tbuckley/cabot-search huggingface dataset:
Interleukin-4 Cytotoxin Therapy Synergizes with Gemcitabine in a Mouse Model of Pancreatic Ductal Adenocarcinoma
Authors: Takeshi Shimamura, Richard E. Royal, Mitomu Kioi, Atsushi Nakajima, Syed R. Husain, Raj K. Puri
Journal: Cancer Research (2007)

Abstract Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for tumor therapy. Here, we show the efficacy of the combination therapy of gemcitabine with an interleukin-4 (IL-4) cytotoxin composed of IL-4 and truncated Pseudomonas exotoxin in animal models of pancreatic ductal adenocarcinoma (PDA). We have observed that 42 of 70 (60%) tumor samples from patients with PDA express moderate- to high-density surface IL-4 receptor (IL-4R), whereas normal pancreatic samples express no or low-density IL-4R. IL-4 cytotoxin was specifically and highly cytotoxic [50% protein synthesis inhibition (IC50) ranging from &amp;gt;0.1 to 13 ng/mL] to six of eight pancreatic cancer cell lines, whereas no cytotoxicity (IC50 &amp;gt;1,000 ng/mL) was observed in normal human pancreatic duct epithelium cells, fibroblasts, and human umbilical vein endothelial cells (HUVEC). We also showed that IL-4 cytotoxin in combination with gemcitabine exhibited synergistic antitumor activity in vitro. To confirm synergistic antitumor activity in vivo and monitor precise real-time disease progression, we used a novel metastatic and orthotopic mouse model using green fluorescent protein–transfected cancer cells and whole-body imaging system. The combination of both agents caused complete eradication of tumors in 40% of nude mice with small established PDA tumors. In addition, combined treatment significantly prolonged the survival of nude mice bearing day 14 advanced distant metastatic PDA tumors. Similar results were observed in mice xenografted with PDA obtained from a patient undergoing surgical resection. These results indicate that IL-4 cytotoxin combined with gemcitabine may provide effective therapy for the treatment of patients with PDA. [Cancer Res 2007;67(20):9903–12]
Dog days and siriasis. How to kill a football player
Authors: J. P. Knochal
Journal: JAMA (1975)

NOT TOO many years ago, the term "dog days" was applied to a period in July and August that was generally hot and miserable. The term originated from the fact that at that time of the year, the dog star, Sirius, rose each morning with the sun. Since heat stroke was apt to occur at this time, it was resolved that the star itself was the instrument of the malady. The name as a consequence became siriasis. I first became aware of the term siriasis while chatting with an engineer at an after-dinner gathering some years ago. He was one of those crafty devils who pitted his personal knowledge of medicine with yours and seemed to thrive on discovery of an intellectual hiatus, be it ever so minuscule. With obvious expectation of erudite comment, he informed me that he had once experienced a severe attack of siriasis. As he anticipated,
Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy
Authors: Jun-ichi Kashiwakura, Tomoaki Ando, Kenji Matsumoto, Miho Kimura, Jiro Kitaura, Michael H. Matho, Dirk M. Zajonc, Tomomitsu Ozeki, Chisei Ra, Susan M. MacDonald, Reuben P. Siraganian, David H. Broide, Yuko Kawakami, Toshiaki Kawakami
Journal: Journal of Clinical Investigation (2011)

