tbuckley/cabot-search huggingface dataset:
PancPRO: Risk Assessment for Individuals With a Family History of Pancreatic Cancer
Authors: Wenyi Wang, Sining Chen, Kieran A. Brune, Ralph H. Hruban, Giovanni Parmigiani, Alison P. Klein
Journal: Journal of Clinical Oncology (2007)

Purpose The rapid fatality of pancreatic cancer is, in large part, the result of an advanced stage of diagnosis for the majority of patients. Identification of individuals at high risk of developing pancreatic cancer is a first step towards the early detection of this disease. Individuals who may harbor a major pancreatic cancer susceptibility gene are one such high-risk group. The goal of this study was to develop and validate PancPRO, a Mendelian model for pancreatic cancer risk prediction in individuals with familial pancreatic cancer, to identify high-risk individuals. Methods PancPRO was built by extending the Bayesian modeling framework developed for BRCAPRO, trained using published data, and validated using independent prospective data on 961 families enrolled onto the National Familial Pancreas Tumor Registry, including 26 individuals who developed incident pancreatic cancer during follow-up. Results We developed a risk prediction model, PancPRO, and free software for the estimation of pancreatic cancer susceptibility gene carrier probabilities and absolute pancreatic cancer risk. Model validation demonstrated an observed to predicted pancreatic cancer ratio of 0.83 (95% CI, 0.52 to 1.20) and high discriminatory ability, with an area under the receiver operating characteristic curve of 0.75 (95% CI, 0.68 to 0.81) for PancPRO. Conclusion PancPRO is the first risk prediction model for pancreatic cancer. When we validated our model using the largest registry of familial pancreatic cancer, our model provided accurate risk assessment. Our findings highlight the importance of detailed family history for clinical cancer risk assessment and demonstrate that accurate genetic risk assessment is possible even when the causative genes are not known.
Prediction of progressive disease using tumor markers in metastatic breast cancer patients without target lesions in first-line chemotherapy
Authors: K. Hashimoto, K. Yonemori, N. Katsumata, C. Shimizu, A. Hirakawa, T. Hirata, T. Kouno, K. Tamura, M. Ando, Y. Fujiwara
Journal: Annals of Oncology (2010)
Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart
Authors: Kazuhiro Yamamoto, Tohru Masuyama, Yasushi Sakata, Nagahiro Nishikawa, Toshiaki Mano, Junichi Yoshida, Takeshi Miwa, Motoaki Sugawara, Yukihiro Yamaguchi, Tomomi Ookawara, Keiichiro Suzuki, Masatsugu Hori
Journal: Cardiovascular Research (2002)

Objectives: Diastolic dysfunction that determines symptoms and prognosis in patients with systolic dysfunction causes heart failure even in the absence of systolic dysfunction. Our recent studies have suggested that myocardial stiffening is likely to play a crucial role in triggering deleterious cardiac disorder. This study investigated differential contribution of left ventricular (LV) hypertrophy and fibrosis to myocardial stiffening in the pressure-overloaded heart. Methods: Dahl-Iwai salt-sensitive rats fed on high-salt diet since 7 weeks transit to congestive heart failure at 20 weeks following development of hypertension, LV hypertrophy and fibrosis, and 20 such rats were divided into three groups: rats treated with angiotensin II type 1 receptor antagonist from 8 weeks (n = 7), rats treated with calcineurin inhibitor from 8 weeks (n = 6), and untreated rats (n = 7). Results: Administration of angiotensin II type 1 receptor antagonist and calcineurin inhibitor did not affect blood pressure and allowed the development of compensatory hypertrophy. However, in contrast to the untreated rats, additive and excessive LV hypertrophy was not observed in either of the treated rats. The blockade of angiotensin II kept LV hydroxyproline content, a ratio of type I to type III collagen mRNA levels, collagen solubility and myocardial stiffness constant at the normal level; however, the calcineurin inhibition failed. Conclusions: Myocardial stiffening may be attributed to progressive collagen accumulation, collagen phenotype shift and enhanced collagen cross-linking, but not to either compensatory LV hypertrophy or LV hypertrophy that progresses from the compensatory stage.
Superoxide anion release induced by platelet-activating factor is increased in human alveolar macrophages from smokers
Authors: T Schaberg, H Haller, M Rau, D Kaiser, M Fassbender, H Lode
Journal: European Respiratory Journal (1992)

