tbuckley/cabot-search huggingface dataset:
Addition of Atrasentan to Renin-Angiotensin System Blockade Reduces Albuminuria in Diabetic Nephropathy
Authors: Donald E. Kohan, Yili Pritchett, Mark Molitch, Shihua Wen, Tushar Garimella, Paul Audhya, Dennis L. Andress
Journal: Journal of the American Society of Nephrology (2011)

Although endothelin-receptor antagonists reduce albuminuria in diabetic nephropathy, fluid retention limits their use. Here, we examined the effect of atrasentan, a selective endothelin A receptor (ET(A)R) antagonist, on albuminuria in a randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy already receiving stable doses of renin-angiotensin system (RAS) inhibitors. We randomly assigned 89 subjects with eGFR >20 ml/min per 1.73 m(2) and a urinary albumin-to-creatinine ratio (UACR) of 100 to 3000 mg/g to placebo or atrasentan (0.25, 0.75, or 1.75 mg daily) for 8 weeks. Compared with placebo, atrasentan significantly reduced UACR only in the 0.75- and 1.75-mg groups (P=0.001 and P=0.011, respectively). Compared with the 11% reduction in the geometric mean of the UACR from baseline to final observation in the placebo group during the study, the geometric mean of UACR decreased by 21, 42, and 35% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups (P=0.291, P=0.023, and P=0.073, respectively). In the placebo group, 17% of subjects achieved ≥40% reduction in UACR from baseline compared with 30, 50, and 38% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups, respectively (P=0.029 for 0.75 mg versus placebo). Peripheral edema occurred in 9% of subjects receiving placebo and in 14, 18, and 46% of those receiving 0.25, 0.5, and 1.75 mg atrasentan, respectively (P=0.007 for 1.75 mg versus placebo). In summary, atrasentan, at the doses tested, is generally safe and effective in reducing residual albuminuria and may ultimately improve renal outcomes in patients with type 2 diabetic nephropathy.
ATIP3, a Novel Prognostic Marker of Breast Cancer Patient Survival, Limits Cancer Cell Migration and Slows Metastatic Progression by Regulating Microtubule Dynamics
Authors: Angie Molina, Lauriane Velot, Lydia Ghouinem, Mohamed Abdelkarim, Benjamin Pierre Bouchet, Anny-Claude Luissint, Imène Bouhlel, Marina Morel, Elène Sapharikas, Anne Di Tommaso, Stéphane Honoré, Diane Braguer, Nadège Gruel, Anne Vincent-Salomon, Olivier Delattre, Brigitte Sigal-Zafrani, Fabrice André, Benoit Terris, Anna Akhmanova, Mélanie Di Benedetto, Clara Nahmias, Sylvie Rodrigues-Ferreira
Journal: Cancer Research (2013)

Metastasis, a fatal complication of breast cancer, does not fully benefit from available therapies. In this study, we investigated whether ATIP3, the major product of 8p22 MTUS1 gene, may be a novel biomarker and therapeutic target for metastatic breast tumors. We show that ATIP3 is a prognostic marker for overall survival among patients with breast cancer. Notably, among metastatic tumors, low ATIP3 levels associate with decreased survival of the patients. By using a well-defined experimental mouse model of cancer metastasis, we show that ATIP3 expression delays the time-course of metastatic progression and limits the number and size of metastases in vivo. In functional studies, ATIP3 silencing increases breast cancer cell migration, whereas ATIP3 expression significantly reduces cell motility and directionality. We report here that ATIP3 is a potent microtubule-stabilizing protein whose depletion increases microtubule dynamics. Our data support the notion that by decreasing microtubule dynamics, ATIP3 controls the ability of microtubule tips to reach the cell cortex during migration, a mechanism that may account for reduced cancer cell motility and metastasis. Of interest, we identify a functional ATIP3 domain that associates with microtubules and recapitulates the effects of ATIP3 on microtubule dynamics, cell proliferation, and migration. Our study is a major step toward the development of new personalized treatments against metastatic breast tumors that have lost ATIP3 expression.
Malabsorption of hemoglobin iron in pernicious anemia: correction with intrinsic factor—containing substances
Authors: Samuel Waxman, Peter Pratt, Victor Herbert
Journal: Journal of Clinical Investigation (1968)

