tbuckley/cabot-search huggingface dataset:
Airway Mechanics and Ventilation in Response to Resistive Loading during Sleep
Authors: GIORA PILLAR, ATUL MALHOTRA, ROBERT FOGEL, JOSÉE BEAUREGARD, ROBERT SCHNALL, DAVID P. WHITE
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The male predominance in obstructive sleep apnea (OSA) is currently poorly understood although differences in pharyngeal airway anatomy and physiology have been proposed. As the response to inspiratory resistive loading (IRL) provides important information on both airway collapsibility (mechanics) and ventilatory control, we compared this respiratory response in eight normal women and eight age and body mass index (BMI)-matched men, during stable nonrapid eye movement (NREM) sleep. Upper airway mechanics, ventilation, plus activation of two dilator muscles (genioglossus [GG] and tensor palatini [TP]) were monitored during basal breathing (BL), followed by four sequentially applied loads (5, 10, 15, 25 cm H2O/L/s) for three breaths each. Men developed more severe hypopnea in response to identical applied external loads than did women. At a resistance of 25 cm H2O/L/s, Vt decreased by 26 ± 1% in women compared with 44 ± 1% in men (differences between sexes p < 0.05). Pharyngeal resistance (Rpha) in response to IRL increased significantly more in men than women (37.3 ± 11.2 cm H2O/L/s in men at maximal load, compared with an increase of 6.6 ± 3.9 cm H2O/L/s in women, p < 0.05). Men and women had near identical minute ventilation responses to total load (applied extrinsic plus measured intrinsic), implying no differences in central drive or load response. There were no significant increases in GG or TP activation in response to IRL in either sex. We conclude that normal men are more vulnerable to load-induced hypoventilation than women, due to increased upper airway collapse, which could not be explained by differences in dilator muscle activation. This implies a fundamental difference in the upper airway anatomy and/or tissue characteristics between the two sexes.
Uterine Cervical Cancer Displaying Tumor-Related Leukocytosis: A Distinct Clinical Entity With Radioresistant Feature
Authors: S. Mabuchi, Y. Matsumoto, M. Kawano, K. Minami, Y. Seo, T. Sasano, R. Takahashi, H. Kuroda, T. Hisamatsu, A. Kakigano, M. Hayashi, K. Sawada, T. Hamasaki, E. Morii, H. Kurachi, N. Matsuura, T. Kimura
Journal: JNCI Journal of the National Cancer Institute (2014)

Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism. Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided. TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P = .006), advanced clinical stage (χ 2 test, P = .01), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P < .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (χ 2 test, P < .001), elevated serum G-CSF levels (Student t test, P = .03), larger spleens (Student t test, P = .045), and increased MDSC frequencies in the blood (Student t test, P < .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P = .008 and P = .02, respectively). TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients.
Interleukin-6: a therapeutic Jekyll and Hyde in gastrointestinal and hepatic diseases
Authors: Silvio Danese, Bin Gao
Journal: Gut (2010)

Interleukin-6 (IL-6) was discovered and cloned in 1986. Its receptor IL-6R (CD126) has an unusual organisation, consisting of two proteins: an 80 kDa IL-6 receptor and a 130 kDa signal transducer (gp130). IL-6 and its receptor interact to form a complex consisting of two IL-6 molecules plus two IL-6 receptor proteins and two gp130 proteins. The dimerised gp130 then transduces the signals, a process known as trans-signalling. In addition, a soluble IL-6 receptor also exists and exerts an agonistic effect in complex with IL-6 and can couple with the gp130 to effect transduction. Activation of gp130 leads to activation of JAK kinases and phosphorylation of STAT3, which is translocated to the nucleus and leads to gene expression.1 However, STAT3 also negatively regulates IL-6 signalling by inducing suppressor of cytokine signalling 3 (SOCS3) that in turns inhibits JAK kinase.1

IL-6 is critically involved in both acute and chronic inflammation. At the beginning of acute inflammation, it plays a key role being the main inducer of acute phase reactants such as C-reactive protein, fibrinogen and serum amyloid A protein. When its activity as a proinflammatory cytokine persists, acute inflammation turns into chronic inflammation that includes immune responses. In particular, IL-6 has a detrimental role that favours mononuclear cell accumulation at sites of injury through MCP-1 production, angioproliferation, anti-apoptotic function on T cells and in promoting Th-17 cell differentiation.2 A large number of studies have demonstrated that IL-6 is over-produced in several diseases, and it plays a fundamental role in …
Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia
Authors: Rajasekhar N. V. S. Suragani, Sharon M. Cawley, Robert Li, Samantha Wallner, Mark J. Alexander, Aaron W. Mulivor, Sara Gardenghi, Stefano Rivella, Asya V. Grinberg, R. Scott Pearsall, Ravindra Kumar
Journal: Blood (2014)
Plasma Adiponectin and Pregnancy-Induced Insulin Resistance
Authors: Károly Cseh, Éva Baranyi, Zsolt Melczer, Edit Kaszás, Éva Palik, Gábor Winkler
Journal: Diabetes Care (2004)