This study was designed to investigate the effects of the platelet-activating factor (PAF) on the superoxide anion production (O2.) of human alveolar macrophages (AM) from nonsmoking (n = 18) and smoking (n = 30) subjects. Freshly isolated cells were stimulated with (PAF) or with a phorbol ester (phorbol 12-myristate 13 acetate (PMA)). Stimulation with PAF led to a dose-dependent increase of O2. production by AM in both groups. The median effective dose (EC50) for PAF action on O2. production of smoker AM was 0.5 x 10(-8) M, compared to nonsmoker AM with an EC50 of 1.0 x 10(-7) M. This effect of PAF was blockable by the PAF-antagonist WEB 2086 in a dose-dependent manner. Comparison of the relative increase of O2. production after PAF-stimulation showed that smoker cells were significantly more sensitive to PAF than nonsmoker cells (p less than 0.01). In contrast to the findings with PAF, the relative increase of O2. production after PMA-stimulation showed no differences between smoker and nonsmoker AM. Our data suggest that AM from smoking subjects are more sensitive to PAF than AM from nonsmokers.
Retrospective Propensity Score Matching and the Selection of Surgical Procedures: How Precise Can a Propensity Estimate Be?
Authors: Michitaka Honda, Kazumichi Yamamoto, Toshi A. Furukawa
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: An article by Kim et al 1 was recently published comparingthesurgicalandoncologicoutcomesbetweenlaparoscopic andopengastrectomyforgastriccancer.Theauthorsusedpropensity scorematchingtominimizetheselectionbiasinaretrospectivecohort of patients from multiple centers. Kim et al tried to adjust for confounding factors by using propensity score matching, and they concluded that laparoscopic gastrectomy for gastric cancer seems comparable with open surgery. However, we have several significant concernsaboutthecase-matchingmethodthatwasusedinthisstudy. The propensity score analysis was developed to minimize the differences in patients’ covariates, which could become confounding factors in the examination of treatment effects in observational stud
Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3–Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma
Authors: Guido Bisping, Doris Wenning, Martin Kropff, Dirk Gustavus, Carsten Müller-Tidow, Matthias Stelljes, Gerd Munzert, Frank Hilberg, Gerald J. Roth, Martin Stefanic, Sarah Volpert, Rolf M. Mesters, Wolfgang E. Berdel, Joachim Kienast
Journal: Clinical Cancer Research (2009)

Novel drugs including targeted approaches have changed treatment paradigms for multiple myeloma (MM) and may also have therapeutic potential in the poor-prognosis t(4;14) subset; t(4;14) results in overexpressed and activated fibroblast growth factor receptor 3 (FGFR3). Blocking this receptor tyrosine kinase (RTK) induces apoptosis in t(4;14)+ MM cells and decreases adhesion to bone marrow stromal cells (BMSC). Using combinations of novel drugs, we investigated potential enhancement of single-agent activities within the tumor cells, targeting of the marrow micromilieu, or circumvention of drug resistance in t(4;14)+ MM.We tested effects on apoptosis and related signaling pathways in the t(4;14)+ MM subset, applying drug combinations including a FGFR3 tyrosine kinase inhibitor (RTKI), the proteasome inhibitor bortezomib, and dexamethasone.RTKI, bortezomib, and dexamethasone were active as single agents in t(4;14)+ MM. RTK inhibition triggered complementary proapoptotic pathways (e.g., decrease of Mcl-1, down-regulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic stress-activated protein/c-Jun NH(2)-terminal kinases). Synergistic or additive effects were found by combinations of RTKI with dexamethasone or bortezomib. In selected cases of t(4;14)+ MM, triple combinations were superior to dual combinations tested. Prevention from MM cell apoptosis by BMSC or exogenous interleukin-6 was circumvented by drug combinations. In t(4;14)+, N-ras-mutated NCI-H929 cells, resistance to RTKI was overcome by addition of dexamethasone. Notably, the combination of RTKI and dexamethasone showed additive proapoptotic effects in bortezomib-insensitive t(4;14)+ MM.Combining novel drugs in poor-prognosis t(4;14)+ MM should take into account at least bortezomib sensitivity and probably Ras mutational status.
Interpretation of Repeated Tuberculin Tests
Authors: DICK MENZIES
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The tuberculin skin test is one of the few tests developed in the 19th century that is still in present use in clinical medicine. The first tuberculin test material was prepared by Robert Koch (1); its use for detection of tuberculosis (TB) infection was first described in 1907 by von Pirquet (2). Given such a long history of use, it may seem surprising that aspects of interpretation of this test remain controversial. However, this reflects changes in the populations affected with tuberculosis and their relative frequency of true positive tests from TB infection, and false-positive tests associated with bacillus Calmette-Guerin (BCG) vaccination, or nontuberculous mycobacteria, as well as the recent human immunodeficiency virus (HIV) epidemic. Particular problems have arisen with use of repeated tuberculin tests to detect new infection in high-risk populations such as initially tuberculin-negative contacts of active cases, and workers with occupational exposure. This has revealed that tuberculin reactions may decrease in size (reversion) or increase in size because of: ( 1 ) random variability from differences in administration, reading, or biologic response; ( 2 ) immunologic recall of preexisting delayed type hypersensitivity to mycobacterial antigens (boosting); or ( 3 ) new infection (conversion). This review has been undertaken to provide information regarding factors causing changes in the size of repeated tuberculin reactions.
EBUS-TBNA for the evaluation of isolated mediastinal and/or hilar lymphadenopathy (IMHL)
Authors: Kah Yee Tham, Shera Tan, Kiran Sharma, Mariko Siyue Koh, Aik Hau Tan, Therese Sophie Lapperre, Chian Min Loo
Journal: European Respiratory Journal (2014)

