tbuckley/cabot-search huggingface dataset:
Risk Factors for the Development of Secondary Malignancy After High-Dose Chemotherapy and Autograft, With or Without Rituximab: A 20-Year Retrospective Follow-Up Study in Patients With Lymphoma
Authors: Corrado Tarella, Roberto Passera, Michele Magni, Fabio Benedetti, Andrea Rossi, Angela Gueli, Caterina Patti, Guido Parvis, Fabio Ciceri, Andrea Gallamini, Sergio Cortelazzo, Valerio Zoli, Paolo Corradini, Alessandra Carobbio, Antonino Mulé, Marco Bosa, Anna Barbui, Massimo Di Nicola, Marco Sorio, Daniele Caracciolo, Alessandro M. Gianni, Alessandro Rambaldi
Journal: Journal of Clinical Oncology (2010)

High-dose chemotherapy with peripheral blood progenitor cell (PBPC) autograft is effective in high-risk lymphoma, particularly with the addition of rituximab; however, it is associated with risk of secondary malignancy. These issues have been addressed in a series of 1,347 patients with lymphoma treated with a high-dose sequential (HDS) program.A total of 1,024 patients with B-cell lymphoma, 234 patients with Hodgkin's lymphoma, and 89 patients with T-cell lymphoma were treated with HDS between 1985 and 2005 at 11 Gruppo Italiano Terapie Innovative Linfomi centers. HDS was given as salvage treatment to 707 patients (52%); 655 patients (49%) received a modified HDS, with high-dose cytarabine and two consecutive PBPC harvests. Rituximab-supplemented HDS was given to 523 patients (39%).At a median follow-up of 7 years, the median overall survival (OS) was 16.2 years; in B-cell lymphoma the OS was significantly superior with rituximab HDS compared to HDS alone. The cumulative incidence at 5 and 10 years of secondary myelodysplasia/acute leukemia (sMDS/AL) were 3.09% and 4.52%, respectively, that of solid tumors were 2.54% and 6.79%, respectively. Factors associated with sMDS/AL were male sex and use of the second harvest PBPC for the graft; factors found to be associated with solid tumor were advanced age, post-HDS radiotherapy, and rituximab addition to HDS. Despite the increased risk of solid tumors, rituximab addition to HDS was still associated with survival advantages.This analysis has relevant implications for the design and use of intensive chemoimmunotherapy with autograft. In addition, it offers useful insights toward the understanding and prevention of tumor development.
Exploiting the noise: improving biomarkers with ensembles of data analysis methodologies
Authors: Maud HW Starmans, Melania Pintilie, Thomas John, Sandy D Der, Frances A Shepherd, Igor Jurisica, Philippe Lambin, Ming-Sound Tsao, Paul C Boutros
Journal: Genome Medicine (2012)

Abstract Background The advent of personalized medicine requires robust, reproducible biomarkers that indicate which treatment will maximize therapeutic benefit while minimizing side effects and costs. Numerous molecular signatures have been developed over the past decade to fill this need, but their validation and up-take into clinical settings has been poor. Here, we investigate the technical reasons underlying reported failures in biomarker validation for non-small cell lung cancer (NSCLC). Methods We evaluated two published prognostic multi-gene biomarkers for NSCLC in an independent 442-patient dataset. We then systematically assessed how technical factors influenced validation success. Results Both biomarkers validated successfully (biomarker #1: hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.21 to 2.19, P = 0.001; biomarker #2: HR 1.42, 95% CI 1.03 to 1.96, P = 0.030). Further, despite being underpowered for stage-specific analyses, both biomarkers successfully stratified stage II patients and biomarker #1 also stratified stage IB patients. We then systematically evaluated reasons for reported validation failures and find they can be directly attributed to technical challenges in data analysis. By examining 24 separate pre-processing techniques we show that minor alterations in pre-processing can change a successful prognostic biomarker (HR 1.85, 95% CI 1.37 to 2.50, P &lt; 0.001) into one indistinguishable from random chance (HR 1.15, 95% CI 0.86 to 1.54, P = 0.348). Finally, we develop a new method, based on ensembles of analysis methodologies, to exploit this technical variability to improve biomarker robustness and to provide an independent confidence metric. Conclusions Biomarkers comprise a fundamental component of personalized medicine. We first validated two NSCLC prognostic biomarkers in an independent patient cohort. Power analyses demonstrate that even this large, 442-patient cohort is under-powered for stage-specific analyses. We then use these results to discover an unexpected sensitivity of validation to subtle data analysis decisions. Finally, we develop a novel algorithmic approach to exploit this sensitivity to improve biomarker robustness.
Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy
Authors: Raquel Franco Leal, Núria Planell, Radhika Kajekar, Juan J Lozano, Ingrid Ordás, Isabella Dotti, Miriam Esteller, M Carme Masamunt, Harsukh Parmar, Elena Ricart, Julián Panés, Azucena Salas
Journal: Gut (2014)