Hemoglobin iron absorption in patients with treated prenicious anemia (PA) and concomitant iron deficiency was low compared to absorption in patients with iron deficiency alone. Crude and purified hog intrinsic factor (IF) concentrates doubled the absorption of hemoglobin iron in these patients as did normal (neutralized depepsinized) human gastric juice. Hemoglobin iron absorption was not significantly enhanced by PA gastric juice. Absorption of heme iron, like that of hemoglobin iron, was enhanced by normal neutralized depepsinized gastric juice. No enhancement of hemoglobin iron absorption by these substances was obtained in the normal or iron-deficient non-PA control subjects. Preincubation of the hog IF concentrate with antisera to IF significantly reduced the enhancement of hemoglobin iron absorption due to the concentrate. In vitro studies suggest that heme complexes with a substance present in IF-containing materials. Whether a gastric glycoprotein similar to IF serves as an intestinal transport factor for heme, similar to transport of vitamin B(12), or whether normal gastric juice acts by another mechanism cannot be determined at this time.
Mammary Gland Tissue Targeted Overexpression of Human Protease-Activated Receptor 1 Reveals a Novel Link to β-Catenin Stabilization
Authors: Yong-Jun Yin, Vered Katz, Zaidoun Salah, Myriam Maoz, Irit Cohen, Beatrice Uziely, Hagit Turm, Sorina Grisaru-Granovsky, Hiromu Suzuki, Rachel Bar-Shavit
Journal: Cancer Research (2006)

Abstract Protease-activated receptor 1 (PAR1) is emerging with distinct assignments in tumor biology. We show that tissue targeted overexpression of hPar1 in mice mammary glands results in precocious hyperplasia, characterized by a dense network of ductal side branching and accelerated proliferation. These glands exhibit increased levels of wnt-4 and wnt-7b and a striking β-catenin stabilization. Nuclear localization of β-catenin is observed in hPar1 transgenic mouse tissue sections but not in the wild-type, age-matched counterparts. PAR1 induces β-catenin nuclear localization also in established epithelial tumor cell lines of intact β-catenin system (transformed on the background of mismatch repair system; RKO cells). We propose hereby that PAR1-mediated β-catenin stabilization is taking place primarily via the increase of Wnt expression. Enforced expression of a specific Wnt antagonist family member, secreted frizzled receptor protein 5 (SFRP5), efficiently inhibited PAR1-induced β-catenin stabilization. Likewise, application of either SFRP2 or SFRP5 on epithelial tumor cells completely abrogated PAR1-induced β-catenin nuclear accumulation. This takes place most likely via inhibition of Wnt signaling at the level of cell surface (forming a neutralizing complex of “Receptors-SFRP-Wnt”). Furthermore, depletion of hPar1 by small interfering RNA (siRNA) vectors markedly inhibited PAR1-induced Wnt-4. The striking stabilization of β-catenin, inhibited by SFRPs on one hand and Wnt-4 silencing by hPar1 siRNA on the other hand, points to a novel role of hPar1 in Wnt-mediated β-catenin stabilization. This link between PAR1 and β-catenin may bear substantial implications both in developmental and tumor progression processes. (Cancer Res 2006; 66(10): 5224-32)
Phosphoinositide Phospholipase Cβ1 (<i>PI-PLC</i>β<i>1</i>) Gene in Myelodysplastic Syndromes and Cytogenetically Normal Acute Myeloid Leukemia: Not a Deletion, but Increased <i>PI-PLC</i>β<i>1</i> Expression Is an Independent Prognostic Factor
Authors: Frederik Damm, Kathrin Lange, Michael Heuser, Tina Oberacker, Michael Morgan, Katharina Wagner, Jürgen Krauter, Brigitte Schlegelberger, Arnold Ganser, Gudren Göhring
Journal: Journal of Clinical Oncology (2010)
Flow into ischemic myocardium and across coronary collateral vessels is modulated by a waterfall mechanism.
Authors: C Eng, E S Kirk
Journal: Circulation Research (1984)

