tbuckley/cabot-search huggingface dataset:
Cardiac findings in the precompetition medical assessment of football players participating in the 2009 African Under-17 Championships in Algeria
Authors: C Schmied, Y Zerguini, A Junge, P Tscholl, A Pelliccia, B M Mayosi, J Dvorak
Journal: British Journal of Sports Medicine (2009)

Objectives: To screen all players registered for the 8th CAF African Under-17 Championship for risk factors of sudden cardiac death. Design: Standardised cardiac evaluation prior to the start of the competition. Study population: 155 male football players from all eight qualified teams; mean age 16.4 (SD 0.68) years (range 14 to 17). Methods: The cardiac evaluation consisted of a medical history, clinical examination, 12-lead resting electrocardiogram (ECG) and echocardiography, and was performed by three experienced cardiologists using established guidelines. Results: Nine (5.8%) players reported cardiac symptoms, and the clinical examination was abnormal in only two players with elevated blood pressure. A total of 40 players (25.8%) showed abnormal ECG patterns. None of the players with a positive ECG showed correlating echocardiographic findings. The echocardiogram of one player appeared highly suspicious for early-stage hypertrophic cardiomyopathy, and in another player the myocardium was suspicious for non-compaction cardiomyopathy, but both had normal ECGs. Thirteen (8.4%) players showed echocardiographic findings that needed further follow-up. The percentage of players with pathological ECG patterns and some abnormal echocardiographic measurements varied substantially between different ethnic groups. Conclusion: Cardiological screening for risk factors of sudden cardiac death of football players prior to an international competition proved feasible, and conduction by independent experts allowed high-quality standards and a consistent protocol for the examinations. Differences observed between ethnic groups indicate that guidelines for the analysis of ECGs and echocardiography might be adjusted to the target population.
Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma
Authors: María Victoria Mateos, Maria Teresa Cibeira, Paul G. Richardson, Felipe Prosper, Albert Oriol, Javier de la Rubia, Juan José Lahuerta, Ramón García-Sanz, Sonia Extremera, Sergio Szyldergemajn, Claudia Corrado, Harald Singer, Constantine S. Mitsiades, Kenneth C. Anderson, Joan Bladé, Jesús San Miguel
Journal: Clinical Cancer Research (2010)

This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma.This was a prospective, multicenter, open-label, single-arm, phase II trial with plitidepsin at 5 mg/m(2) as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral dexamethasone every two weeks.Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18 evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia (29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue (16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase (27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects. A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients (P = 0.009).Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens were well tolerated in this heavily pretreated population.
Transforming growth factor-beta 1 potentiated alpha 1-adrenergic and stretch-induced c-fos mRNA expression in rat myocardial cells.
Authors: N Miki, Y Hamamori, K Hirata, M Suematsu, S Kawashima, H Akita, M Yokoyama
Journal: Circulation Research (1994)

Since transforming growth factor-beta 1 (TGF-beta 1) has been recently shown to be expressed in the heart by mechanical stretch and ischemic injury, we examined the modulation of c-fos mRNA expression and amino acid uptake by TGF-beta 1 in rat myocardial cells. Pretreatment with TGF-beta 1 potentiated norepinephrine (NE)-induced and stretch-induced (+10% and +20% elongation, for 30 minutes) c-fos mRNA expression by 2.2-fold, whereas TGF-beta 1 alone did not induce c-fos mRNA expression in Northern blot analysis. NE-induced [14C]phenylalanine uptake was also potentiated with TGF-beta 1 pretreatment. The effect of TGF-beta 1 on the NE action was not blocked by propranolol but by prazosin. The protein kinase C activators (12-O-tetradecanoylphorbol 13-acetate [TPA], phorbol 12,13-dibutyrate, and 1-oleyl-2-acetyl-rac-glycerol) induced c-fos mRNA expression, which was also potentiated by TGF-beta 1. Cycloheximide (protein synthesis inhibitor) could not suppress the TGF-beta 1 actions. In nonmuscle cells, TGF-beta 1 modified neither adrenergic nor TPA-induced c-fos mRNA expression. These data suggested that TGF-beta 1 potentiated the c-fos mRNA expression and amino acid incorporation by modification of the alpha 1-adrenergic and stretch-activated protein kinase C pathway. This mechanism did not require protein synthesis.
Novel Vascular Graft Grown Within Recipient’s Own Peritoneal Cavity
Authors: Julie H. Campbell, Johnny L. Efendy, Gordon R. Campbell
Journal: Circulation Research (1999)

