tbuckley/cabot-search huggingface dataset:
Advancing Basal Insulin Replacement in Type 2 Diabetes Inadequately Controlled With Insulin Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP-1 Receptor Agonist, Versus Thrice-Daily Prandial Insulin Lispro
Authors: Julio Rosenstock, Vivian A. Fonseca, Jorge L. Gross, Robert E. Ratner, Bo Ahrén, Francis C.C. Chow, Fred Yang, Diane Miller, Susan L. Johnson, Murray W. Stewart, Lawrence A. Leiter
Journal: Diabetes Care (2014)

GLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, active-controlled trial testing once-weekly albiglutide vs. thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine.Patients taking basal insulin (with or without oral agents) with HbA1c 7-10.5% (53-91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro (n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of <5.6 mmol/L, and lispro was adjusted based on glucose monitoring. The primary end point was the difference in the HbA1c change from baseline at week 26.At week 26, HbA1c decreased from baseline by -0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and -0.66 ± 0.06% (7.2 mmol/mol) with lispro; treatment difference, -0.16% (95% CI -0.32 to 0.00; 1.8 mmol/mol; P < 0.0001), meeting the noninferiority end point (margin, 0.4%). Weight decreased with albiglutide but increased with lispro (-0.73 ± 0.19 kg vs. +0.81 ± 0.19 kg). The mean glargine dose increased from 47 to 53 IU (albiglutide) and from 44 to 51 IU (lispro). Adverse events for albiglutide versus lispro included severe hypoglycemia (0 vs. 2 events), documented symptomatic hypoglycemia (15.8% vs. 29.9%), nausea (11.2% vs. 1.4%), vomiting (6.7% vs. 1.4%), and injection site reactions (9.5% vs. 5.3%).Weekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA1c reduction with weight loss and lower hypoglycemia risk.
Modulation of Monoamine Receptors by Adaptor Proteins and Lipid Rafts: Role in Some Effects of Centrally Acting Drugs and Therapeutic Agents
Authors: Karl Björk, Per Svenningsson
Journal: The Annual Review of Pharmacology and Toxicology (2011)

The monoamines and their cognate receptors are widespread in the central nervous system and are vital for normal brain function. Dysfunction in these systems underlies several psychiatric and neurological disease states, and consequently monoamines are targets of a host of pharmacotherapies. This review provides an overview on how monoamine receptors are regulated by adaptor proteins and lipid rafts with emphasis on interactions in nerve cells. Monoamine receptors have prominent intracellular loops that provide binding sites for adaptor proteins. Receptor function is further modulated by cholesterol and submembranous microdomains termed lipid rafts. These interactions determine several facets of G protein-coupled receptor (GPCR) function including trafficking, localization, and signaling. Possible roles of adaptor proteins and lipid rafts in disease states and in mediating actions of drugs and therapeutic agents are also discussed.
Cytokine concentrations in sputum from patients with cystic fibrosis and their relation to eosinophil activity.
Authors: D Y Koller, I Nething, J Otto, R Urbanek, I Eichler
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

To evaluate whether concentrations of cytokines supposed to be involved in eosinophil recruitment and activation were elevated in cystic fibrosis (CF), we assessed interleukin-3 (IL-3), IL-5, IL-8, regulated on activation, normal T-cell expressed and secreted (RANTES); and granulocyte-macrophage colony stimulating factor (GM-CSF) in sputa from 32 patients with CF, eight patients with atopic bronchial asthma, and six patients with bacterial pneumonia. In addition, eosinophil cationic protein (ECP) and eosinophil protein X (EPX) were measured as markers of eosinophil activation. In patients with CF, sputum levels of IL-8 were elevated (p < 0.01) as compared with asthmatic patients. Concentrations of IL-3, ECP, and EPX were not different in the two groups. However, IL-5 (p < 0.0001), RANTES (p < 0.003), and GM-CSF (p < 0.0001) were significantly lower in the CF group than in subjects with asthma. IL-5 was detected only in sputum samples from CF patients with Aspergillus sensitization. In patients with pneumonia, IL-8 levels only were increased. In CF sputum, ECP levels were significantly correlated with the levels of IL-8 (r = 0.626, p < 0.0001) and IL-3 (r = 0.642; p < 0.0001), whereas in asthmatic patients IL-5, IL-8, and RANTES concentrations were significantly related to ECP in sputum. These findings suggest that different cytokine profiles are responsible for eosinophil activation in patients with CF as compared with asthmatic patients. In CF, IL-8 and IL-3 appear to be responsible for increased degranulation of eosinophils.
Massive Thymic Deletion Results in Systemic Autoimmunity through Elimination of CD4+ CD25+ T Regulatory Cells
Authors: Fei F. Shih, Laura Mandik-Nayak, Brian T. Wipke, Paul M. Allen
Journal: The Journal of Experimental Medicine (2004)