If a coronary artery is ligated and the distal end cannulated, blood flows retrograde from the cannula when vented to the atmosphere. By varying the height of the outflow tubing, and thereby changing the outflow pressure, pressure-flow relationships can be constructed. We used this technique in eight dogs to assess the characteristics of blood flow into ischemic myocardium. Above a back pressure of 10 mm Hg, increasing back pressure resulted in a decrease of retrograde blood flow. However, below a back pressure of about 10 mm Hg (10.7 +/- 2.7 mm Hg), alterations in back pressure did not result in changes in retrograde blood flow (back pressure-independent region). The transition at 10 mm Hg is interpreted as the critical waterfall pressure in ischemic myocardium. In another group of eight dogs, the ischemic bed was completely embolized with 25-micron sized microspheres to prevent RBF from entering the tissue as back pressure was raised. Pressure-flow relationships performed in this group revealed a back pressure-independent region that extended to approximately 20 mm Hg (23.0 +/- 2.5 mm Hg). This behavior of the pressure-flow relationship is consistent with a waterfall phenomenon on the collateral vessels. To the extent that collateral vessels in the dog are mainly epicardial in location, the findings suggest that extravascular pressures of 20 mm Hg can occur in the more superficial layers of the heart. In addition, the waterfall on the collaterals indicates that this mechanism can operate on nonvenous vessels. Our results suggest separate waterfall phenomena operating on the collateral vessels (20 mm Hg) and on the vessels in the ischemic myocardium (10 mm Hg).
But the schizophrenia connection . . .
Authors: Jeffrey A. Gray
Journal: Behavioral and Brain Sciences (1999)

As well as data indicating relationships (emphasised in the target article) (1) between dopaminergic transmission in the nucleus accumbens and positive incentive motivation, and (2) between dopaminergic transmission and extraversion, other data (not accounted for by the hypotheses developed in the target article) indicate relationships (3) between accumbens dopaminergic transmission and cognitive, especially perceptual, processes that are disrupted in schizophrenia, and (4) between dopaminergic transmission and psychoticism. The tension between relationships 1 + 2 and 3 + 4 is discussed and a tentative resolution proposed.
MOTOR VEHICLE-RELATED DEATH RATES-UNITED STATES, 1999-2005
Authors: N Adekoya
Journal: MMWR Morbidity and Mortality Weekly Report (2009)

In 2005, the most recent year for which data are available, 45,520 deaths in the United States were related to motor vehicles. A Healthy People 2010 objective calls for reducing the rate of deaths related to motor vehicles to 9.2 per 100,000 population from a baseline of 15.6 in 1998. To assess progress toward the Healthy People objective and to examine characteristics of motor vehicle--related death rates, CDC analyzed data from the National Vital Statistics System (NVSS) for the period 1999--2005. This report summarizes the results of that analysis, which determined that, during 1999--2005, although annual age-adjusted motor vehicle--related death rates overall were nearly unchanged (range: 15.2--15.7 per 100,000 population), substantial differences were observed by state, U.S. Census region, sex, race, and age group. Among states, the average annual death rate ranged from 7.9 per 100,000 population in Massachusetts to 31.9 in Mississippi. Among regions, the rate ranged from 9.8 per 100,000 population in the Northeast to 19.5 in the South. The rate for men (21.7 per 100,000 population) was more than double the rate for women (9.4); the rate for American Indians/Alaska Natives (27.2) was nearly twice the rate for whites (15.7) and blacks (15.2), and the rate for persons aged 15--24 years (26.8) was 74% higher than the average annual rate overall (15.4). Additional analysis and research to determine the causes of geographic and demographic variations in motor vehicle--related deaths might result in more effective targeted interventions among the states, regions, and populations at greatest risk. Language: en
Fatal CNS Trichinosis
Authors: Ted Gay
Journal: JAMA (1982)

CENTRAL nervous system involvement by trichinosis has been recognized since the early part of this century.<sup>1</sup>The reported incidence of trichinosis in the United States now averages less than 150 cases a year.<sup>2</sup>Because only a small percentage of infected patients have CNS involvement, many physicians might fail to recognize this entity. We report the case of a patient who died of CNS trichinosis. <h3>Report of a Case</h3> A 50-year-old woman from southwestern Louisiana was in excellent health until late April 1980, when intermittent diarrhea and nausea developed. On May 13, she noted headache, photophobia, myalgias, and periorbital edema. She was admitted to a local hospital with a temperature of 39.5 °C and a WBC count of 12,800/cu mm, with 10% eosinophils. Dexamethasone therapy for a presumed allergic reaction resulted in improvement. When the dexamethasone administration was discontinued after ten days, fever and myalgias returned. Seizures and a
Lymphocyte studies in rheumatoid arthritis. II. Antibody-mediated and mitogen-induced lymphocyte cytotoxicity in synovial fluid and peripheral blood.
Authors: V.M Corrigall, G.S Panayi
Journal: Annals of the Rheumatic Diseases (1978)