Background: There has been emerging data to support the use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an initial investigation for patients with IMHL. [Navani, AJRCCM 2012; Boujaoude, J Bronch Interv Pulmonol. 2012]

Aim: To examine the overall and disease specific diagnostic utility of EBUS-TBNA in the diagnosis of IMHL.

Methods: Retrospective analysis of a prospectively collected EBUS-TBNA database from August 2008 to June 2013 at Singapore General Hospital. IMHL of unknown origin, in the absence of pulmonary masses, were included. Final diagnoses were determined by EBUS-TBNA, surgery or clinical follow-up for at least 6 months. Sensitivity, specificity, positive (PPV), negative predictive values (NPV) and accuracy were determined.

Results: We identified 184 patients with IMHL. EBUS was diagnostic in 145 patients (78.8%): 4.8% lymphoma, 10.3% sarcoidosis, 17.9% tuberculosis, 20.7% metastatic carcinoma, 15.9% small-cell lung cancer and 30% miscellaneous diagnoses. Of 68 EBUS-negative patients, 9.8% were diagnosed by mediastinoscopy, 2.9% by video-assisted thoracoscopy, 54% on clinical follow-up, 2.9% by lymph node excision. 33% were non-diagnostic. The overall and disease-specific results on utility of EBUS-TBNA are shown in the table.

View this table:





Conclusion: EBUS-TBNA as an initial investigation in patients with IMHL provides a good diagnostic yield.
Novel prognostic targets identified using integrated analysis of copy number and expression data in oesophageal adenocarcinoma
Authors: X. Y. Goh, M. A. Alvi, J. Rees, S. F. Chin, J. Weaver, C. Caldas, R. Fitzgerald
Journal: Gut (2011)

