tbuckley/cabot-search huggingface dataset:
Effect of Factor XIII on Endothelial Barrier Function
Authors: Thomas Noll, Gernold Wozniak, Karin McCarson, Amir Hajimohammad, Hubert J. Metzner, Javier Inserte, Wolfgang Kummer, Friedrich Wilhelm Hehrlein, Hans Michael Piper
Journal: The Journal of Experimental Medicine (1999)

The effect of factor XIII on endothelial barrier function was studied in a model of cultured monolayers of porcine aortic endothelial cells and saline-perfused rat hearts. The thrombin-activated plasma factor XIII (1 U/ml) reduced albumin permeability of endothelial monolayers within 20 min by 30 ± 7% (basal value of 5.9 ± 0.4 × 10−6 cm/s), whereas the nonactivated plasma factor XIII had no effect. Reduction of permeability to the same extent, i.e., by 34 ± 9% could be obtained with the thrombin-activated A subunit of factor XIII (1 U/ml), whereas the iodoacetamide-inactivated A subunit as well as the B subunit had no effect on permeability. Endothelial monolayers exposed to the activated factor XIII A exhibited immunoreactive deposition of itself at interfaces of adjacent cells; however, these were not found on exposure to nonactivated factor XIII A or factor XIII B. Hyperpermeability induced by metabolic inhibition (1 mM potassium cyanide plus 1 mM 2-deoxy-d-glucose) was prevented in the presence of the activated factor XIII A. Likewise, the increase in myocardial water content in ischemic-reperfused rat hearts was prevented in its presence. This study shows that activated factor XIII reduces endothelial permeability. It can prevent the loss of endothelial barrier function under conditions of energy depletion. Its effect seems related to a modification of the paracellular passageways in endothelial monolayers.
Gene Expression Signature Predicting Pathologic Complete Response With Gemcitabine, Epirubicin, and Docetaxel in Primary Breast Cancer
Authors: Olaf Thuerigen, Andreas Schneeweiss, Grischa Toedt, Patrick Warnat, Meinhard Hahn, Heidi Kramer, Benedikt Brors, Christian Rudlowski, Axel Benner, Florian Schuetz, Bjoern Tews, Roland Eils, Hans-Peter Sinn, Christof Sohn, Peter Lichter
Journal: Journal of Clinical Oncology (2006)

Purpose Primary systemic therapy (PST) with gemcitabine (G), epirubicin (E), and docetaxel (Doc) has resulted in a pathologic complete response (pCR) in 26% of primary breast cancer patients. This study was aimed at the identification of a gene expression signature in diagnostic core biopsy tissue samples that predicts pCR. Patients and Methods Core biopsy samples from patients with operable primary breast cancer, T2-4N0-2M0, enrolled onto two phase I and II trials evaluating GEDoc (n = 48) and GE sequentially followed by Doc (GEsDoc; n = 52) as PST were snap frozen and subjected to RNA expression profiling. A signature predicting pCR was discovered in the training set (GEsDoc) applying a support vector machine algorithm, and performance of this classifier was validated on the independent test set (GEDoc) by receiver operator characteristics analysis. Results We identified a signature consisting of 512 genes, which was enriched in genes involved in transforming growth factor beta and RAS-mediated signaling pathways, that predicts pCR with a sensitivity of 78%, a specificity of 90%, and an overall accuracy of 88% (95% CI, 75% to 95%). Apart from our signature, only HER2 overexpression was an independent predictor of pCR in multivariate analysis. Conclusion In conclusion, our gene expression signature allows prediction of pCR to PST containing G, E, and Doc with unprecedented high overall accuracy and robustness.
Donor T cell–derived TNF is required for graft-versus-host disease and graft-versus-tumor activity after bone marrow transplantation
Authors: Cornelius Schmaltz, Onder Alpdogan, Stephanie J. Muriglan, Barry J. Kappel, Jimmy A. Rotolo, Eric T. Ricchetti, Andrew S. Greenberg, Lucy M. Willis, George F. Murphy, James M. Crawford, Marcel R. M. van den Brink
Journal: Blood (2003)
Regulation of immune responses by I-J gene products. VI. Recognition of I-E molecules by I-J-bearing suppressor factors.
Authors: C Waltenbaugh, L Sun, H Y Lei
Journal: The Journal of Experimental Medicine (1986)

