exposure was not changed by CP co-administration. Conclusions: The combination of oral rucaparib and CP is well tolerated and exhibits activity at clinically relevant doses of each agent. Further studies in platinum-sensitive and homologous recombination repair deficient populations are warranted. Clinical trial information: NCT01009190.
mAb Das-1 is specific for high-risk and malignant intraductal papillary mucinous neoplasm (IPMN)
Authors: Koushik K Das, Hong Xiao, Xin Geng, Carlos Fernandez-del-Castillo, Vicente Morales-Oyarvide, Ebubekir Daglilar, David G Forcione, Brenna C Bounds, William R Brugge, Martha B Pitman, Mari Mino-Kenudson, Kiron M Das
Journal: Gut (2013)

<h3>Objective</h3> Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes that correlate with histological grades and risks for malignant transformation. mAb Das-1 is a monoclonal antibody against a colonic epithelial phenotype that is reactive to premalignant conditions of the upper GI tract. We sought to assess the ability of mAb Das-1 to identify IPMN with high risk of malignant transformation. <h3>Design</h3> mAb Das-1 reactivity was evaluated in 94 patients with IPMNs by immunohistochemistry. Lesional fluid from 38 separate patients with IPMN (n=27), low-grade non-mucinous cystic neoplasms (n=7) and pseudocysts (n=4) was analysed by ELISA and western blot. <h3>Results</h3> <i>Immunohistochemistry—</i>Normal pancreatic ducts were non-reactive and low-grade gastric-type IPMN (IPMN-G) (1/17) and intermediate-grade IPMN-G (1/23) were minimally reactive with mAb Das-1. In contrast, mAb Das-1 reactivity was significantly higher in high-risk/malignant lesions (p&lt;0.0001) including: intestinal-type IPMN with intermediate-grade dysplasia (9/10); high-grade dysplasia of gastric (4/7), intestinal (12/12), oncocytic (2/2) and pancreatobiliary types (2/2); and invasive tubular (8/12), colloid (7/7) and oncocytic (2/2) carcinoma. The sensitivity and specificity of mAb Das-1 for high-risk/malignantIPMNs were 85% and 95%, respectively. <i>Lesional fluid</i>—Samples from low- and intermediate-grade IPMN-G (n=9), and other low-grade/benign non-mucinous lesions demonstrated little reactivity with mAb Das-1. Conversely, cyst fluid from high-risk/malignant IPMNs (n=18) expressed significantly higher reactivity (p&lt;0.0001). The sensitivity and specificity of mAbDas-1 in detecting high-risk/malignant IPMNs were 89% and 100%, respectively. <h3>Conclusions</h3> mAb Das-1 reacts with high specificity to tissue and cyst fluid from high-risk/malignant IPMNs and thus may help in preoperative clinical risk stratification.
Sleep Fragmentation, Awake Blood Pressure, and Sleep-Disordered Breathing in a Population-based Study
Authors: MARY J. MORRELL, LAUREL FINN, HYON KIM, PAUL E. PEPPARD, M. SAFWAN BADR, TERRY YOUNG
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Arousal from sleep produces transient increases in systemic blood pressure, leading to the suggestion that repeated arousals are associated with a sustained increase in daytime blood pressure. Using data from the Wisconsin Sleep Cohort Study, a population-based study, we tested the hypothesis that sleep fragmentation is associated with elevated awake blood pressure. Sleep, breathing, and seated blood pressure measurements from 1,021 participants (age 42 ± 8 yr; 590 males) were analyzed. Sleep fragmentation was defined as the total number of awakenings and shifts to Stage 1 sleep divided by the total sleep time (sleep fragmentation index: SFI). To reduce the confounding influence of sleep-disordered breathing, which is related to both increased daytime blood pressure and sleep fragmentation, all participants with an apnea–hypopnea index (AHI) ⩾ 1 were analyzed separately. Accounting for the influences of sex, age, body mass index, and antihypertensive medication use, the SFI was significantly associated with higher levels of awake systolic blood pressure in people with an AHI < 1; a 2 standard deviation increase in the SFI was associated with a 3.1 mm Hg rise in awake systolic blood pressure. In participants with an AHI ⩾ 1, there was no independent association between the SFI and awake blood pressure after controlling for the influence of the AHI.
Modulation of leucocyte adhesion molecules, a T-cell chemotaxin (IL-8) and a regulatory cytokine (TNF-α) in allergic contact dermatitis (rhus dermatitis)
Authors: C.E.M. GRIFFITHS, J.N.W.N. BARKER, S. KUNKEL, B.J. NICKOLOFF
Journal: British Journal of Dermatology (1991)