<h3>Background</h3> Anti-tumour necrosis factor α (TNFα) therapy effectively induces and maintains remission in Crohn9s disease (CD). Up to 40% of patients, however, fail to respond to anti-TNFα. <h3>Objective</h3> To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNFα therapy. <h3>Design</h3> An observational study based on whole-genome transcriptional analysis was carried out using intestinal biopsy specimens from patients with CD receiving (n=12) or not (n=10) anti-TNFα therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNFα therapy. Controls with non-inflammatory bowel disease (non-IBD) (n=17) were used for comparisons. Genes of interest were validated by real-time RT-PCR in an independent cohort of patients with CD receiving (n=17) or not (n=16) anti-TNFα and non-IBD controls (n=7). <h3>Results</h3> We confirmed that response to anti-TNFα is accompanied by significant regulation of a large number of genes, including IL1B, S100A8, CXCL1, which correlated with endoscopic activity. Remarkably, patients who failed to respond to anti-TNFα showed a mixed signature, maintaining increased expression of IL1B, IL17A and S100A8, while showing significant modulation of other genes commonly upregulated in active CD, including IL6 and IL23p19. <h3>Conclusions</h3> Our results show that anti-TNFα therapy significantly downregulates a subset of inflammatory genes even in patients who fail to achieve endoscopic remission, suggesting that these genes may not be dominant in driving inflammation in non-responders. On the other hand, we identified IL1B and IL17A as genes that remained altered in non-responders, pointing to potentially more relevant targets for modulating mucosal damage in refractory patients.
Focus: Brussels Which "Europe" should deal with ethical issues?
Authors: R Watson
Journal: BMJ (1994)

Advances in medical science and the increasing cross border opportunities offered by the evolving European Union (EU) have brought a new dimension to ethical issues. The wide ranging debate surrounding the news that a 59 year old British woman who travelled to Italy for in vitro fertilisation treatment, which made her a mother of twins, provides a perfect example.

Angry at the ability of a British citizen to circumvent domestic standards preventing her from having the same treatment at home and use the services available in another member state, the British health minister, Virginia Bottomley, demanded action at the European level. The call was soon taken up by her French colleague, Philippe Douste-Blazy, a former member of the European parliament and mayor of Lourdes. He spoke more graphically of the dangers of in vitro tourism.

The initial reference to a Brussels role perplexed officials. Few could see grounds for …
Excision Repair Cross-Complementation Group 1 Polymorphism Predicts Overall Survival in Advanced Non-Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy
Authors: Wei Zhou, Sarada Gurubhagavatula, Geoffrey Liu, Sohee Park, Donna S. Neuberg, John C. Wain, Thomas J. Lynch, Li Su, David C. Christiani
Journal: Clinical Cancer Research (2004)

Abstract DNA repair is a critical mechanism of resistance to platinum-based chemotherapy. Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process. Increased ERCC1 mRNA levels are related directly to platinum resistance in various cancers. We examined the association between two polymorphisms of ERCC1, codon 118 C/T and C8092A, which are associated with altered ERCC1 mRNA levels and mRNA stability, and overall survival (OS) in 128 advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. The two polymorphisms were in linkage disequilibrium. There was a statistically significant association between the C8092A polymorphism and OS (P = 0.006, by log-rank test), with median survival times of 22.3 (C/C) and 13.4 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with poor outcome. No statistically significant association was found for the codon 118 polymorphism and OS (P = 0.41, by log-rank test), with median survival times of 19.9 (T/T), 16.1 (C/T), and 13.3 (C/C) months, respectively. In conclusion, the ERCC1 C8092A polymorphism may be a useful predictor of OS in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.
Effect of Low Glutamine/Glucose on Hypoxia-Induced Elevation of Hypoxia-Inducible Factor-1α in Human Pancreatic Cancer MiaPaCa-2 and Human Prostatic Cancer DU-145 Cells
Authors: Seok Joon Kwon, Yong J. Lee
Journal: Clinical Cancer Research (2005)

