tbuckley/cabot-search huggingface dataset:
Serum vitamin D levels and exercise-induced bronchoconstriction in children with asthma
Authors: I. Chinellato, M. Piazza, M. Sandri, D.G. Peroni, F. Cardinale, G.L. Piacentini, A.L. Boner
Journal: European Respiratory Journal (2010)

Epidemiological studies have established a relationship between low levels of serum vitamin D and reduced lung function in healthy adults, and asthma onset and severity in children. However, no study has examined the relationship between vitamin D levels and exercise-induced bronchoconstriction in asthmatic children. We evaluated the relationship between 25-hydroxyvitamin D concentrations and baseline forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and change in FEV1 (ΔFEV1) after a standardised exercise challenge in 45 children with intermittent asthma. Only 11% of the children had desirable serum vitamin D levels (at least 30-40 ng·mL(-1)). A positive correlation was found between serum 25-hydroxyvitamin D and both FVC (r=0.34; p=0.037) and FEV1 (r=0.32; p=0.037). Subjects with a positive response to the exercise challenge (ΔFEV1≥10%) presented lower serum levels of 25-hydroxyvitamin D than children with a negative challenge (mean±sd 16.2±5.2 versus 23.4±7.0 ng·mL(-1), respectively; p=0.001). Our results indicate that hypovitaminosis D is frequent in asthmatic children who live in a Mediterranean country. In those children, lower levels of vitamin D are associated with reduced lung function and increased reactivity to exercise.
Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33
Authors: Ninel Azoitei, Christopher M. Hoffmann, Jana M. Ellegast, Claudia R. Ball, Kerstin Obermayer, Ulrike Gößele, Britta Koch, Katrin Faber, Felicitas Genze, Mark Schrader, Hans A. Kestler, Hartmut Döhner, Gabriela Chiosis, Hanno Glimm, Stefan Fröhling, Claudia Scholl
Journal: The Journal of Experimental Medicine (2012)

Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential.
Deamidation of Asparagine in a Major Histocompatibility Complex–Bound Peptide Affects T Cell Recognition but Does Not Explain Type B Reactivity
Authors: Thomas P. Cirrito, Zheng Pu, M. Brian Deck, Emil R. Unanue
Journal: The Journal of Experimental Medicine (2001)

We have analyzed a panel of T cell hybridomas specific for the chemically dominant epitope of hen egg-white lysozyme 48-61 which has asparagine 59 as an important T cell receptor contact residue. A number of T cells recognize 48-61 with asparagine at position 59, but not the aspartic acid or isoaspartic acid derivatives. Conversely, we find T cells that specifically recognize 48-61 bearing an isoaspartic acid at residue 59, but not asparagine. For other T cells, asparagine, aspartic acid, or isoaspartic acid at residue 59 is irrelevant. We present evidence that our previous distinction between type A and type B T cells is not explained by asparagine deamidation at residue 59.
The Nedd8-Activating Enzyme Inhibitor MLN4924 Thwarts Microenvironment-Driven NF-κB Activation and Induces Apoptosis in Chronic Lymphocytic Leukemia B Cells
Authors: J. Claire Godbersen, Leigh Ann Humphries, Olga V. Danilova, Peter E. Kebbekus, Jennifer R. Brown, Alan Eastman, Alexey V. Danilov
Journal: Clinical Cancer Research (2014)

