tbuckley/cabot-search huggingface dataset:
MRI of the knee in asymptomatic adolescent swimmers: a controlled study
Authors: Ricardo Bernardi Soder, Mariana Damian Mizerkowski, Rose Petkowicz, Matteo Baldisserotto
Journal: British Journal of Sports Medicine (2011)

Swimming is a widespread sporting activity generally regarded as an ideal form of exercise, which has little or no impact on the knees. However, overuse or repetitive microtrauma injuries may often affect the knee joint of young competitive swimmers. These early lesions are frequently asymptomatic for a considerable period of time before causing discomfort or joint pain.The aim of the present study is to use MRI to evaluate the knee joints of asymptomatic young elite swimmers and to compare them with age- and sex-matched controls who do not practice any impact sports regularly.Cross-sectional case-control study.The authors performed a cross-sectional controlled study to evaluate 54 knees of 27 asymptomatic male adolescents aged 14-15 years, paired by age and weight. Participants were divided in two groups: 13 elite swimmers and 14 control adolescents. The authors performed all the exams using a 0.35-T open-field MRI unit and evaluated by two experienced radiologists blinded to study groups. The images were evaluated to detect the presence or absence of abnormalities.One or more imaging abnormalities were detected in 18 knees in the group of swimmers (69.2%; p=0.013). The most prevalent findings in the athletes were infrapatellar fat pad edema (53.8%; p=0.049), followed by bone marrow edema (26.9%; p=0.022), edema of prefemoral fat pad (19%; p=0.022) and joint effusion (15.3%; p=0.047).Significantly more MRI abnormalities were found in the knee joints of asymptomatic adolescent elite swimmers. This high prevalence of positive imaging findings in swimmers may correspond to benign changes or preclinical lesions, which should be evaluated in a follow-up study.
Organophosphorus Ester-Induced Delayed Neurotoxicity
Authors: M B Abou-Donia
Journal: The Annual Review of Pharmacology and Toxicology (1981)

In certain animals, including humans, exposure to some organophosphorus esters causes delayed neurotoxicity (OPIDN). The clinical condition becomes manifest after a delay period, first as ataxia, followed by paralysis. Lesions are characterized by degeneration of axons with subsequent secondary degeneration of myelin in the peripheral and central nervous systems. Recovery is only likely in mild cases, whereas more severe cases show symptoms of an upper motor neuron lesion in the lower limbs. The risk of use of these chemicals is related not only to human sensitivity to this syndrome, but also to the fact that in most disasters involving OPIDN, humans were the prime victims. Therefore, the neurotoxic action of a chemical is of great significance, since pesticides with this property are not recommended for use. Although OPIDN has been recognized for over a half a century, its mechanism of action is still unknown. It is believed, however, that the initial target in OPIDN is the phosphorylation of a neurotoxicity target protein in the nervous system. Study of the relationship between the chemical structure of organophosphorus esters and their neurotoxic potencies suggests that two hydrophobic areas may be present in the vicinity of the active site of the neurotoxicity protein. This article attempts to present an up-to-date overview of OPIDN. Despite the difficulties attributed to experimental variations of the reported studies, I feel that several significant points have come forth from the data.
Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS)
Authors: Azra Raza, Naomi Galili, Deborah Mulford, Scott E Smith, Gail L Brown, David P Steensma, Roger M Lyons, Ralph Boccia, Mikkael A Sekeres, Guillermo Garcia-Manero, Ruben A Mesa
Journal: Journal of Hematology & Oncology (2012)

Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells. Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1–21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non-hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10 mg doses recommended for future studies. The tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active. Clinicaltrials.gov: NCT01062152
“Big data” needs an analysis of decision processes
Authors: Pantelis P. Analytis, Mehdi Moussaïd, Florian Artinger, Juliane E. Kämmer, Gerd Gigerenzer
Journal: Behavioral and Brain Sciences (2014)