Abstract Purpose and Experimental Design: Tumor microenvironment is characterized by regions of fluctuating and chronic hypoxia, low extracellular pH, and nutrient depletion. Although it is well known that hypoxia stimulates the accumulation of hypoxia-inducible factor-1α (HIF-1α), the role of low extracellular pH and nutrient depletion on hypoxia up-regulation of HIF-1α is not well known. In this study, human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells were exposed to hypoxia in the presence or absence of glucose, glutamine, and/or pyruvate. Results: We observed that low glucose and low glutamine, but not low pyruvate, effectively suppressed the elevation of HIF-1α level during hypoxia (0.1-1% oxygen). Deprivation of glutamine or glucose inhibited the accumulation of HIF-1α in the presence of MG-132, a protease inhibitor, regardless of oxygen tensions. Data from reverse transcription-PCR analysis revealed that the levels of HIF-1α mRNA were not significantly changed at different concentrations of glutamine or glucose under hypoxia. The amount of HIF-1α suppression was proportional to protein synthesis inhibition. Conclusions: Our data suggest that glutamine or glucose deprivation inhibits the accumulation of HIF-1α under hypoxic conditions by disrupting translational processes rather than transcriptional or proteasomal degradation processes.
Neural activation, information, and phenomenal consciousness
Authors: Max Velmans
Journal: Behavioral and Brain Sciences (1999)

O'Brien &amp; Opie defend a “vehicle” rather than a “process” theory of consciousness largely on the grounds that only conscious information is “explicit.” I argue that preconscious and unconscious representations can be functionally explicit (semantically well-formed and causally active). I also suggest that their analysis of how neural activation space mirrors the information structure of phenomenal experience fits more naturally into a dual-aspect theory of information than into their reductive physicalism.
Phase III Study Comparing Three Cycles of Infusional Carmustine and Cisplatin Followed by Radiation Therapy With Radiation Therapy and Concurrent Carmustine in Patients With Newly Diagnosed Supratentorial Glioblastoma Multiforme: Eastern Cooperative Oncology Group Trial 2394
Authors: Stuart A. Grossman, Anne O’Neill, Margaret Grunnet, Minesh Mehta, James L. Pearlman, Henry Wagner, Mark Gilbert, Herbert B. Newton, Richard Hellman
Journal: Journal of Clinical Oncology (2003)

This phase III Eastern Cooperative Oncology Group-Southwest Oncology Group intergroup study was conducted to determine whether three 72-hour infusions of carmustine (BiCNU) and cisplatin administered monthly before external-beam radiotherapy would improve the survival of patients with newly diagnosed glioblastoma multiforme. The control arm consisted of radiation with standard adjuvant BiCNU.A total of 223 patients were accrued from 1996 to 1999. Of these, 219 patients were eligible; 109 were randomly assigned to the experimental arm, and 110 were randomly assigned to the control arm. Randomization was stratified by age, performance status, and extent of resection.The median age of the patients was 55 years; 55% were male, 93% were white, 26% had a biopsy only, and 84% were ambulatory. Treatment arms were well balanced with respect to baseline characteristics. Median follow-up time of the 15 patients still alive at the time of analysis was 3.3 years (range, 2 to 5 years). Median survival times for the standard and experimental arms were 11.2 and 11.0 months (P =.33, two-sided log-rank test), and survival at 1 year was 45% versus 44%, respectively. Fifty-six percent of patients received all three cycles of BiCNU/cisplatin, 12% received two cycles, and 31% received only one cycle. Toxicity was primarily hematologic and was more common in the experimental arm (P <.01).This study demonstrates that 72-hour infusions of BiCNU and cisplatin followed by radiation do not improve median survival, survival at 1 year, or time to progression. Furthermore, this treatment requires more time in the hospital and is associated with more serious toxicities than standard therapy.
Evidence for a switching mechanism in the invasion of erythrocytes by Plasmodium falciparum.
Authors: S A Dolan, L H Miller, T E Wellems
Journal: Journal of Clinical Investigation (1990)