A comparison was made of the activity of synovial fluid (SF) lymphocytes with peripheral blood lymphocytes in antibody-mediated and mitogen-induced lymphocyte cytotoxicity in patients with a variety of inflammatory joint diseases. SF lymphocytes consistently showed little or no antibody-mediated cytotoxicity (AMC) although mitogen-induced cytotoxic activity was comparable with that of the peripheral blood lymphocytes. Blocking substances on the cell surface were not responsible for the lack of AMC by SF lymphocytes as preincubation at 37 degrees C and enzyme treatment (trypsin, neuraminidase) of the cells did not restore activity. The lack of AMC by SF cells from a variety of inflammatory joint fluids demonstrates that this may be a consequence of inflammation in the joint and excludes the possibility that this is a specific property of fluids from certain conditions such as rheumatoid arthritis. Lymphocytes thought to be involved in AMC have a characteristic surface morphology (Fc receptor positive, E rosette negative, surface immunoglobulin negative). Such lymphocytes are present in synovial fluid in comparable proportions to those in blood. Hence the absence of AMC indicates that functional assays must be used in determining the presence or absence of cells with special functions.
The Activation-induced Deaminase Functions in a Postcleavage Step of the Somatic Hypermutation Process
Authors: F. Nina Papavasiliou, David G. Schatz
Journal: The Journal of Experimental Medicine (2002)

Activation of B cells by antigen fuels two distinct molecular modifications of immunoglobulin (Ig) genes. Class-switch recombination (CSR) replaces the Igμ heavy chain constant region with a downstream constant region gene, thereby altering the effector function of the resulting antibodies. Somatic hypermutation (SHM) introduces point mutations into the variable regions of Ig genes, thereby changing the affinity of antibody for antigen. Mechanistic overlap between the two reactions has been suggested by the finding that both require the activation-induced cytidine deaminase (AID). It has been proposed that AID initiates both CSR and SHM by activating a common nuclease. Here we provide evidence that cells lacking AID, or expressing a dominant negative form of the protein, are still able to incur DNA lesions in SHM target sequences. The results indicate that an intact cytidine deaminase motif is required for AID function, and that AID acts downstream of the initial DNA lesions in SHM.
Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010
Authors: D E Furst, E C Keystone, J Braun, F C Breedveld, G R Burmester, F De Benedetti, T Dörner, P Emery, R Fleischmann, A Gibofsky, J R Kalden, A Kavanaugh, B Kirkham, P Mease, J Sieper, N G Singer, J S Smolen, P L C M Van Riel, M H Weisman, K Winthrop
Journal: Annals of the Rheumatic Diseases (2011)

As in previous years, the consensus group to consider the use of biological agents in the treatment of rheumatic diseases met during the 13th Annual Workshop on Advances in Targeted Therapies in April, 2011. The group consisted of rheumatologists from a number of universities among the continents of Europe, North America, South America, Australia and Asia.

Pharmaceutical industry support was obtained from a number of companies for the annual workshop itself, but these companies had no part in the decisions about the specific programme or about the academic participants at this conference. Representatives of the supporting sponsors participated in the initial working groups to supply factual information. The sponsors did not participate in the drafting of the consensus statement.

This consensus was prepared from the perspective of the treating physician.

In view of the new data for abatacept, B cell-specific agents, interleukin 1 (IL-1) antagonists, tocilizumab (TCZ) and tumour necrosis factor α blocking agents (TNF inhibitors), an update of the previous consensus statement is appropriate. To allow ease of updating, the 2010 (data from March 2009 to January 2010) updates are incorporated into the body of the article, while 2011 updates (February 2010–January 2011) are separated and highlighted. The consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 1.1 We have modified the Shekelle annotation by designating all abstracts as ‘category D evidence’, whether they describe well-controlled trials or not, as details of the study were often not available in the abstracts. Further, the number of possible references has become so large that reviews are sometimes included; if they contain category A references, they will be referred to as category A evidence.