IgE-mediated activation of mast cells and basophils underlies allergic diseases such as asthma. Histamine-releasing factor (HRF; also known as translationally controlled tumor protein [TCTP] and fortilin) has been implicated in late-phase allergic reactions (LPRs) and chronic allergic inflammation, but its functions during asthma are not well understood. Here, we identified a subset of IgE and IgG antibodies as HRF-interacting molecules in vitro. HRF was able to dimerize and bind to Igs via interactions of its N-terminal and internal regions with the Fab region of Igs. Therefore, HRF together with HRF-reactive IgE was able to activate mast cells in vitro. In mouse models of asthma and allergy, Ig-interacting HRF peptides that were shown to block HRF/Ig interactions in vitro inhibited IgE/HRF-induced mast cell activation and in vivo cutaneous anaphylaxis and airway inflammation. Intranasally administered HRF recruited inflammatory immune cells to the lung in naive mice in a mast cell- and Fc receptor-dependent manner. These results indicate that HRF has a proinflammatory role in asthma and skin immediate hypersensitivity, leading us to suggest HRF as a potential therapeutic target.
YOUNG PATIENTS WITH A FAMILY HISTORY OF CORONARY ARTERY DISEASE HAVE HIGHER PREVALENCE, INCREASED SEVERITY, AND WORSE PROGNOSIS OF CORONARY ATHEROSCLEROSIS: RESULTS FROM 6308 PATIENTS IN THE PROSPECTIVE MULTINATIONAL CONFIRM REGISTRY (CORONARY CT ANGIOGRAPHY EVALUATION FOR CLINICAL OUTCOMES: AN INTERNATIONAL MULTICENTER REGISTRY)
Authors: Yuka Otaki, Troy LaBounty, Allison Dunning, Heidi Gransar, Fay Lin, Stephan Achenbach, Mouaz Al-Mallah, Matthew Budoff, Filippo Cademartiri, Victor Cheng, Kavitha Chinnaiyan, Benjamin J.W. Chow, Augustin DeLago, Martin Hadamitzky, Joerg Hausleiter, Philipp Kaufmann, Gilbert Raff, Leslee Shaw, Todd Villines, Daniel Berman, James Min
Journal: Journal of the American College of Cardiology (2012)
Chemokine and Chemokine Receptor Expression in a Novel Human Mesangial Cell Line
Authors: BERNHARD BANAS, BRUNO LUCKOW, MARCUS MO[Combining Diaeresis]LLER, CHRISTIANE KLIER, PETER J. NELSON, ERIK SCHADDE, MANFRED BRIGL, DANIEL HALEVY, HARRY HOLTHO[Combining Diaeresis]FER, BRIGITTE REINHART, DETLEF SCHLO[Combining Diaeresis]NDORFF
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Chemokines are thought to play a pivotal role in mediating the selective migration of leukocytes into sites of tissue injury. The local production of chemokines by mesangial cells (MC) has been linked to inflammatory processes within the glomerulus. To study the chemokine biology of human MC, an immortalized human MC line was generated and then chemokine and chemokine receptor expression was examined in response to various proinflammatory stimuli. The results show that human MC have a specific and limited repertoire of chemokine expression. The stimulus-specific regulation of the chemokines monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), interleukin-8 (IL-8), and IP-10 was demonstrated using RNase protection assays. Transcripts for the chemokines MIP-1α, MIP-1β, I-309, or lymphotactin could not be detected. The expression of CC chemokine receptors was investigated by reverse transcription-PCR and RNase protection assays. MC stimulated with interferon-γ (IFN-γ) expressed mRNA for the chemokine receptor CCR1. The expression could be further increased by activating the cells with a combination of tumor necrosis factor-α (TNF-α), IL-1β, and IFN-γ. Under these conditions, no mRNA for CCR2, CCR3, CCR4, CCR5, or CCR8 was detected. A comparison of the immortalized human mesangial cells with primary cells showed identical expression patterns of chemokine receptors. To demonstrate functional activity of chemokine receptors expressed by human MC, chemotaxis assays were performed. MC stimulated with a combination of TNF-α, IL-1β, and IFN-γ, but not unstimulated MC, migrated toward a RANTES gradient. Eotaxin did not enhance the migratory activity of human MC. In summary, a novel human mesangial cell line was established and the pattern of chemokine expression was examined. For the first time, the inducible expression of functionally active CCR1 by human MC was shown.
HRCT-defined emphysema is not COPD to be treated with inhalers
Authors: Paul Enright
Journal: Thorax (2014)

The COPDGene Study1 is providing important new information about the natural history of several chronic obstructive pulmonary disease (COPD) phenotypes.2 This multicentre study enrolled a large number of current and former smokers with a wide range of spirometry results (from normal to very severe airflow obstruction), carefully characterised them during their baseline examination, and has been following them for several important outcome measures. The key phenotypes include (1) chronic airflow obstruction (CAO) defined by a low post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), (2) high-resolution CT (HRCT)-defined emphysema (low attenuation at maximal inhalation, total lung capacity), (3) hyperinflation or gas trapping on HRCT, defined as low attenuation of the lungs at low lung volume (around functional residual capacity), and (4) airway inflammation (defined by bronchial wall thickening on HRCT, also known as bronchiectasis). A comparison of two of these phenotypes—CAO versus emphysema—has been described.3 Not surprisingly, the analyses showed ‘striking disagreement’ between spirometric CAO (regardless of how mild airway obstruction was defined) and HRCT-defined emphysema. Only 13% of smokers with CAO had emphysema, while 39% had air trapping.

