tbuckley/cabot-search huggingface dataset:
Abstract 142: A human DNA methylation analysis microarray
Authors: Michael Ruvolo, Alexander Wong, A. Ashutosh, Shane Giles, Zohar Yakhini, Douglas Roberts
Journal: Cancer Research (2010)

Abstract CpG islands are stretches of high GC content DNA containing multiple CpG dinucleotides. When CpG dinucleotides within these islands are methylated, especially in promoter regions, expression of the corresponding downstream genes is often repressed. Aberrant CpG island methylation is implicated in cancer. We have refined a protocol for methylated DNA immunoprecipitation (mDIP) and coupled it with microarray detection. DNA isolated by mDIP is fluorescently labeled and hybridized to an oligonucleotide microarray that specifically represents putative methylation target regions in the human genome. This microarray contains ∼237,000 oligo probes tiling ∼28,000 CpG islands along with ∼5000 recently identified regions determined to be undermethylated across multiple tissue types. As proof of concept we perform mDIP and microarray analysis of human genomic DNA samples from normal tissues. We compare our mDIP array data with bisulfite sequencing data. Performing analysis with Agilent Genomic Workbench we demonstrate the ability to distinguish probes corresponding to methylated regions from probes corresponding to unmethylated regions. We then apply the assay to tumor and normal DNA and identify differential methylation patterns. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 142.
Morbidity and mortality associated with the restrictive spirometric pattern: a longitudinal study
Authors: S. Guerra, D. L. Sherrill, C. Venker, C. M. Ceccato, M. Halonen, F. D. Martinez
Journal: Thorax (2010)

Recent studies have suggested that a restrictive pattern assessed with a single spirometric test is associated with increased morbidity and mortality. This study was undertaken to determine demographic, clinical and mortality profiles of subjects with either a recurrent or an inconsistent restrictive spirometric pattern assessed prospectively.Data from 2048 adult participants in the population-based TESAOD study were analysed. Normal (forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) ratio >or=70% and FVC >or=80% predicted), restrictive (FEV(1)/FVC >or=70% and FVC <80% predicted) and obstructive (FEV(1)/FVC <70%) patterns were assessed at the enrollment survey in 1972 and in 11 subsequent follow-up surveys up to 1996. Demographic and clinical characteristics were measured at enrollment and vital status and cause of death were assessed at January 2005.Overall, 12% of participants had a restrictive spirometric pattern at enrollment. They were less likely to be male, to smoke and to have asthma, and had lower IgE levels than subjects in the obstructive group. Among subjects with a restrictive pattern at enrollment, 38% developed an obstructive pattern during follow-up. The remaining 62% had either a recurrent (restrictive pattern >or=50% of follow-up surveys) or inconsistent (restrictive pattern <50% of follow-up surveys) longitudinal restrictive pattern. The recurrent and inconsistent restrictive groups had increased mortality risk for all-cause (adjusted HR 1.7 (95% CI 1.3 to 2.3) and 1.9 (95% CI 1.4 to 2.6), respectively), heart disease (2.0 (95% CI 1.3 to 3.1) and 2.7 (95% CI 1.7 to 4.3)), stroke (2.4 (95% CI 0.9 to 6.3) and 3.5 (95% CI 1.2 to 9.8)) and diabetes (8.0 (95% CI 2.9 to 21.8) and 6.0 (95% CI 1.9 to 19.2)).The restrictive spirometric pattern identifies a pulmonary condition that is distinguishable from obstructive lung disease and is associated with an increased risk of life-threatening comorbidities.
Pneumococcal pneumonia presenting with septic shock: host- and pathogen-related factors and outcomes
Authors: C Garcia-Vidal, C Ardanuy, F Tubau, D Viasus, J Dorca, J Linares, F Gudiol, J Carratala
Journal: Thorax (2009)