Poly(Glu50Tyr50) (GT) is not immunogenic in most inbred mouse strains. GT injection produces an I-J--bearing, GT-specific T-cell--derived suppressor factor (GT-TsF1) in H-2b,d,k haplotype mice. GT-TsF1 generates second-order suppressor T cells (Ts2) in H-2a,d,k haplotype mice. Here, we show that in order for GT-TsF1 to act, the recipient strain must express I-E molecules. This suggests that T cells are not the primary target of GT-TsF1. GT-TsF1 can be presented by Ia+ A20-2J B lymphoma cells. GT-TsF1 presentation is blocked by anti-I-E, but not by anti--I-A, mAb, whereas GAT presentation is blocked by anti-I-A, but not by anti--I-E, mAbs. These data suggest that I-J recognizes (or is recognized by) I-E. The existence and role of I-J molecules in immune regulation are discussed in light of these data.
Acute poststreptococcal glomerulonephritis in Maracaibo. II: Studies on the incidence, nature, and significance of circulating anti-immunoglobulins.
Authors: R.M McIntosh, D Rabideau, J.E Allen, R Garcia, L Rubio, R.I Carr, B Rodriguez-Iturbe
Journal: Annals of the Rheumatic Diseases (1979)

Antiglobulins were measured in the sera of 82 patients with acute poststreptococcal glomerulonephritis and correlated with C1q binding activity, serum levels of immunoglobulins and C3, site of infection, antibody titres to streptococcal enzymes, and the duration of the nephritis and interval from infection. Raised serum antiglobulins were found in 89.2% of the patients. In addition, raised titres were detected at any time during the course of the disease and very early after streptococcal infection. The finding of antiglobulins soon after the infection suggests the possibility that they appear as a primary event in the disease.
Terminology and definitions on groin pain in athletes: building agreement using a short Delphi method
Authors: Adam Weir, Per Hölmich, Anthony G Schache, Eamonn Delahunt, Robert-Jan de Vos
Journal: British Journal of Sports Medicine (2015)

Groin pain in athletes occurs frequently and can be difficult to treat, which may partly be due to the lack of agreement on diagnostic terminology.To perform a short Delphi survey on terminology agreement for groin pain in athletes by a group of experts.A selected number of experts were invited to participate in a Delphi questionnaire. The study coordinator sent a questionnaire, which consisted of demographic questions and two 'real-life' case reports of athletes with groin pain. The experts were asked to complete the questionnaire and to provide the most likely diagnosis for each case. Questionnaire responses were analysed by an independent researcher. The Cohen's κ statistic was used to evaluate the level of agreement between the diagnostic terms provided by the experts.Twenty-three experts participated (96% of those invited). For case 1, experts provided 9 different terms to describe the most likely diagnosis; for case 2, 11 different terms were provided to describe the most likely diagnosis. With respect to the terms provided for the most likely diagnosis, the Cohen's κ was 0.06 and 0.002 for case 1 and 2, respectively. This heterogeneous taxonomy reflects only a slight agreement between the various diagnostic terms provided by the selected experts.This short Delphi survey of two 'typical, straightforward' cases demonstrated major inconsistencies in the diagnostic terminology used by experts for groin pain in athletes. These results underscore the need for consensus on definitions and terminology on groin pain in athletes.
The TIM and TAM Families of Phosphatidylserine Receptors Mediate Dengue Virus Entry
Authors: Laurent Meertens, Xavier Carnec, Manuel Perera Lecoin, Rasika Ramdasi, Florence Guivel-Benhassine, Erin Lew, Greg Lemke, Olivier Schwartz, Ali Amara
Journal: Cell Host & Microbe (2012)

Dengue viruses (DVs) are responsible for the most medically relevant arboviral diseases. However, the molecular interactions mediating DV entry are poorly understood. We determined that TIM and TAM proteins, two receptor families that mediate the phosphatidylserine (PtdSer)-dependent phagocytic removal of apoptotic cells, serve as DV entry factors. Cells poorly susceptible to DV are robustly infected after ectopic expression of TIM or TAM receptors. Conversely, DV infection of susceptible cells is inhibited by anti-TIM or anti-TAM antibodies or knockdown of TIM and TAM expression. TIM receptors facilitate DV entry by directly interacting with virion-associated PtdSer. TAM-mediated infection relies on indirect DV recognition, in which the TAM ligand Gas6 acts as a bridging molecule by binding to PtdSer within the virion. This dual mode of virus recognition by TIM and TAM receptors reveals how DVs usurp the apoptotic cell clearance pathway for infectious entry.
Hypertensive Cardiovascular Disease Induced by Desoxycorticosterone in Hypophysectomized Rats Bearing Pituitary Autotransplants
Authors: C. E. HALL, O. HALL
Journal: Circulation Research (1959)

