tbuckley/cabot-search huggingface dataset:
Klotho: An important protein in the formation and development of emphysema
Authors: Xin Yao, Cheng Yuan, Jingying Zhang, Lin Zhou, Mao Huang, Ian Adcock, Peter Barnes
Journal: European Respiratory Journal (2012)

Objective: K lotho is an anti-aging protein which also possesses anti-inflammatory actions and modulates the cellular responses to oxidative stress. Knock out of klotho in the mouse caused the formation of emphysema. The aim of this study is to investigate the expression of klotho in human emphysema and factors affecting its expression and activity in human bronchial epithelial cells.   Methods:  Lung tissue from 5 COPD patients, 8 smokers without COPD and 13 non-smoking, non-COPD. Klotho expression was determined by quantitative real-time PCR, Western blotting and immunohistochemistry. Human bronchial epithelial cells (HBE) were treated with tumor necrosis factor (TNF)-α and hydrogen peroxide (H 2 O 2 ), and the expression of klotho mRNA in cells and protein in cell supernatants was detected by RT-PCR and enzyme-linked immune sorbent assay (ELISA) respectively. Exogenous klotho was also added to HBE and A549 cell cultures and MTT assays were used to detect cell apoptosis.   Results:  Klotho was detected in human lung tissue with a clear localization to airway epithelial cells. The level of klotho mRNA and protein in smokers with normal lung function was similar to that in non-smokers but was reduced in COPD patients The level of klotho expression was similar in COPD patients with emphysema compared with that in non-emphysematous COPD patients. In addition, we found that both TNF-α and H 2 O 2  could significantly inhibit the expression and release of klotho in HBE cells. Exogenous klotho inhibited apoptosis in HBE) and A549 cells).   Conclusions:  Klotho may play an important role in the formation and development of emphysema in COPD. However, further research is needed to explore the underlying mechanism.
Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis
Authors: Martin C Herzig, David T Winkler, Patrick Burgermeister, Michelle Pfeifer, Esther Kohler, Stephen D Schmidt, Simone Danner, Dorothee Abramowski, Christine Stürchler-Pierrat, Kurt Bürki, Sjoerd G van Duinen, Marion L C Maat-Schieman, Matthias Staufenbiel, Paul M Mathews, Mathias Jucker
Journal: Nature Neuroscience (2004)
Neural Mechanisms of Orientation Selectivity in the Visual Cortex
Authors: David Ferster, Kenneth D. Miller
Journal: Annual Review of Neuroscience (2000)

The origin of orientation selectivity in the responses of simple cells in cat visual cortex serves as a model problem for understanding cortical circuitry and computation. The feed-forward model posits that this selectivity arises simply from the arrangement of thalamic inputs to a simple cell. Much evidence, including a number of recent intracellular studies, supports a primary role of the thalamic inputs in determining simple cell response properties, including orientation tuning. This mechanism alone, however, cannot explain the invariance of orientation tuning to changes in stimulus contrast. Simple cells receive push-pull inhibition: ON inhibition in OFF subregions and vice versa. Addition of such inhibition to the feed-forward model can account for this contrast invariance, provided the inhibition is sufficiently strong. The predictions of “normalization” and “feedback” models are reviewed and compared with the predictions of this modified feed-forward model and with experimental results. The modified feed-forward and the feedback models ascribe fundamentally different functions to cortical processing.
Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs
Authors: B. Velkeniers, A. Van Meerhaeghe, K. Poppe, D. Unuane, H. Tournaye, P. Haentjens
Journal: Human Reproduction Update (2013)

BACKGROUNDPrevious meta-analyses of observational data indicate that pregnant women with subclinical hypothyroidism have an increased risk of adverse pregnancy outcome. Potential benefits of levothyroxine (LT4) supplementation remain unclear, and no systematic review or meta-analysis of trial findings is available in a setting of assisted reproduction technologies (ART).
Tadalafil Reduces Myeloid-Derived Suppressor Cells and Regulatory T Cells and Promotes Tumor Immunity in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Donald T. Weed, Jennifer L. Vella, Isildinha M. Reis, Adriana C. De la fuente, Carmen Gomez, Zoukaa Sargi, Ronen Nazarian, Joseph Califano, Ivan Borrello, Paolo Serafini
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC. Experimental Design: First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 mg/day, 20 mg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8+ T-cell reactivity to tumor antigens were evaluated before and after treatment. Results: MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P &amp;lt; 0.05). In addition, the concentration of blood CD8+ T cells reactive to autologous tumor antigens significantly increased after treatment (P &amp;lt; 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity. Conclusions: Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8+ T cells in a dose-dependent fashion. Clin Cancer Res; 21(1); 39–48. ©2014 AACR.
Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors
Authors: Claudio Anasetti, Brent R. Logan, Stephanie J. Lee, Edmund K. Waller, Daniel J. Weisdorf, John R. Wingard, Corey S. Cutler, Peter Westervelt, Ann Woolfrey, Stephen Couban, Gerhard Ehninger, Laura Johnston, Richard T. Maziarz, Michael A. Pulsipher, David L. Porter, Shin Mineishi, John M. McCarty, Shakila P. Khan, Paolo Anderlini, William I. Bensinger, Susan F. Leitman, Scott D. Rowley, Christopher Bredeson, Shelly L. Carter, Mary M. Horowitz, Dennis L. Confer
Journal: New England Journal of Medicine (2012)

Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia.
Cancer and Leukemia Group B Leukemia Correlative Science Committee: Major Accomplishments and Future Directions
Authors: Clara D. Bloomfield, Krzysztof Mrózek, Michael A. Caligiuri
Journal: Clinical Cancer Research (2006)

The Cancer and Leukemia Group B (CALGB) Leukemia Correlative Science Committee (LCSC) has a remarkable history of outstanding productivity and has been at the cutting edge of correlative science for adult leukemia for almost 25 years. Its work, initially focused on the use of immunophenotyping for diagnosis and prognosis of acute lymphoblastic leukemia and acute myeloid leukemia, has, for the last 15 years, focused on the clinical use of cytogenetic and molecular genetic markers in acute myeloid leukemia and acute lymphoblastic leukemia as well as in chronic lymphocytic leukemia. Numerous CALGB LCSC studies have had a major effect on the way we currently diagnose, predict outcome, select appropriate treatment, document complete remission, and monitor residual disease in adults with acute leukemia. In part as a result of the work of the CALGB LCSC, we are increasingly moving toward molecularly targeted therapy in acute and chronic leukemias. In this report, we briefly review those contributions from the CALGB LCSC that have had, or are likely to have in the future, a major effect on how we currently manage leukemia and outline directions of ongoing and future research conducted by the CALGB LCSC.
Vascular Endothelial Growth Factor A Signaling in the Podocyte-Endothelial Compartment Is Required for Mesangial Cell Migration and Survival
Authors: Vera Eremina, Shiying Cui, Hanspeter Gerber, Napoleone Ferrara, Jody Haigh, Andras Nagy, Masatsugu Ema, Janet Rossant, Serge Jothy, Jeffrey H. Miner, Susan E. Quaggin
Journal: Journal of the American Society of Nephrology (2006)

The glomerular filtration barrier separates the blood from the urinary space and consists of two major cell types: podocytes and fenestrated endothelial cells. Mesangial cells sit between the capillary loops and provide structural support. Proliferation and loss of mesangial cells both are central findings in a number of renal diseases, including diabetic nephropathy and mesangiolysis, respectively. Using cell-specific gene targeting, it was shown previously that vascular endothelial growth factor A (VEGF-A) production by podocytes is required for glomerular endothelial cell migration, differentiation, and survival. For further investigation of the effect of gene dose and VEGF-A knockdown within the glomerulus, mice that carry one hypomorphic VEGF-A allele and one podocyte-specific null VEGF-A allele (VEGFhypo/loxP,Neph-Cre+/-) were generated; in these mice, the "allelic dose" of VEGF-A is intermediate between glomerular-specific heterozygous and null states. VEGFhypo/loxP,Neph-Cre+/- mice die at 3 wk of age from renal failure. Although endothelial cell defects are observed, striking loss of mesangial cells occurs postnatally. In addition, differentiated mesangial cells cannot be found in glomeruli of podocyte-specific null VEGF-A mice (VEGFloxP/loxP,Cre+/-). Together, these results demonstrate a key role for VEGF-A production in the podocyte for mesangial cell survival and differentiation.
Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans.
Authors: P Vollenweider, L Tappy, D Randin, P Schneiter, E Jéquier, P Nicod, U Scherrer
Journal: Journal of Clinical Investigation (1993)

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation of carbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic [6 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle.
Suicidal ideation and suicide plans or attempts in adults with Asperger's syndrome attending a specialist diagnostic clinic: a clinical cohort study
Authors: Sarah Cassidy, Paul Bradley, Janine Robinson, Carrie Allison, Meghan McHugh, Simon Baron-Cohen
Journal: The Lancet Psychiatry (2014)