Abstract We demonstrate by means of a simulation that the conceptual map presented by Bentley et al. is incomplete without taking into account people's decision processes. Within the same environment, two decision processes can generate strikingly different collective behavior; in two environments that fundamentally differ in transparency, a single process gives rise to virtually identical behavior.
Role of CYB5A in Pancreatic Cancer Prognosis and Autophagy Modulation
Authors: Elisa Giovannetti, Qiuyan Wang, Amir Avan, Niccola Funel, Tonny Lagerweij, Jih-Hsiang Lee, Viola Caretti, Arjan van der Velde, Ugo Boggi, Yisong Wang, Enrico Vasile, Godefridus J. Peters, Thomas Wurdinger, Giuseppe Giaccone
Journal: JNCI Journal of the National Cancer Institute (2013)

Loss of 18q22.3 is a prognostic marker in pancreatic ductal adenocarcinoma (PDAC). This study investigated genes encoded by this cytoband.We studied mRNA/protein expression in radically resected (n = 130) and metastatic patients (n = 50). The role of CYB5A was tested in 11 PDAC cell lines and five primary cultures through retrovirus-mediated upregulation and small interfering RNA using wound-healing, invasion, annexin-V, electron microscopy, and autophagic assays, as well as autophagy genes and kinases arrays. CYB5A+ orthotopic models (n = 6 mice/group) were monitored by Firefly and Gaussia-luciferase bioluminescence, magnetic resonance imaging, and high-frequency ultrasound. Data were analyzed by t test, Fisher exact-test, log-rank test and Cox proportional hazards models. All statistical tests were two-sided.Both resected and metastatic patients with low mRNA or protein expression of CYB5A had statistically significantly shorter survival (eg, median = 16.7 months, 95% confidence interval [CI] = 13.5 to 19.9; vs median = 24.8 months, 95% CI = 12.8 to 36.9; P = .02, two-sided log-rank test; n = 82 radically resected PDACs), and multivariable analyses confirmed prognostic relevance. Moreover, we characterized a novel function to CYB5A, autophagy induction, concomitant with reduced proliferation and migration/invasion of PDAC cells. Network analysis of proautophagic pathways suggested CYB5A interaction with TRAF6, which was confirmed by TRAF6 downregulation after CYB5A reconstitution (-69% in SU.86.86-CYB5A+; P = .005, two-sided t test). CYB5A silencing had opposite effects, restoring TRAF6 expression and wound healing. In vivo studies showed that CYB5A induced autophagy while inhibiting tumor growth/metastasis and increasing survival (median = 57 days, 95% CI = 52 to 61; vs median = 44 days, 95% CI = 21 to 57; P = .03, two-sided log-rank test).These results define CYB5A as a novel prognostic factor for PDAC that exerts its tumor-suppressor function through autophagy induction and TRAF6 modulation.
Novel Biomarker Signature That May Predict Aggressive Disease in African American Men With Prostate Cancer
Authors: Kosj Yamoah, Michael H. Johnson, Voleak Choeurng, Farzana A. Faisal, Kasra Yousefi, Zaid Haddad, Ashley E. Ross, Mohammed Alshalafa, Robert Den, Priti Lal, Michael Feldman, Adam P. Dicker, Eric A. Klein, Elai Davicioni, Timothy R. Rebbeck, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2015)

We studied the ethnicity-specific expression of prostate cancer (PC) -associated biomarkers to evaluate whether genetic/biologic factors affect ethnic disparities in PC pathogenesis and disease progression.
Efficacy and Safety of Axitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Phase II Study
Authors: Joan H. Schiller, Timothy Larson, S.-H. Ignatius Ou, Steven Limentani, Alan Sandler, Everett Vokes, Sinil Kim, Katherine Liau, Paul Bycott, Anthony J. Olszanski, Joachim von Pawel
Journal: Journal of Clinical Oncology (2009)

