tbuckley/cabot-search huggingface dataset:
Treatment Results in Localized Primary Gastric Lymphoma: Data of Patients Registered Within the German Multicenter Study (GIT NHL 02/96)
Authors: Peter Koch, Andreas Probst, Wolfgang E. Berdel, Normann A. Willich, Gabriele Reinartz, Jens Brockmann, Rüdiger Liersch, Francisco del Valle, Hermann Clasen, Carsten Hirt, Regine Breitsprecher, Rudolf Schmits, Mathias Freund, Rainer Fietkau, Peter Ketterer, Eva-Maria Freitag, Margit Hinkelbein, Achim Heinecke, Reza Parwaresch, Markus Tiemann
Journal: Journal of Clinical Oncology (2005)

In the prospective study 02/96 on primary GI lymphoma, we have collected data on histology, clinical features, and treatment results. In particular, in stages I and II localized primary gastric lymphoma (PGL), our objectives were to reduce treatment intensity and to confirm our hypothesis from study 01/92, which maintained that an organ-preserving approach is not inferior to primary surgery.Patients receiving radiotherapy and/or chemotherapy were stratified for histologic grade, stage, and whether surgery had been carried out or not (as decided by each participating center). Patients with aggressive PGL received six cycles of CHOP-14 (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by involved-field radiotherapy (40 Gy). Patients with indolent PGL (including patients experiencing treatment failure with antibiotic therapy for Helicobacter pylori) were treated with extended-field radiotherapy. The volume depended on stage. The irradiation dose was 30 Gy, followed by a boost of 10 Gy (the latter omitted after complete resection) to the tumor region.Seven hundred forty-seven patients were accrued. Of these patients, 393 with localized PGL were treated with radiotherapy and/or chemotherapy only or additional surgery between December 1996 and December 2003. The survival rate at 42 months for patients treated with surgery was 86% compared with 91.0% for patients without surgery.In this nonrandomized study (02/96), we reproduced the previous results of study 01/92 showing no disadvantage for an organ-preserving treatment. Therefore, primary stomach resection should be questioned.
Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors
Authors: Patricia M. LoRusso, Antonio Jimeno, Grace Dy, Alex Adjei, Jordan Berlin, Lawrence Leichman, Jennifer A. Low, Dawn Colburn, Ilsung Chang, Sravanthi Cheeti, Jin Y. Jin, Richard A. Graham
Journal: Clinical Cancer Research (2011)

This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing.Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS.The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results.Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.
Nutritional medicine as mainstream in psychiatry
Authors: Jerome Sarris, Alan C Logan, Tasnime N Akbaraly, G Paul Amminger, Vicent Balanzá-Martínez, Marlene P Freeman, Joseph Hibbeln, Yutaka Matsuoka, David Mischoulon, Tetsuya Mizoue, Akiko Nanri, Daisuke Nishi, Drew Ramsey, Julia J Rucklidge, Almudena Sanchez-Villegas, Andrew Scholey, Kuan-Pin Su, Felice N Jacka
Journal: The Lancet Psychiatry (2015)
Complications of flexible bronchoscopy in children: prospective study of 1,328 procedures
Authors: J. de Blic, V. Marchac, P. Scheinmann
Journal: European Respiratory Journal (2002)