Incomplete deletion of KRN T cells that recognize the ubiquitously expressed self-antigen glucose-6-phosphate-isomerase (GPI) initiates an anti-GPI autoimmune cascade in K/BxN mice resulting in a humorally mediated arthritis. Transgenic (Tg) expression of a KRN T cell receptor (TCR) agonist under the major histocompatibility complex class II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double Tg mice succumbed to systemic autoimmunity with multiorgan inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by cotransfer of CD4+ CD25+ Tregs. Moreover, we extended our findings to another TCR system (anti–hen egg lysozyme [HEL] TCR/HEL mice) where similarly extensive thymic deletion also resulted in disease. Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion. Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.
Legal responsibilities of physicians when making participation decisions in athletes with cardiac disorders: Do guidelines provide a solid legal footing?
Authors: Nicole M Panhuyzen-Goedkoop, Joep L R M Smeets
Journal: British Journal of Sports Medicine (2014)

Safe sports participation involves protecting athletes from injury and life-threatening situations. Preparticipation cardiovascular screening (PPS) in athletes is intended to prevent exercise-related sudden cardiac death by medical management of athletes at risk, which may include disqualification from sports participation. The screening physician relies on current guidelines and expert recommendations for management and decision-making. There is concern about false-positive screening results and wrongly grounding an athlete. Similarly, there is a concern about false-negative screening results and athletes participating with potentially lethal disorders. Who is legally responsible if an athlete suddenly dies after a proper PPS resulting in low risk? Several consensus documents based on expert opinion describe only a few lines on legal responsibilities in eligibility screening and disqualification decision-making in athletes. This article discusses legal responsibilities and concerns in eligibility decision-making for physicians.
Tumor-Associated Endothelial Cells with Cytogenetic Abnormalities
Authors: Kyoko Hida, Yasuhiro Hida, Dhara N. Amin, Alan F. Flint, Dipak Panigrahy, Cynthia C. Morton, Michael Klagsbrun
Journal: Cancer Research (2004)

Abstract Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels have been shown to differ from normal counterparts, for example, by changes in morphology. An important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, although these endothelial cells are structurally and functionally abnormal. However, we hypothesized that given the phenotypic differences between tumor and normal blood vessels, there may be genotypic alterations as well. Mouse endothelial cells were isolated from two different human tumor xenografts, melanoma and liposarcoma, and from two normal endothelial cell counterparts, skin and adipose. Tumor-associated endothelial cells expressed typical endothelial cell markers, such as CD31. They had relatively large, heterogeneous nuclei. Unexpectedly, tumor endothelial cells were cytogenetically abnormal. Fluorescence in situ hybridization (FISH) analysis showed that freshly isolated uncultured tumor endothelial cells were aneuploid and had abnormal multiple centrosomes. The degree of aneuploidy was exacerbated by passage in culture. Multicolor FISH indicated that the structural chromosomal aberrations in tumor endothelial cells were heterogeneous, indicating that the cytogenetic alterations were not clonal. There was no evidence of human tumor-derived chromosomal material in the mouse tumor endothelial cells. In marked contrast, freshly isolated normal skin and adipose endothelial cells were diploid, had normal centrosomes, and remained cytogenetically stable in culture even up to 20 passages. FISH analysis of tumor sections also showed endothelial cell aneuploidy. We conclude that tumor endothelial cells can acquire cytogenetic abnormalities while in the tumor microenvironment.
Echocardiographic features of constrictive pericarditis.
Authors: A G Voelkel, D A Pietro, E D Folland, M L Fisher, A F Parisi
Journal: Circulation (1978)