Stromal-mediated signaling enhances NF-κB pathway activity in chronic lymphocytic leukemia (CLL) B cells, leading to cell survival and chemoresistance. Ubiquitination of IκBα may partially account for constitutive activation of NF-κB. MLN4924 is an investigational agent that inhibits the Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and preventing degradation of their substrates.We conducted a preclinical assessment of MLN4924 in CLL. Primary CLL cells were cocultured in vitro with CD40L-expressing stroma to mimic the prosurvival conditions present in lymphoid tissue. The effect of MLN4924 on CLL cell apoptosis, NF-κB pathway activity, Bcl-2 family members, and cell cycle was assessed by flow cytometry, Western blotting, PCR, and immunocytochemistry.CD40L-expressing stroma protected CLL cells from spontaneous apoptosis and induced resistance to multiple drugs, accompanied by NF-κB activation and Bim repression. Treatment with MLN4924 induced CLL cell apoptosis and circumvented stroma-mediated resistance. This was accompanied by accumulation of phospho-IκBα, decreased nuclear translocation of p65 and p52 leading to inhibition of both the canonical and noncanonical NF-κB pathways, and reduced transcription of their target genes, notably chemokines. MLN4924 promoted induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins. siRNA-mediated knockdown of Bim or Noxa decreased sensitivity to MLN4924. MLN4924 enhanced the antitumor activity of the inhibitors of B-cell receptor (BCR)-associated kinases.MLN4924 disrupts NF-κB activation and induces Bim expression in CLL cells, thereby preventing stroma-mediated resistance. Our data provide rationale for further evaluation of MLN4924 in CLL.
Reproducibility and clinical utility of tendon palpation to detect patellar tendinopathy in young basketball players
Authors: J L Cook, K M Khan, Z S Kiss, C R Purdam, L Griffiths
Journal: British Journal of Sports Medicine (2001)

Background —Palpation is an important clinical test for jumper's knee. Objectives —To ( a ) test the reproducibility of palpation tenderness, ( b ) evaluate the sensitivity and specificity of palpation in subjects with clinical symptoms of jumper's knee, and ( c ) determine whether tenderness to palpation may serve as a useful screening test for patellar tendinopathy. The yardstick for diagnosis of patellar tendinopathy was ultrasonographic abnormality. Methods —In 326 junior symptomatic and asymptomatic athletes' tendons, palpation was performed by a single examiner before ultrasonographic examination by a certified ultrasound radiologist. In 58 tendons, palpation was performed twice to test reliability. Tenderness to palpation was scored on a scale from 0 to 3 where 0 represented no pain, and 1, 2, and 3 represented mild, moderate, and severe tenderness respectively. Results —Patellar tendon palpation was a reliable examination for a single examiner (Pearson r = 0.82). In symptomatic tendons, the positive predictive value of palpation was 68%. As a screening examination in asymptomatic subjects, the positive predictive value of tendon palpation was 36–38%. Moderate and severe palpation tenderness were better predictors of ultrasonographic tendon pathology than absent or mild tenderness (p&lt;0.001). Tender and symptomatic tendons were more likely to have ultrasound abnormality than tenderness alone (p&lt;0.01). Conclusions —In this age group, palpation is a reliable test but it is not cost effective in detecting patellar tendinopathy in a preparticipation examination. In symptomatic tendons, palpation is a moderately sensitive but not specific test. Mild tenderness in the patellar tendons in asymptomatic jumping athletes should be considered normal.
Outcomes of Growth Hormone Replacement Therapy in Survivors of Childhood Acute Lymphoblastic Leukemia
Authors: Wing Leung, Susan R. Rose, Yinmei Zhou, Michael L. Hancock, Stephen Burstein, Elizabeth A. Schriock, Robert Lustig, Robert K. Danish, William E. Evans, Melissa M. Hudson, Ching-Hon Pui
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Little is known about the long-term efficacy or adverse effects of growth hormone (GH) replacement therapy in survivors of childhood acute lymphoblastic leukemia (ALL) who have GH deficiency. We investigated the adult height of patients who had received GH and estimated their risk of leukemia relapse or development of a second malignancy. PATIENTS AND METHODS: Of 910 patients treated for ALL at a single institution, 47 had received GH replacement therapy. The linear growth of these 47 patients was retrospectively evaluated. Their risk of leukemia relapse or second malignancy was compared with that of survivors who did not undergo GH therapy. RESULTS: The median height SD score at the start of GH therapy had decreased by 1.0 since the time of diagnosis of ALL. After a median duration of 4.5 years of GH therapy, adult height SD scores improved and approached height SD scores at the time of diagnosis of ALL. The median adult height for male patients was 173.2 cm (range, 157 to 191.9 cm), and for female patients, it was 158.1 cm (range, 141 to 168 cm). None of the patients developed adverse effects requiring discontinuation of GH treatment. At the 7-year and 11-year landmarks in continuous hematologic remission, there was no statistical evidence that GH therapy was associated with leukemia relapse or development of a second malignancy. CONCLUSION: This study suggests that GH replacement therapy is safe and efficacious for the correction of GH deficiency in survivors of childhood ALL.
Enhanced Leptin-Stimulated Pi3k Activation in the CNS Promotes White Adipose Tissue Transdifferentiation
Authors: Leona Plum, Eva Rother, Heike Münzberg, F. Thomas Wunderlich, Donald A. Morgan, Brigitte Hampel, Marya Shanabrough, Ruth Janoschek, A. Christine Könner, Jens Alber, Akira Suzuki, Wilhelm Krone, Tamas L. Horvath, Kamal Rahmouni, Jens C. Brüning
Journal: Cell Metabolism (2007)
Work Stress and Low Sense of Coherence Is Associated With Type 2 Diabetes in Middle-Aged Swedish Women
Authors: Emilie E. Agardh, Anders Ahlbom, Tomas Andersson, Suad Efendic, Valdemar Grill, Johan Hallqvist, Anders Norman, Claes-Göran Östenson
Journal: Diabetes Care (2003)