Complications of flexible bronchoscopy (FB) were prospectively evaluated during 1,328 diagnostic procedures in children, not in intensive care units. A total 92.8% of the procedures were performed in conscious patients under sedation and 7.2% under deep sedation. Supplementary oxygen was provided in approximately 80% of cases via endoscopic face mask (n=783) or nasal prongs (n=290). At least one complication was recorded in 91 cases (6.9%). Minor complications (n=69; 5.2%) included moderate and transient episodes of desaturation (n=15), isolated excessive coughing (n=22), excessive nausea reflex with coughing (n=20), transient laryngospasm (n=6) and epistaxis (n=6). Major complications (n=22; 1.7%) included oxygen desaturation to <90%, either isolated (n=10) or associated with laryngospasm (n=6), coughing (n=4), bronchospasm (n=1), and pneumothorax (n=1). Major complications involving oxygen desaturation were associated with age <2 yrs (13 of 529 versus 8 of 778) and laryngotracheal abnormalities (7 of 85 versus 14 of 1,222). The overall frequency of complications was similar in conscious (6.7%) but sedated patients and patients under deep (7.3%) sedation. However, the frequency of transient desaturation was significantly higher in children undergoing FB under deep sedation. Transient fever after bronchoalveolar lavage was observed in 52 of 277 cases (18.8%). Flexible bronchoscopy is a safe procedure with <2% major complications. Careful analysis of indications and clinical status for each patient, and proper anaesthesia and monitoring during the examination ensure that the procedure is successful, with a minimum of complications.
DNA damage and donor livers: Disease unbidden?
Authors: Kathleen Schwarz
Journal: Hepatology (1995)

Endogenous DNA adducts may contribute to the etiology of human genetic disease and cancer. One potential source of endogenous DNA adducts is lipid peroxidation, which generates mutagenic carbonyl compounds such as malondialdehyde. A sensitive mass spectrometric method permitted detection and quantitation of the major malondialdehyde-DNA adduct, a pyrimidopurinone derived from deoxyguanosine. DNA from disease-free human liver was found to contain 5400 adducts per cell, a frequency comparable to that of adducts formed by exogenous carcinogens. Reprinted with permission from Science 1994;265:1580-1581.
Changing the Definition of Impaired Fasting Glucose
Authors: Olga Vaccaro, Gabriele Riccardi
Journal: Diabetes Care (2005)

OBJECTIVE—This study evaluates the impact of lowering the diagnostic threshold for impaired fasting glucose (IFG) from 6.1 to 5.6 mmol/l as proposed by the American Diabetes Association (ADA) on the prevalence of the condition, classification of individuals, and risk definition. RESEARCH DESIGN AND METHODS—A total of 1,285 employees of the Italian Telephone Company aged 35–59 years without known diabetes underwent an oral glucose tolerance test (OGTT). BMI, serum cholesterol, triglycerides, and blood pressure were measured. Medication use was recorded. RESULTS—With the new ADA criterion, the proportion of people diagnosed with IFG increased from 3.2 to 9.7%. The newly proposed IFG category identified 41% of all subjects with impaired glucose tolerance (IGT) compared with 16.2% identified with the use of the World Health Organization criterion for IFG; the improvement in accuracy has been achieved at the cost of classifying more previously “normal” subjects as having IFG (from 2.3 to 7.3%). Both IFG and IGT were associated with an unfavorable risk profile for diabetes and cardiovascular disease, with a higher estimated risk for IGT than IFG. CONCLUSIONS—Even with the revised diagnostic criterion, IFG and IGT identify distinct groups that have a different background risk. The cost/benefit of preventive measures tested in people with IGT may not apply to the new IFG category.
Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study
Authors: K. Scott Baker, James G. Gurney, Kirsten K. Ness, Ravi Bhatia, Stephen J. Forman, Liton Francisco, Philip B. McGlave, Leslie L. Robison, David S. Snyder, Daniel J. Weisdorf, Smita Bhatia
Journal: Blood (2004)
Ambient and Microenvironmental Particles and Exhaled Nitric Oxide Before and After a Group Bus Trip
Authors: Sara Dubowsky Adar, Gary Adamkiewicz, Diane R. Gold, Joel Schwartz, Brent A. Coull, Helen Suh
Journal: Environmental Health Perspectives (2006)