The most characteristic echocardiographic features of 12 patients with constrictive pericarditis were compared with the findings in 10 normal volunteers. Left ventricular posterior wall (LVPW) "flatness" was quantified by measuring the diastolic change in distance from the crystal artifact to the LVPW endocardium. In 11 of 12 patients the net diastolic LVPW endocardial movement was less than 1 mm. In 10 normal volunteers LVPW endocardium moved posteriorly in diastole from 1.5 to 4 mm (mean 2.2 +/- 0.8). Abnormal septal motion was present in five of 12 patients with constriction. Pericardial thickness measured using standard damping techniques for both cnstriction and normal population did not distinguish the two groups. The "flattening" of the left ventricular endocardium as quantified above verifies earlier qualitative observations and was the most consistent finding in this series of patients with constrictive pericarditis.
Delineation of the Dimensions and Permeability Characteristics of the Two Major Diffusion Barriers to Passive Mucosal Uptake in the Rabbit Intestine
Authors: Henrik Westergaard, John M. Dietschy
Journal: Journal of Clinical Investigation (1974)

THE RATE OF PASSIVE ABSORPTION INTO THE INTESTINAL MUCOSAL CELL IS DETERMINED BY AT LEAST TWO MAJOR DIFFUSION BARRIERS: an unstirred water layer and the cell membrane. This study defines the morphology and permeability characteristics of these two limiting structures. The unstirred water layer was resolved into two compartments: one behaves like a layer of water overlying the upper villi while the other probably consists of solution between villi. The superficial layer is physiologically most important during uptake of highly permeant compounds and varies in thickness from 115 to 334 mum as the rate of mixing of the bulk mucosal solution is varied. From data derived from a probe molecule whose uptake was limited by the unstirred layer, the effective surface area of this diffusion barrier also was determined to vary with stirring rate and equaled only 2.4 cm(2).100 mg(-1) in the unstirred condition but increased to 11.3 cm(2).100 mg(-1) with vigorous mixing. This latter value, however, was still only 1/170 of the anatomical area of the microvillus membrane. With these values, uptake rates for a number of passively absorbed probe molecules were corrected for unstirred layer resistance, and these data were used to calculate the incremental free energy changes associated with uptake of the -CH(2)- (-258 cal.mol(-1)), -OH (+564), and taurine (+1,463) groups. These studies, then, have defined the thickness and area of the unstirred layer in the intestine and have shown that this barrier is rate-limiting for the mucosal uptake of compounds such as fatty acids and cholesterol; in addition, the lipid membrane of the microvillus surface has been shown to be a relatively polar structure.
Angiosarcomas, a heterogeneous group of sarcomas with specific behavior depending on primary site: a retrospective study of 161 cases
Authors: J. Fayette, E. Martin, S. Piperno-Neumann, A. Le Cesne, C. Robert, S. Bonvalot, D. Ranchère, P. Pouillart, J.M. Coindre, J.Y. Blay
Journal: Annals of Oncology (2007)
Cerebral Blood Flow in Subjects With Social Phobia During Stressful Speaking Tasks: A PET Study
Authors: Maria Tillfors, Tomas Furmark, Ina Marteinsdottir, Håkan Fischer, Anna Pissiota, Bengt Långström, Mats Fredrikson
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The central nervous system representation of social phobia (social anxiety disorder) is largely unknown. The aim of this study was to examine brain activity during symptom provocation in social phobics. METHOD: Positron emission tomography with the use of 15O water was used to measure regional cerebral blood flow (rCBF) in 18 subjects with DSM-IV-defined social phobia and a nonphobic comparison group while they were speaking in front of an audience and in private. Heart rate and subjective anxiety were also recorded. RESULTS: During public versus private speaking, subjective anxiety increased more in the social phobics than in the comparison group. Increased anxiety was accompanied by enhanced rCBF in the amygdaloid complex in the social phobics relative to the comparison subjects. Cortically, brain blood flow decreased in the social phobics and increased in the comparison subjects more during public than private speaking in the orbitofrontal and insular cortices as well as in the temporal pole and increased less in the social phobics than in the comparison group in the parietal and secondary visual cortices. Furthermore, rCBF increased in the comparison group, but not in the social phobics, in the perirhinal and retrosplenial cortices. CONCLUSIONS: An rCBF pattern of relatively increased cortical rather than subcortical perfusion was observed in the nonphobic subjects, indicating that cortical evaluative processes were taxed by public performance. In contrast, the social phobia symptom profile was associated with increased subcortical activity. Thus, the functional neuroanatomy of social phobia involves the activation of a phylogenetically older danger-recognition system.
Inverse PCR-Based RFLP Scanning Identifies Low-Level Mutation Signatures in Colon Cells and Tumors
Authors: Wei-Hua Liu, Manjit Kaur, Gang Wang, Penny Zhu, Yuzhi Zhang, G. Mike Makrigiorgos
Journal: Cancer Research (2004)

