tbuckley/cabot-search huggingface dataset:
Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for local-regional cancer of the esophagus.
Authors: A A Forastiere, M B Orringer, C Perez-Tamayo, S G Urba, S Husted, B J Takasugi, M Zahurak
Journal: Journal of Clinical Oncology (1990)

Forty-three patients with local-regional squamous-cell carcinoma of the esophagus or adenocarcinoma of the esophagus, cardia, or gastroesophageal junction were treated with concurrent cisplatin, vinblastine, fluorouracil (5-FU), and radiation therapy (RT) over 21 days. A transhiatal esophagectomy (THE) was planned on day 42. Seventy-nine percent had T2 primaries by clinical staging and 56% had enlarged regional nodes (N) on computed tomographic (CT) scan. Forty-one patients completed the preoperative treatment and went to surgery (95% operability rate), and 36 (84%) were completely resected. Ten of the 41 operative candidates had no evidence of tumor in the resected esophagus and nodal tissue (tumor0 node0; T0N0), 24% complete response (CR). Myelosuppression was the major toxicity with grade 3 or 4 leukopenia in 93% of patients and two preoperative treatment-related deaths. At a median follow-up of 26 months, the median survival time (MST) of all 43 patients registered on study has not been reached. The MST of the 36 completely resected patients and the 10 complete responders has not been reached; 70% and 100%, respectively, are alive at 24 months. The MST by histology is 21 months for the 22 squamous patients and has not been reached for the 21 adenocarcinoma patients registered on study. In a prognostic factor analysis, clinical N status, histology, and the percent of cisplatin and vinblastine tolerated were significant predictors for survival. These survival results suggest a significant improvement over the 14-month MST observed in our previous trial using preoperative chemotherapy only in a similar patient population, and a 12-month MST in a historic control group undergoing THE. A randomized trial is now in progress to convincingly determine if survival is prolonged by this therapy.
GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation
Authors: Makoto Shigeto, Reshma Ramracheya, Andrei I. Tarasov, Chae Young Cha, Margarita V. Chibalina, Benoit Hastoy, Koenraad Philippaert, Thomas Reinbothe, Nils Rorsman, Albert Salehi, William R. Sones, Elisa Vergari, Cathryn Weston, Julia Gorelik, Masashi Katsura, Viacheslav O. Nikolaev, Rudi Vennekens, Manuela Zaccolo, Antony Galione, Paul R.V. Johnson, Kohei Kaku, Graham Ladds, Patrik Rorsman
Journal: Journal of Clinical Investigation (2015)

Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca2+ channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na+. The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na+-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca2+ from thapsigargin-sensitive Ca2+ stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.
Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors
Authors: S.J. Wong, T. Karrison, D.N. Hayes, M.S. Kies, K.J. Cullen, T. Tanvetyanon, A. Argiris, N. Takebe, D. Lim, N.F. Saba, F.P. Worden, J. Gilbert, H.J. Lenz, A.R.A. Razak, J.D. Roberts, E.E. Vokes, E.E.W. Cohen
Journal: Annals of Oncology (2015)
Evolutionary Study of Birds’ Sense of Smell Reveals Important Clues for Behavior and Adaptation
Authors: Joseph Caspermeyer
Journal: Molecular Biology and Evolution (2015)

