tbuckley/cabot-search huggingface dataset:
MicroRNA miR145 Regulates TGFBR2 Expression and Matrix Synthesis in Vascular Smooth Muscle Cells
Authors: Ning Zhao, Sara N. Koenig, Aaron J. Trask, Cho-Hao Lin, Chetan P. Hans, Vidu Garg, Brenda Lilly
Journal: Circulation Research (2014)

MicroRNA miR145 has been implicated in vascular smooth muscle cell differentiation, but its mechanisms of action and downstream targets have not been fully defined.
Stromal cell–derived factor 1 promotes angiogenesis via a heme oxygenase 1–dependent mechanism
Authors: Jessy Deshane, Sifeng Chen, Sergio Caballero, Anna Grochot-Przeczek, Halina Was, Sergio Li Calzi, Radoslaw Lach, Thomas D. Hock, Bo Chen, Nathalie Hill-Kapturczak, Gene P. Siegal, Jozef Dulak, Alicja Jozkowicz, Maria B. Grant, Anupam Agarwal
Journal: The Journal of Experimental Medicine (2007)

Stromal cell–derived factor 1 (SDF-1) plays a major role in the migration, recruitment, and retention of endothelial progenitor cells to sites of ischemic injury and contributes to neovascularization. We provide direct evidence demonstrating an important role for heme oxygenase 1 (HO-1) in mediating the proangiogenic effects of SDF-1. Nanomolar concentrations of SDF-1 induced HO-1 in endothelial cells through a protein kinase C ζ–dependent and vascular endothelial growth factor–independent mechanism. SDF-1–induced endothelial tube formation and migration was impaired in HO-1–deficient cells. Aortic rings from HO-1−/− mice were unable to form capillary sprouts in response to SDF-1, a defect reversed by CO, a byproduct of the HO-1 reaction. Phosphorylation of vasodilator-stimulated phosphoprotein was impaired in HO-1−/− cells, an event that was restored by CO. The functional significance of HO-1 in the proangiogenic effects of SDF-1 was confirmed in Matrigel plug, wound healing, and retinal ischemia models in vivo. The absence of HO-1 was associated with impaired wound healing. Intravitreal adoptive transfer of HO-1–deficient endothelial precursors showed defective homing and reendothelialization of the retinal vasculature compared with HO-1 wild-type cells following ischemia. These findings demonstrate a mechanistic role for HO-1 in SDF-1–mediated angiogenesis and provide new avenues for therapeutic approaches in vascular repair.
DEVELOPMENT AND MATURATION OF SECONDARY LYMPHOID TISSUES
Authors: Yang-Xin Fu, David D. Chaplin
Journal: Annual Review of Immunology (1999)

▪ Abstract The secondary lymphoid tissues are located at strategic sites where foreign antigens can be efficiently brought together with immune system regulatory and effector cells. The organized structure of the secondary lymphoid tissues is thought to enhance the sensitivity of antigen recognition and to support proper regulation of the activation and maturation of the antigen-responsive lymphoid cells. Although a substantial amount is known about the cellular elements that compose the lymphoid and nonlymphoid components of the secondary lymphoid tissues, information concerning the signals that control the development of the tissues and that maintain the organized tissue microenvironment remain undefined. Studies over the past few years have identified lymphotoxin as a critical signaling molecule not only for the organogenesis of secondary lymphoid tissues but for the maintenance of aspects of their microarchitecture as well. Additional signaling molecules that contribute to the formation of normal lymphoid tissue structure are being identified at an accelerating pace. Analyses of mouse strains with congenital defects in different aspects of secondary lymphoid tissue development are beginning to clarify the role of these tissues in immune responses and host defense. This review focuses on studies defining recently identified crucial signals for the biogenesis of secondary lymphoid organs and for the maintenance of their proper microarchitecture. It also discusses new insights into how the structure of these tissues supports effective immune responses.
Efficacy, Toxicity, and Quality of Life in Older Women With Early-Stage Breast Cancer Treated With Letrozole or Placebo After 5 Years of Tamoxifen: NCIC CTG Intergroup Trial MA.17
Authors: Hyman B. Muss, Dongsheng Tu, James N. Ingle, Silvana Martino, Nicholas J. Robert, Joseph L. Pater, Timothy J. Whelan, Michael J. Palmer, Martine J. Piccart, Lois E. Shepherd, Kathleen I. Pritchard, Zhi He, Paul E. Goss
Journal: Journal of Clinical Oncology (2008)