ObjectivesAirborne particles have been linked to pulmonary oxidative stress and inflammation. Because these effects may be particularly great for traffic-related particles, we examined associations between particle exposures and exhaled nitric oxide (FENO) in a study of 44 senior citizens, which involved repeated trips aboard a diesel bus.MethodsSamples of FENO collected before and after the trips were regressed against microenvironmental and ambient particle concentrations using mixed models controlling for subject, day, trip, vitamins, collection device, mold, pollen, room air nitric oxide, apparent temperature, and time to analysis. Although ambient concentrations were collected at a fixed location, continuous group-level personal samples characterized microenvironmental exposures throughout facility and trip periods.ResultsIn pre-trip samples, both microenvironmental and ambient exposures to fine particles were positively associated with FENO. For example, an interquartile increase of 4 μg/m3 in the daily microenvironmental PM2.5 concentration was associated with a 13% [95% confidence interval (CI), 2–24%) increase in FENO. After the trips, however, FENO concentrations were associated pre-dominantly with microenvironmental exposures, with significant associations for concentrations measured throughout the whole day. Associations with exposures during the trip also were strong and statistically significant with a 24% (95% CI, 15–34%) increase in FENO predicted per interquartile increase of 9 μg/m3 in PM2.5. Although pre-trip findings were generally robust, our post-trip findings were sensitive to several influential days.ConclusionsFine particle exposures resulted in increased levels of FENO in elderly adults, suggestive of increased airway inflammation. These associations were best assessed by microenvironmental exposure measurements during periods of high personal particle exposures.
CD28-independent, TRAF2-dependent Costimulation of Resting T Cells by 4-1BB Ligand
Authors: Katina Saoulli, Soo Young Lee, Jennifer L. Cannons, Wen Chen Yeh, Angela Santana, Marni D. Goldstein, Naveen Bangia, Mark A. DeBenedette, Tak W. Mak, Yongwon Choi, Tania H. Watts
Journal: The Journal of Experimental Medicine (1998)

4-1BB ligand (4-1BBL) is a member of the tumor necrosis factor (TNF) family expressed on activated antigen-presenting cells. Its receptor, 4-1BB, is a member of the TNF receptor family expressed on activated CD4 and CD8 T cells. We have produced a soluble form of 4-1BBL using the baculovirus expression system. When coimmobilized on plastic with anti-CD3, soluble 4-1BBL induces interleukin (IL)-2 production by resting CD28+ or CD28− T cells, indicating that 4-1BBL can function independently of other cell surface molecules, including CD28, in costimulation of resting T cell activation. At low concentrations of anti-CD3, 4-1BBL is inferior to anti-CD28 in T cell activation. However, when 4-1BB ligand is provided together with strong TCR signals, then 4-1BBL and anti-CD28 are equally potent in stimulation of IL-2 production by resting T cells. We find that TNF receptor–associated factor (TRAF)1 or TRAF2 associate with a glutathione S-transferase–4-1BB cytoplasmic domain fusion protein in vitro. In T cells, we find that association of TRAF1 and TRAF2 with 4-1BB requires 4-1BB cross-linking. In support of a functional role for TRAF2 in 4-1BB signaling, we find that resting T cells isolated from TRAF2-deficient mice or from mice expressing a dominant negative form of TRAF2 fail to augment IL-2 production in response to soluble 4-1BBL. Thus 4-1BB, via the TRAF2 molecule, can provide CD28-independent costimulatory signals to resting T cells.
Idealism, the lost spirit of medicine
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2013)

Is idealism in medicine dead? Did the inspirations and role models that motivated successive generations of doctors disappear when professional lives became dominated by contracts, working time directives, politically motivated targets and perpetual reorganization? Perhaps idealism in medicine is a myth, as elaborate a hoax as any history of Keyser Soze; it simply never existed. Humans are beasts driven by greed, lust and vanity. Why should doctors be any different?