To understand the molecular events which are important in leucocyte trafficking in cutaneous inflammation, poison ivy/oak extract was applied topically to the skin, and the simultaneous assessment of a variety of clinical and immunopathological parameters performed. The clinical response of subjects was divided into three main groups: I. 2–24 h after application, before the onset of erythema; II, 48 h‐1 week after application during maximal clinical changes; III, 2–3 weeks after application when the inflammation had subsided. Six different biopsies per subject were evaluated over the study period and the density of dermal cellular infiltrate, and the distribution of intercellular adhesion molecule‐1, (ICAM‐1), endothelial leucocyte adhesion molecule‐1, (ELAM‐1), vascular cell adhesion molecule‐1, (VCAM‐1), interleukin 8 (IL‐8) and tumour necrosis factor‐alpha (TNF‐α), determined. Eight hours after exposure, before lymphocytes and monocytes had entered the dermal interstitium or epidermis, the keratinocytes expressed TNF‐α and TCAM‐1, whilst the endothelial cells expressed ELAM‐1, VCAM‐1 and ICAM‐1. Group II biopsies revealed increasing keratinocyte expression of TNF‐α and ICAM‐1 with the appearance of IL‐8, which correlated with the onset of epidermal T‐cell trafficking. The endothelium was strongly positive for ELAM‐1 and VCAM‐1, but there was no influx of neutrophils. Group III biopsies showed a decrease in the expression of ICAM‐1, VCAM‐1 and FLAM‐1 by both keratinocytes and endothelium with a reduction in epidermal/dermal inflammation, although the endothelial cell staining of VCAM‐1 and ELAM‐1 did not completely disappear. These results suggest that on exposure to poison ivy/oak, keratinocytes rapidly produce TNF‐α which leads to an early autoinduction of ICAM‐1, and later IL‐8. There is also a paracrine‐mediated induction and augmentation of underlying endothelial cell ELAM‐1, VCAM‐1 and ICAM‐1.
Whole microvascular unit deletions in dermatomyositis
Authors: Cyril Gitiaux, Enis Kostallari, Peggy Lafuste, Francois-Jerome Authier, Christo Christov, Romain K Gherardi
Journal: Annals of the Rheumatic Diseases (2012)