This phase II study evaluated efficacy and safety of single-agent axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, in patients with advanced non-small-cell lung cancer (NSCLC).This was an open-label, single-arm, multicenter, phase II study with a Simon two-stage minimax design. Patients received a starting dose of axitinib 5 mg orally BID. The primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) -defined objective response rate. Secondary end points included safety and tolerability, overall survival (OS), and progression-free survival (PFS).Thirty-two patients were enrolled, with a median age of 66.5 years. The majority of patients (75%) had adenocarcinoma. Nine patients (28%) had received no prior chemotherapy for metastatic disease, and 23 (72%) had received > or = one regimen. Three patients (9%) had a RECIST investigator-assessed, confirmed partial response (PR); disease control rate (PR + stable disease) was 41%. Median PFS was 4.9 months overall (95% CI, 3.6 to 7.0 months). Median OS was 14.8 months (95% CI, 10.7 months to not estimable) overall and 14.8 months (95% CI, 12.5 months to not estimable) in patients receiving first-line axitinib. One-year survival rates for patients with or without prior therapy for metastatic disease were 57% and 78%, respectively. Grade 3 treatment-related adverse events in > or = 5% of patients comprised fatigue (22%), hypertension (9%), and hyponatremia (9%).Axitinib demonstrated single-agent activity in patients with advanced NSCLC. Therapy was well tolerated with manageable toxicities. Further investigation of this VEGFR inhibitor in NSCLC is of interest.
Selection of Immunostimulant AS15 for Active Immunization With MAGE-A3 Protein: Results of a Randomized Phase II Study of the European Organisation for Research and Treatment of Cancer Melanoma Group in Metastatic Melanoma
Authors: Wim H.J. Kruit, Stefan Suciu, Brigitte Dreno, Laurent Mortier, Caroline Robert, Vanna Chiarion-Sileni, Michele Maio, Alessandro Testori, Thierry Dorval, Jean-Jacques Grob, Juergen C. Becker, Alan Spatz, Alexander M.M. Eggermont, Jamila Louahed, Frédéric F. Lehmann, Vincent G. Brichard, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2013)

Active immunization against the tumor-specific MAGE-A3 antigen is followed by a few but impressive and durable clinical responses. This randomized phase II trial evaluated two different immunostimulants combined with the MAGE-A3 protein to investigate whether a more robust and persistent immune response could be associated with increased clinical benefit.Patients with MAGE-A3-positive stage III or IV M1a melanoma were randomly assigned to receive the MAGE-A3 protein combined either with AS02B or with AS15 immunostimulant. Clinical end points were toxicity and rates of objective clinical responses, progression-free survival (PFS), and overall survival (OS).Seventy-five patients were treated, with 36 eligible patients per arm. Both treatments were well tolerated. In the AS15 arm, four objective responses were observed (three complete responses and one partial response) versus one partial response in the AS02B arm. In the AS15 and AS02B arms, the PFS rates after 6 months were 25% and 14%, respectively; and the median OS times were 33 months and 19.9 months, respectively, with a median observation period of 48 months. Antibodies against MAGE-A3, found in all patients, showed three-fold higher titers in the AS15 arm. The anti-MAGE-A3 cellular response was also more pronounced in the AS15 arm.In the MAGE-A3+AS15 arm, clinical activity was higher and the immune response more robust. Therefore, the AS15 immunostimulant was selected for combination with the MAGE-A3 protein in phase III trials.
The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis
Authors: Dragana Lazarevic, Angela Pistorio, Elena Palmisani, Paivi Miettunen, Angelo Ravelli, Clarissa Pilkington, Nico M Wulffraat, Clara Malattia, Stella Maris Garay, Michael Hofer, Pierre Quartier, Pavla Dolezalova, Inmaculada Calvo Penades, Virginia P L Ferriani, Gerd Ganser, Ozgur Kasapcopur, Jose Antonio Melo-Gomes, Ann M Reed, Malgorzata Wierzbowska, Lisa G Rider, Alberto Martini, Nicolino Ruperto
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM). <h3>Methods</h3> The Paediatric Rheumatology International Trials Organisation (PRINTO) database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physician9s and parent9s global disease activity/damage evaluations, inactive disease criteria derived from the literature and other ad hoc criteria were evaluated for sensitivity, specificity and Cohen9s κ agreement. <h3>Results</h3> The individual measures that best characterised inactive disease (sensitivity and specificity &gt;0.8 and Cohen9s κ &gt;0.8) were manual muscle testing (MMT) ≥78, physician global assessment of muscle activity=0, physician global assessment of overall disease activity (PhyGloVAS) ≤0.2, Childhood Myositis Assessment Scale (CMAS) ≥48, Disease Activity Score ≤3 and Myositis Disease Activity Assessment Visual Analogue Scale ≤0.2. The best combination of variables to classify a patient as being in a state of inactive disease on or off therapy is at least three of four of the following criteria: creatine kinase ≤150, CMAS ≥48, MMT ≥78 and PhyGloVAS ≤0.2. After 24 months, 30/31 patients (96.8%) were inactive off therapy and 69/145 (47.6%) were inactive on therapy. <h3>Conclusion</h3> PRINTO established data-driven criteria with clearly evidence-based cut-off values to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice.
The influence of antihypertensive drug treatment on the prevention and regression of left ventricular hypertrophy
Authors: P A van Zwieten
Journal: Cardiovascular Research (2000)