National Cancer Institute of Canada Clinical Trials Group trial MA.17 randomly assigned 5,187 postmenopausal, hormone-receptor-positive patients with early breast cancer who completed 5 years of tamoxifen to receive either letrozole or placebo. At 30 months median follow-up, letrozole significantly improved disease-free survival (DFS) in all patients and overall survival (OS) in node-positive patients. Breast cancer incidence increases with age and more than 1,300 women age 70 years or older were enrolled onto MA.17, making it ideal to explore the benefits, toxicities, and quality of life (QOL) impact of letrozole on older women.In this study, 5,169 randomly assigned patients were divided into three age groups: younger than 60 years (n = 2,152), 60 to 69 years (n = 1,694), and >or= 70 years (n = 1,323). Log-rank test was used to compare differences in DFS, distant-disease-free survival, and OS between age and treatment groups, and Cox models were used to estimate hazard ratios and associated 95% CIs. QOL was measured using the Medical Outcomes Short Form-36 and the Menopause-Specific Quality-of-Life questionnaire.At 4 years, DFS demonstrated statistically significant differences favoring letrozole only in patients age younger than 60 years (hazard ratio = 0.46; P = .0004); there was no interaction between age and treatment, indicating a similar effect of letrozole among all age groups. There was no difference in toxicity or QOL at 24 months among letrozole- and placebo-treated patients age >or= 70 years.Healthy patients age 70 years and older completing 5 years of tamoxifen should be considered for extended adjuvant therapy with letrozole.
BMI May Be Better Than Waist Circumference for Defining Metabolic Syndrome in Japanese Women
Authors: Masaru Sakurai, Toshinari Takamura, Katsuyuki Miura, Shuichi Kaneko, Hideaki Nakagawa
Journal: Diabetes Care (2008)

We previously addressed sex differences in the associations between anthropometric indexes of obesity and blood pressure and showed that blood pressure was more strongly related to BMI than to waist circumference in Japanese women (1). As hypertension is a major component of metabolic syndrome in Japanese patients, a similar sex difference may exist in the association between anthropometric indexes and the metabolic components of metabolic syndrome. We investigated the possible sex differences of these associations.

Study subjects consisted of 2,935 men and …
Marked Impairment of Protease-Activated Receptor Type 1-Mediated Vasodilation and Fibrinolysis in Cigarette Smokers
Authors: Ninian N. Lang, Ingibjörg J. Guðmundsdóttir, Nicholas A. Boon, Christopher A. Ludlam, Keith A. Fox, David E. Newby
Journal: Journal of the American College of Cardiology (2008)
Randomized Phase II Trial of Onartuzumab in Combination With Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: David R. Spigel, Thomas J. Ervin, Rodryg A. Ramlau, Davey B. Daniel, Jerome H. Goldschmidt, George R. Blumenschein, Maciej J. Krzakowski, Gilles Robinet, Benoit Godbert, Fabrice Barlesi, Ramaswamy Govindan, Taral Patel, Sergey V. Orlov, Michael S. Wertheim, Wei Yu, Jiping Zha, Robert L. Yauch, Premal H. Patel, See-Chun Phan, Amy C. Peterson
Journal: Journal of Clinical Oncology (2013)

Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) -targeted drugs in patients with non-small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC.Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety.There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients.Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.
The father figure in coeliac disease
Authors: L GRECO
Journal: Gut (2001)

See article on page 169 

It is surprising that although clear reports were given in the pilot work of Ferguson and colleagues,1 Farthing and colleagues,2 and others about 20 years ago, coeliac disease (CD) has not yet gained popularity among obstetricians. In the subsequent two decades, many epidemiological studies clearly showed that it is a very common disease, that it affects women more than men, and that it has to be considered in relation to reproductive function.

In the past few years several groups have shown that untreated CD is an important cause of abortion, poor outcome of pregnancy, and intrauterine growth retardation.3 4 Most authors agree that malnutrition could not have explained the reproductive difficulties of many, now most, coeliac women. Martinelli and colleagues5 recently found that 1 in every 70 pregnant women admitted to a major city hospital suffered …
A Lecture ON SKIN RASHES IN CHILDREN: Delivered at the Medical Graduates' College and Polyclinic
Authors: J. L. Bunch
Journal: BMJ (1912)