Asperger's syndrome in adulthood is frequently associated with depression, but few studies have explored the lifetime experience of self-reported suicidal ideation and suicide plans or attempts in this clinical group. We aimed to assess this prevalence in a clinical cohort of patients in the UK.
Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study
Authors: Tony Reid, Bryan Oronsky, Jan Scicinski, Curt L Scribner, Susan J Knox, Shoucheng Ning, Donna M Peehl, Ron Korn, Meaghan Stirn, Corey A Carter, Arnold Oronsky, Michael J Taylor, William L Fitch, Pedro Cabrales, Michelle M Kim, Howard A Burris, Christopher D Lao, Nacer E D Abrouk, Gary R Fanger, Jeffrey R Infante
Journal: The Lancet Oncology (2015)
Inhibition of Mammalian Target of Rapamycin Reverses Alveolar Epithelial Neoplasia Induced by Oncogenic <i>K-ras</i>
Authors: Marie Wislez, M. Loreto Spencer, Julie G. Izzo, Denise M. Juroske, Kamna Balhara, Dianna D. Cody, Roger E. Price, Walter N. Hittelman, Ignacio I. Wistuba, Jonathan M. Kurie
Journal: Cancer Research (2005)

Abstract The serine/threonine kinase AKT and its downstream mediator mammalian target of rapamycin (mTOR) are activated in lung adenocarcinoma, and clinical trials are under way to test whether inhibition of mTOR is useful in treating lung cancer. Here, we report that mTOR inhibition blocked malignant progression in K-rasLA1 mice, which undergo somatic activation of the K-ras oncogene and display morphologic changes in alveolar epithelial cells that recapitulate those of precursors of human lung adenocarcinoma. Levels of phospho-S6Ser236/235, a downstream mediator of mTOR, increased with malignant progression (normal alveolar epithelial cells to adenocarcinoma) in K-rasLA1 mice and in patients with lung adenocarcinoma. Atypical alveolar hyperplasia, an early neoplastic change, was prominently associated with macrophages and expressed high levels of phospho-S6Ser236/235. mTOR inhibition in K-rasLA1 mice by treatment with the rapamycin analogue CCI-779 reduced the size and number of early epithelial neoplastic lesions (atypical alveolar hyperplasia and adenomas) and induced apoptosis of intraepithelial macrophages. LKR-13, a lung adenocarcinoma cell line derived from K-rasLA1 mice, was resistant to treatment with CCI-779 in vitro. However, LKR-13 cells grown as syngeneic tumors recruited macrophages, and those tumors regressed in response to treatment with CCI-779. Lastly, conditioned medium from primary cultures of alveolar macrophages stimulated the proliferation of LKR-13 cells. These findings provide evidence that the expansion of lung adenocarcinoma precursors induced by oncogenic K-ras requires mTOR-dependent signaling and that host factors derived from macrophages play a critical role in adenocarcinoma progression.
STUDIES ON THE ANTIBACTERIAL ACTION OF THE SULFONAMIDE DRUGS
Authors: W. Barry Wood, Robert Austrian
Journal: The Journal of Experimental Medicine (1942)

1. In cultures of Staphylococus aureus in a synthetic medium nicotinamide and cozymase were shown to block the bacteriostatic action of chemically unrelated sulfonamide drugs as well as the chemically related compound sulfapyridine. The antibacterial properties of organic dyes totally unrelated to the sulfonamide compounds (methylene blue and thionine) were also nullified by the addition of cozymase to the culture medium. 2. The antagonistic action of the pyridine-containing coenzyme, cozymase, was found, by quantitative study, to be no greater against sulfapyridine than against other structurally dissimilar sulfonamide compounds. 3. The antidrug effects of nicotinamide and cozymase in staphylococcus cultures were observed to be directly proportional to their ability to stimulate the growth of the organism in the synthetic medium. When tested in cultures of B. coli in which they failed to accelerate bacterial growth, these same substances failed to influence the bacteriostatic action of the sulfonamide drugs. 4. The in vitro action of the coenzyme, cocarboxylase, as measured in the Warburg respirometer, was shown to be unaffected by the chemically related drug, sulfathiazole, even when the latter was present in great excess. The above observations fail to support the theory that sulfapyridine, sulfathiazole, and sulfadiazine prevent bacterial growth by interfering with the functioning of the chemically related coenzymes, cozymase, and cocarboxylase. The mode of action of sulfanilamide and its more common derivatives is discussed in the light of these observations, and a tentative theory is offered to explain the differences in bacteriostatic potency exhibited by the various sulfonamide compounds.
Spiral enteroscopy with the new DSB overtube: a novel technique for deep peroral small-bowel intubation
Authors: P. Akerman, D. Agrawal, D. Cantero, J. Pangtay
Journal: Endoscopy (2008)