The pathophysiology of dermatomyositis (DM) remains unclear, combining immunopathological mechanisms with ischaemic changes regarded as a consequence of membranolytic attack complex (MAC)-induced capillary destruction. The study is a reappraisal of the microvascular involvement in light of the microvascular organisation in normal human muscle.Muscle microvasculature organisation was analysed using 3D reconstructions of serial sections immunostained for CD31, and histoenzymatic detection of endogenous alkaline phosphatase activity of microvessels. An unbiased point pattern analysis-based method was used to evaluate focal capillary loss. Double immunostainings identified cell types showing MAC deposits.The normal arterial tree includes perimysial arcade arteries, transverse arteries penetrating perpendicularly into the endomysium and terminal arterioles feeding a microvascular unit (MVU) of six to eight capillaries contacting an average of five myofibres. Amyopathic DM cases (n=3) and non-necrotic fascicles of early DM cases (n=27), showed patchy capillary loss in the form of 6-by-6 capillary drop-out, corresponding to depletion of one or multiple MVUs. MAC deposits were also clustered (5-8 immunostained structures, including endothelial cells, but also pericytes, mesenchymal cells and myosatellite cells).Capillary loss may not be the primary cause of muscle ischaemia in DM. The primary event rather stands upstream, probably at the level of perimysial arcade arteries around which inflammatory infiltrates predominate and which lumen may show narrowing in chronic DM. Ischaemia-reperfusion injury, which is favoured by autoimmune backgrounds in experimental models and which activates the complement cascade in capillaries, could represent an hitherto unsuspected (and potentially preventable) mechanism of muscle damage in DM.
Endogenous regeneration after collagenase-induced knee joint damage in the adult newt Notophthalmus viridescens
Authors: M. Geyer, T. Borchardt, C. Schreiyack, A. Wietelmann, F. Muller-Schrobsdorff, C. Muller, U. Muller-Ladner, R. Dinser
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> To determine whether adult newts (<i>Notophthalmus viridescens</i>) are able to repair experimentally-induced joint damage in order to generate a model system for the study of endogenous joint regeneration. <h3>Methods</h3> Joint instability and articular cartilage lesions of the knee joint of adult newts (<i>N viridescens</i>) were induced by intra-articular injection of collagenase. The changes over time were analysed clinically, by MRI, histologically and by reverse transcription PCR to detect selected relevant markers. <h3>Results</h3> After rapid onset of disease with joint luxation, loss of proteoglycans and cartilage volume, the signs ameliorated continuously by regeneration of the affected joint compartments. The majority of joints were morphologically intact and functionally operative after 10 weeks. Upregulation of chondrogenic key genes, homogenous expression levels of factors implicated in cartilage homeostasis and limb regeneration as well as the distribution of the blastemal marker 22/18 in both treated and untreated knees suggest that joint regeneration in adult newts only partially invokes pathways of embryological organogenesis. <h3>Conclusions</h3> Newts are able to regenerate articular cartilage injuries and to restore tissue integrity and function after induction of damage using a procedure known to induce experimental osteoarthritis in murine models. Further analysis of the underlying molecular mechanisms may contribute to the development of novel treatment approaches in joint failure.
Prevalence of Cardiomyopathy in Italian Asymptomatic Children With Electrocardiographic T-Wave Inversion at Preparticipation Screening
Authors: Federico Migliore, Alessandro Zorzi, Pierantonio Michieli, Martina Perazzolo Marra, Mariachiara Siciliano, Ilaria Rigato, Barbara Bauce, Cristina Basso, Daniela Toazza, Maurizio Schiavon, Sabino Iliceto, Gaetano Thiene, Domenico Corrado
Journal: Circulation (2011)

T-wave inversion on a 12-lead ECG is usually dismissed in young people as normal persistence of the juvenile pattern of repolarization. However, T-wave inversion is a common ECG abnormality of cardiomyopathies such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, which are leading causes of sudden cardiac death in athletes. We prospectively assessed the prevalence, age relation, and underlying cardiomyopathy of T-wave inversion in children undergoing preparticipation screening.The study population included 2765 consecutive Italian children (1914 male participants; mean age, 13.9±2.2 years; range 8-18 years) undergoing preparticipation screening including an ECG. Of 229 children (8%) who underwent further evaluation because of positive findings at initial preparticipation screening, 33 (1.2%) were diagnosed with cardiovascular disease. T-wave inversion was recorded in 158 children (5.7%) and was localized in the right precordial leads in 131 (4.7%). The prevalence of right precordial T-wave inversion decreased significantly with increasing age (8.4% in children <14 years of age versus 1.7% in those ≥14 years; P<0.001), pubertal development (9.5% of children with incomplete versus 1.6% with complete development; P<0.001), and body mass index below the 10th percentile (P<0.001). Incomplete pubertal development was the only independent predictor for right precordial T-wave inversion (odds ratio, 3.6; 95% confidence interval, 1.9-6.8; P<0.001). Of 158 children with T-wave inversion, 4 (2.5%) had a diagnosis of cardiomyopathy, including arrhythmogenic right ventricular cardiomyopathy (n=3) and hypertrophic cardiomyopathy (n=1).The prevalence of T-wave inversion decreases significantly after puberty. Echocardiographic investigation of children with postpubertal persistence of T-wave inversion at preparticipation screening is warranted because it may lead to presymptomatic diagnosis of a cardiomyopathy that could lead to sudden cardiac death during sports.
SpeCond: a method to detect condition-specific gene expression
Authors: Florence MG Cavalli, Richard Bourgon, Wolfgang Huber, Juan M Vaquerizas, Nicholas M Luscombe
Journal: Genome biology (2011)