From slight sparrows to preening peacocks to soaring falcons, birds have long been known to possess distinct abilities in their sense of smell, but little has been known about the evolution of olfaction. Now, a large comparative genomic study of the olfactory genes tied to a bird’s sense of smell has revealed important differences that correlate with their ecological niches and specific behaviors. Khan et al. (2015) analyzed olfactory receptor genes (OR gene families) from 48 ecologically diverse bird and two reptilian genomes. In vertebrates, ORs are considered to be one the largest multigene families, ranging from a single gene in elephant sharks to more than 1,000 genes in mammals. The study provides evidence that specific OR genes are used not only to detect a range of chemicals governing a bird’s ability to smell, but that the dominant bird behavior such as those found in birds of prey or aquatic birds—was often mirrored by the genetic diversity of their OR gene families. In the study, drastic expansion of specific OR’s gene families, such as OR51 and OR52, were seen in sea turtles and aquatic birds to detect water-loving (hydrophilic) compounds. In contrast, the expansion of OR14 was found in the birds that could smell volatile compounds (terrestrial birds). Overall, OR families 2, 13, 51, and 52 were more common in aquatic birds and 6 and 10 were associated with vocal learners. Birds of prey had a comparatively high percentage of OR families 5, 8, and 9. These were also the largest OR families observed in alligators, which like birds of prey, depend on hunting or scavenging for food, which also suggests that these genes are needed for adaptation in carnivores. Finally, the research team related the genetic differences to bird anatomy, and the size of the olfactory bulb, the main neurological structure involved in smell. The relative size of the olfactory bulb in birds was also found to correlate with ecological adaptations, including habitat association (e.g., water birds), type of nesting strategy, and diet. For example, birds of prey, including vultures and seabirds, hunt and recognize food by smell, and have relatively large olfactory bulbs, whereas song birds that rely more on cognitive abilities helpful in tool making, vocal learning, and feeding innovations have reduced olfactory bulb sizes. Overall, the role of ecological adaptation in shaping the OR gene families has been found to be consistent in both birds and mammals, indicating the importance of a sense of smell to an animal’s fitness, survival, and niche.
More work needed to crack the nut
Authors: M. Vazquez-Ortiz
Journal: British Journal of Dermatology (2015)

The STOP II study provides high‐quality evidence on the efficacy, safety and impact on quality of life of oral immunotherapy (OIT) in peanut‐allergic children. Although the results are promising, significant concerns and knowledge gaps remain regarding the safety of OIT, its ability to induce long‐term tolerance once regular peanut intake is stopped and, accordingly, long‐term adherence. Peanut OIT therefore needs to be restricted to research studies aiming to complete the current evidence gaps.
Scoring system developed for drug related morbidity
Authors: C F A Pantin, R King, U Pathak, D R Baldwin, P S. Burge, M J Cushley
Journal: BMJ (1995)

EDITOR,—Nick Steen and colleagues describe the development of a symptom based outcome measure for asthma.1 The Midlands Thoracic Society's research group is developing a simple scoring system for morbidity related to drugs used for asthma. This will be used in asthma clinics to monitor individual patients and audit the clinic. The morbidity measures include scales for the highest peak expiratory flow in the clinic as a percentage of the predicted flow (10 items); the variability in peak expiratory flow in the week before the clinic …
A rare cause of obscure gastrointestinal bleeding
Authors: W-L Wang, J-Y Lee, J-T Lin, K-L Liu, H-P Wang
Journal: Gut (2008)

A 45-year-old man was referred to our hospital because of repeated gastrointestinal bleeding from an unknown origin. The bleeding had been recurrent over a period of 4 months and was usually preceded by postprandial epigastric pain. …
First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies
Authors: Pamela Munster, Rahul Aggarwal, David Hong, Jan H.M. Schellens, Ruud van der Noll, Jennifer Specht, Petronella O. Witteveen, Theresa L. Werner, E. Claire Dees, Emily Bergsland, Neeraj Agarwal, Joseph F. Kleha, Michael Durante, Laurel Adams, Deborah A. Smith, Thomas A. Lampkin, Shannon R. Morris, Razelle Kurzrock
Journal: Clinical Cancer Research (2015)

Abstract Purpose: GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. Materials and Methods: Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts. Results: One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea, n = 4; fatigue and rash, n = 1) occurred in 5 patients (n = 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated with PIK3CA mutations (OR rate: 5% wild-type vs. 6% mutant). Conclusions: Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however, PIK3CA mutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K. Clin Cancer Res; 22(8); 1932–9. ©2015 AACR.
Poor working conditions in England pose threat to health, says expert
Authors: Matthew Limb
Journal: BMJ (2015)

“Shocking” levels of poverty among working households and rising occupational illness are threatening England’s economic recovery, a leading expert on health inequality has said.