Spiral enteroscopy is a new technique for deep small-bowel intubation that uses a special overtube (Discovery Small Bowel, DSB) to pleat small bowel. The aims of this prospective study were to evaluate the use of a new-design DSB over new, longer and smaller-diameter enteroscopes, the Fujinon EN-450T5 and the Olympus SIF-Q180.This is a prospective study of 75 patients at two referral centers. All enteroscopies were performed by two experienced endoscopists. Patients underwent spiral enteroscopy perorally with the DSB and either the Fujinon EN-450T5 or the Olympus SIF-Q180 enteroscope. Procedure time and depth of insertion past the ligament of Treitz were determined for all patients.Peroral spiral enteroscopy with DSB was performed in 50 patients with the Fujinon enteroscope and in 25 patients with the Olympus. Average estimated depth of insertion was 243 cm (range 50 - 380 cm) vs. 256 cm (range 50 - 400 cm) and the average time to reach this depth was 18.7 minutes (range 7 - 52 minutes) vs. 16.2 minutes (range 7 - 33 minutes) in the Fujinon and the Olympus groups respectively. Overall findings were 10 angiodysplasias, 2 small-bowel tumors, 1 Peutz-Jeghers polyp, 1 case of celiac sprue, 2 of small-bowel strongyloidiasis, and 2 small-bowel ulcers. All angiodysplasias were treated with bipolar cauterization. Biopsies were taken from the small-bowel tumors. There were no major complications.The new DSB is a means of rapid, safe, and effective deep small-bowel intubation. Depth of insertion into the small bowel and total procedure time compare favorably with other deep enteroscopy techniques. The DSB performed equally well with both enteroscopes.
Myofibrillar Adenosine Triphosphatase Activity of Human Heart Tissue in Congestive Failure: Effects of Ouabain and Calcium
Authors: Michael S. Gordon, Arnold L. Brown
Journal: Circulation Research (1966)

Ouabain had no effect on myofibrillar adenosine triphosphatase (ATPase) activity in normal, hypertrophic, and failing hearts with concentrations of calcium chloride varying from 0 to 5.0 mM. The quantitative effects of CaCl 2 on myofibrillar ATPase were the same in all groups studied. At necropsy it was found that myofibrillar ATPase activity of heart tissue from patients with clinical and pathologic diagnoses of failure from left ventricular volume and pressure overload was significantly lower than that of normal controls. The ATPase activity in patients with failure due to right ventricular volume and pressure overload was not significantly lower than that in normal controls. There was no difference in myofibrillar ATPase activity between normal left and normal right and between failing left and failing right ventricles. The difference demonstrated at necropsy between normal and failing hearts was not a function of age or of hypertrophy per se. Myofibrillar ATPase activity of hypertrophic nonfailing surgical pulmonary infundibular tissue was the same as that of normal postmortem ventricles. The ATPase activity of failing surgical papillary muscle in a small number of experiments was in the range of that found in failing postmortem ventricles.
High Risk of Cardiovascular Mortality in Individuals With Impaired Fasting Glucose Is Explained by Conversion to Diabetes
Authors: Josina M. Rijkelijkhuizen, Giel Nijpels, Robert J. Heine, Lex M. Bouter, Coen D.A. Stehouwer, Jacqueline M. Dekker
Journal: Diabetes Care (2007)

To optimize identification of future diabetic patients, the American Diabetes Association (ADA) introduced criteria for impaired fasting glucose (IFG) in 1997 (IFG 6.1 mmol/l [IFG6.1]) and lowered the threshold from 6.1 to 5.6 mmol/l (IFG5.6) in 2003. Our aim was to assess the consequences of lowering the IFG cutoff on the risk of cardiovascular disease (CVD) mortality and to evaluate whether this risk is explained by a conversion to type 2 diabetes within 6.4 years.In a population-based cohort, the Hoorn Study, plasma glucose was determined in 1989 and 1996 (n = 1,428). Subjects were classified in 1989 according to 1997 and 2003 ADA criteria. Subjects with IFG in 1989 were further classified according to diabetes status in 1996. Hazard ratios for CVD mortality (n = 81) in the period 1996-2005 were adjusted for age and sex.Subjects with IFG6.1, but not IFG5.6, had a significantly higher CVD mortality risk than normal fasting glucose (NFG) subjects. Subjects who converted from IFG to diabetes (IFG6.1: 42%; IFG5.6: 21%) had a more than twofold risk of CVD mortality (IFG6.1: 2.47 [1.17-5.19]; IFG5.6: 2.14 [1.12-4.10]) than subjects with NFG. IFG subjects who did not develop diabetes did not have significantly higher CVD mortality risks (IFG6.1: 1.50 [0.72-3.15]; IFG5.6: 1.15 [0.69-1.93]).The lower cutoff for IFG (ADA 2003 criteria) results in a category of IFG that no longer represents a high-risk state of CVD. Furthermore, only subjects who convert from IFG to diabetes have a high risk of CVD mortality.