Abstract Transcriptomic studies routinely measure expression levels across numerous conditions. These datasets allow identification of genes that are specifically expressed in a small number of conditions. However, there are currently no statistically robust methods for identifying such genes. Here we present SpeCond, a method to detect condition-specific genes that outperforms alternative approaches. We apply the method to a dataset of 32 human tissues to determine 2,673 specifically expressed genes. An implementation of SpeCond is freely available as a Bioconductor package at http://www.bioconductor.org/packages/release/bioc/html/SpeCond.html .
Combined Adenovirus-Mediated Nitroreductase Gene Delivery and CB1954 Treatment: A Well-Tolerated Therapy for Established Solid Tumors
Authors: A.Hakim Djeha, T.Andrew Thomson, Hing Leung, Peter F. Searle, Lawrence S. Young, David J. Kerr, Peter A. Harris, Andrew Mountain, Christopher J. Wrighton
Journal: Molecular Therapy (2001)

Gene-directed enzyme prodrug therapy (GDEPT) is a refinement of cancer chemotherapy that generates a potent cell-killing drug specifically in tumor cells by enzymatic activation of an inert prodrug. We describe in vivo studies that evaluate the efficacy and safety of intratumoral (i.t.) injection of an adenovirus vector (CTL102) expressing Escherichia coli nitroreductase (NTR) combined with systemic prodrug (CB1954) treatment. A single i.t. injection of CTL102 (7.5 × 109 to –2 × 1010 particles) followed by CB1954 treatment produced clear anti-tumor effects in subcutaneous (s.c.) xenograft models of four cancers that are likely candidates for GDEPT (i.e., primary liver, head and neck, colorectal and prostate). Virus dose–response studies (s.c. liver model) revealed a steep increase and subsequent rapid plateauing of both NTR gene delivery and anti-tumor efficacy. Evidence of minor virus spread (toxicity) was observed in a s.c. head and neck xenograft model. This was eliminated by passive immunization with neutralizing anti-Ad5 antibodies prior to virus injection without reducing the magnitude of the anti-tumor effect. Preexisting anti-Ad5 neutralizing antibodies may therefore be an advantage rather than an issue in the clinical use of this new therapy.
Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic.
Authors: M S Brown, J L Goldstein
Journal: Journal of Clinical Investigation (1983)

A decade of intense investigation has established a central role for lipoprotein receptors in regulating plasma cholesterol traffic. These receptors bind cholesterol-carrying lipoproteins and transport them into cells by receptor-mediated endocytosis. The receptor for low density lipoprotein (LDL) was the first discovered; it has been purified and its structure characterized. The LDL receptor was described in cultured human fibroblasts; identical receptors are now known to function in liver as well as in extrahepatic tissues. Operationally, the LDL/LDL receptor system can be considered the primary transport mechanism for endogenous cholesterol. Dietary cholesterol, on the other hand, is transported from the intestine in chylomicron remnants, which enter hepatocytes via distinct chylomicron remnant receptors. The chylomicron remnant/remnant receptor system is to exogenous cholesterol transport as the LDL/LDL receptor system is to endogenous cholesterol transport. In this article, we review recent developments in this rapidly advancing field.