<h3>Background:</h3> Host- and pathogen-related factors associated with septic shock in pneumococcal pneumonia are not well defined. The aim of this study was to identify risk factors for septic shock and to ascertain patient outcomes. Serotypes, genotypes and antibiotic resistance of isolated strains were also analysed. <h3>Methods:</h3> Observational analysis of a prospective cohort of non-severely immunosuppressed hospitalised adults with pneumococcal pneumonia. Septic shock was defined as a systolic blood pressure of &lt;90 mm Hg and peripheral hypoperfusion with the need for vasopressors for &gt;4 h after fluid replacement. <h3>Results:</h3> 1041 patients with pneumococcal pneumonia diagnosed by Gram stain and culture of appropriate samples and/or urine antigen test were documented, of whom 114 (10.9%) had septic shock at admission. After adjustment, independent risk factors for shock were current tobacco smoking (OR, 2.11; 95% CI, 1.02 to 4.34; p = 0.044), chronic corticosteroid treatment (OR, 4.45; 95% CI, 1.75 to 11.32; p = 0.002) and serotype 3 (OR, 2.24; 95% CI, 1.12 to 4.475; p = 0.022). No significant differences were found in genotypes and rates of antibiotic resistance. Compared with the remaining patients, patients with septic shock required mechanical ventilation more frequently (37% vs 4%; p&lt;0.001) and had longer length of stay (11 vs 8 days; p&lt;0.001). The early (10% vs 1%; p&lt;0.001) and overall case fatality rates (25% vs 5%; p&lt;0.001) were higher in patients with shock. <h3>Conclusions:</h3> Septic shock is a frequent complication of pneumococcal pneumonia and causes high morbidity and mortality. Current tobacco smoking, chronic corticosteroid treatment and infection caused by serotype 3 are independent risk factors for this complication.
Establishment and characterization of a human combined hepatocholangiocarcinoma cell line and its heterologous transplantation in nude mice
Authors: Tastuo Murakami, Hirohisa Yano, Masafumi Maruiwa, Shigetaka Sugihara, Masamichi Kojiro
Journal: Hepatology (1987)

A human cell line (KMCH-1) derived from a surgical specimen of combined hepatocellular and cholangiocarcinoma has been established. The original tumor consisted of both hepatocellular carcinoma of the trabecular type and cholangiocellular carcinoma. This cell line has been maintained for 26 months through 75 passages. KMCH-1 cells show characteristics of adenocarcinoma on light and electron microscopy. They proliferate in culture in a pave stone arrangement. The doubling time of these cells at the 24th passage was 39 hr. Chromosome analysis revealed a chromosome number ranging from 60 to 98, with a modal number of 74. KMCH-1 cells produced tumors several months after subcutaneous and intraperitoneal transplantations into athymic nude mice. Histologically, the subcutaneous tumors were poorly differentiated adrenocarcinoma, while intraperitoneal tumors were moderately to well-differentiated adenocarcinoma. Hepatocellular carcinoma components were not observed. Thus, KMCH-1 cells demonstrate the feature of cholangiocellular carcinoma in vitro and in vivo . This KMCH-1 cell line is the first established combined hepatocellular and cholangiocarcinoma cell line and may contribute to further investigation of combined hepatocellular and cholangiocarcinoma.
Genetic Susceptibility to Head and Neck Squamous Cell Carcinoma
Authors: J. Cloos, M. R. Spitz, S. P. Schantz, T. C. Hsu, Z.-f. Zhang, H. Tobi, B. J. M. Braakhuis, G. B. Snow
Journal: JNCI Journal of the National Cancer Institute (1996)

Background:In addition to influences of exposure to carcinogenic compounds, the development of cancer may depend on an individual intrinsic cancer susceptibility. Biomarkers for cancer susceptibility can be powerful additions to epidemiologic analyses.
Arterial Remodeling Associates with CKD Progression
Authors: Marie Briet, Cédric Collin, Alexandre Karras, Stéphane Laurent, Erwan Bozec, Christian Jacquot, Bénédicte Stengel, Pascal Houillier, Marc Froissart, Pierre Boutouyrie
Journal: Journal of the American Society of Nephrology (2011)