The responsiveness of hypophysectomized female rats bearing pituitary autotransplants to chronic, low dosage treatment with desoxycorticosterone acetate was compared with that of intact females. Intact animals reacted rapidly, developed malignant hypertension, and died within 10 weeks. By contrast hypophysectomized autograft-bearing rats developed hypertension more slowly, and the majority of them were alive at 16 weeks when the experiment was concluded. At autopsy, as compared with intact animals which had died earlier from the sequelae of malignant hypertension, hypophysectomized animals were found to have far more severe periarteritis nodosa, but a lesser development of nephrosclerosis and an extremely low incidence of cardiac damage. Hypertensive cardiovascular disease occurred in these animals despite extreme atrophy of the thyroid and adrenal glands, of the ovaries and uteri, and cessation of somatic growth. Therefore, except for LTH which such autografts are known to elaborate, or trace amounts of the other principals, none of the known regulatory hormones of the anterior pituitary singly or in combination is essential to this effect of DCA.
Determinants and Prognostic Value of Cardiovascular Autonomic Function in Coronary Artery Disease Patients With and Without Type 2 Diabetes
Authors: Jaana J. Karjalainen, Antti M. Kiviniemi, Arto J. Hautala, Olli-Pekka Piira, E. Samuli Lepojärvi, Mirja A. Peltola, Olavi H. Ukkola, Pirjo S.M. Hedberg, Heikki V. Huikuri, Mikko Paavo Tulppo
Journal: Diabetes Care (2013)

OBJECTIVE Cardiovascular autonomic dysfunction is a common finding among patients with coronary artery disease (CAD) and type 2 diabetes (T2D). The reasons and prognostic value of autonomic dysfunction in CAD patients with T2D are not well known. RESEARCH DESIGN AND METHODS We examined the association between heart rate recovery (HRR), 24-h heart rate (HR) variability (SD of normal R-R interval [SDNN]), and HR turbulence (HRT), and echocardiographic parameters, metabolic, inflammatory, and coronary risk variables, exercise capacity, and the presence of T2D among 1,060 patients with CAD (mean age 67 ± 8 years; 69% males; 50% patients with T2D). Second, we investigated how autonomic function predicts a composite end point of cardiovascular death, acute coronary event, stroke, and hospitalization for heart failure during a 2-year follow-up. RESULTS In multiple linear regression model, exercise capacity was a strong predictor of HRR (R = 0.34, P < 0.001), SDNN (R = 0.33, P < 0.001), and HRT (R = 0.13, P = 0.001). In univariate analyses, a composite end point was predicted by reduced HRR (hazard ratio 1.7 [95% CI 1.1-2.6]; P = 0.020), reduced SDNN (2.0 [95% CI 1.2-3.1]; P = 0.005), and blunted HRT (2.1 [1.3-3.4]; P = 0.003) only in patients with T2D. After multivariate adjustment, none of the autonomic markers predicted the end point, but high-sensitivity C-reactive protein (hs-CRP) remained an independent predictor. CONCLUSIONS Cardiovascular autonomic function in CAD patients is associated with several variables, including exercise capacity. Autonomic dysfunction predicts short-term cardiovascular events among CAD patients with T2D, but it is not as strong an independent predictor as hs-CRP.
Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines
Authors: Belén Blanco, José A. Pérez-Simón, Luis I. Sánchez-Abarca, Xonia Carvajal-Vergara, Juan Mateos, Belén Vidriales, Natalia López-Holgado, Patricia Maiso, Mercedes Alberca, Eva Villarón, David Schenkein, Atanasio Pandiella, Jesús San Miguel
Journal: Blood (2005)
Thrombolytic therapy for submassive pulmonary embolus? PRO viewpoint
Authors: Luke S Howard
Journal: Thorax (2013)

If we had robust evidence one way or the other to inform us on the use of thrombolytics in submassive pulmonary embolus (PE), we would not need this debate. But, we do not and, so, we do. The stakes are considered high both in favour and against thromobolysing submassive PE, so we cannot brush the debate under the carpet while we await the evidence. It is accepted that high-risk/massive PE, defined as haemodynamic instability, merits aggressive treatment due to unacceptable mortality, which outweighs the risk of haemorrhage. At the other end of the spectrum, patients with low-risk PE do not, such that they may even be treated as outpatients.

