tbuckley/cabot-search huggingface dataset:
Noninvasive Diagnosis of Nonalcoholic Fatty Liver Disease and Quantification of Liver Fat Using a New Quantitative Ultrasound Technique
Authors: Steven C. Lin, Elhamy Heba, Tanya Wolfson, Brandon Ang, Anthony Gamst, Aiguo Han, John W. Erdman, William D. O’Brien, Michael P. Andre, Claude B. Sirlin, Rohit Loomba
Journal: Clinical Gastroenterology and Hepatology (2014)
Blockade of clearance of immune complexes by an anti-F(cγ) receptor monoclonal antibody
Authors: SB Clarkson, RP Kimberly, JE Valinsky, MD Witmer, JB Bussel, RL Nachman, JC Unkeless
Journal: The Journal of Experimental Medicine (1986)

Clearance of immune complexes by the mononuclear phagocyte system is important for maintaining normal host defenses against bacterial and viral assault (1), but also contributes to the pathogenesis of a variety of immune- mediated diseases . For example, removal from the circulation of IgG-coated erythrocytes and platelets by the MPS is the sine qua non of immune-mediated cytopenias (2, 3). On the other hand, abnormally decreased removal by the MPS of smaller, soluble immune complexes may play a role in the pathogenesis of immune complex-mediated tissue damage found in such autoimmune diseases as SLE (4). Although the physicochemical nature and the size of immune complexes can influence rates of clearance and sites of deposition (reviewed in 5), interactions between immune complexes and the MPS in vivo are poorly understood. The inability to directly measure binding or internalization of immune complexes by cells in the liver and spleen has made the analysis of the molecular basis of immune complex clearance very difficult . Receptors for the Fc portion of IgG (FcγR) and for complement (CR) undoubtedly play a role in the removal of immune complexes, but the relative importance of these receptors is not known.
A New Monoclonal Antibody, mAb 4A12, Identifies a Role for the Glycosaminoglycan (GAG) Binding Domain of RANTES in the Antiviral Effect against HIV-1 and Intracellular Ca2+ Signaling
Authors: Jennifer M. Burns, Robert C. Gallo, Anthony L. DeVico, George K. Lewis
Journal: The Journal of Experimental Medicine (1998)

The β-chemokine RANTES (regulated on activation, normal T cell expressed and secreted) suppresses the infection of susceptible host cells by macrophage tropic strains of HIV-1. This effect is attributed to interactions of this chemokine with a 7-transmembrane domain receptor, CCR5, that is required for virus–cell fusion and entry. Here we identify domains of RANTES that contribute to its biological activities through structure–function studies using a new monoclonal antibody, mAb 4A12, isolated from mice immunized with recombinant human RANTES. This monoclonal antibody (mAb) blocked the antiviral activity of RANTES in infectivity assays with HIV-1Bal, and inhibited the mobilization of intracellular Ca2+ elicited by RANTES, yet recognized this chemokine bound to cell surfaces. Epitope mapping using limited proteolysis, reversed phase high-performance liquid chromatography, and mass spectrometry suggest that residues 55–66 of RANTES, which include the COOH-terminal α-helical region implicated as the glycosaminoglycan (GAG) binding domain, overlap the determinant recognized by mAb 4A12. This is supported by affinity chromatography studies, which showed that RANTES could be eluted specifically by heparin from a mAb 4A12 immunoaffinity matrix. Removal of cell surface GAGs by enzymatic digestion greatly reduced the ability of mAb 4A12 to detect RANTES passively bound on cell surfaces and abrogated the ability of RANTES to elicit an intracellular Ca2+ signal. Taken together, these studies demonstrate that the COOH-terminal α-helical region of RANTES plays a key role in GAG-binding, antiviral activity, and intracellular Ca2+ signaling and support a model in which GAGs play a key role in the biological activities of this chemokine.
Sorafenib Potently Inhibits Papillary Thyroid Carcinomas Harboring RET/PTC1 Rearrangement
Authors: Ying C. Henderson, Soon-Hyun Ahn, Ya'an Kang, Gary L. Clayman
Journal: Clinical Cancer Research (2008)

Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignancy with one of the two mutations, RET/PTC rearrangement or BRAF mutation. Both mutations are able to activate the MEK/ERK signaling transduction pathway and result in the activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis. Sorafenib (Nexavar, BAY 43-9006) is a multikinase inhibitor, and in this study, we tested its effects on PTC cells carrying either mutation.The effects of sorafenib on cell proliferation and signaling were evaluated in vitro on PTC cells using growth curves, cell cycle analysis, and immunoblotting. Using an orthotopic mouse model, we determined the antitumor effects of sorafenib in vivo.The concentration needed for 50% growth inhibition (GI(50)) by sorafenib was 0.14 mumol/L for the PTC cells with the RET/PTC1 rearrangement, and 2.5 mumol/L for PTC cells with a BRAF mutation, both readily achievable serum concentrations. After 3 weeks of oral administration of sorafenib (80 mg/kg/d) in mice, small (94% reduction compared with controls) or no tumor growth was detected in mice inoculated with PTC cells bearing the RET/PTC1 rearrangement, whereas the tumor volume of the orthotopic tumor implants of PTC cells with a BRAF mutation was reduced 53% to 54% (as compared with controls).PTC cells carrying the RET/PTC1 rearrangement were more sensitive to sorafenib than PTC cells carrying a BRAF mutation. Because RET/PTC rearrangements are unique to thyroid carcinomas, our findings support the clinical evaluation of sorafenib for patients with PTC and the identification of patients most likely to respond to sorafenib treatment.
Study of the Murmur Produced by Acute Pulmonary Artery Constriction
Authors: Pwr Moedjono, Robert C. Little, Robert A. Orlando, Bruce H. Brundage
Journal: Circulation Research (1962)

The murmur produced by acute graded constriction of the base of the pulmonary artery was studied in the anesthetized dog by means of intraluminal phonocardiograms recorded from the pulmonary artery. In addition, right ventricular and distal pulmonary artery pressures were recorded, and the cardiac output was determined for each degree of pulmonary artery stenosis utilized in the study. A small diamond-shaped midsystolic murmur is normally recorded from inside the pulmonary artery. This murmur increases in intensity and duration with constriction of the base of the artery. A constant relationship was not found between the degree of pulmonary stenosis or pulmonary flow and the intensity of the murmur. The intensity did correlate, in an essentially linear fashion, with the average velocity of flow through the constricted area. The timing of the peak intensity of the murmur did not change in any consistent fashion with increasing degrees of pulmonary artery stenosis. Cardiac output and the velocity of flow through the constricted area of the pulmonary artery tended to increase with moderate degrees of constriction. When the lumen of the pulmonary artery was reduced 40 to 45 per cent, cardiac output and pulmonary artery pressure fell below control levels. With further constriction, cardiac output and pulmonary flow decreased; however, the velocity of flow through the stenotic area remained relatively rapid.
Dermoscopy structures as predictors of sentinel lymph node positivity in cutaneous melanoma
Authors: T. González-Álvarez, C. Carrera, A. Bennassar, A. Vilalta, R. Rull, L. Alos, J. Palou, S. Vidal-Sicart, J. Malvehy, S. Puig
Journal: British Journal of Dermatology (2014)

Histological features such as Breslow thickness, ulceration and mitosis are the main criteria to guide sentinel lymph node biopsy (SLNB) in melanoma. Dermoscopy may add complementary information to these criteria.To evaluate the correlation between dermoscopy structures and SLNB positivity.Retrospective analysis of 123 consecutive melanomas with Breslow thickness > 0·75 mm, SLNB performed during follow-up and dermoscopic images.Men were more likely to have a positive SLNB. The presence of ulceration and blotch and the absence of a pigmented network in dermoscopy correlated with positive SLNB. Histological ulceration also correlated with positive SLNB. A dermoscopy SCORE predicted SLN status with a sensitivity of 96·3% and a specificity of 30·2%. When sex and Breslow thickness were added (SCOREBRESEX), the sensitivity remained at 96·3% but the specificity increased to 52·1%. This study is limited by the number of patients and was performed in only one institution.Dermoscopy allowed a more precise prediction of SLN status. If a combined SCOREBRESEX was used to select patients for SLNB, 41·5% of procedures might be avoided.
T Cell Costimulation: A Rational Target in the Therapeutic Armamentarium for Autoimmune Diseases and Transplantation
Authors: Flavio Vincenti, Michael Luggen
Journal: Annual Review of Medicine (2006)