CHILDRE.N.T1IE nomenclature and classification of skin diseases has always been a more or less well deserved subject of reproach to dermatologists, and even at the present day there are still grounds for criticism.The old-fashioned grouping of skin diseases,
Barriers to the Treatment of Social Anxiety
Authors: Mark Olfson, Mary Guardino, Elmer Struening, Franklin R. Schneier, Fred Hellman, Donald F. Klein
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: This article evaluates barriers to treatment reported by adults with social anxiety who participated in the 1996 National Anxiety Disorders Screening Day. METHOD: The background characteristics of screening day participants with symptoms of social anxiety (N=6,130) were compared with those of participants without social anxiety (N=4,507). Barriers to previous mental health treatment reported by participants with and without symptoms of social anxiety were compared. RESULTS: Social anxiety was strongly associated with functional impairment, feelings of social isolation, and suicidal ideation. Compared to participants without social anxiety, those with social anxiety were significantly more likely to report that financial barriers, uncertainty over where to go for help, and fear of what others might think or say prevented them from seeking treatment. However, they were significantly less likely to report they avoided treatment because they did not believe they had an anxiety disorder. Roughly one-third (N=1,400 of 3,682, 38.0%) of the participants with symptoms of social anxiety who were referred for further evaluation were specifically referred for an evaluation for social phobia. CONCLUSIONS: Social anxiety is associated with a distinct pattern of treatment barriers. Treatment access may be improved by building public awareness of locally available services, easing the psychological and financial burden of entering treatment, and increasing health care professionals' awareness of its clinical significance.
Vertebral and carotid blood distribution in the brain of the dog and the cat
Authors: R. S. RENEMAN, D. WELLENS, A. H. M. JAGENEAU, L. STYNEN
Journal: Cardiovascular Research (1974)

Vertebral and carotid blood distribution in the brain of dogs and cats was studied with radioactive microspheres. The most pronounced difference between these species was that in the cat, the pontomedullary region received in an absolute sense, and compared to the thalamus and hypothalamus, significantly more blood from the vertebral artery than in the dog. This finding might be important for the localization of the central activity of cardiovascular active substances.
Phase I Dose-Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer
Authors: A. Jo Chien, Pamela N. Munster, Michelle E. Melisko, Hope S. Rugo, John W. Park, Andrei Goga, Glenna Auerback, Elham Khanafshar, Karen Ordovas, Kevin M. Koch, Mark M. Moasser
Journal: Journal of Clinical Oncology (2014)

The highly effective treatment of human epidermal growth factor receptor (HER) 2-amplified breast cancer has proven challenging because of a signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis.We conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring.Forty patients were evaluable for toxicity, and 34 patients were evaluable for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000 ng/mL.Lapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses.
NETWORK COMMUNICATIONS: Lymphotoxins, LIGHT, and TNF
Authors: Carl F. Ware
Journal: Annual Review of Immunology (2004)

▪ Abstract Lymphotoxins (LT) provide essential communication links between lymphocytes and the surrounding stromal and parenchymal cells and together with the two related cytokines, tumor necrosis factor (TNF) and LIGHT (LT-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells), form an integrated signaling network necessary for efficient innate and adaptive immune responses. Recent studies have identified signaling pathways that regulate several genes, including chemokines and interferons, which participate in the development and function of microenvironments in lymphoid tissue and host defense. Disruption of the LT/TNF/LIGHT network alleviates inflammation in certain autoimmune disease models, but decreases resistance to selected pathogens. Pharmacological disruption of this network in human autoimmune diseases such as rheumatoid arthritis alleviates inflammation in a significant number of patients, but not in other diseases, a finding that challenges our molecular paradigms of autoimmunity and perhaps will reveal novel roles for this network in pathogenesis.
The Argyll Robertson Sign in Cerebral and Spinal Syphilis
Authors: J. M. Clarke
Journal: BMJ (1911)

tomed, however, to pay much attention to the history of the case, but to judge each on its merits, as I see it, though it may be taken, as a rule to which there are few excep.-tions, that in severe cases the severity of the disease directly depends upon its duration.Severity of attack is shown by extent of exudation and symptoms of toxaemia.
Physical chemistry of the lipids of human atherosclerotic lesions. Demonstration of a lesion intermediate between fatty streaks and advanced plaques.
Authors: S S Katz, G G Shipley, D M Small
Journal: Journal of Clinical Investigation (1976)