A method by which to overcome the clinical symptoms of atherosclerosis is the insertion of a graft to bypass an artery blocked or impeded by plaque. However, there may be insufficient autologous mammary artery for multiple or repeat bypass, saphenous vein may have varicose degenerative alterations that can lead to aneurysm in high-pressure sites, and small-caliber synthetic grafts are prone to thrombus induction and occlusion. Therefore, the aim of the present study was to develop an artificial blood conduit of any required length and diameter from the cells of the host for autologous transplantation. Silastic tubing, of variable length and diameter, was inserted into the peritoneal cavity of rats or rabbits. By 2 weeks, it had become covered by several layers of myofibroblasts, collagen matrix, and a single layer of mesothelium. The Silastic tubing was removed from the harvested implants, and the tube of living tissue was everted such that it now resembled a blood vessel with an inner lining of nonthrombotic mesothelial cells (the "intima"), with a "media" of smooth muscle-like cells (myofibroblasts), collagen, and elastin, and with an outer collagenous "adventitia." The tube of tissue (10 to 20 mm long) was successfully grafted by end-to-end anastomoses into the severed carotid artery or abdominal aorta of the same animal in which they were grown. The transplant remained patent for at least 4 months and developed structures resembling elastic lamellae. The myofibroblasts gained a higher volume fraction of myofilaments and became responsive to contractile agonists, similar to the vessel into which they had been grafted. It is suggested that these nonthrombogenic tubes of living tissue, grown in the peritoneal cavity of the host, may be developed as autologous coronary artery bypass grafts or as arteriovenous access fistulae for hemodialysis patients.
Masked Hypertension, Urinary Albumin Excretion Rate, and Echocardiographic Parameters in Putatively Normotensive Type 2 Diabetic Patients
Authors: Cristiane B. Leitão, Luís H. Canani, Caroline K. Kramer, Juliana C. Boza, Antônio F. Pinotti, Jorge L. Gross
Journal: Diabetes Care (2007)

OBJECTIVE—To evaluate the impact of masked hypertension in normotensive type 2 diabetic patients on microvascular complications and echocardiographic parameters. RESEARCH DESIGN AND METHODS—A cross-sectional study was conducted in 135 normotensive patients with type 2 diabetes. Patients underwent urinary albumin excretion rate (UAER) measurement, echocardiography, and 24-h ambulatory blood pressure monitoring (ABPM). Patients with increased daytime blood pressure levels (≥135/85 mmHg) were classified as having masked hypertension. RESULTS—The prevalence of masked hypertension was 30% (n = 41). Normotensive and masked hypertensive subjects, based on ambulatory blood pressure, were not different in terms of age, diabetes duration, smoking status, BMI, waist circumference, serum creatinine, glycemic, or lipid profiles. The office systolic blood pressure was higher in those with masked hypertension (127.8 ± 7.5 vs. 122.9 ± 10.2 mmHg, P = 0.003) than in the normotensive group. UAER also was increased in the group with masked hypertension (21.3 μg/min [range 2.5–1,223.5] vs. 8.1 μg/min [1.0–1,143.0], P = 0.001), as was the interventricular septum (1.01 ± 0.15 vs. 0.94 ± 0.13 cm, P = 0.015) and posterior wall (0.96 ± 0.12 vs. 0.90 ± 0.10 cm, P = 0.006) thickness. After adjustments for diabetes duration, sex, smoking, LDL cholesterol, and A1C values, all associations were sustained for daytime systolic blood pressure but not for office systolic blood pressure. CONCLUSIONS—Type 2 diabetic patients with masked hypertension have higher UAER as well as enlargement of ventricular walls compared with the normotensive patients, according to ABPM. Therefore, ABPM is important to identify this high-risk group so as to be able to take interventionist measures.
The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells
Authors: Shuichiro Takashima, Masanori Kadowaki, Kazutoshi Aoyama, Motoko Koyama, Takeshi Oshima, Kazuma Tomizuka, Koichi Akashi, Takanori Teshima
Journal: The Journal of Experimental Medicine (2011)

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.
Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase.
Authors: L A Smedly, M G Tonnesen, R A Sandhaus, C Haslett, L A Guthrie, R B Johnston, P M Henson, G S Worthen
Journal: Journal of Clinical Investigation (1986)