The human malaria parasite Plasmodium falciparum demonstrates variability in its dependence upon erythrocyte sialic acid residues for invasion. Some lines of P. falciparum invade neuraminidase-treated or glycophorin-deficient red blood cells poorly, or not at all, while other lines invade such cells at substantial rates. To explore the molecular basis of non-sialic acid dependent invasion, we selected parasite lines from a clone (Dd2) that initially exhibited low invasion of neuraminidase-treated erythrocytes. After maintaining Dd2 for several cycles in neuraminidase-treated erythrocytes, parasite lines were recovered that invaded both untreated and neuraminidase-treated erythrocytes at equivalently high rates (Dd2/NM). The change in phenotype was maintained after removal of selection pressure. Four subclones of Dd2 were isolated and each readily converted from sialic acid dependence to non-sialic acid dependence during continuous propagation in neuraminidase-treated erythrocytes. The neuraminidase-selected lines and the Dd2 clone demonstrated identical restriction fragment length polymorphism markers indicating that the Dd2 clone was not contaminated during the selection process. Parasite proteins that bound to neuraminidase-treated and untreated erythrocytes were indistinguishable among the parent Dd2 clone and the neuraminidase-selected lines. The ability of the Dd2 parasite to change its invasion requirements for erythrocyte sialic acid suggests a switch mechanism permitting invasion by alternative pathways.
[566] PRE-TREATMENT FACTORS PREDICTING SUSTAINED VIROLOGICAL RESPONSE IN TREATMENT-NAIVE HCV GENOTYPE 1 PATIENTS PARTICIPATING IN A LARGE, PRACTICE-BASED NATIONWIDE OBSERVATIONAL STUDY
Authors: A. Alberti, A. Ascione, M. Colombo, A. Craxi, F. Piccinino, M. Rizzetto, M. Sarracino
Journal: Journal of Hepatology (2007)
Cooperativity between the J and S elements of class II major histocompatibility complex genes as enhancers in normal and class II-negative patient and mutant B cell lines.
Authors: M Sugawara, T Scholl, S K Mahanta, P D Ponath, J L Strominger
Journal: The Journal of Experimental Medicine (1995)

The class II major histocompatibility complex genes all contain in their proximal promoters three cis-elements called S, X, and Y that are conserved in both sequence and position, and a fourth element, J, conserved in sequence but not in position. J, X, and Y and, to some extent, S, have been shown to be functionally important in regulation of expression of these genes. In the present study, a protein factor that binds cooperatively to the S plus J elements of the promoter of the class II major histocompatibility complex gene DPA has been detected. Moreover, functional cooperativity between S and J in activation of the enhancerless -40 interferon-beta (-40 IFN-beta) promoter has been demonstrated. Finally, the latter assay appears to subdivide complementation group A of class II negative human B cell lines that includes both mutants generated in vitro and cells from patients with the bare lymphocyte syndrome (type II). In three of these cell lines, the enhancerless -40 IFN-beta promoter containing the S plus J elements was functionally active, while in the others it was inactive.
Long-Term Ozone Exposure and Mortality
Authors: Michael Jerrett, Richard T. Burnett, C. Arden Pope, Kazuhiko Ito, George Thurston, Daniel Krewski, Yuanli Shi, Eugenia Calle, Michael Thun
Journal: New England Journal of Medicine (2009)

Although many studies have linked elevations in tropospheric ozone to adverse health outcomes, the effect of long-term exposure to ozone on air pollution–related mortality remains uncertain. We examined the potential contribution of exposure to ozone to the risk of death from cardiopulmonary causes and specifically to death from respiratory causes.
Immunohistochemical Detection Using the New Rabbit Monoclonal Antibody SP1 of Estrogen Receptor in Breast Cancer Is Superior to Mouse Monoclonal Antibody 1D5 in Predicting Survival
Authors: Maggie C.U. Cheang, Diana O. Treaba, Caroline H. Speers, Ivo A. Olivotto, Chris D. Bajdik, Stephen K. Chia, Lynn C. Goldstein, Karen A. Gelmon, David Huntsman, C. Blake Gilks, Torsten O. Nielsen, Allen M. Gown
Journal: Journal of Clinical Oncology (2006)

