tbuckley/cabot-search huggingface dataset:
Preexisting epithelial diversity in normal human livers: A tissue-tethered cytometric analysis in portal/periportal epithelial cells
Authors: Kumiko Isse, Andrew Lesniak, Kedar Grama, John Maier, Susan Specht, Marcela Castillo-Rama, John Lunz, Badrinath Roysam, George Michalopoulos, Anthony J. Demetris
Journal: Hepatology (2012)

Routine light microscopy identifies two distinct epithelial cell populations in normal human livers: hepatocytes and biliary epithelial cells (BECs). Considerable epithelial diversity, however, arises during disease states when a variety of hepatocyte-BEC hybrid cells appear. This has been attributed to activation and differentiation of putative hepatic progenitor cells (HPC) residing in the canals of Hering and/or metaplasia of preexisting mature epithelial cells. A novel analytic approach consisting of multiplex labeling, high-resolution whole-slide imaging (WSI), and automated image analysis was used to determine if more complex epithelial cell phenotypes preexist in normal adult human livers, which might provide an alternative explanation for disease-induced epithelial diversity. "Virtually digested" WSI enabled quantitative cytometric analyses of individual cells displayed in a variety of formats (e.g., scatterplots) while still tethered to the WSI and tissue structure. We employed biomarkers specifically associated with mature epithelial forms (HNF4α for hepatocytes, CK19 and HNF1β for BEC) and explored for the presence of cells with hybrid biomarker phenotypes. The results showed abundant hybrid cells in portal bile duct BEC, canals of Hering, and immediate periportal hepatocytes. These bipotential cells likely serve as a reservoir for the epithelial diversity of ductular reactions, appearance of hepatocytes in bile ducts, and the rapid and fluid transition of BEC to hepatocytes, and vice versa.Novel imaging and computational tools enable increased information extraction from tissue samples and quantify the considerable preexistent hybrid epithelial diversity in normal human liver. This computationally enabled tissue analysis approach offers much broader potential beyond the results presented here.
A Phase II Clinical Trial of Ixabepilone (Ixempra; BMS-247550; NSC 710428), an Epothilone B Analog, in Patients with Metastatic Renal Cell Carcinoma
Authors: Hui Huang, Michael Menefee, Maureen Edgerly, Sen Zhuang, Herb Kotz, Marianne Poruchynsky, Lyn Mickley Huff, Susan Bates, Tito Fojo
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Ixabepilone (Ixempra; BMS-247550) is an epothilone B analog and nontaxane microtubule-stabilizing compound with clinical activity in a range of solid tumors. This phase II study was conducted to assess the efficacy and safety of ixabepilone in patients with metastatic renal cell carcinoma. Experimental Design: Patients with metastatic renal cell carcinoma who had measurable disease and had not received previous cytotoxic or targeted therapy were treated with 6 mg/m2 ixabepilone i.v. daily for 5 days every 3 weeks. Levels of Glu-terminated and acetylated tubulin, markers of microtubule stabilization, were assessed by Western blot. VHL gene mutation status was determined by sequencing. Results: Eighty-seven patients received a total of 590 cycles, with a median of 5 cycles (range, 1-29). The overall response rate was 13% (Response Evaluation Criteria in Solid Tumor). One patient had a complete response, 10 patients had partial responses, and 59 patients had stable disease. The median duration of response was 5.5 months. The median overall survival of renal cell carcinoma Motzer grade 0 and 1 patients with clear cell histology was 19.25 months. Treatment-related adverse events were primarily alopecia, gastrointestinal toxicity, neuropathy, and fatigue. Biopsies were done at baseline and after five doses of ixabepilone. Microtubule target engagement was achieved in 84.6% to 92.3% of patients evaluated. No correlation was identified between the target engagement, VHL gene mutation status, and clinical response. Conclusion: Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies. Clin Cancer Res; 16(5); 1634–41
Targeting Interleukin-1 in Heart Disease
Authors: Benjamin W. Van Tassell, Stefano Toldo, Eleonora Mezzaroma, Antonio Abbate
Journal: Circulation (2013)

I nflammation is a coordinated cellular-humoral response to injury.A close interaction between resident cells (ie, endothelial cells, fibroblasts, and dendritic cells) and leukocytes regulates the initiation and resolution of the acute inflammatory response.Constitutive membrane and cytoplasmic receptors function as guardians that "signal the alarm" when activated by products of cell destruction or microbial invasion.This first-line innate immune response initiates a process of leukocyte mobilization from the bone marrow, recruitment to the "activated" endothelium, and migration to the site of tissue injury to prevent infection and to facilitate tissue repair.Although critical for many forms of repair, the inflammatory response may also become a mechanism for progressive injury, impaired healing, and disease.
C-Peptide Signals via Gαi to Protect against TNF-α–Mediated Apoptosis of Opossum Kidney Proximal Tubular Cells
Authors: Nawal M. Al-Rasheed, Gary B. Willars, Nigel J. Brunskill
Journal: Journal of the American Society of Nephrology (2006)