e read with interest the article by Aso et al. (1) showing greater plasma concentrations of interleukin-18 (IL-18) in type 2 diabetic patients compared with matched control subjects.While the authors found no significant associations between fasting levels of IL-18 and homeostasis model assessment, a measure of insulin resistance, they found associations between IL-18 and C-reactive protein concentrations.Moreover, carotid intima-media thickness, a validated surrogate measure of atherosclerosis, was greater in diabetic patients with high IL-18 than in those with normal IL-18.As a whole, these data add to the mounting evidence that diabetes may be regarded as a chronic lowgrade inflammatory state.However, we disagree with the authors' conclusions that "the present study demonstrated for the first time that plasma IL-18 concentrations were significantly higher in type 2 diabetic patients than in age-matched control subjects" because we have reported similar findings in Diabetes Care (2).In that study, we demonstrated that 30 newly diagnosed, slightly overweight (BMI 26.9 Ϯ 1.2 kg/m 2 , means Ϯ SD) type 2 diabetic patients without clinical or instrumental evidence of micro-and macrovascular complications presented higher circulating concentrations of IL-18 compared with nondiabetic subjects matched for sex, age, and body weight (205 Ϯ 39 vs. 120 Ϯ 25 pg/ml, P Ͻ 0.01).It is reassuring to see that the fasting values of IL-18 in the Japanese diabetic patients studied by Aso et al. (1) were quite similar (203 Ϯ 153 pg/ml) to those of our Caucasian diabetic patients and that the relation between fasting plasma glucose and IL-18 concentrations was present in both studies (r ϭ 0.31, P Ͻ 0.05; r ϭ 0.24, P Ͻ 0.02, respectively).These results suggest that ethnicity does not to play a major role in these associations.IL-18 is a potent proinflammatory cy-tokine reported to play a role in plaque destabilization (3) and predict cardiovascular death in patients with coronary artery disease (4).Although IL-18 is produced mainly by monocyte/macrophages, a contribution from adipose tissue has recently been suggested (5).In the light of the evidence that IL-18 circulating levels are higher in type 2 diabetic patients than matched nondiabetic subjects and correlate with fasting glucose levels, it does not seem hazardous to hypothesize that IL-18 may play a role in acute coronary syndromes through plaque destabilization ( 6).This working hypothesis, which deserves further investigation, also finds support in the observation that acute hyperglycemia may increase circulation levels of IL-18 in both normal subjects and patients with impaired glucose tolerance (7).
Increased levels of surfactant protein A and D in bronchoalveolar lavage fluids in patients with bronchial asthma
Authors: G Cheng, T Ueda, T Numao, Y Kuroki, H Nakajima, Y Fukushima, S Motojima, T Fukuda
Journal: European Respiratory Journal (2000)

Surfactant proteins (SP)-A and SP-D are collagen-like glycoproteins belonging to the "collectin" class of C-type lectins, which are primarily synthesized in type II cells. Recent studies reported the possibility of local production of SP-A and SP-D in the airways, but the amounts of surfactant proteins in patients with bronchial asthma have not been studied. The composition of surfactant proteins in mild, stable asthmatics in the first lavage as bronchial lavage (BL) and the second and third lavages consecutively as alveolar lavages (AL) were therefore, analysed separately. The co-relationships in the BL between the amounts of surfactant proteins and those of fucose, which is one of the markers of submucosal secretion were also analysed. Increased amounts of SP-A in BL and AL of in asthmatics were found as compared with those in controls. A high concentration of SP-D in the AL asthma patients was also found. The levels of SP-A correlated with those of fucose in patients with bronchial asthma (r=0.849, p<0.01). The observations in the present study suggested that surfactant protein A may be secreted from the airways with allergic inflammation in a different manner from the alveoli. The increased levels of surfactant proteins A and D may play a protective role in an allergic inflammation in the pathogenesis of bronchial asthma.
Perturbed Length-Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations
Authors: Vasco Sequeira, Paul J.M. Wijnker, Louise L.A.M. Nijenkamp, Diederik W.D. Kuster, Aref Najafi, E. Rosalie Witjas-Paalberends, Jessica A. Regan, Nicky Boontje, Folkert J. ten Cate, Tjeerd Germans, Lucie Carrier, Sakthivel Sadayappan, Marjon A. van Slegtenhorst, Ruud Zaremba, D. Brian Foster, Anne M. Murphy, Corrado Poggesi, Cris dos Remedios, Ger J.M. Stienen, Carolyn Y. Ho, Michelle Michels, Jolanda van der Velden
Journal: Circulation Research (2013)