The rheumatologists and bioscientists who attended …
Entrainment of pulsatile insulin secretion by oscillatory glucose infusion.
Authors: J Sturis, E Van Cauter, J D Blackman, K S Polonsky
Journal: Journal of Clinical Investigation (1991)

Ultradian "oscillations" or "pulses" of insulin secretion with periods around 120 min occur in man. It is not known whether glucose plays an active role in generating these oscillations, or if an intrapancreatic pacemaker generates oscillations in insulin secretion that entrain glucose passively. To determine if the frequency of pulses of insulin secretion could be modified by oscillatory glucose infusion, seven normal men were studied on three separate occasions. The first study involved a constant glucose infusion administered at a rate of 6 mg/kg per min for 28 h. During the two subsequent studies, the subjects received an oscillatory glucose infusion for 28 h with the same mean rate, an amplitude of 33% above and below the mean infusion rate, a sinusoidal waveshape and a period either 20% longer ("slow oscillatory infusion") or 20% shorter ("rapid oscillatory infusion") than the periodicity observed during constant glucose infusion. Samples for insulin, C-peptide, and glucose were drawn at 10-min intervals during the last 24 h of each study. Insulin secretion rates were calculated by deconvolution of C-peptide levels. During constant glucose infusion, the respective periods of oscillation of glucose and insulin secretion averaged 126 +/- 5 min and 118 +/- 3 min (mean +/- SEM). During the slow oscillatory infusion, the period of infusion was 155 +/- 7 min and the periods of insulin secretion and glucose were, respectively, 155 +/- 7 min and 150 +/- 5 min. During rapid oscillatory infusion, the period of infusion was 103 +/- 5 min and the period of both insulin secretion and glucose was 105 +/- 5 min. Thus the periodicity of both insulin secretion and plasma glucose changed in parallel with the exogenous periodicity, indicating complete entrainment of the secretory oscillations. These results suggest that the ultradian oscillations of insulin secretion are caused by the feedback loop linking glucose and insulin.
Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations
Authors: A Andersson, P Edén, D Lindgren, J Nilsson, C Lassen, J Heldrup, M Fontes, Å Borg, F Mitelman, B Johansson, M Höglund, T Fioretos
Journal: Leukemia (2005)
Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial
Authors: Jeffrey R Infante, Leslie A Fecher, Gerald S Falchook, Sujatha Nallapareddy, Michael S Gordon, Carlos Becerra, Douglas J DeMarini, Donna S Cox, Yanmei Xu, Shannon R Morris, Vijay GR Peddareddigari, Ngocdiep T Le, Lowell Hart, Johanna C Bendell, Gail Eckhardt, Razelle Kurzrock, Keith Flaherty, Howard A Burris, Wells A Messersmith
Journal: The Lancet Oncology (2012)
Effect of simulated commercial flight on oxygenation in patients with interstitial lung disease and chronic obstructive pulmonary disease
Authors: L M Seccombe, P T Kelly, C K Wong, P G Rogers, S Lim, M J Peters
Journal: Thorax (2004)

<b>Background:</b> Commercial aircraft cabins provide a hostile environment for patients with underlying respiratory disease. Although there are algorithms and guidelines for predicting in-flight hypoxaemia, these relate to chronic obstructive pulmonary disease (COPD) and data for interstitial lung disease (ILD) are lacking. The purpose of this study was to evaluate the effect of simulated cabin altitude on subjects with ILD at rest and during a limited walking task. <b>Methods:</b> Fifteen subjects with ILD and 10 subjects with COPD were recruited. All subjects had resting arterial oxygen pressure (Pao<sub>2</sub>) of &gt;9.3 kPa. Subjects breathed a hypoxic gas mixture containing 15% oxygen with balance nitrogen for 20 minutes at rest followed by a 50 metre walking task. Pulse oximetry (Spo<sub>2</sub>) was monitored continuously with testing terminated if levels fell below 80%. Arterial blood gas tensions were taken on room air at rest and after the resting and exercise phases of breathing the gas mixture. <b>Results:</b> In both groups there was a statistically significant decrease in arterial oxygen saturation (Sao<sub>2</sub>) and Pao<sub>2</sub> from room air to 15% oxygen at rest and from 15% oxygen at rest to the completion of the walking task. The ILD group differed significantly from the COPD group in resting 15% oxygen Sao<sub>2</sub>, Pao<sub>2</sub>, and room air pH. Means for both groups fell below recommended levels at both resting and when walking on 15% oxygen. <b>Conclusion:</b> Even in the presence of acceptable arterial blood gas tensions at sea level, subjects with both ILD and COPD fall below recommended levels of oxygenation when cabin altitude is simulated. This is exacerbated by minimal exercise. Resting sea level arterial blood gas tensions are similarly poor in both COPD and ILD for predicting the response to simulated cabin altitude.