In CKD, large arteries remodel and become increasingly stiff. The greater pulsatile pressure reaching the glomerulus as a result of increased aortic stiffness could induce renal damage, suggesting that the stiffening and remodeling of large arteries could affect the progression of CKD. We measured carotid-femoral pulse wave velocity, aortic pressure and carotid remodeling and stiffness parameters in 180 patients with CKD (mean measured GFR, 32 ml/min per 1.73 m<sup>2</sup>) and followed them prospectively for a mean of 3.1 years. During follow-up, carotid stiffness significantly increased (+0.28 ± 0.05 m/s; <i>P</i> &lt; 0.0001) but aortic stiffness did not. Carotid intima-media thickness decreased significantly during follow-up and the internal diameter of the carotid increased, producing increased circumferential wall stress (+2.08 ± 0.43 kPa/yr; <i>P</i> &lt; 0.0001). In a linear mixed model, circumferential wall stress significantly associated with faster GFR decline after adjustment for risk factors of cardiovascular disease and progression of CKD. In a multivariable Cox model, carotid circumferential wall stress and pulse pressure independently associated with higher risk for ESRD. None of the arterial stiffness parameters associated with progression of CKD. In conclusion, maladaptive remodeling of the carotid artery and increased pulse pressure independently associate with faster decline of renal function and progression to ESRD.
Effects of weight loss on asthma control in obese patients with severe asthma
Authors: Sérvulo Azevedo Dias-Júnior, Monica Reis, Regina Maria de Carvalho-Pinto, Rafael Stelmach, Alfredo Halpern, Alberto Cukier
Journal: European Respiratory Journal (2013)

Studies on the effects of weight loss in patients with asthma are scarce. No studies have been performed in patients with severe asthma. Therefore, the aim of the present study was to assess the impact of weight loss in patients with severe asthma associated with obesity. This was an open, prospective, randomised study of two parallel groups, in patients with severe uncontrolled asthma and moderate obesity. The primary outcome was the level of asthma control 6 months after initiation of the weight reduction programme, quantified using the Asthma Control Questionnaire (ACQ). We evaluated clinical parameters, lung function, markers of airway inflammation and circulating cytokines. 22 patients were randomised to undergo treatment for obesity and 11 to the control group. The weight reduction programme was associated with significant improvements in asthma control (mean± se ACQ score 3.02±0.19 to 2.25±0.28 in the treatment group versus 2.91±0.25 to 2.90±0.16 in the controls, p=0.001). This improvement was not accompanied by changes in markers of airway inflammation or bronchial reactivity, but by an increase in forced vital capacity. Our results suggest that weight reduction in obese patients with severe asthma improves asthma outcomes by mechanisms not related to airway inflammation.
Cladribine improves lung cysts and pulmonary function in a child with histiocytosis
Authors: Ralph Epaud, Hubert Ducou Le Pointe, Sylvie Fasola, Sandra Ploussard, Celine Delestrain, Chiara Sileo, Jean Donadieu
Journal: European Respiratory Journal (2014)

Langerhans' cell histiocytosis (LCH) is a rare disease of unknown aetiology involving accumulation of Langerhans' cells organised in granuloma, in various organs [1]. Pulmonary LCH (PLCH) is characterised by focal Langerhans' cell granulomas infiltrating and destroying distal bronchioles, which results in cysts, major destruction of the pulmonary tissue and pneumothorax [2, 3]. PLCH is rare in children <18 years old. Cladribine treatment has marked efficacy for clinical, functional and imaging outcomes in a child with PCLH <http://ow.ly/CK3XJ> The authors thank the patient and the family for their participation. The authors thank Abdellatif Tazi (Service de pneumologie, Hôpital Saint-Louis, Paris, France) for council.
T cells learn quickly
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2007)

Young T cells are fast learners, according to McCaughtry et al. (page 2513). They finish part of their schooling in the thymus in just four days.

Upon entering the thymus, young T cells are first tested for correctly rearranged T cell receptors (TCRs). Those that pass the exam are selected for further training in the thymic medulla. There, T cells that react to self-antigens are killed off. The rest graduate into functional, proliferating adults.

This training program was previously estimated to last for two to three weeks. This notion was based on methods that did not differentiate between young T cells, mature T cells that reentered the thymus, and other thymic TCR-bearing immune cell subsets.

McCaughtry and colleagues now reanalyze the kinetics of T cell training with this distinction in mind. Maturation stages were identified by specific markers and by labeling proliferating cells with BrdU. The results revealed that T cells took just four days to pass through the medulla and enter the circulation.

The team also found that T cells were educated on a first-come, first-served basis. As they passed the first selection test, the cells shut off expression of a fluorescent protein, resulting in a gradual decrease in brightness. Only dim cells expressed receptors that mark exiting cells, suggesting that the emigration follows a first-in, first-out assembly-line pattern.