The neutrophil has been implicated as an important mediator of vascular injury, especially after endotoxemia. This study examines neutrophil-mediated injury to human microvascular endothelial cells in vitro. We found that neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, or lipopolysaccharide (LPS) (1-1,000 ng/ml) alone produced minimal endothelial injury over a 4-h assay. In contrast, neutrophils incubated with endothelial cells in the presence of low concentrations of LPS (1-10 ng/ml) could then be stimulated by FMLP or C5a to produce marked endothelial injury. Injury was maximal at concentrations of 100 ng/ml LPS and 10(-7) M FMLP. Pretreatment of neutrophils with LPS resulted in a similar degree of injury, suggesting that LPS effects were largely on the neutrophil. Endothelial cell injury produced by LPS-exposed, FMLP-stimulated neutrophils had a time course similar to that induced by the addition of purified human neutrophil elastase, and different from that induced by hydrogen peroxide (H2O2). Further, neutrophil-mediated injury was not inhibited by scavengers of a variety of oxygen radical species, and occurred with neutrophils from a patient with chronic granulomatous disease, which produced no H2O2. In contrast, the specific serine elastase inhibitor methoxy-succinyl-alanyl-alanyl-prolyl-valyl-chloromethyl ketone inhibited 63% of the neutrophil-mediated injury and 64% of the neutrophil elastase-induced injury. However, neutrophil-mediated injury was not inhibited significantly by 50% serum, 50% plasma, or purified alpha 1 proteinase inhibitor. These results suggest that, in this system, chemotactic factor-stimulated human neutrophil injury of microvascular endothelial cells is enhanced by small amounts of LPS and may be mediated in large part by the action of neutrophil elastase.
Severe respiratory failure requiring ICU admission in bone marrow transplant recipients
Authors: D. Gruson, G. Hilbert, L. Portel, J.m Boiron, C.m Bebear, F. Vargas, Ch Bebear, J Reiffers, G. Gbikpi-Benissan, J.P. Cardinaud
Journal: European Respiratory Journal (1999)

Two groups of bone marrow transplant (BMT) recipients with febrile noncardiogenic respiratory failure requiring intensive care unit (ICU) admission, in the early phase of bone marrow transplantation were compared: those who had proven infectious pneumonia and those in whom bronchoalveolar lavage (BAL) failed to establish a diagnosis. Thirty-eight consecutive neutropenic BMT recipients admitted to an ICU with febrile noncardiogenic respiratory failure were enrolled. All of them underwent a BAL with viral, fungal, bacterial, and histopathological examinations. Lung biopsies were performed in nonsurviving patients in order to compare with BAL results. Haematological, biological, respiratory failure and other organ failure parameters, infectious results, outcome, and lung biopsy results were evaluated. BAL allowed an infectious diagnosis to be established in 16 BMT recipients. No aetiology was proven in 22 patients. Without a significant difference in respiratory failure parameters on ICU admission, noninvasive continuous positive airway pressure ventilation, which was given to 11 patients in each group, was significantly more successful in patients with proven infectious pneumonia (6 of 11 versus 0 of 11 patients) and enabled endotracheal intubation to be avoided in significantly more patients with infectious disease (10 of 16 versus 22 of 22 patients). The evolution of patients without diagnosis was significantly different with more frequent renal failure, hepatic failure, and death (20 of 22 versus 9 of 16 patients). Post mortem biopsies confirmed the absence of micro-organisms, but endothelial damage and fibrosis was found in 14 of the 22 patients. In conclusion, in the early phase of bone marrow transplantation the recipients without proven aetiology of pneumonia have a worse outcome than grafted patients with proven infectious pneumonia.
A Phase I, open-label, dose escalation study of MGA271 in combination with ipilimumab in patients with B7-H3-expressing melanoma, squamous cell cancer of the head and neck or non-small cell lung cancer
Authors: Walter Urba, Bartosz Chmielowski, Deryk Loo, Jan Baughman, Francine Chen, Paul Moore, Ezio Bonvini, James Vasselli, Jon Wigginton, Naiyer Rizvi
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts MGA271 is an Fc optimized, humanized IgG1 monoclonal antibody targeting B7-H3 (CD276), a member of the B7 family, and is currently undergoing Phase I testing. The Fc domain is engineered for enhanced binding to the activating FcγR, CD16A, and decreased binding to the inhibitory
Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen
Authors: Laura Haynes, Sheri M. Eaton, Eve M. Burns, Troy D. Randall, Susan L. Swain
Journal: The Journal of Experimental Medicine (2005)