High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce.To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins.Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values.High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.
Protein Kinase CK2α as an Unfavorable Prognostic Marker and Novel Therapeutic Target in Acute Myeloid Leukemia
Authors: Jin Seok Kim, Ju In Eom, June-Won Cheong, Ae Jin Choi, Jin Koo Lee, Woo Ick Yang, Yoo Hong Min
Journal: Clinical Cancer Research (2007)

Abstract Introduction: Protein kinase CK2 is implicated in cellular proliferation and transformation. However, the clinical and biological significances of CK2 have not been elucidated in acute myeloid leukemia (AML). Experimental Design: We evaluated the biological significances of catalytic subunit of CK2 (CK2α) expression in leukemia cell lines and primary leukemic blasts obtained from AML patients. Results: In this study, the expression of CK2α was elevated in a substantial proportion of AML. In AML patients with normal karyotype, the disease-free survival and overall survival rates were significantly lower in the CK2α-high compared with the CK2α-low AML cases (P = 0.0252 and P = 0.0392, respectively). An induced overexpression of CK2α increased the levels of Ser473 phosphorylated (p)-Akt/protein kinase B (PKB), p-PDK1, pFKHR, p-BAD, Bcl-2, Bcl-xL, Mcl-1, and XIAP. Treatment of U937 cell line and primary AML blasts with selective CK2 inhibitor, tetrabromobenzotriazole or apigenin, reduced the levels of these molecules in a dose-dependent manner. CK2α small interfering RNA treatment also resulted in a down-regulation of p-Akt/PKB and Bcl-2 in U937 cells. Apigenin-induced cell death was preferentially observed in the CK2α-high leukemia cell lines, HL-60 and NB4, which was accompanied by cytoplasmic release of SMAC/DIABLO and proteolytic cleavage of procaspase-9, procaspase-3, procaspase-8, and poly(ADP)ribose polymerase. An induced overexpression of CK2α potentially enhanced the sensitivity of U937 cells to the apigenin-induced cell death. Apigenin-induced cell death was significantly higher in CK2α-high AML compared with CK2α-low AML (P &amp;lt; 0.0001) or normal bone marrow samples (P &amp;lt; 0.0001). Conclusion: These findings strongly suggest protein kinase CK2α as an unfavorable prognostic marker and novel therapeutic target in AML.
Induced pluripotent stem cells model personalized variations in liver disease resulting from α1‐antitrypsin deficiency
Authors: Edgar N. Tafaleng, Souvik Chakraborty, Bing Han, Pamela Hale, Wanquan Wu, Alejandro Soto‐Gutierrez, Carol A. Feghali‐Bostwick, Andrew A. Wilson, Darrell N. Kotton, Masaki Nagaya, Stephen C. Strom, Jayanta Roy‐Chowdhury, Donna B. Stolz, David H. Perlmutter, Ira J. Fox
Journal: Hepatology (2015)

In the classical form of α1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1-antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient-specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte-like cells (iHeps) having many characteristics of hepatocytes. Pulse-chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild-type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD.iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that "proteostasis" mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies.
Therapeutic Implications of Leukemic Stem Cell Pathways
Authors: Saranya Chumsri, William Matsui, Angelika M. Burger
Journal: Clinical Cancer Research (2007)

Abstract An emerging concept in cancer biology is that a rare population of cancer stem cells exists among the heterogeneous cell mass that constitutes a tumor. This concept is best understood in human myeloid leukemia. Normal and malignant hematopoietic stem cell functions are defined by a common set of critical stemness genes that regulate self-renewal and developmental pathways. Several stemness factors, such as Notch or telomerase, show differential activation in normal hematopoietic versus leukemia stem cells. These differences could be exploited therapeutically even with drugs that are already in clinical use for the treatment of leukemia. The translation of novel and existing leukemic stem cell–directed therapies into clinical practice, however, will require changes in clinical trial design and the inclusion of stem cell biomarkers as correlative end points.
The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus
Authors: G Oroszi
Journal: Annals of the Rheumatic Diseases (2006)