The authors now want to understand how the plumbing of the thymus helps T cells so rapidly sample the different self-antigens expressed by each epithelial cell.
Critical role of the extracorporeal blood temperature in the hemodynamic response during hemofiltration.
Authors: W H van Kuijk, D Hillion, C Savoiu, K M Leunissen
Journal: Journal of the American Society of Nephrology (1997)

Impaired vascular reactivity during combined ultrafiltration-hemodialysis (UF+HD) compared with hemofiltration (HF) remains a rather enigmatic problem, the causes of which are still not well understood. Although a number of factors have been claimed to be responsible, most recent studies point to a major role of the extracorporeal blood temperature, which is usually lower during HF compared with UF + HD. However, previous studies in which hemodynamics were studied during UF + HD and HF in relation to the extracorporeal blood temperature are limited by the use of acetate in UF + HD, and measurements were often confined to BP and heart rate. Therefore, arterial BP, as well as forearm vascular resistance (FVR) and venous tone (strain-gauge plethysmography), was measured in 11 hemodialysis patients during 3 h UF + HD (37.5 degrees C) and predilution HF (39.0 degrees C = warm HF), resulting in equivalent extracorporeal blood temperatures. Patients were also studied during cold HF at an infusate temperature of 36.0 degrees C. UF + HD and HF were matched with respect to the dialysate and infusate composition (bicarbonate), bio-compatibility factors, and small molecule clearance. At equivalent temperatures, UF + HD and HF were associated with a comparable vascular and BP response. Only cold HF was associated with a significant increase in FVR. In addition, FVR and venous tone, as well as arterial BP, were all significantly higher during cold HF compared with both UF + HD and warm HF. These results indicate that the disparity in vascular reactivity between UF + HD and HF is primarily related to differences in the extracorporeal blood temperature.
The airspace dimension test – A new way to diagnose emphysema?
Authors: Per Wollmer, Jonas Jakobsson, Tobias Andersson, Jakob Löndahl
Journal: European Respiratory Journal (2014)

Emphysema is a common feature of chronic obstructive pulmonary disease (COPD). Current diagnostic methods with high specificity for emphysema are computed tomography (CT) and magnetic resonance imaging (MRI) using hyperpolarised gases. CT is relatively expensive and carries a radiation dose. MRI is inaccessible and very expensive. We describe a single-breath technique for measurement of the dimensions of distal airspaces, potentially suitable for diagnosing emphysema.  An aerosol containing nanoparticles is inhaled with a vital capacity manoeuvre and the subject holds his breath at maximum inspiration for 10 s. Particle concentration is measured in the inspired gas and in an alveolar sample obtained from the ensuing exhalation. Since nanoparticles are deposited in the lungs purely by diffusion and the time available for diffusion is controlled, the deposited fraction of aerosol (DF) will reflect the diffusion distances in the distal airspaces.  We studied 23 normal subjects and 45 patients suffering from a variety of lung diseases and referred for pulmonary function tests. The most common diagnosis was COPD.  As a group, the patients showed airflow obstruction. The range of DF found in normal subjects was very narrow. The ADF was lower in the patients than in normal subjects, compatible with increased diffusion distances in distal airspaces.  This preliminary study shows promise for the Airspace Dimension Test as a diagnostic test. Further studies are required to elucidate its relation to emphysema.
MDM2 Small-Molecule Antagonist RG7112 Activates p53 Signaling and Regresses Human Tumors in Preclinical Cancer Models
Authors: Christian Tovar, Bradford Graves, Kathryn Packman, Zoran Filipovic, Brian Higgins Mingxuan Xia, Christine Tardell, Rosario Garrido, Edmund Lee, Kenneth Kolinsky, Kwong-Him To, Michael Linn, Frank Podlaski, Peter Wovkulich, Binh Vu, Lyubomir T. Vassilev
Journal: Cancer Research (2013)