OBJECTIVE—The risk of type 2 diabetes is suggested to be increased for individuals exposed to stress. We analyzed the association of work stress by high demands, low decision latitude, and job strain (combination of high demands and low decision latitude) with type 2 diabetes. We also studied low sense of coherence (SOC) (a factor for successful coping with stressors) in association with type 2 diabetes. Finally, we investigated the combination of SOC and demands or SOC and decision latitude in association with the disease. RESEARCH DESIGN AND METHODS—This cross-sectional study recruited 4,821 healthy Swedish women (aged 35–56 years) residing in five municipalities in the Stockholm area. An oral glucose tolerance test identified 52 women with type 2 diabetes. Relative risks (RRs) with 95% CIs were estimated in a logistic multiple regression analysis. RESULTS—No association was found between high demands and type 2 diabetes (RR 1.1 [CI 0.5–2.2]). Low decision latitude was associated with type 2 diabetes with a RR of 2.2 (1.0–4.8). The RR of type 2 diabetes with low SOC was 3.7 (1.2–11.2). The combination of low SOC and low decision latitude was associated with type 2 diabetes with a RR of 2.6 (1.2–5.7). Homeostasis model assessment revealed an association of 4.2 (1.2–15.0) between low SOC and insulin resistance. CONCLUSIONS—This study provided new evidence that stress factors such as low decision latitude at work and low SOC were associated with type 2 diabetes in middle-aged Swedish women.
Cardiac Myosin Binding Protein-C Phosphorylation in a β-Myosin Heavy Chain Background
Authors: Sakthivel Sadayappan, James Gulick, Raisa Klevitsky, John N. Lorenz, Michelle Sargent, Jeffery D. Molkentin, Jeffrey Robbins
Journal: Circulation (2009)

Background— Cardiac myosin binding protein-C (cMyBP-C) phosphorylation modulates cardiac contractility. When expressed in cMyBP-C–null (cMyBP-C (t/t) ) hearts, a cMyBP-C phosphomimetic (cMyBP-C AllP+ ) rescued cardiac dysfunction and protected the hearts from ischemia/reperfusion injury. However, cMyBP-C function may be dependent on the myosin isoform type. Because these replacements were performed in the mouse heart, which contains predominantly α-myosin heavy chain (α-MyHC), the applicability of the data to humans, whose cardiomyocytes contain predominantly β-MyHC, is unclear. We determined the effect(s) of cMyBP-C phosphorylation in a β-MyHC transgenic mouse heart in which &gt;80% of the α-MyHC was replaced by β-MyHC, which is the predominant myosin isoform in human cardiac muscle. Methods and Results— To determine the effects of cMyBP-C phosphorylation in a β-MyHC background, transgenic mice expressing normal cMyBP-C (cMyBP-C WT ), nonphosphorylatable cMyBP-C (cMyBP-C AllP − ), or cMyBP-C AllP+ were bred into the β-MyHC background (β). These mice were then crossed into the cMyBP-C (t/t) background to ensure the absence of endogenous cMyBP-C. cMyBP-C (t/t)/β and cMyBP-C AllP − :(t/t)/β mice died prematurely because of heart failure, confirming that cMyBP-C phosphorylation is essential in the β-MyHC background. cMyBP-C AllP+:(t/t)/β and cMyBP-C WT:(t/t)/β hearts showed no morbidity and mortality, and cMyBP-C AllP+:(t/t)/β hearts were significantly cardioprotected from ischemia/reperfusion injury. Conclusions— cMyBP-C phosphorylation is necessary for basal myocardial function in the β-MyHC background and can preserve function after ischemia/reperfusion injury. Our studies justify exploration of cMyBP-C phosphorylation as a therapeutic target in the human heart.
Conditional Deletion of the Focal Adhesion Kinase FAK Alters Remodeling of the Blood–Brain Barrier in Glioma
Authors: Jisook Lee, Alexandra K. Borboa, Hyun Bae Chun, Andrew Baird, Brian P. Eliceiri
Journal: Cancer Research (2010)