<h3>Introduction</h3> The incidence of oesophageal adenocarcinoma (OAC) has increased sixfold in the west over the last 30 years, with a dismal survival rate of less than 20%. Understanding the genomic aberrations and biology of this cancer may enhance disease interventions. We aim to identify novel molecular targets with clinical relevance using an integrated approach in analysing genomewide data of OAC, and to correlate reduced expression of molecular targets with promoter hypermethylation in OAC. <h3>Methods</h3> 30 k oligonucleotide array comparative genomic hybridisation (CGH) and gene expression microarray profiling were performed on 56 OAC resection samples with long-term clinical follow-up data to identify regions of copy number changes leading to differential expression levels. Fluorescence in situ hybridisation (FISH) assays were carried out using bacterial artificial chromosome probes on touch-imprinted slides of frozen tumour samples to confirm their amplification status. Immunohistochemistry (IHC) assays on tissue microarrays (TMAs) on the same cohort (n=56) and on an independent cohort of OAC samples (n=371) were used for subsequent validation at the protein level. Kaplan-Meier survival analyses were performed based on IHC data to determine prognostic significance of novel molecular targets. An Illumina Infinium Array was used to investigate the methylation status of 24 independent OAC tumours, compared with 24 premalignant Barrett9s Oesophagus (BE) samples. <h3>Results</h3> Integrated array CGH data with matched gene expression microarray data highlighted 4 genes with copy number gains and increased expression: <i>EGFR</i>, <i>WT1</i>, <i>NEIL2</i> and <i>MTMR9</i>. FISH assays confirmed amplifications of these genes (&gt;6 copies/centromere) in 11% of OAC samples and IHC assays (n=371 independent cases) demonstrated protein over-expression: <i>EGFR</i> (10%)<i>, WT1</i> (20%)<i>, NEIL2</i> (14%) and <i>MTMR9</i> (25%), corroborating findings from the integrated analysis. These targets individually had prognostic significance (p&lt;0.060). Interestingly, reduced expressions of <i>WT1</i> (p=0.037) and <i>NEIL2</i> (p=0.051) were associated with poorer prognosis in OAC. In order to investigate the mechanism of reduced expression of these targets which might have contributed to a worse prognosis, methylation array data was utilised from an independent dataset. This showed increased methylation of <i>WT1</i> in OAC (63%) compared to BE (55%; t test p=0.028) and normal controls (50%), but no difference in methylation status of <i>NEIL2</i> between disease states. <h3>Conclusion</h3> Integration of array CGH and gene expression data identified novel genes not previously associated with OAC with prognostic potential that require further study.
Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3α
Authors: Björn Lamprecht, Stephan Kreher, Ioannis Anagnostopoulos, Korinna Jöhrens, Giovanni Monteleone, Franziska Jundt, Harald Stein, Martin Janz, Bernd Dörken, Stephan Mathas
Journal: Blood (2008)
Local and Systemic Inflammation in Patients with Chronic Obstructive Pulmonary Disease
Authors: Juanita H. Vernooy, Mehmet Küçükaycan, Jan A. Jacobs, Niels H. Chavannes, Wim A. Buurman, Mieke A. Dentener, Emiel F. Wouters
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Chronic obstructive pulmonary disease (COPD) is characterized by significant chronic inflammation in the pulmonary compartment as well as in the circulation. This study aimed to elucidate the relationship between local and systemic inflammation in smoking-induced COPD by assessing levels of soluble (s) tumor necrosis factor (TNF) receptors, TNF-alpha, and interleukin-8 (IL-8) in induced sputum and in plasma. Sputum induction was performed in 18 subjects with COPD (FEV(1) 56% predicted) and 17 healthy smokers (FEV(1) 99% predicted). Patients with COPD showed significantly higher percentages of neutrophils and levels of sTNF-R55 and IL-8 in sputum as compared with control subjects, whereas sputum sTNF-R75 levels tended to be higher in COPD. Sputum TNF-alpha levels were similar in both groups. When comparing sTNF receptors in sputum and plasma, no direct correlations were found despite elevation of circulating sTNF-R75 levels in patients with COPD. In addition, sputum sTNF receptors were inversely related to the FEV(1) in patients with COPD, whereas circulating sTNF receptors were not, suggesting different regulation of inflammation in the pulmonary and systemic compartment. When subjects were divided according to their current smoking status, levels of sTNF-R55, sTNF-R75, and IL-8 in sputum were significantly elevated in ex-smoking versus currently smoking patients with COPD, suggesting ongoing inflammation in airways and circulation of patients with COPD after smoking cessation.
Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial
Authors: Ludwig Kappos, David Li, Peter A Calabresi, Paul O'Connor, Amit Bar-Or, Frederik Barkhof, Ming Yin, David Leppert, Robert Glanzman, Jeroen Tinbergen, Stephen L Hauser
Journal: The Lancet (2011)
Transplantation of spermatogonial stem cells isolated from leukemic mice restores fertility without inducing leukemia
Authors: Kazutoshi Fujita, Hiroshi Ohta, Akira Tsujimura, Tetsuya Takao, Yasushi Miyagawa, Shingo Takada, Kiyomi Matsumiya, Teruhiko Wakayama, Akihiko Okuyama
Journal: Journal of Clinical Investigation (2005)