T cells are central mediators of adaptive immunity. As such, they are involved in both normal immune responses (e.g., rejection of a transplanted organ) and abnormal ones (e.g., rheumatoid arthritis). T cells require both antigen-specific and costimulatory signals for their full activation. Advances in protein engineering and an increased understanding of the immune response have culminated in the evolution and creation of protein therapeutics that target specific costimulatory molecules. The selective costimulation modulator abatacept (CTLA-4Ig) binds to CD80 and CD86, blocking interaction with CD28, and is approved for the treatment of moderate to severe rheumatoid arthritis. Belatacept, currently enrolling phase III trials in renal transplantation, was rationally designed from abatacept to bind with more avidity to CD86, providing the more potent immunosuppressive properties required for immunosuppression in transplantation. This review describes the relevant immunology and summarizes recent clinical findings on these two molecules. Although both inhibit the CD28 costimulatory pathway, they are tailored for specific disease states--abatacept for autoimmune diseases and belatacept for transplantation.
Combining Multiple Data Sets in a Likelihood Analysis: Which Models are the Best?
Authors: Tal Pupko, Dorothée Huchon, Ying Cao, Norihiro Okada, Masami Hasegawa
Journal: Molecular Biology and Evolution (2002)

Until recently, phylogenetic analyses have been routinely based on homologous sequences of a single gene. Given the vast number of gene sequences now available, phylogenetic studies are now based on the analysis of multiple genes. Thus, it has become necessary to devise statistical methods to combine multiple molecular data sets. Here, we compare several models for combining different genes for the purpose of evaluating the likelihood of tree topologies. Three methods of branch length estimation were studied: assuming all genes have the same branch lengths (concatenate model), assuming that branch lengths are proportional among genes (proportional model), or assuming that each gene has a separate set of branch lengths (separate model). We also compared three models of among-site rate variation: the homogenous model, a model that assumes one gamma parameter for all genes, and a model that assumes one gamma parameter for each gene. On the basis of two nuclear and one mitochondrial amino acid data sets, our results suggest that, depending on the data set chosen, either the separate model or the proportional model represents the most appropriate method for branch length analysis. For all the data sets examined, one gamma parameter for each gene represents the best model for among-site rate variation. Using these models we analyzed alternative mammalian tree topologies, and we describe the effect of the assumed model on the maximum likelihood tree. We show that the choice of the model has an impact on the best phylogeny obtained.
Massive Expansion of Ubiquitination-Related Gene Families within the Chlamydiae
Authors: Daryl Domman, Astrid Collingro, Ilias Lagkouvardos, Lena Gehre, Thomas Weinmaier, Thomas Rattei, Agathe Subtil, Matthias Horn
Journal: Molecular Biology and Evolution (2014)

Gene loss, gain, and transfer play an important role in shaping the genomes of all organisms; however, the interplay of these processes in isolated populations, such as in obligate intracellular bacteria, is less understood. Despite a general trend towards genome reduction in these microbes, our phylogenomic analysis of the phylum Chlamydiae revealed that within the family Parachlamydiaceae, gene family expansions have had pronounced effects on gene content. We discovered that the largest gene families within the phylum are the result of rapid gene birth-and-death evolution. These large gene families are comprised of members harboring eukaryotic-like ubiquitination-related domains, such as F-box and BTB-box domains, marking the largest reservoir of these proteins found among bacteria. A heterologous type III secretion system assay suggests that these proteins function as effectors manipulating the host cell. The large disparity in copy number of members in these families between closely related organisms suggests that nonadaptive processes might contribute to the evolution of these gene families. Gene birth-and-death evolution in concert with genomic drift might represent a previously undescribed mechanism by which isolated bacterial populations diversify.
115 INFLUENCE OF BMI AND ALCOHOL ON LIVER-RELATED MORBIDITY AND MORTALITY IN A COHORT OF 108,000 WOMEN FROM THE GENERAL POPULATION FROM UKCTOCS
Authors: P.M. Trembling, S. Apostolidou, J. Parkes, A. Ryan, A. Gentry-Maharaj, S. Tanwar, U. Menon, W.M. Rosenberg
Journal: Journal of Hepatology (2013)
Exploring the Convergence of Posttraumatic Stress Disorder and Mild Traumatic Brain Injury
Authors: Murray B. Stein, Thomas W. McAllister
Journal: American Journal of Psychiatry (2009)