<h3>Abstract</h3> <h3>Background</h3> Estimating the actual number of COVID-19 infections is crucial for steering through the COVID-19 pandemic crisis. It is, however, notoriously difficult, as many cases have no or only mild symptoms. Surveillance data for in-household secondary infections offers unbiased samples for COVID-19 prevalence estimation. <h3>Methods</h3> We analyse 16 115 Polish surveillance records to obtain key figures of the COVID-19 pandemic. We propose conservative upper and lower bound estimators for the number of SARS-CoV-2 infections. Further, we estimate age-dependent bounds on the severe case rate, death rate, and the in-household attack rate. <h3>Results</h3> By maximum likelihood estimates, the total number of COVID-19 cases in Poland as of July 22nd, 2020, is at most around 13 times larger and at least 1.6 times larger than the recorded number. The lower bound on the severeness rate ranges between 0.2% for the 0–39 year-old to 5.7% for older than 80, while the upper bound is between 2.6% and 34.1%. The lower bound on the death rate is between 0.04% for the age group 40–59 to 1.34% for the oldest. Overall, the severeness and death rates grow exponentially with age. The in-household attack ratio is 8.18% for the youngest group and 16.88% for the oldest. <h3>Conclusions</h3> The proposed approach derives highly relevant figures on the COVID-19 pandemic from routine surveillance data, under assumption that household members of detected infected are tested and all severe cases are diagnosed. <h3>MOCOS</h3> The MOCOS (<b>MO</b>delling <b>CO</b>rona <b>S</b>pread) international research group is an interdisciplinary scientific consortium. The following authors are MOCOS members: Barbara Adamik, Marek Bawiec, Viktor Bezborodov, Przemyslaw Biecek, Wolfgang Bock, Marcin Bodych, Jan Pablo Burgard, Tyll Krueger, Agata Migalska, Tomasz Ożański, Barbara Pabjan, Magdalena Rosińska, Piotr Sobczyk and Ewa Szczurek
Side Effects of Bacillus Calmette-Guérin (BCG) in the Treatment of Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Bladder: Results of the EORTC Genito-Urinary Cancers Group Randomised Phase 3 Study Comparing One-third Dose with Full Dose and 1 Year with 3 Years of Maintenance BCG
Authors: Maurizio Brausi, Jorg Oddens, Richard Sylvester, Aldo Bono, Cees van de Beek, George van Andel, Paolo Gontero, Levent Turkeri, Sandrine Marreaud, Sandra Collette, Willem Oosterlinck
Journal: European Urology (2013)
Innovations and Challenges in Melanoma: Summary Statement from the First Cambridge Conference
Authors: Michael B. Atkins, David E. Elder, Richard Essner, Keith T. Flaherty, Thomas F. Gajewski, Frank G. Haluska, Patrick Hwu, Ulrich Keilholz, John M. Kirkwood, James W. Mier, Merrick I. Ross, Craig L. Slingluff, Vernon K. Sondak, Jeffrey A. Sosman, Martin A. Weinstock, Laura King
Journal: Clinical Cancer Research (2006)

Innovations and Challenges in Melanoma, chaired by Michael Atkins and cochaired by Ulrich Keilholz, John Kirkwood, and Jeffrey Sosman, was held July 15 to 16, 2005, in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, surgical oncology, anatomic pathology, dermatology, and immunotherapy who wished to advance the field of melanoma treatment by exchanging information and perspectives regarding recent advances and recommendations for further study. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on how genetics, biology, and data information can enhance our understanding of melanoma biology and help inform the use of therapies for this disease.
Effect of methacholine induced bronchoconstriction on the spectral characteristics of breath sounds in asthma.
Authors: D P Spence, S Bentley, D H Evans, M D Morgan
Journal: Thorax (1992)

BACKGROUND: Analysis of breath sounds by digital techniques offers an attractive non-invasive method of monitoring changes in airway calibre. Asthmatic breath sounds have been analysed and related to changes in forced expiratory volume in one second (FEV1). METHODS: Bronchoconstriction was induced with methacholine in six asthmatic subjects on two occasions and changes in FEV1 and breath sound spectra were measured. RESULTS: Audible wheeze appeared after a mean (SE) fall in FEV1 of 35% (6.3%) but the level was not reproducible within patients. The mean and median frequency of the spectra of breath sounds correlated with the percentage of predicted FEV1 (r = -0.5 and -0.6 respectively; p &lt; 0.001). Inclusion of the quartile frequencies in a stepwise multiple regression reduced the residual variance by a further 9%. CONCLUSION: Detecting changes in airway calibre by this method of sound analysis so far produces qualitative data only and will not yield quantitative data in individual patients.