95 individual human atherosclerotic lesions from 26 persons were classified into three groups under the dissecting microscope: fatty streaks, fibrous plaques, and gruel (atheromatous) plaques. Each lesion was isolated by microdissection, its lipid composition determined by chromatography, and the physical states of the lipids identified by polarizing microscopy and in some cases by X-ray diffraction. The composition of each lesion was plotted on the in vitro phase diagram of the major lipids of plaques: cholesterol, cholesterol ester, and phospholipid. The observed physical states were compared with those predicted by the location of the lipid composition on the phase diagram. The most severe lesions (gruel plaques) had an average lipid composition of cholesterol 31.5+/-1.9%, cholesterol ester 47.2+/-2.3%, and phospholipid 15.3+/-0.5%. Their compositions fell within the three-phase zone of the phase diagram, predicting the lipids to be separated into a cholesterol crystal phase, a cholesterol ester oily phase and a phospholipid liquid crystalline phase. In addition to the phospholipid liquid crystalline phase of membranes and myelin-like figures demonstrable by electron microscopy, polarizing microscopy revealed the other two predicted phases, isotropic cholesterol ester-rich droplets and cholesterol crystals. X-ray diffraction studies verified the identity of the crystals as cholesterol monohydrate. Fibrous plaques also had an average lipid composition within the three-phase zone of the phase diagram. Polarizing microscopy revealed the presence of cholesterol monohydrate crystals and lipid droplets in all of these lesions; the droplets were predominately isotropic in 28 of the 31 fibrous plaques. Although these lesions had less free cholesterol and more cholesterol ester than gruel plaques, they were otherwise similar. Fatty streaks had compositions within both the two- and three-phase zones of the phase diagram. Compared with gruel plaques, the fatty streaks within the two-phase zone, defined as "ordinary," had more cholesterol ester, less free cholesterol, a higher cholesteryl oleate/cholesteryl linoleate ratio, a lower sphingomyelin/lecithin ratio, more anisotropic lipid droplets, and rare or no cholesterol crystals. Those lesions within the three-phase zone had many chemical and physical features intermediate between ordinary fatty streaks and gruel plaques. Moreover, 68% of these "intermediate" lesions had no cholesterol crystals by polarizing microscopy in spite of their compositions being within the three-phase zone, indicating the cholesterol ester oily phase or the phospholipid phase or both were supersaturated with cholesterol. Identification of this group of intermediate lesions provides evidence that some fatty streaks may be precursors of advanced plaques.
Rapid Expansion of Microsatellite Sequences in Pines
Authors: A. Karhu, J.-H. Dieterich, O. Savolainen
Journal: Molecular Biology and Evolution (2000)

Microsatellite persistence time and evolutionary change was studied among five species of pines, which included a pair of closely related species (Pinus sylvestris and Pinus resinosa) in the subgenus Pinus, their relative Pinus radiata, and another closely related species pair (Pinus strobus and Pinus lambertiana) in the subgenus Strobus. The effective population sizes of these species are known to have ranged from the very small bottlenecks of P. resinosa to vast populations of P. sylvestris. This background allowed us to place the microsatellite evolution in a well-defined phylogenetic setting. Of 30 loci originating from P. strobus and P. radiata, we were able to consistently amplify 4 in most of the these pine species. These priming sites had been conserved for over 100 Myr. The four microsatellites were sequenced in the five species. Flanking sequences were compared to establish that the loci were orthologous. All microsatellites had persisted in these species, despite very different population sizes. We found a recent microsatellite duplication: a closely related pair of loci in P. strobus, where the other four species had just one locus. On two independent occasions, the repeat area of this same microsatellite (locus RPS 105a/b) had grown from a very low repeat number to 15 or 17 in the last 10–25 Myr. Other parts of the same compound microsatellite had remained virtually unchanged. Locus PR 4.6 is known to be polymorphic in both P. radiata and P. sylvestris, but the polymorphism in the two species is due to different motifs. The very large pine genomes are highly repetitive, and microsatellite loci also occur as gene families.
Is low-level lead pollution dangerous?
Authors: R R Jones
Journal: BMJ (1981)

sprinters lack stamina, but I imagine that no one would question their cardiopulmonary fitness-while in training.I am also worried by the modified physical fitness index, as this fails to take account of the resting pulse rate.Surely a formula based on percentage increase over resting rate at two, five, and 10 minutes would seem more reasonable, since the normal resting pulse rate can vary from the 40s to the 90s at least-or does a naturally slow pulse rate confer a fitness advantage ?Interestingly, Lieutenant-ColonelPearn referred to Zatopek's fitness index of 172; he was a distance runner with a resting pulse rate of about 40 per minute.But I wonder how Zatopek would have fared on the squash court, where explosive bursts of energy are required, or in gymnastics, in which a completely different sort of fitness and body control is demanded, or in the swimming pool.He certainly would have been