The authors examine the relationship of the two signature injuries experienced by military personnel serving in Afghanistan and Iraq: posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mild TBI). Studies show that a substantial minority of those serving develop persistent emotional sequelae (such as PTSD and other psychological health problems) and/or somatic or cognitive sequelae (postconcussive symptoms) of traumatic exposure. Remarkably, the mechanism (emotional versus biomechanical) and locus (head versus other regions) of injury are weak determinants of whether an individual develops PTSD, persistent postconcussive symptoms, or both. Preexisting or traumatically acquired cognitive dysfunction can increase the risk for these syndromes, probably by reducing cognitive reserve. Structural and functional neuroimaging studies can be interpreted to explain part of the shared symptomatic and functional variance in these syndromes, but this literature is far from consistent and serves mainly to raise new, challenging questions about mutual pathophysiology. The frequent confluence of PTSD and persistent postconcussive symptoms in military personnel strains the bounds of these constructs. New studies are needed to improve our understanding of how emotional and biomechanical stressors can yield these adverse outcomes and how such outcomes can be prevented and treated.
Inflammation, Insulin Resistance, and Adiposity
Authors: Adamandia D. Kriketos, Jerry R. Greenfield, Phil W. Peake, Stuart M. Furler, Gareth S. Denyer, John A. Charlesworth, Lesley V. Campbell
Journal: Diabetes Care (2004)

OBJECTIVE—Inflammatory markers such as C-reactive protein (CRP) are associated with insulin resistance, adiposity, and type 2 diabetes. Whether inflammation causes insulin resistance or is an epiphenomenon of obesity remains unresolved. We aimed to determine whether first-degree relatives of type 2 diabetic subjects differ in insulin sensitivity from control subjects without a family history of diabetes, whether first-degree relatives of type 2 diabetic subjects and control subjects differ in CRP, adiponectin, and complement levels, and whether CRP is related to insulin sensitivity independently of adiposity. RESEARCH DESIGN AND METHODS—We studied 19 young normoglycemic nonobese first-degree relatives of type 2 diabetic subjects and 22 control subjects who were similar for age, sex, and BMI. Insulin sensitivity (glucose infusion rate [GIR]) was measured by the euglycemic-hyperinsulinemic clamp. Dual-energy X-ray absorptiometry determined total and abdominal adiposity. Magnetic resonance imaging measured abdominal adipose tissue volumes. RESULTS—First-degree relatives of type 2 diabetic subjects had a 20% lower GIR than the control group (51.8 ± 3.9 vs. 64.9 ± 4.6 μmol · min−1 · kg fat-free mass−1, P = 0.04). However, first-degree relatives of subjects with type 2 diabetes and those without a family history of diabetes had normal and comparable levels of CRP, adiponectin, and complement proteins. When the cohort was examined as a whole, CRP was inversely related to GIR (r = −0.33, P = 0.04) and adiponectin (r = −0.34, P = 0.03) and positively related to adiposity (P &amp;lt; 0.04). However, CRP was not related to GIR independently of fat mass. In contrast to C3 (r = 0.41, P = 0.009) and factor B (r = 0.43, P = 0.005), CRP was unrelated to factor D. CONCLUSIONS—The insulin-resistant state is not associated with changes in inflammatory markers or complement proteins in subjects at high risk of type 2 diabetes. Our study confirms a strong relationship between CRP and fat mass. Increasing adiposity and insulin resistance may interact to raise CRP levels.
Two Cases of Phthisis in which Hyperventilation was Employed
Authors: C. H. Jones
Journal: BMJ (1880)