Cell loss by apoptosis occurs in renal injury such as diabetic nephropathy. TNF-α is a cytokine that induces apoptosis and has been implicated in the pathogenesis of diabetic nephropathy. The aim was to investigate whether C-peptide or insulin could modulate TNF-α–mediated cell death in opossum kidney proximal tubular cells and to examine the mechanism(s) of any effects observed. C-peptide and insulin protect against TNF-α–induced proximal tubular cell toxicity and apoptosis. Cell viability was analyzed by methylthiazoletetrazolium assay; cell viability was reduced to 60.8 ± 2.7% of control after stimulation with 300 ng/ml TNF-α. Compromised cell viability was reversed by pretreatment with 5 nM C-peptide or 100 nM insulin. TNF-α–induced apoptosis was detected by DNA nick-end labeling and by measuring histone associated DNA fragments using ELISA. By ELISA assay, 300 ng/ml TNF-α increased apoptosis by 145.8 ± 4.9% compared with controls, whereas 5 nM C-peptide and 100 nM insulin reduced apoptosis to 81.6 ± 4.8 and 77.4 ± 3.1% of control, respectively. The protective effects of C-peptide and insulin were associated with activation of NF-κB. Activation of NF-κB by C-peptide was pertussis toxin sensitive and dependent on activation of Gαi. Phosphatidylinositol 3-kinase but not extracellular signal regulated mitogen-activated protein kinase mediated C-peptide and insulin activation of NF-κB. The cytoprotective effects of both C-peptide and insulin were related to increased expression of TNF receptor–associated factor 2, the product of an NF-κB–dependent survival gene. These data suggest that C-peptide and/or insulin activation of NF-κB–regulated survival genes protects against TNF-α–induced renal tubular injury in diabetes. The data further support the concept of C-peptide as a peptide hormone in its own right and suggest a potential therapeutic role for C-peptide.
The central melanocortin system directly controls peripheral lipid metabolism
Authors: Ruben Nogueiras, Petra Wiedmer, Diego Perez-Tilve, Christelle Veyrat-Durebex, Julia M. Keogh, Gregory M. Sutton, Paul T. Pfluger, Tamara R. Castaneda, Susanne Neschen, Susanna M. Hofmann, Philip N. Howles, Donald A. Morgan, Stephen C. Benoit, Ildiko Szanto, Brigitte Schrott, Annette Schürmann, Hans-Georg Joost, Craig Hammond, David Y. Hui, Stephen C. Woods, Kamal Rahmouni, Andrew A. Butler, I. Sadaf Farooqi, Stephen O’Rahilly, Françoise Rohner-Jeanrenaud, Matthias H. Tschöp
Journal: Journal of Clinical Investigation (2007)

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.
Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry
Authors: Christopher P Denton, Thomas Krieg, Loic Guillevin, Barbara Schwierin, Daniel Rosenberg, Mariabeth Silkey, Maurice Zultak, Marco Matucci-Cerinic
Journal: Annals of the Rheumatic Diseases (2012)

Objectives The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). Methods The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. Results Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. Conclusions This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies.
Pathophysiology and Prevention of Atrial Fibrillation
Authors: Maurits A. Allessie, Penelope A. Boyden, A. John Camm, André G. Kléber, Max J. Lab, Marianne J. Legato, Michael R. Rosen, Peter J. Schwartz, Peter M. Spooner, David R. Van Wagoner, Albert L. Waldo
Journal: Circulation (2001)

A trial fibrillation (AF) is a ubiquitous yet diverse cardiac arrhythmia whose incidence increases with age; with most forms of cardiac and some pulmonary diseases; and with a number of metabolic, toxic, endocrine, or genetic abnormalities. 1,2Classification of clinical AF subtypes can be achieved on the basis of the ease by which episodes of the arrhythmia terminate as follows 3 : "Paroxysmal" AF refers to episodes that generally stop spontaneously after no more than a few days."Persistent" AF occurs less frequently than paroxysmal AF and, rather than self-terminating, requires cardioversion to restore sinus rhythm."Permanent" AF cannot be converted to sinus rhythm.These terms apply strictly to chronic AF, because a single episode of the arrhythmia cannot be fully categorized.Although there are some mixed patterns, they generally derive from physician impatience for early cardioversion or from pragmatic clinical considerations (eg, to avoid thrombus formation or hemodynamic decompensation).Patients initially presenting with paroxysmal AF often progress to longer, non-self-terminating bouts.An exception may be paroxysmal AF during intense vagotonia.Moreover, AF initially responsive to pharmacological or electrical cardioversion tends to become resistant and cannot then be converted to sinus rhythm.To some extent, the failure of the physician to suggest or the patient to accept further cardioversion attempts may lead to diagnosis of "permanent" AF.Thus, the "point of no return" may be determined by true pathophysiological abnormalities or may merely be an artifact of clinical pragmatism.Effective prevention is essential in managing this arrhythmia whose occurrence is widespread, progression is relentless, and morbidity and mortality are significant.To focus on means for prevention necessitates considering both clinical risk factors and pathophysiology.
Respiratory Medicine Team of the Year
Authors: A. O'Dowd
Journal: BMJ (2014)