Left ventricular hypertrophy (LVH) has been recognized as an important cardiovascular risk factor. Hypertensive disease is the most frequent background of LVH and it is generally felt that anti-hypertensive treatment should not only lower blood pressure but also cause regression of LVH. In the present survey the patho-physiology of LVH, its measurements and animal models used to study LVH are briefly discussed. Subsequently, the effects of various drugs in animal models and in human hypertensives are reviewed. It has been shown repeatedly that various types of antihypertensive drugs show differential activities on the prevention or regression of LVH. It is not only the lowering of blood pressure which determines the anti-LVH activity, but also the interaction of drugs with neuro-endocrine mechanisms such as the renin-angiotensin-aldosterone system and the sympathetic nervous system.
Identifying severe community-acquired pneumonia: moving beyond mortality
Authors: James D Chalmers
Journal: Thorax (2015)

Hospitalisations for community-acquired pneumonia (CAP) are increasing in the UK and internationally.1 Five to fifteen per cent of patients admitted to hospital with CAP die, and improvements in supportive care have maintained this death rate in the face of rising co-morbidity but have not resulted in substantial improvements.2 This lack of progress contrasts sharply with other medical emergencies such as acute myocardial infarction where there is an established pathway from recognition to early management and long-term care, which has brought substantial reductions in mortality.3

Kolditz et al 4 report a new concept in CAP management, the idea of ‘emergency CAP’ to define patients at increased risk of early deterioration. In a large database of 3427 prospectively recruited patients with CAP from the multicentre CAPNETZ cohort only 173 (5%) required mechanical ventilation and/or vasopressor support (MV/VS) or died within 7 days of admission. Twenty-seven per cent of such patients died within 30 days while in contrast only 2% of patients not requiring MV/VS in the first week of admission ultimately died.4

Importantly they demonstrated, as other authors have found in the past, that deterioration was largely predictable.5–7 The absence of any of the nine Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) criteria for severe pneumonia had a 99.7% negative predictive value and effectively excluded a poor outcome.4 This study also extended previous observations that the highest mortality in CAP is reserved for patients who deteriorate later in admission.8 Patients who required invasive MV/VS immediately on admission had a 30-day mortality rate of 24%. In patients who did not require this intervention on …
Immature Dendritic Cells Acquire Cd8+Cytotoxic T Lymphocyte Priming Capacity upon Activation by T Helper Cell–Independent or–Dependent Stimuli
Authors: Danita H. Schuurhuis, Sandra Laban, René E.M. Toes, Paola Ricciardi-Castagnoli, Monique J. Kleijmeer, Ellen I.H. van der Voort, Delphine Rea, Rienk Offringa, Hans J. Geuze, Cornelis J.M. Melief, Ferry Ossendorp
Journal: The Journal of Experimental Medicine (2000)