B Sethia argues in this month’s issue that advocates for idealism and altruism are to be found in abundance among new recruits to the medical profession.1 But materialism and pragmatism dilute or extinguish compassion and dedication. When the Department of Health wavers on introducing plain packs for cigarettes, the idealism reflex in medical professionals immediately twitches;2 a reflex that supports Sethia’s argument. The question that Sethia poses is an important one: how can medical leaders nurture these attributes more effectively?

One focus is the evolution from medical student to doctor. What occurs at that transition? The process should convert a diligent student into a competent professional. Instead an idealistic, compassionate creature is transformed into a materialistic, pragmatic beast. Does the problem lie with the annual introduction of the most junior doctors in August? Senior consultants traditionally flee to warmer climes to escape the chill of transition, leaving patients in less-experienced hands.

Mark Edwards and colleagues focus on competence not idealism but argue that the preparation of junior doctors to enter the medical workplace requires examination and reform.3 They ask: how well does the medical profession perform in its task of producing competent junior doctors who are sufficiently self-aware and confident in their abilities? Not nearly well enough is the answer.

Perhaps the medical profession is distracted by pragmatic woes? In the spirit of idealism doctors would not strike and withdraw care from patients. Yet on 21 June 2012 the British Medical Association sanctioned medical practitioners to take industrial action in a disagreement over government pension reforms, the first doctors’ strike in England since 1975. Emergency and urgent cases were dealt with as usual and only around 8% of doctors took industrial action, but a new analysis by Milagros Ruiz and colleagues suggests that the 24-hour strike significantly affected provision of healthcare by NHS hospitals.4

Philosopher Bertrand Russell said that ‘much that passes as idealism is disguised hatred or disguised love of power’. If Russell is right then Sethia’s call for genuine idealism requires broad and staunch support. In reaching out further to that lost spirit of medicine, we begin a two-part series on the origins of vaccination that remember an age when idealism reigned supreme and pragmatism was unknown.5
Emerging Role of Platelet-Derived Growth Factor Receptor-β Inhibition in Radioimmunotherapy of Experimental Pancreatic Cancer
Authors: Janina Baranowska-Kortylewicz, Michio Abe, Jessica Nearman, Charles A. Enke
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Thus far, the therapy of pancreatic cancer remains an insurmountable challenge. Not a solitary therapeutic modality in the battery of available therapeutic options is capable to cure or, at the very least, stop the progression of this disease in any meaningful way. The purpose of reported here studies was to implement a multimodality approach to radioimmunotherapy of pancreatic cancer and, ultimately, to develop a course of therapy with the clinical value. Experimental Design: Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on 131ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-β. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of 131ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy. Results: Biodistribution studies revealed a 50% improvement in the tumor uptake of 131ICC49 in mice treated with imatinib. Tumor development was practically arrested for ∼3 weeks in response to the treatment composed of 131ICC49 and imatinib with tumor quadrupling time (TQ) of 40.8 days. 131ICC49 alone and imatinib alone also delayed the tumor growth to TQ of 30.2 and 31.2 days, respectively. Unanticipated was the significant response of SW1990 to a brief treatment with imatinib given i.p. at 100 mg/kg b.i.d. for 3 days. Xenografts in control mice receiving injection of PBS had TQ of 23 days. Conclusions: The inclusion of imatinib in the radioimmunotherapy regimen is beneficial and it does not produce any overt side effects. The improved responses of pancreatic cancer xenografts to the multimodality treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-β inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.
Subcellular localization and dynamics of Mac-1 (alpha m beta 2) in human neutrophils.
Authors: H Sengeløv, L Kjeldsen, M S Diamond, T A Springer, N Borregaard
Journal: Journal of Clinical Investigation (1993)