This leaves a grey area in between. When faced with a patient with a large thrombus load with a right ventricle (RV) that is dilated and pressure-loaded, but who is normotensive, as the attending clinician, we know they are at increased risk of death and long-term complications, such as chronic thromboembolic pulmonary hypertension (CTEPH).1 ,2 We may fall back on the Hippocratic Oath to ‘ first, do no harm ’, but the fuller translation reads ‘I will use treatments for the benefit of the ill in accordance with my ability and my judgment, but from what is to their harm and injustice I will keep them ’. Thus, rather than hide behind a lack of evidence, we must review what we have and come to a balanced decision, and justify it.

In proposing the argument that submassive PE should be treated with thrombolysis, we must first accept that direct mortality due to the PE itself, not confounding conditions, remains unacceptably high with anticoagulation alone. A more aggressive strategy is required. As long as the benefits of thrombolysis outweigh the risks, then thrombolysis offers the best currently available approach. When …
Randomized Controlled Study of an Oral Jaw-Positioning Appliance for the Treatment of Obstructive Sleep Apnea in Children with Malocclusion
Authors: MARIA P. VILLA, EDOARDO BERNKOPF, JACOPO PAGANI, VANNA BROIA, MARILISA MONTESANO, ROBERTO RONCHETTI
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

To evaluate the clinical usefulness and tolerability of an oral jaw-positioning appliance in the treatment of obstructive sleep apnea syndrome in children, we studied 32 patients (mean age, 7.1 ± 2.6 yr; 20 males) with symptoms of obstructive sleep apnea, malocclusion, and a baseline apnea index > 1 event/h. A group of 19 subjects was randomly assigned to a 6-mo trial of an oral appliance; the remainder acted as control subjects. At baseline and after the trial all patients underwent physical examination, a standard polysomnography, and orthodontic assessment. A modified version of the Brouillette questionnaire related to obstructive sleep apnea symptoms was administered to parents before and after the trial and a clinical score was calculated. Of the 32 subjects enrolled, 4 treated subjects and 5 control subjects were lost to follow-up. Polysomnography after the trial showed that treated subjects all had significantly lower apnea index (p < 0.001) and hypopnea index values (p < 0.001) than before the trial, whereas in untreated control subjects these values remained almost unchanged. Clinical assessment before and after treatment showed that in 7 of the 14 subjects (50%) the oral appliance had reduced (a fall of at least 2 points in the respiratory score) and in 7 had resolved the main respiratory symptoms, whereas untreated patients continued to have symptoms. In conclusion, treatment of obstructive sleep apnea syndrome with an oral appliance in children with malocclusion is effective and well tolerated.
<i>STAT3</i> Plays a Critical Role in <i>KRAS</i>-Induced Pancreatic Tumorigenesis
Authors: Ryan B. Corcoran, Gianmarco Contino, Vikram Deshpande, Alexandros Tzatsos, Claudius Conrad, Cyril H. Benes, David E. Levy, Jeffrey Settleman, Jeffrey A. Engelman, Nabeel Bardeesy
Journal: Cancer Research (2011)

The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development, whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis. Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a more than 30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine-phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component. Correspondingly, upregulation of the IL6/LIF-gp130 pathway accounted for the strong STAT3 activation in PDAC subsets. To define functions of STAT3 in vivo, we developed mouse models that test the impact of conditional inactivation of STAT3 in KRAS-driven PDAC. We showed that STAT3 is required for the development of the earliest premalignant pancreatic lesions, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Moreover, acute STAT3 inactivation blocked PDAC initiation in a second in vivo model. Our results show that STAT3 has critical roles throughout the course of PDAC pathogenesis, supporting the development of therapeutic approaches targeting this pathway. Moreover, our work suggests that gp130 and phospho-STAT3 expression may be effective biomarkers for predicting response to JAK2 inhibitors.
Longitudinal Study of the National Kidney Foundation’s (NKF) Kidney Early Evaluation Program (KEEP)
Authors: Suzanne E. Ohmit, John M. Flack, Rosalind M. Peters, Wendy W. Brown, Richard Grimm
Journal: Journal of the American Society of Nephrology (2003)