Abstract Gliomas generally infiltrate the surrounding normal brain parenchyma, a process associated with increased vascular permeability (VP) and dysregulation of the blood–brain barrier (BBB). However, the molecular mechanisms underlying glioma-induced VP in the brain remain poorly understood. Using a conditional, endothelium-specific deletion of the focal adhesion kinase (FAK) in the mouse (FAK CKO), we show that FAK is critical for destabilization of the tumor endothelium in tumor-bearing mice, with mutant mice exhibiting a relatively normalized vasculature compared with wild-type mice (FAK WT). Tumor vessels in the FAK CKO mice displayed reduced VP compared with FAK WT mice, resulting in reduced tumor growth. Additionally, FAK CKO mice displayed partial restoration of cell–cell junction proteins in the tumor vessels and astrocyte–endothelium interactions in tumors, revealing an additional role of astrocytes in mediating tumor-induced VP. Together, these results provide genetic evidence that FAK is a mediator of tumor-induced VP in the brain. Our findings may help understand how therapeutics might be used to regulate specific cell-type interactions to restore BBB structure/function in cancer and perhaps other pathologic conditions. Cancer Res; 70(24); 10131–40. ©2010 AACR.
How Many Sonograms Are Needed to Reliably Predict the Absence of Fetal Overgrowth in Gestational Diabetes Mellitus Pregnancies?
Authors: Ute M. Schaefer-Graf, Luise Wendt, David A. Sacks, Öemer Kilavuz, Bettina Gaber, Sabine Metzner, Klaus Vetter, Michael Abou-Dakn
Journal: Diabetes Care (2010)

Serial measurements of the fetal abdominal circumference have been used to guide metabolic management of pregnancies complicated by gestational diabetes mellitus (GDM). A reduction in the number of repeat ultrasound examinations would save resources. Our purpose was to determine the number of serial abdominal circumference measurements per patient necessary to reliably predict the absence of fetal overgrowth.Women who had GDM were asked to return for repeat ultrasound at 3- to 4-week intervals starting at initiation of care (mean 26.9 ± 5.7 weeks). Maternal risk factors associated with fetal overgrowth were determined.A total of 4,478 ultrasound examinations were performed on 1,914 subjects (2.3 ± 1.2 per pregnancy). Of the 518 women with fetal abdominal circumference >90th percentile, it was diagnosed in 73.9% with the first ultrasound examination at entry and in 13.1% with the second ultrasound examination. Of the fetuses, 85.9 and 86.9% of the fetuses were born non-large for gestational age (LGA) when abdominal circumference was <90th percentile at 24-27 weeks and 28-32 weeks, respectively, and 88.0% were born non-LGA when both scans showed normal growth. For those women who had no risk factors for fetal overgrowth (risk factors: BMI >30 kg/m², history of macrosomia, and fasting glucose > 100 mg/dl), the accuracy of prediction of a non-LGA neonate was 90.0, 89.5, and 95.2%. The predictive ability did not increase with more than two normal scans.The yield of sonographic diagnosis of a large fetus drops markedly after the finding of a fetal abdominal circumference <90th percentile on two sonograms, which excludes with high reliability the risk of a LGA newborn. The ability was enhanced in women who had no risk factors for neonatal macrosomia.
Rugby Union: faster, higher, stronger: keeping an evolving sport safe
Authors: Andrew D Murray, Iain Robert Murray, James Robson
Journal: British Journal of Sports Medicine (2012)

Since the International Rugby Board (IRB) declared Rugby Union an ‘open’ game thus effectively ushering in professionalism, players have become faster and stronger.1 Force equals mass multiplied by acceleration: logically increased force at collision will lead to more injuries. Surveillance studies and injury databases have provided comprehensive datasets which confirm changing patterns of injury in rugby.2 We examine what is being done, and how safety can be improved in rugby.