The Respiratory Medicine Team of the Year recognises a project or initiative that has measurably improved care in respiratory medicine. Adrian O’Dowd meets the candidates

Making greater use of visits to the pharmacy by patients with respiratory problems to help boost their health and quality of life is central to the approach taken by four pharmacy companies. This service was launched in 2012 in the Wirral, Merseyside, after Boots UK, Lloydspharmacy, Rowlands Pharmacy, and the Co-operative Pharmacy, created the Community Pharmacy Future project team.

The service, run within 34 community pharmacies, helps patients when they are visiting to collect their prescriptions. It seeks to raise awareness of risk factors for chronic obstructive pulmonary disease (COPD), identify those potentially at risk, and make referrals to general practitioners for diagnosis.

Patients with known COPD are offered lifestyle advice, help with smoking cessation, and help to reduce exacerbations through improved medicines adherence as well as support to manage their condition better and improve their quality of life. This includes helping patients to recognise when their symptoms are worsening and enabling them to manage this.

Patients are also advised on their medicines, good inhaler technique, and problems such as breathing and sleeping and offered help to reduce risk factors.

Independent evaluation of the service six months after launch showed the various interventions led to improvements in patients’ quality of life and adherence to medicines and reductions in the use of NHS resources.

Jonathan Buisson, healthcare policy manager for Alliance Boots, speaking on behalf of the project team, says: “As a service, it worked and did what we aimed to do. It’s making every contact count so when people come in, these patients are getting a higher level of intervention, directed, tailored, and using validating tools such as quality of life scores and …
Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome
Authors: Hiroshi Morita, Shiho Takenaka Morita, Satoshi Nagase, Kimikazu Banba, Nobuhiro Nishii, Yoshinori Tani, Atsuyuki Watanabe, Kazufumi Nakamura, Kengo Fukushima Kusano, Tetsuro Emori, Hiromi Matsubara, Kazumasa Hina, Toshimasa Kita, Tohru Ohe
Journal: Journal of the American College of Cardiology (2003)
STUDIES ON INFLUENZA INFECTION IN FERRETS BY MEANS OF FLUORESCEIN-LABELLED ANTIBODY
Authors: Ch'ien Liu
Journal: The Journal of Experimental Medicine (1955)

Yellow-green fluorescence representing viral antigens was detected in both the nucleus and cytoplasm of epithelial cells of the respiratory tract in ferrets infected with influenza virus. This nuclear fluorescence was the chief manifestation of cross-fluorescent staining reactions among three strains of influenza A virus studied, PR8, Farrington, and Fm(1). Absorption experiments with influenza viral V and soluble S antigens showed that S antigen was responsible for the presence of fluorescence in the nucleus and for the cross-staining reactions among these strains.
Effect of Torcetrapib on Glucose, Insulin, and Hemoglobin A <sub>1c</sub> in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial
Authors: Philip J. Barter, Kerry-Anne Rye, Jean-Claude Tardif, David D. Waters, S. Matthijs Boekholdt, Andrei Breazna, John J.P. Kastelein
Journal: Circulation (2011)