Abstract MDM2 negatively regulates p53 stability and many human tumors overproduce MDM2 as a mechanism to restrict p53 function. Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies. RG7112 binds MDM2 with high affinity (KD ∼ 11 nmol/L), blocking its interactions with p53 in vitro. A crystal structure of the RG7112–MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 showed potent antitumor activity against a panel of solid tumor cell lines. However, its apoptotic activity varied widely with the best response observed in osteosarcoma cells with MDM2 gene amplification. Interestingly, inhibition of caspase activity did not change the kinetics of p53-induced cell death. Oral administration of RG7112 to human xenograft-bearing mice at nontoxic concentrations caused dose-dependent changes in proliferation/apoptosis biomarkers as well as tumor inhibition and regression. Notably, RG7112 was highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53. Cancer Res; 73(8); 2587–97. ©2013 AACR.
Apex-to-Base Dispersion in Regional Timing of Left Ventricular Shortening and Lengthening
Authors: Partho P. Sengupta, Bijoy K. Khandheria, Josef Korinek, Jianwen Wang, Arshad Jahangir, James B. Seward, Marek Belohlavek
Journal: Journal of the American College of Cardiology (2005)
Prediction of Nodal Involvement in Breast Cancer Based on Multiparametric Protein Analyses from Preoperative Core Needle Biopsies of the Primary Lesion
Authors: Georg Sauer, Nicole Schneiderhan-Marra, Cornelia Kazmaier, Kathrin Hutzel, Karin Koretz, Rainer Muche, Rolf Kreienberg, Thomas Joos, Helmut Deissler
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Identification of molecular characteristics that are useful to define subgroups of patients fitting into differential treatment schemes is considered a most promising approach in cancer research. In this first study of such type, we therefore investigated the potential of multiplexed sandwich immunoassays to define protein expression profiles indicative of clinically relevant properties of malignant tumors. Experimental Design: Lysates prepared from large core needle biopsies of 113 invasive breast carcinomas were analyzed with bead-based miniaturized sandwich immunoassays specific for 54 preselected proteins. Results: Five protein concentrations [fibroblast growth factor-2 (FGF-2), Fas, Fas ligand, tissue inhibitor of metalloproteinase-1, and RANTES] were significantly different in the groups of patients with or without axillary lymph node metastasis. All 15 protein parameters that resulted in P values &amp;lt;0.2 and other diagnostic information [estrogen receptor (ER) status, tumor size, and histologic grading] were analyzed together by multivariate logistic regression. This yielded sets of five (FGF-2, Fas, Fas ligand, IP10, and PDGF-AB/BB) or six (ER staining intensity, FGF-2, Fas ligand, matrix metalloproteinase-13, PDGF-AB/BB, and IP10) parameters for which receiver-operator characteristic analyses revealed high sensitivities and specificities [area under curve (AUC) = 0.75 and AUC = 0.83] to predict the nodal status. A similar analysis including all identified parameters of potential value (15 proteins, ER staining intensity, T) without selection resulted in a receiver-operator characteristic curve with an AUC of 0.87. Conclusion: We clearly showed that this approach can be used to quantify numerous proteins from breast biopsies accurately in parallel and define sets of proteins whose combined analyses allow the prediction of nodal involvement with high specificity and sensitivity.
An Antibody–Drug Conjugate Directed against Lymphocyte Antigen 6 Complex, Locus E (LY6E) Provides Robust Tumor Killing in a Wide Range of Solid Tumor Malignancies
Authors: Jyoti Asundi, Lisa Crocker, Jarrod Tremayne, Peter Chang, Chie Sakanaka, Josh Tanguay, Susan Spencer, Sreedevi Chalasani, Elizabeth Luis, Karen Gascoigne, Rupal Desai, Rajiv Raja, Brad A. Friedman, Peter M. Haverty, Paul Polakis, Ron Firestein
Journal: Clinical Cancer Research (2015)

Chemotherapies are limited by a narrow therapeutic index resulting in suboptimal exposure of the tumor to the drug and acquired tumor resistance. One approach to overcome this is through antibody-drug conjugates (ADC) that facilitate greater potency via target-specific delivery of highly potent cytotoxic agents.In this study, we used a bioinformatics approach to identify the lymphocyte antigen 6 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models.Using in silico approaches, we found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. IHC analysis revealed high LY6E protein expression in a number of tumor types, such as breast, lung, gastric, ovarian, pancreatic, kidney and head/neck carcinomas. Characterization of the endocytic pathways for LY6E revealed that the LY6E-specific antibody is internalized into cells leading to lysosomal accumulation. Consistent with this, a LY6E-specific ADC inhibited in vitro cell proliferation and produced durable tumor regression in vivo in clinically relevant LY6E-expressing xenograft models.Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumor types with current unmet medical need.