The authors then compared the prevalence of HRCT-defined emphysema in smokers with borderline to mild CAO defined by the faulty fixed ratio versus the lower limit of the normal range (LLN) for FEV1/FVC. About 7% of the adult smokers in the cohort had an FEV1/FVC below 0.70 but above the LLN (a discordant CAO classification). This ‘fixed-only’ subgroup of …
Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial
Authors: Sunil Sazawal, Robert E Black, Mahdi Ramsan, Hababu M Chwaya, Rebecca J Stoltzfus, Arup Dutta, Usha Dhingra, Ibrahim Kabole, Saikat Deb, Mashavi K Othman, Fatma M Kabole
Journal: The Lancet (2006)
Anaplastic Lymphoma Kinase Aberrations in Rhabdomyosarcoma: Clinical and Prognostic Implications
Authors: J. Carlijn van Gaal, Uta E. Flucke, Melissa H.S. Roeffen, Eveline S.J.M. de Bont, Stefan Sleijfer, Annelies M.C. Mavinkurve-Groothuis, Albert J.H. Suurmeijer, Winette T.A. van der Graaf, Yvonne M.H. Versleijen-Jonkers
Journal: Journal of Clinical Oncology (2011)

The aim of this study is to investigate anaplastic lymphoma kinase (ALK) protein expression and underlying genetic aberrations in rhabdomyosarcoma (RMS), with special attention to clinical and prognostic implications.A total of 189 paraffin-embedded RMS tumor specimens from 145 patients were collected on tissue microarray. ALK protein expression was evaluated by immunohistochemistry. ALK gene (2p23) copy number and translocations were determined by in situ hybridization. cDNA sequencing of the receptor tyrosine kinase domain of the ALK gene was assessed in 43 samples.Strong cytoplasmic ALK protein expression was more frequently observed in alveolar RMS (ARMS) than in embryonal RMS (ERMS) (81% v 32%, respectively; P < .001). ALK gene copy number gain was detected in the vast majority of ARMS (88%), compared with 52% of ERMS (P < .001). ALK copy number correlated with protein expression in primary tumors (n = 107). We identified one point mutation (2%) and seven tumors harboring whole exon deletions (16%). In ERMS, specific ALK gain in the primary tumor correlated with metastatic disease (100% in metastatic disease v 29% in nonmetastatic disease; P = .004) and poor disease-specific survival (5-year disease-specific survival: 62% v 82% for nonspecific or no gain; P = .046).Because ALK aberrations on genomic and protein levels are frequently found in RMSs, in particular ARMS, and are associated with disease progression and outcome in ERMS, ALK may play a role in tumor biology and may provide a potential therapeutic target for these tumors. Future research should aim at the oncogenic role of ALK and the potential effect of ALK inhibitors in RMS.
Differences in negativity bias probably underlie variation in attitudes toward change generally, not political ideology specifically
Authors: Steven G Ludeke, Colin G DeYoung
Journal: Behavioral and Brain Sciences (2014)

Abstract Many of the characteristics cited in Hibbing et al.'s account are ineffective predictors of economic conservatism. However, these same characteristics are often associated with differences not only in social conservatism but also in religiousness and authoritarianism. Hibbing et al. may have offered a useful explanation of traditionalism and attitudes toward change across domains rather than of general political attitudes.
Somatic Hypermutation Introduces Insertions and Deletions into Immunoglobulin V Genes
Authors: Patrick C. Wilson, Odette de Bouteiller, Yong-Jun Liu, Kathleen Potter, Jacques Banchereau, J. Donald Capra, Virginia Pascual
Journal: The Journal of Experimental Medicine (1998)