Using a T cell receptor transgenic (TCR Tg) mouse model, we have shown that TCR Tg CD4 cells from aged mice retain a naive phenotype, but exhibit reduced proliferation and IL-2 production in response to the antigen compared with cells from young mice. We hypothesize that age-related decreases in T cell function may be partly related to the age of the T cells. Because thymic output is decreased with age, peripheral T cells in older individuals are likely to be older than those in younger individuals. To investigate this possibility, we have manipulated the age of CD4 T cells in the periphery of young and aged mice. The production of new T cells was induced by depleting peripheral CD4 T cells or by creating bone marrow chimeras. In both young and aged individuals where we induced the production of new T cells, these newly generated cells exhibited robust responses to antigen ex vivo and in vivo, exhibiting good expansion, IL-2 production, and cognate helper function. Our results suggest that age-related defects in response to antigenic stimulation, in part, are caused by the age of the CD4 T cells.
Prognostic Value of Angiotensin-I Converting Enzyme I/D Polymorphism for Nephropathy in Type 1 Diabetes Mellitus
Authors: SAMY HADJADJ, RIADH BELLOUM, BÉATRICE BOUHANICK, YVES GALLOIS, GÉRARD GUILLOTEAU, GILLES CHATELLIER, FRANC[COMBINING CEDILLA]OIS ALHENC-GELAS, MICHEL MARRE
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Angiotensin-I converting enzyme (ACE) regulates renal hemodynamics. Its insertion/deletion (I/D) polymorphism, which determines most of ACE interindividual variance, was proposed as a genetic marker for diabetic nephropathy. A substitution (M235T) polymorphism in angiotensinogen (AGT) may interact with ACE I/D polymorphism for the risk of diabetic nephropathy, but their prognostic values have to be established by follow-up studies. A total of 310 type 1 diabetes mellitus patients who attended the diabetic clinic in Angers (France) took part in a prospective, observational, follow-up study. Glycohemoglobin, BP, plasma creatinine, and urinary albumin excretion were determined periodically. Nephropathy was classified as absent, incipient (microalbuminuria), established (proteinuria), advanced (plasma creatinine ≥ 150 μmol/L), and terminal (renal replacement therapy). The main end point was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) had established nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT polymorphisms were in Hardy-Weinberg equilibrium in the patients. The median duration of follow-up was 6 yr (range, 2 to 9 yr). The occurrence of renal events was significantly influenced by ACE genotype (log-rank II versus ID versus DD, P &lt; 0.03) with a dominant deleterious effect of the D allele: ID or DD versus II (adjusted hazard ratio, 5.0; 95% confidence interval, 1.5 to 16.6). Other contributors were high glycohemoglobin and systolic BP. In the patients who initially were free of nephropathy, baseline plasma ACE concentration was higher in patients who progressed to microalbuminuria (571 ± 231 versus 466 ± 181 μg/L; P = 0.0032); the D allele independently favored the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95% confidence interval, 1.1 to 19.4); other contributors were male gender, baseline systolic BP, and urinary albumin excretion. The AGT M235T polymorphism was not associated with renal events. The D allele of the ACE I/D polymorphism is an independent risk factor for both the onset and the progression of diabetic nephropathy in type 1 diabetes mellitus patients.
Notch Signaling Determines the M1 versus M2 Polarization of Macrophages in Antitumor Immune Responses
Authors: Yao-Chun Wang, Fei He, Fan Feng, Xiao-Wei Liu, Guang-Ying Dong, Hong-Yan Qin, Xing-Bin Hu, Min-Hua Zheng, Liang Liang, Lei Feng, Ying-Min Liang, Hua Han
Journal: Cancer Research (2010)

Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear. Here, we show that the M2-like tumor-associated macrophages (TAM) have a lower level of Notch pathway activation in mouse tumor models. Forced activation of Notch signaling increased M1 macrophages which produce IL12, no matter whether M1 or M2 inducers were applied. When Notch signaling was blocked, the M1 inducers induced M2 response in the expense of M1. Macrophages deficient in canonical Notch signaling showed TAM phenotypes. Forced activation of Notch signaling in macrophages enhanced their antitumor capacity. We further show that RBP-J-mediated Notch signaling regulates the M1 versus M2 polarization through SOCS3. Therefore, Notch signaling plays critical roles in the determination of M1 versus M2 polarization of macrophages, and compromised Notch pathway activation will lead to the M2-like TAMs. These results provide new insights into the molecular mechanisms of macrophage polarization and shed light on new therapies for cancers through the modulation of macrophage polarization through the Notch signaling.