under whom, however, it has been destroyed by the superiority of English weapons and organisation.Five crania of Zulus who were killed in the fatal battle of Isandthlwana last year have already reached -the museum through the kindness of Mr. Fynn, a magistrate in 'Natal, Colonel Mitchell, the Colonial Secretary, and Dr. R. J. Mann; and their uniformity of characters is such, that they probably -are very fair average specimens of the race.They are the skulls of large powerful men in the prime of life.The capacity of their cranitl cavity is remarkable, far above that of the ordinary Negro, even above that of the lower class of Englishmen, the average of the five being I,58o cubic centimi/res; but one measures as much as 1,745.Their average latitudinal index is 75I; the altitudinal index 76.6.Their orbits *are remarkably small and low, the index being 81.7.The form of the nasal bones and the nasal index, which is 60.7, are characteristically negroid; but they differ from ordinary Negroes in two important points: they are not truly prognathous!, but mesognathous; the alveolar index, which is 100.4,being intermediate between that of the Negro and the European; and their teeth are small, the index being only 40.7.The crania of other Zulu and Kaffir tribes previously examined give similar results, especially a large cranial capacity, and a less degree of pro--gnathism than is found in the equatorial Negro.Another great division of South African people comprises those popularly known as Hottentots and Bushmen, or, in their own lan-
Ventricular Conduction Delay and Arrhythmias during Regional Hyperkalemia in the Dog
Authors: PHILIP O. ETTINGER, TIMOTHY J. REGAN, HENRY A. OLDEWURTEL, MOHAMMAD I. KHAN
Journal: Circulation Research (1973)

Coronary arterial potassium (K + ) infusion induces RS-T elevation and ventricular arrhythmias. To explore electrical and metabolic events in this model, which simulates ischemia-induced injury currents and rhythm disturbances, isotonic KCl was infused at 0.5-2.0 ml/min into the left anterior descending or the left circumflex coronary artery of 37 intact anesthetized dogs. Conduction was monitored with His and left bundle branch recording catheters and with bipolar electrodes at endocardial and epicardial levels in the perfused zone. RS-T segments rose progressively in the perfused region despite normal coronary blood flow ( 85 Kr) some dogs progressed rapidly to multifocal ventricular extrasystoles and ventricular fibrillation (group 1), but others continued for 20 minutes without developing fibrillation (group 2). His-Q and bundle branch conduction times were not altered by regional perfusion, but the QRS complex was locally prolonged. Ventricular extrasystoles were frequently coupled and left bundle branch depolarizations never preceded them, suggesting origin within the myocardium. Intramural electrodes showed increasing delay in the perfused region; epicardial depression was uniformly more profound and preceded significant arrhythmias, often with 2:1 or higher intramural block and slowing sufficient to allow reentry. Epicardial activation preceding endocardial activation was observed during extrasystoles in the perfused zone, further indicating origin within the myocardium. These phenomena were associated with tissue concentrations of K + in the outer wall significantly higher than those in the inner wall; and sodium was also significantly elevated. Therefore, it was postulated that reentry from depressed epicardial layers into more normal surrounding tissue constitutes a possible basis for the arrythmias in this model.
Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas
Authors: Matthias A. Karajannis, Geneviève Legault, Mari Hagiwara, Marc S. Ballas, Krysten Brown, Annette O. Nusbaum, Tsivia Hochman, Judith D. Goldberg, Kevin M. Koch, John G. Golfinos, J. Thomas Roland, Jeffrey C. Allen
Journal: Neuro-Oncology (2012)

This single-institution phase II study was performed to estimate the response rate to lapatinib in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Twenty-one eligible patients were enrolled. Brain and spine MRIs, including 3-dimensional volumetric tumor analysis, and audiograms were performed once at baseline and again every 12 weeks. The primary response end point was evaluable in 17 patients and defined as ≥15% decrease in VS volume. Hearing was evaluable as a secondary end point in 13 patients, with responses defined as an improvement in the pure tone average of at least 10 dB or a statistically significant increase in word recognition scores. Four of 17 evaluable patients experienced an objective volumetric response (23.5%; 95% confidence interval [CI], 10%–47%), with median time to response of 4.5 months (range, 3–12). In responders, reduction in VS volumes ranged from −15.7% to −23.9%. Four of 13 patients evaluable for hearing met hearing criteria for response (30.8%; 95% CI, 13%–58%). One sustained response exceeded 9 months in duration. Median time to overall progression (ie, volumetric progression or hearing loss) was 14 months. The estimated overall progression-free survival and volumetric progression-free survival at 12 months were 64.2% (95% CI, 36.9%–82.1%) and 70.6% (95% CI, 43.1%–86.6%), respectively. Toxicity was generally minor, and no permanent dose modifications were required. Lapatinib carries minor toxicity and has objective activity in NF2 patients with progressive VS, including volumetric and hearing responses. Future studies could explore combination therapy with other molecular targeted agents such as bevacizumab.