During a germinal center reaction, random mutations are introduced into immunoglobulin V genes to increase the affinity of antibody molecules and to further diversify the B cell repertoire. Antigen-directed selection of B cell clones that generate high affinity surface Ig results in the affinity maturation of the antibody response. The mutations of Ig genes are typically basepair substitutions, although DNA insertions and deletions have been reported to occur at a low frequency. In this study, we describe five insertion and four deletion events in otherwise somatically mutated VH gene cDNA molecules. Two of these insertions and all four deletions were obtained through the sequencing of 395 cDNA clones (∼110,000 nucleotides) from CD38+IgD− germinal center, and CD38−IgD− memory B cell populations from a single human tonsil. No germline genes that could have encoded these six cDNA clones were found after an extensive characterization of the genomic VH4 repertoire of the tonsil donor. These six insertions or deletions and three additional insertion events isolated from other sources occurred as triplets or multiples thereof, leaving the transcripts in frame. Additionally, 8 of 9 of these events occurred in the CDR1 or CDR2, following a pattern consistent with selection, and making it unlikely that these events were artifacts of the experimental system. The lack of similar instances in unmutated IgD+CD38− follicular mantle cDNA clones statistically associates these events to the somatic hypermutation process (P = 0.014). Close scrutiny of the 9 insertion/deletion events reported here, and of 25 additional insertions or deletions collected from the literature, suggest that secondary structural elements in the DNA sequences capable of producing loop intermediates may be a prerequisite in most instances. Furthermore, these events most frequently involve sequence motifs resembling known intrinsic hotspots of somatic hypermutation. These insertion/deletion events are consistent with models of somatic hypermutation involving an unstable polymerase enzyme complex lacking proofreading capabilities, and suggest a downregulation or alteration of DNA repair at the V locus during the hypermutation process.
Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck
Authors: R. Mesía, F. Rivera, A. Kawecki, S. Rottey, R. Hitt, H. Kienzer, D. Cupissol, D. De Raucourt, M. Benasso, P. Koralewski, J.-P. Delord, C. Bokemeyer, D. Curran, A. Gross, J.B. Vermorken
Journal: Annals of Oncology (2010)

Background: A phase III trial demonstrated that cetuximab is the first agent in 30 years to improve survival when added to platinum-based chemotherapy (platinum-fluorouracil) first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). This analysis of the trial assessed the impact of treatment on quality of life (QoL).Patients and methods: The European Organisation for Research and Treatment of Cancer QoL Questionnaire-Core 30 (QLQ-C30) and QLQ-Head and Neck 35 (QLQ-H&N35) module were used to assess QoL.Results: Of 442 patients randomly assigned, 291 (QLQ-C30) and 289 (QLQ-H&N35) patients completed at least one evaluable questionnaire. For QLQ-C30, cycle 3 and month 6 mean scores for platinum–fluorouracil plus cetuximab were not significantly worse than those for platinum–fluorouracil. Pattern-mixture analysis demonstrated a significant improvement in the global health status/QoL score in the cetuximab arm (P = 0.0415) but no treatment differences in the social functioning scale. For QLQ-H&N35, the mean score for the cetuximab arm was not significantly worse than that for the chemotherapy arm for all symptom scales at all post-baseline visits. At cycle 3, some symptom scores significantly favored the cetuximab arm (pain, swallowing, speech problems, and social eating).Conclusion: Adding cetuximab to platinum–fluorouracil does not adversely affect the QoL of patients with recurrent and/or metastatic SCCHN.
IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice
Authors: Jau-Yi Li, Patrizia D’Amelio, Jerid Robinson, Lindsey D. Walker, Chiara Vaccaro, Tao Luo, Abdul Malik Tyagi, Mingcan Yu, Michael Reott, Francesca Sassi, Ilaria Buondonno, Jonathan Adams, M. Neale Weitzmann, Giovanni Carlo Isaia, Roberto Pacifici
Journal: Cell Metabolism (2015)
Preoperative quadriceps strength is a significant predictor of knee function two years after anterior cruciate ligament reconstruction
Authors: I Eitzen, I Holm, M A Risberg
Journal: British Journal of Sports Medicine (2009)