Abstract Detecting the presence and diversity of low-level mutations in human tumors undergoing genomic instability is desirable due to their potential prognostic value and their putative influence on the ability of tumors to resist drug treatment and/or metastasize. However, direct measurement of these genetic alterations in surgical samples has been elusive, because technical hurdles make mutation discovery impractical at low-mutation frequency levels (&amp;lt;10−2). Here, we describe inverse PCR-based amplified restriction fragment length polymorphism (iFLP), a new technology that combines inverse PCR, RFLP, and denaturing high-performance liquid chromatography to allow scanning of the genome at several thousand positions per experiment for low-level point mutations. Using iFLP, widespread, low-level mutations at mutation frequency 10−2–10−4 were discovered in genes located on different chromosomes, e.g., OGG1, MSH2, PTEN, β-catenin, Bcl-2, P21, ATK3, and Braf, in human colon cancer cells that harbor mismatch repair deficiency whereas mismatch repair-proficient cells were mutation free. Application of iFLP to the screening of sporadic colon cancer surgical specimens demonstrated widespread low-level mutations in seven out of 10 samples, but not in their normal tissue counterparts, and predicted the presence of millions of diverse, low-incidence mutations in tumors. Unique low-level mutational signatures were identified for each colon cancer cell line and tumor specimen. iFLP allows the high-throughput discovery and tracing of mutational signatures in human cells, precancerous lesions, and primary or metastatic tumors and the assessment of the number and heterogeneity of low-level mutations in surgical samples.
GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS–induced lung cancer
Authors: Anna-Karin M. Sjogren, Karin M.E. Andersson, Meng Liu, Briony A. Cutts, Christin Karlsson, Annika M. Wahlstrom, Martin Dalin, Carolyn Weinbaum, Patrick J. Casey, Andrej Tarkowski, Birgitta Swolin, Stephen G. Young, Martin O. Bergo
Journal: Journal of Clinical Investigation (2007)

Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the posttranslational lipidation of CAAX proteins such as RHOA, RAC1, and cell division cycle 42 (CDC42). Inhibition of GGTase-I has been suggested as a strategy to treat cancer and a host of other diseases. Although several GGTase-I inhibitors (GGTIs) have been synthesized, they have very different properties, and the effects of GGTIs and GGTase-I deficiency are unclear. One concern is that inhibiting GGTase-I might lead to severe toxicity. In this study, we determined the effects of GGTase-I deficiency on cell viability and K-RAS–induced cancer development in mice. Inactivating the gene for the critical β subunit of GGTase-I eliminated GGTase-I activity, disrupted the actin cytoskeleton, reduced cell migration, and blocked the proliferation of fibroblasts expressing oncogenic K-RAS. Moreover, the absence of GGTase-I activity reduced lung tumor formation, eliminated myeloproliferative phenotypes, and increased survival of mice in which expression of oncogenic K-RAS was switched on in lung cells and myeloid cells. Interestingly, several cell types remained viable in the absence of GGTase-I, and myelopoiesis appeared to function normally. These findings suggest that inhibiting GGTase-I may be a useful strategy to treat K-RAS–induced malignancies.
Insulin Resistance, Brain Atrophy, and Cognitive Performance in Late Middle–Aged Adults
Authors: Auriel A. Willette, Guofan Xu, Sterling C. Johnson, Alex C. Birdsill, Erin M. Jonaitis, Mark A. Sager, Bruce P. Hermann, Asenath La Rue, Sanjay Asthana, Barbara B. Bendlin
Journal: Diabetes Care (2012)

Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether insulin resistance among late middle-aged, cognitively healthy individuals was associated with 1) less gray matter in Alzheimer disease-sensitive brain regions and 2) worse cognitive performance.Homeostasis model assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy.Higher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region-of-interest analysis, independent of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse RAVLT encoding performance.These results suggest that insulin resistance in an asymptomatic, late middle-aged cohort is associated with progressive atrophy in regions affected by early Alzheimer disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe.
Comparative Effectiveness of Ductal Carcinoma In Situ Management and the Roles of Margins and Surgeons
Authors: A. W. Dick, M. S. Sorbero, G. M. Ahrendt, J. A. Hayman, H. T. Gold, L. Schiffhauer, A. Stark, J. J. Griggs
Journal: JNCI Journal of the National Cancer Institute (2011)

BackgroundThe high incidence of ductal carcinoma in situ (DCIS) and variations in its treatment motivate inquiry into the comparative effectiveness of treatment options. Few such comparative effectiveness studies of DCIS, however, have been performed with detailed information on clinical and treatment attributes.
Making a case for mirror-neuron system involvement in language development: What about autism and blindness?
Authors: Hugo Théoret, Shirley Fecteau
Journal: Behavioral and Brain Sciences (2005)

The notion that manual gestures played an important role in the evolution of human language was strengthened by the discovery of mirror neurons in monkey area F5, the proposed homologue of human Broca's area. This idea is central to the thesis developed by Arbib, and lending further support to a link between motor resonance mechanisms and language/communication development is the case of autism and congenital blindness. We provide an account of how these conditions may relate to the aforementioned theory.
GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions
Authors: Su-Ning Zhu, Mian Chen, Jenny Jongstra-Bilen, Myron I. Cybulsky
Journal: The Journal of Experimental Medicine (2009)

The contribution of intimal cell proliferation to the formation of early atherosclerotic lesions is poorly understood. We combined 5-bromo-2'-deoxyuridine pulse labeling with sensitive en face immunoconfocal microscopy analysis, and quantified intimal cell proliferation and Ly-6C(high) monocyte recruitment in low density lipoprotein receptor-null mice. Cell proliferation begins in nascent lesions preferentially at their periphery, and proliferating cells accumulate in lesions over time. Although intimal cell proliferation increases in parallel to monocyte recruitment as lesions grow, proliferation continues when monocyte recruitment is inhibited. The majority of proliferating intimal cells are dendritic cells expressing CD11c and major histocompatibility complex class II and 33D1, but not CD11b. Systemic injection of granulocyte/macrophage colony-stimulating factor (GM-CSF) markedly increased cell proliferation in early lesions, whereas function-blocking anti-GM-CSF antibody inhibited proliferation. These findings establish GM-CSF as a key regulator of intimal cell proliferation in lesions, and demonstrate that both proliferation and monocyte recruitment contribute to the inception of atherosclerosis.