Rugby Union is experiencing unprecedented global growth. In total, 3.5 million men, women and children play worldwide, with 117 Unions in membership of the IRB.3 Modern rugby is ever more physically demanding due to increases in ball in play time, and speed of play. A fourfold increase in tackles and rucks per game has been noted.4–6 Teams with the tallest and heaviest players outperformed others in the Rugby World Cup.7 The IRB have appointed a Chief Medical Officer, a safety consultant and working groups to ensure that safety is maintained.

Epidemiological data provide insight into changes in the nature and frequency of injuries. Some injuries are unavoidable and ‘uncontrollable’, whereas others result from dangerous play. An international consensus statement on definitions and procedures used for injury surveillance has allowed meaningful comparisons of results across studies.8 The establishment of major event surveillance studies including the (2007) Rugby World Cup Injury Surveillance Study,2 …
Comparison of telomerase activity in malignant and benign pleural effusions
Authors: Mousavi S.A.J., R Bahari, Karimi
Journal: European Respiratory Journal (2011)

Background:  Despite advances in diagnosis and treatment of lung cancer, patients survival has just improved in those with early stages. Telomerase is a tumor marker that has been focused recently as a novel tool for early diagnosis of lung cancer.   Objective:  To compare telomerase activity in malignant and benign pleural effusions in Rasoul-e-Akram Hospital of Tehran.   Methods & materials:  Telomerase activity in 28 consecutive pleural effusions (19 malignant and 9 benign; histopathologic diagnosis) assessed with telomeric repeat amplification protocol (TRAP) between Apr. 2006 and Sep. 2007. Data analysis was performed by chi-squared test and t-test; results expressed as frequency, percent, and mean ± SD.   Result:  20 cases (71.4%) from the total of 28 pleural effusions were positive for telomerase activity. Telomerase activity was positive in all 19 malignant effusions, while only one effusions from benign conditions (TB) had telomerase activity (P 0.05).   Conclusion:  Telomerase activity is a highly sensitive and specific diagnostic biomarker for malignancy and may be used as an adjunct to other diagnostic tools such as cytological findings for malignant pleural effusions.
Geohelminth infections: a review of the role of IgE and assessment of potential risks of anti‐IgE treatment
Authors: P. J. Cooper, G. Ayre, C. Martin, J. A. Rizzo, E. V. Ponte, A. A. Cruz
Journal: Allergy (2008)

Geohelminth infections are major parasitic infections with a worldwide distribution. Immunoglobulin E (IgE) is considered to play a central role in protective immunity against these parasites although the evidence from experimental animal models infected with helminth parasites and treated with anti‐IgE antibodies and from observational studies in human populations of the immunologic correlates of protective immunity against helminths do not support a critical role for IgE in mediating protection against helminths. Anti‐IgE treatment of human allergic disorders using a humanized monoclonal IgE antibody (omalizumab, Xolair) has been approved for clinical use in the USA and Europe and there is concern that this treatment may be associated with increased morbidity in populations exposed to helminth infections. A recently published randomized controlled trial investigating the risk of geohelminth infections in allergic patients receiving omalizumab in Brazil has provided some evidence that omalizumab may not be associated with increased morbidity attributable to these parasites. This review examines the evidence for a role of IgE in protective immunity against helminth parasites, discusses the findings of the randomized controlled trial, assesses the potential risks and provides recommendations for anti‐IgE treatment in groups of allergic patients with different exposure risks for helminth infections.
Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer
Authors: F.-C. Bidard, C.K.Y. Ng, P. Cottu, S. Piscuoglio, L. Escalup, R.A. Sakr, F. Reyal, P. Mariani, R. Lim, L. Wang, L. Norton, V. Servois, B. Sigal, A. Vincent-Salomon, B. Weigelt, J.-Y. Pierga, J.S. Reis-Filho
Journal: Annals of Oncology (2015)