Estrogen receptor (ER) expression predicts improved breast cancer-specific survival and reduced risk of recurrence and is targeted in breast cancer therapy. A high-quality antibody to identify ER-positive patients plays an important role in clinical decision making for women with breast cancer. This study evaluates immunohistochemistry using two anti-ER antibodies, a new rabbit monoclonal antibody (SP1) and the mouse monoclonal antibody (1D5), in relation to biochemical ER assay results and clinical data on survival and adjuvant systemic therapy.A population-based tissue microarray series of 4,150 invasive breast cancers was constructed. All patients had staging, pathology, treatment, and follow-up information. The median follow-up was 12.4 years and the median age at diagnosis 60 years. Survival analysis and log-rank tests were used to evaluate the prognostic value of ER status and correlations with clinical data.Among the 4,105 samples interpretable for both antibodies, SP1 detected ER positivity in 69.5% and 1D5 in 63.1% of cases. Both monoclonal antibodies are demonstrated to be good prognostic indictors for breast cancer-specific and relapse-free survival. In multivariate analysis, including age, tumor size, grade, and lymphovascular and nodal status, SP1 was a better independent prognostic factor than 1D5. Among patients with discrepant ER results, the 8% of patients who were SP1 positive/1D5 negative showed good outcomes, and the 2% SP1-negative/1D5 positive had poor outcomes. Maintaining the same 92% specificity and 98% positive predictive value, SP1 is 8% more sensitive than 1D5 using biochemical assay as gold standard.SP1 represents an improved standard for ER immunohistochemistry assessment in breast cancer.
Quality of life measured by the St George's Respiratory Questionnaire and spirometry
Authors: M. Weatherall, S. Marsh, P. Shirtcliffe, M. Williams, J. Travers, R. Beasley
Journal: European Respiratory Journal (2009)

The present authors aimed to determine if the criteria for the diagnosis of chronic obstructive pulmonary disease (COPD) and its classification by severity as recommended by the Global Initiative for Chronic Obstructive Lung Disease are supported by measurements of respiratory health-related quality of life. A community-based sample of adults aged 25-75 yrs had pre- and post-bronchodilator spirometry and completed the St George's Respiratory Questionnaire (SGRQ). Loess scatter plot smoothers of the SGRQ versus post-bronchodilator forced expiratory volume in one second (FEV(1))/forced vital capacity (FVC) ratio and post-bronchodilator FEV(1) % predicted together with receiver operating characteristic (ROC) curve analysis were used to determine the relationship between spirometric variables and clinically important differences in the SGRQ score. The scatter plot smoother and ROC curve analyses supported the value of 0.7 for post-bronchodilator FEV(1)/FVC ratio, which was approximately 4 units higher than the nadir of the SGRQ. To represent a distance of 8 units on the SGRQ, the cut-off points for post-bronchodilator FEV(1) that delimit COPD severity stages were 80, 60 and 40% pred for mild, moderate and severe COPD, respectively. To diagnose chronic obstructive pulmonary disease the use of post-bronchodilator forced expiratory volume in one second/forced vital capacity ratio of 0.7 is supported by health-related quality of life measurements. There may be advantages in using forced expiratory volume in one second cut-off points of 80, 60 and 40% predicted for the classification of mild, moderate and severe chronic obstructive pulmonary disease, respectively, similar to the approach recommended for asthma.
Isolation and characterization of the nephritogenic antigen producing anti-tubular basement membrane disease.
Authors: M D Clayman, A Martinez-Hernandez, L Michaud, R Alper, R Mann, N A Kefalides, E G Neilson
Journal: The Journal of Experimental Medicine (1985)

Using monoclonal antibody affinity chromatography, we isolated a 48,000 mol wt, glucose-rich glycoprotein (3M-1) from collagenase-solubilized rabbit renal tubular basement membrane (SRTA). The purified 3M-1 protein is noncollagenous, and is capable of inducing anti-TBM (tubular basement membrane) antibodies and interstitial nephritis in susceptible hosts. Further, when SRTA, at a normally nephritogenic dose, was selectively depleted of 3M-1, it lost its ability to induce disease. As shown by immunofluorescent techniques, 3M-1 appears to be localized on rodent TBM to the exclusion of the glomerular basement membrane, but was lacking in the TBM of the LEW rat, a strain devoid of the relevant antigen of anti-TBM disease. Immunoelectron microscopy revealed that 3M-1 was associated with the most lateral aspect of the TBM, which borders, and lies in the interstitium. These results indicate that 3M-1 is the nephritogenic antigen producing experimental anti-TBM disease.