High-density lipoproteins have antidiabetic properties in vitro. Furthermore, elevated high-density lipoprotein levels accompanying a genetic deficiency of cholesteryl ester transfer protein are associated with decreased levels of plasma glucose. We now investigate effects on glucose homeostasis of inhibiting cholesteryl ester transfer protein with torcetrapib.A post hoc analysis of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was conducted to investigate effects of the cholesteryl ester transfer protein inhibitor torcetrapib on glycemic control in the 6661 diabetic patients in the trial. At baseline, there were no differences between the 2 treatment arms with respect to plasma glucose, insulin, hemoglobin A(1c), or the homeostasis model assessment of insulin resistance. After 3 months, the diabetic subjects taking the combination of torcetrapib plus atorvastatin had plasma glucose levels 0.34 mmol/L lower (P<0.0001) and insulin levels 11.7 μU/mL lower (P<0.0001) than in those receiving atorvastatin alone. Homeostasis model assessment of insulin resistance values decreased from 49.1 to 47.3 (P<0.0001) in the torcetrapib/atorvastatin arm compared with an increase in homeostasis model assessment of insulin resistance in the atorvastatin arm. At the 6-month time point, the mean hemoglobin A(1c) level in the atorvastatin arm was 7.29% compared with 7.06% in the torcetrapib/atorvastatin arm (P<0.0001). These effects of torcetrapib remained apparent for up to 12 months. Torcetrapib also lowered both glucose and insulin levels in the participants without diabetes mellitus, although the effects were not as great as in those with diabetes mellitus.Treatment with torcetrapib improves glycemic control in atorvastatin-treated patients with type 2 diabetes mellitus. It remains to be determined whether this effect is the consequence of raising high-density lipoprotein.athttp:www.clinicaltrials.gov. Unique identifier: NCT00134264.
Antidepressants--yes or no?
Authors: J G Edwards
Journal: BMJ (1978)

perimentally it is well established that once the endothelial barrier is breeched the stage is set for atherosclerosis and even a mild rise in plasma cholesterol concentration above 5 5 mmol/l (220 mg/100 ml) is sufficient to induce atherosclerotic change.However, changes may develop before there is any detectable rise in blood lipids.4It is hardly to be expected that dietary cholesterol as calculated from tables and on a single occasion would be representative of the usual amount consumed from day to day and over the many years of developing athero- sclerosis.However, it is known that dietary cholesterol contributes about one-quarter to one-third to plasma cholesterol,> which is a very substantial amount since the body synthesises all its requirements.Plasma concentrations are also greatly influenced by the amount and composition of fat in the diet.Professor Yudkin makes no reference to these important aspects, an appreciation of which puts the situation into better prospective.
The epidemiology of multiple births
Authors: R Bortolus
Journal: Human Reproduction Update (1999)

On the basis of MEDLINE and manual searches, we examined the main papers in the English literature regarding risk factors for spontaneous (i.e. not related to fertility drug use) multiple births. The constant frequency of monozygotic (MZ) pregnancies over time and in different geographical areas suggests that the determination of MZ twins is largely unchanged over time, and that a genetic mechanism may have a role. In contrast, temporal and geographical trends observed in dizygotic (DZ) pregnancies suggest that environmental factors play a role in determining this condition. At present, maternal age and hereditary components are the best-defined determinants for spontaneous multiple births.
Are you pulling my airway?
Authors: C. Y. Seow
Journal: European Respiratory Journal (2005)

Excessive airway narrowing is a hallmark of asthma. This is due to unencumbered shortening of airway smooth muscle, leading to severe airways obstruction and even closure of airways. Remarkably, in healthy subjects, this does not occur, and there is little doubt that the explanation of this apparent “protection” in normal subjects will be essential for our understanding of asthma. Parenchymal attachment to the adventitial wall of the airways in the lung is widely believed to contribute, at least in part, to the loads seen by the airway smooth muscle, and, hence, it is assumed to be a significant factor in limiting airway narrowing in healthy individuals 1–13. In this issue of the European Respiratory Journal , Noble et al . 14 have raised questions on this common belief. In a carefully designed experiment, they found, in mid-sized porcine bronchi, that the force pulling on the smooth muscle layer by the parenchyma surrounding the adventitial airway wall was insignificant and that it did not restrict lumen narrowing of the airway. The results suggest that parenchymal tethering may not play an important role in the altered airway calibre and smooth muscle function observed at different lung volumes and some disease states.

Comparing airway narrowing in its intact in vivo environment and airway narrowing in an isolated bronchial segment is not a small feat. First, one has to make sure that the same generation of bronchi are compared. Secondly, the geometric distortion of airways at different lung volumes has to be mimicked in vitro . Thirdly, the history of stress and strain …
High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia
Authors: Dheeraj Malhotra, Shane McCarthy, Jacob J. Michaelson, Vladimir Vacic, Katherine E. Burdick, Seungtai Yoon, Sven Cichon, Aiden Corvin, Sydney Gary, Elliot S. Gershon, Michael Gill, Maria Karayiorgou, John R. Kelsoe, Olga Krastoshevsky, Verena Krause, Ellen Leibenluft, Deborah L. Levy, Vladimir Makarov, Abhishek Bhandari, Anil K. Malhotra, Francis J. McMahon, Markus M. Nöthen, James B. Potash, Marcella Rietschel, Thomas G. Schulze, Jonathan Sebat
Journal: Neuron (2011)