More than 70% of patients survive childhood leukemia, but chemotherapy and radiation therapy cause irreversible impairment of spermatogenesis. Although autotransplantation of germ cells holds promise for restoring fertility, contamination by leukemic cells may induce relapse. In this study, we isolated germ cells from leukemic mice by FACS sorting. The cell population in the high forward-scatter and low side-scatter regions of dissociated testicular cells from leukemic mice were analyzed by staining for MHC class I heavy chain (H-2K/H-2D) and for CD45. Cells that did not stain positively for H-2K/H-2D and CD45 were sorted as the germ cell-enriched fraction. The sorted germ cell-enriched fractions were transplanted into the testes of recipient mice exposed to alkylating agents. Transplanted germ cells colonized, and recipient mice survived. Normal progeny were produced by intracytoplasmic injection of sperm obtained from recipient testes. When unsorted germ cells from leukemic mice were transplanted into recipient testes, all recipient mice developed leukemia. The successful birth of offspring from recipient mice without transmission of leukemia to the recipients indicates the potential of autotransplantation of germ cells sorted by FACS to treat infertility secondary to anticancer treatment for childhood leukemia.
Rhinovirus infections in infancy and early childhood
Authors: Elisabeth Kieninger, Oliver Fuchs, Philipp Latzin, Urs Frey, Nicolas Regamey
Journal: European Respiratory Journal (2012)

Rhinovirus (RV) infections occur early and recurrently in life, imposing a significant burden of disease on infants and young children. They are the most frequent causative agents of both upper and lower respiratory tract infections in this age group and are associated with a broad variety of clinical outcomes, ranging from asymptomatic infections to severe respiratory disease requiring hospitalisation. In addition to their impact on short-term morbidity, RVs are also debated as important pathogens in the development of recurrent wheeze and/or asthma. Several studies in infants at high-risk for atopy and asthma and in hospitalised children have demonstrated that recurrent wheezing illnesses induced by RVs early in life are a risk factor for the development of asthma later in childhood. However, underlying mechanisms are poorly understood. The question whether RVs are directly involved in the development of childhood wheeze and asthma, or whether symptomatic RV infections only represent a proxy for infants prone to develop obstructive lung diseases, is still open. In this review we provide an overview on the role of RVs as important disease-causing agents from infancy to early childhood and discuss their contribution to the subsequent development of childhood wheeze and/or asthma.
Chronic Endoplasmic Reticulum Stress Activates Unfolded Protein Response in Arterial Endothelium in Regions of Susceptibility to Atherosclerosis
Authors: Mete Civelek, Elisabetta Manduchi, Rebecca J. Riley, Christian J. Stoeckert, Peter F. Davies
Journal: Circulation Research (2009)

Rationale : Endothelial function and dysfunction are central to the focal origin and regional development of atherosclerosis; however, an in vivo endothelial phenotypic footprint of susceptibility to atherosclerosis preceding pathological change remains elusive. Objective : To conduct a comparative multi-site genomics study of arterial endothelial phenotype in atherosusceptible and atheroprotected regions. Methods and Results : Transcript profiles of freshly isolated endothelial cells from 7 discrete arterial regions in normal swine were analyzed to determine the steady state in vivo endothelial phenotypes in regions of varying susceptibilities to atherosclerosis. The most abundant common feature of the endothelium of all atherosusceptible regions was the upregulation of genes associated with endoplasmic reticulum (ER) stress. The unfolded protein response pathway, induced by ER stress, was therefore investigated in detail in endothelium of the atherosusceptible aortic arch and was found to be partially activated. ER transmembrane signal transducers IRE1α and ATF6α and their downstream effectors, but not PERK, were activated concomitant with a higher transcript expression of protein folding enzymes and chaperones, indicative of ER stress in vivo. Conclusions : The findings demonstrate the prevalence of chronic endothelial ER stress and activated unfolded protein response in vivo at atherosusceptible arterial sites. We propose that chronic localized biological stress is linked to spatial susceptibility of the endothelium to the initiation of atherosclerosis.
Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections
Authors: Judith N Mandl, Ashley P Barry, Thomas H Vanderford, Natalia Kozyr, Rahul Chavan, Sara Klucking, Franck J Barrat, Robert L Coffman, Silvija I Staprans, Mark B Feinberg
Journal: Nature Medicine (2008)
Pulmonary infections: what to do when it's a bug that you do not know
Authors: M. Woodhead, A. Ortqvist
Journal: European Respiratory Journal (2003)

Infectious diseases are making a comeback, both in the lung and elsewhere. The reasons for this are diverse and range from changes in the causative bugs to changes in human habits. Infections in the lung have always been important, both because they are very common and because they have a high morbidity and mortality. Community-acquired pneumonia occurs at a rate of one per 1,000 of the adult population, which means that some 300,000 cases occur every year in Eurozone countries. European studies suggest a mortality of ∼7% for those admitted to hospital, rising to nearly 50% for those …