The subcellular localization of Mac-1 was determined in resting and stimulated human neutrophils after disruption by nitrogen cavitation and fractionation on two-layer Percoll density gradients. Light membranes were further separated by high voltage free flow electrophoresis. Mac-1 was determined by an ELISA with monoclonal antibodies that were specific for the alpha-chain (CD11b). In unstimulated neutrophils, 75% of Mac-1 colocalized with specific granules including gelatinase granules, 20% with secretory vesicles and the rest with plasma membranes. Stimulation with nanomolar concentrations of FMLP resulted in the translocation of Mac-1 from secretory vesicles to the plasma membrane, and only minimal translocation from specific granules and gelatinase granules. Stimulation with PMA or Ionomycin resulted in full translocation of Mac-1 from secretory vesicles and gelatinase granules to the plasma membrane, and partial translocation of Mac-1 from specific granules. These findings were corroborated by flow cytometry, which demonstrated a 6-10-fold increase in the surface membrane content of Mac-1 in response to stimulation with FMLP, granulocyte-macrophage colony stimulating factor, IL-8, leukotriene B4, platelet-activating factor, TNF-alpha, and zymosan-activated serum, and a 25-fold increase in response to Ionomycin. Thus, secretory vesicles constitute the most important reservoir of Mac-1 that is incorporated into the plasma membrane during stimulation with inflammatory mediators.
Rational Design Leads to More Potent RNA Interference Against Hepatitis B Virus: Factors Effecting Silencing Efficiency
Authors: Kathy Keck, Esther M Volper, Ryan M Spengler, Dang D Long, Chi Y Chan, Ye Ding, Anton P McCaffrey
Journal: Molecular Therapy (2008)

RNA interference (RNAi) can be an effective antiviral agent; however, overexpression of RNAi can be toxic through competition with the endogenous microRNA (miRNA) machinery. We used rational design to identify highly potent RNAi that is effective at nontoxic doses. A statistical analysis was conducted to pinpoint thermodynamic characteristics correlated with activity. Sequences were selected that conformed to a consensus internal stability profile (ISP) associated with active RNAi, and RNAi triggers were expressed in the context of an endogenous miRNA. These approaches yielded highly active hepatitis B virus (HBV) RNAi. A statistical analysis found a correlation between activity and nucleation by binding within the seed sequence to accessible regions in the target RNA. Guide strands were selected for favorable strand biasing, but increased strand biasing did not correlate with potency, suggesting a threshold effect. Exogenous short hairpin RNAs (shRNAs), but not miRNAs were previously reported to compete with miRNAs for the miRNA/RNAi machinery. In contrast, we show that exogenous Polymerase III- but not Polymerase II-driven miRNAs compete with exogenous miRNAs, at multiple steps in the miRNA pathway. Exogenous miRNAs also compete with endogenous miR-21. Thus, competition with endogenous miRNAs should be monitored even when using miRNA-based therapeutics. However, potent silencing was achieved at doses where competition was not observed.
Interferon Regulatory Factor 4 (IRF4) Interacts with NFATc2 to Modulate Interleukin 4 Gene Expression
Authors: Jyothi Rengarajan, Kerri A. Mowen, Kathryn D. McBride, Erica D. Smith, Harinder Singh, Laurie H. Glimcher
Journal: The Journal of Experimental Medicine (2002)

Proteins of the nuclear factor of activated T cells (NFAT) family of transcription factors are critical for lymphocyte activation in the immune system. In particular, NFATs are important regulators of inducible IL-4 gene expression. Interferon regulatory factor 4 (IRF4) is an immune system–restricted interferon regulatory factor that is required for lymphocyte activation, but its molecular functions in the T lineage remain to be elucidated. We demonstrate that IRF4 potently synergizes with NFATc2 to specifically enhance NFATc2-driven transcriptional activation of the IL-4 promoter. This function is dependent on the physical interaction of IRF4 with NFATc2. IRF4 synergizes with NFATc2 and the IL-4–inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production. Furthermore, naïve T helper cells from mice lacking IRF4 are compromised severely for the production of IL-4 and other Th2 cytokines. The identification of IRF4 as a partner for NFATc2 in IL-4 gene regulation provides an important molecular function for IRF4 in T helper cell differentiation.