Objective: To identify preoperative predictive factors for knee function two years after reconstructive surgery of the anterior cruciate ligament (ACL). The main hypothesis was that preoperative quadriceps strength would be the most significant predictor for knee function two years after reconstructive surgery. Design: Cohort study. Setting: ACL injured individuals treated at a University Hospital and an outpatient clinic in Oslo, Norway. Participants: Seventy-three individuals with complete unilateral rupture of the ACL scheduled for reconstruction with a bone-patellar-bone autograft were included in the study, from where 60 were available for two-year follow up and included in the final analyses. Interventions: Not applicable. Main outcome measurements: Identification of baseline independent variables that may predict knee function assessed with the Cincinnati Knee Score as dependent variable two years after ACL reconstruction. Results: Quadriceps muscle strength, meniscus injury and the Short-Form-36 Bodily Pain sub score were identified as significant predictors for knee function assessed from the Cincinnati Knee Score two years after ACL reconstruction. Individuals with preoperative quadriceps strength deficits above 20% also had persistent significantly larger strength deficits two years after surgery. Conclusions: Preoperative quadriceps muscle strength deficits and meniscus injuries have significant negative consequences for the long-term functional outcome after ACL reconstruction. From our findings we suggest that ACL reconstruction should not be performed before quadriceps muscle strength deficits of the injured limb is less than 20% of the uninjured limb.
Platelet-activating factor contributes to the induction of nitric oxide synthase by bacterial lipopolysaccharide.
Authors: C Szabó, C C Wu, J A Mitchell, S S Gross, C Thiemermann, J R Vane
Journal: Circulation Research (1993)

This study investigates the role of endogenous platelet-activating factor (PAF) in the production of nitric oxide (NO) by constitutive and inducible isoforms of NO synthase (NOS) in endotoxin shock. In anesthetized rats, 3 hours of endotoxemia resulted in a fall in mean arterial blood pressure (MAP) from 127 +/- 5 (control) to 61 +/- 7 mm Hg and a reduction of the pressor responses to norepinephrine (NE, 1 microgram.kg-1) from 33 +/- 3 (control) to 17 +/- 2 mm Hg. Endotoxemia for 3 hours also resulted in a significant reduction in the contractile effects of NE (10(-8) to 10(-6) mol/L) in thoracic aortas ex vivo. This hyporeactivity to NE was due to an enhanced formation of NO, for it was restored by the NOS inhibitor NG-nitro-L-arginine methyl ester. Animals pretreated with the PAF receptor antagonist WEB 2086 maintained higher MAP (MAP at 180 minutes, 98 +/- 6 mm Hg) and exhibited more pronounced pressor responses to NE at 180 minutes after LPS injection. Moreover, WEB 2086 attenuated by 58% the lipopolysaccharide (LPS)-induced hyporeactivity of the rat aortic rings ex vivo. At 3 hours after LPS injection, calcium-independent NOS activity was induced in the lung. The activity of inducible NOS was significantly lower (by 31%) in lungs of rats pretreated with WEB 2086. The hypothesis that WEB 2086 attenuates the induction of NOS in vivo was substantiated in vitro by the finding that pretreatment with WEB 2086 for 30 minutes inhibited the LPS-stimulated NO production in cultured murine macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients
Authors: Mark Levandovsky, Danielle Harvey, Primo Lara, Ted Wun
Journal: Journal of Hematology & Oncology (2008)

Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome (TTP-HUS) are related and uncommon disorders with a high fatality and complication rate if untreated. Plasma exchange therapy has been shown to produce high response rates and improve survival in patients with many forms of TTP-HUS. We performed a retrospective cohort study of 178 consecutively treated patients with TTP-HUS and analyzed whether clinical or laboratory characteristics could predict for important short- and long-term outcome measures.Overall 30-day mortality was 16% (n = 27). 171 patients (96%) received plasma exchange as the principal treatment, with a mean of 8 exchanges and a mean cumulative infused volume of 42 +/- 71 L of fresh frozen plasma. The rate of complete response was 65% or 55% depending on whether this was defined by a platelet count of 100,000/microl or 150,000/microl, respectively. The rate of relapse was 18%. The Clinical Severity Score did not predict for 30-day mortality or relapse. The time to complete response did not predict for relapse. Renal insufficiency at presentation was associated with a decreased risk of relapse, with each unit increase in serum creatinine associated with a 40% decreased odds of relapse. 72% of our cohort had an idiopathic TTP-sporadic HUS, while 17% had an underlying cancer, received a solid organ transplant or were treated with a mitomycin-based therapy. The estimated overall 5-year survival was 55% and was significantly better in those without serious underlying conditions.Plasma exchange therapy produced both high response and survival rates in this large cohort of patients with TTP-HUS. The Clinical Severity Score did not predict for 30-day mortality or relapse, contrary to our previous findings. Interestingly, the presence of renal insufficiency was associated with a decreased risk of relapse. The most important predictor of mortality was the presence or absence of a serious underlying disorder.