The well defined, immature murine dendritic cell (DC) line D1 was used to study the role of DC maturation in CTL induction in vitro and in vivo. Maturation of D1 cells, characterized by markedly increased expression of MHC and costimulatory molecules, was induced by incubation with lipopolysaccharide, agonistic CD40 antibody, or specific CD4+ T helper (Th) cells. Activated, but not immature, D1 cells efficiently primed alloreactive T cell responses in vitro. Similarly, priming of CTL immunity in vivo in CD4-depleted mice was only observed if these mice were immunized with activated D1 cells. This study provides formal evidence that activation of DCs, induced by Th-independent as well as Th-dependent stimuli, is essential for efficient induction of CTL responses.
Restricted MHC–peptide repertoire predisposes to autoimmunity
Authors: Nadezda N. Logunova, Christophe Viret, Leonid A. Pobezinsky, Sara A. Miller, Dmitri B. Kazansky, John P. Sundberg, Alexander V. Chervonsky
Journal: The Journal of Experimental Medicine (2005)

MHC molecules associated with autoimmunity possess known structural features that limit the repertoire of peptides that they can present. Such limitation gives a selective advantage to TCRs that rely on interaction with the MHC itself, rather than with the peptide residues. At the same time, negative selection is impaired because of the lack of negatively selecting peptide ligands. The combination of these factors may predispose to autoimmunity. We found that mice with an MHC class II–peptide repertoire reduced to a single complex demonstrated various autoimmune reactions. Transgenic mice bearing a TCR (MM14.4) cloned from such a mouse developed severe autoimmune dermatitis. Although MM14.4 originated from a CD4+ T cell, dermatitis was mediated by CD8+ T cells. It was established that MM14.4+ is a highly promiscuous TCR with dual MHC class I/MHC class II restriction. Furthermore, mice with a limited MHC–peptide repertoire selected elevated numbers of TCRs with dual MHC class I/MHC class II restriction, a likely source of autoreactivity. Our findings may help to explain the link between MHC class I responses that are involved in major autoimmune diseases and the well-established genetic linkage of these diseases with MHC class II.
Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial
Authors: Ian Sanne, Catherine Orrell, Matthew P Fox, Francesca Conradie, Prudence Ive, Jennifer Zeinecker, Morna Cornell, Christie Heiberg, Charlotte Ingram, Ravindre Panchia, Mohammed Rassool, René Gonin, Wendy Stevens, Handré Truter, Marjorie Dehlinger, Charles van der Horst, James McIntyre, Robin Wood
Journal: The Lancet (2010)
EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis
Authors: Jianchun Chen, Jian-Kang Chen, Kojiro Nagai, David Plieth, Mingqi Tan, Tang-Cheng Lee, David W. Threadgill, Eric G. Neilson, Raymond C. Harris
Journal: Journal of the American Society of Nephrology (2011)

The mechanisms by which angiotensin II (Ang II) promotes renal fibrosis remain incompletely understood. Ang II both stimulates TGFβ signaling and activates the EGF receptor (EGFR), but the relative contribution of these pathways to renal fibrogenesis is unknown. Using a murine model with EGFR-deficient proximal tubules, we demonstrate that upstream activation of EGFR-dependent ERK signaling is critical for mediating sustained TGFβ expression in renal fibrosis. Persistent activation of the Ang II receptor stimulated ROS-dependent phosphorylation of Src, leading to sustained EGFR-dependent signaling for TGFβ expression. Either genetic or pharmacologic inhibition of EGFR significantly decreased TGFβ-mediated fibrogenesis. We conclude that TGFβ-mediated tissue fibrosis relies on a persistent feed-forward mechanism of EGFR/ERK activation through an unexpected signaling pathway, highlighting EGFR as a potential therapeutic target for modulating tissue fibrogenesis.