In 2000, the National Kidney Foundation implemented the Kidney Early Evaluation Program (KEEP 2.0) to increase awareness of kidney disease among those at highest risk, and improve outcomes through early detection and referral for care. The KEEP 2.0 screening program identified significant numbers of persons with reduced kidney function, with previously undetected kidney disease risk factors, and with inadequate risk factor control. These data support the evolution to KEEP 3.0, which will continue to identify individuals at high risk for kidney disease, and will address the educational needs of health care providers and consumers, given that preventing and managing kidney disease requires their joint effort. Consumers need to embrace lifestyle behaviors that reduce risk, and adhere to medical recommendations in managing their existing conditions. At the same time, providers need to ensure that the latest evidence-based guidelines in diagnosis and treatment are being implemented in their clinical practice. KEEP 3.0 participants will be randomly assigned to one of several educational programs that vary on whether they provide individually tailored or nontailored information, with long-term follow-up for evaluation of clinical outcomes. Tailored programs may be more successful in supporting behavioral change as these consider the individuals' "readiness to change." In addition, participant-identified providers will be randomly assigned to one of several educational protocols designed to provide evidence-based recommendations for clinical and pharmaceutical management of kidney disease and risk factors; these programs vary on whether they require active or passive participation of providers. Analytic evaluations will examine changes from baseline in participant kidney disease and risk factor status during follow-up, and estimate the influence of the various educational protocols on both process of care measures and clinical outcomes. E-mail: jflack@intmed.wayne.edu
Cardiovascular Risk Factors in Childhood and Carotid Artery Intima-Media Thickness in Adulthood
Authors: Olli T. Raitakari, Markus Juonala, Mika Kähönen, Leena Taittonen, Tomi Laitinen, Noora Mäki-Torkko, Mikko J. Järvisalo, Matti Uhari, Eero Jokinen, Tapani Rönnemaa, Hans K. Åkerblom, Jorma S. A. Viikari
Journal: JAMA (2003)

<h3>Context</h3> Exposure to cardiovascular risk factors during childhood and adolescence may be associated with the development of atherosclerosis later in life. <h3>Objective</h3> To study the relationship between cardiovascular risk factors measured in childhood and adolescence and common carotid artery intima-media thickness (IMT), a marker of preclinical atherosclerosis, measured in adulthood. <h3>Design, Setting, and Participants</h3> Population-based, prospective cohort study conducted at 5 centers in Finland among 2229 white adults aged 24 to 39 years who were examined in childhood and adolescence at ages 3 to 18 years in 1980 and reexamined 21 years later, between September 2001 and January 2002. <h3>Main Outcome Measures</h3> Association between cardiovascular risk variables (levels of low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides; LDL-C/HDL-C ratio; systolic and diastolic blood pressure; body mass index; smoking) measured in childhood and adulthood and common carotid artery IMT measured in adulthood. <h3>Results</h3> In multivariable models adjusted for age and sex, IMT in adulthood was significantly associated with childhood LDL-C levels (<i>P</i>= .001), systolic blood pressure (<i>P</i>&lt;.001), body mass index (<i>P</i>= .007), and smoking (<i>P</i>= .02), and with adult systolic blood pressure (<i>P</i>&lt;.001), body mass index (<i>P</i>&lt;.001), and smoking (<i>P</i>= .004). The number of risk factors measured in 12- to 18-year-old adolescents, including high levels (ie, extreme age- and sex-specific 80th percentile) of LDL-C, systolic blood pressure, body mass index, and cigarette smoking, were directly related to carotid IMT measured in young adults at ages 33 through 39 years (<i>P</i>&lt;.001 for both men and women), and remained significant after adjustment for contemporaneous risk variables. The number of risk factors measured at ages 3 to 9 years demonstrated a weak direct relationship with carotid IMT at ages 24 to 30 years in men (<i>P</i>= .02) but not in women (<i>P</i>= .63). <h3>Conclusions</h3> Risk factor profile assessed in 12- to 18-year-old adolescents predicts adult common carotid artery IMT independently of contemporaneous risk factors. These findings suggest that exposure to cardiovascular risk factors early in life may induce changes in arteries that contribute to the development of atherosclerosis.
Removal of Microsatellite Interruptions by DNA Replication Slippage: Phylogenetic Evidence from Drosophila
Authors: Bettina Harr, Barbara Zangerl, Christian Schlötterer
Journal: Molecular Biology and Evolution (2000)

Microsatellites are tandem repetitions of short (1–6 bp) motifs. It is widely assumed that microsatellites degenerate through the accumulation of base substitutions in the repeat array. Using a phylogenetic framework, we studied the evolutionary dynamics of interruptions in three Drosophila microsatellite loci. For all three loci, we show that the interruptions in a microsatellite can be lost, resulting in a longer uninterrupted microsatellite stretch. These results indicate that mutations in the microsatellite array do not necessarily lead to decay but may represent only a transition state during the evolution of a microsatellite. Most likely, this purification of interrupted microsatellites is caused by DNA replication slippage.