Michael Marmot said that “poor quality jobs” and unacceptably low pay risked increasing levels of harm as more people entered such jobs. He issued the latest “Marmot indicators” for health inequalities on Friday 27 November,1 shortly after the UK government scrapped its planned cuts to working tax credits in its autumn financial statement. 

Marmot said that this policy “U turn” meant short term relief for people on low incomes but would not tackle long term problems, such as increasing “segregation” in the labour market between people with good education and well paid, secure jobs and people who could get only poor quality, insecure or part time, low …
Chronic myeloid leukemia: First‐line drug of choice
Authors: Elias Jabbour
Journal: American Journal of Hematology (2015)

The advent of tyrosine kinase inhibitors (TKIs) has drastically changed the treatment outcome of chronic myeloid leukemia (CML). Imatinib was the first TKI approved, and has been considered the standard of care for more than a decade. Second generation compounds, namely dasatinib and nilotinib, are highly effective in newly diagnosed patients as well as those who fail imatinib. Second generation TKIs have been demonstrated to induce deeper and faster responses compared to imatinib, however no survival advantage has been observed so far. Today, the expected survival of CML patients, if properly managed, is likely to be similar to the general population. Clinicians are faced the challenge of making decision for which TKI to choose upfront. Comorbidities of the patient, the side effect profile, and the cost of the TKI of interest should be an important consideration in decision making. Whatever TKI is chosen as frontline, noncompliance or treatment failure should be recognized early as a prompt intervention increases the chance of achieving best possible response. Herein, we review the frontline options for the management of patients with CML and how to best choose these agents.
Phase II trial of intermittent high-dose recombinant interferon alfa-2a in mycosis fungoides and the Sézary syndrome.
Authors: E C Kohn, R G Steis, E A Sausville, S R Veach, J L Stocker, R Phelps, S Franco, D L Longo, P A Bunn, D C Ihde
Journal: Journal of Clinical Oncology (1990)

We previously demonstrated that recombinant interferon alfa-2a (IFN-alfa) in a dose of 50 X 10(6) U million units (MU)/m2 intramuscularly (IM) three times per week has efficacy against mycosis fungoides (MF) and the Sézary syndrome (SS). However, this regimen given to patients with refractory disease was uniformly complicated by toxicities requiring major dose reductions. The present study was designed to determine if intermittent high-dose IFN-alfa would preserve efficacy and decrease toxicity in a similar patient population. Twenty-four patients with advanced disease refractory to one or more standard therapies received IFN-alfa, 10 MU/m2 IM on day 1 followed by 50 MU/m2 IM on days 2 to 5 every 3 weeks; after the first four cycles, stable and partially responding patients underwent dose escalation to twice the starting dose. One complete (CR) and six partial responses (PRs) were observed (response rate, 29%; 95% confidence interval, 13% to 51%) lasting 4 to 19 months (median, 8 months). No improvement in objective response was seen in the eight patients who received dose escalation. Dose reductions were necessary in eight of 22 patients receiving one or more cycles of therapy. Weighted mean dose rate intensity for patients on this study over the first four cycles of treatment was 65.5 MU/m2/wk compared with 73.2 MU/m2/wk over the first 12 weeks of treatment in patients from the previous study, in which all 19 patients receiving more than 1 week of treatment required dose reduction. IFN-alfa is effective against previously treated MF and the SS and is better tolerated on this intermittent schedule.
Loci associated with N-glycosylation of human IgG are not associated with rheumatoid arthritis: a Mendelian randomisation study
Authors: Annie Yarwood, Sebastien Viatte, Yukinori Okada, Robert Plenge, Kazuhiko Yamamoto, Anne Barton, Deborah Symmons, Soumya Raychaudhuri, Lars Klareskog, Peter Gregersen, Jane Worthington, Steve Eyre
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> A recent study identified 16 genetic variants associated with N-glycosylation of human IgG. Several of the genomic regions where these single nucleotide polymorphisms (SNPs) reside have also been associated with autoimmune disease (AID) susceptibility, suggesting there may be pleiotropy (genetic sharing) between loci controlling both N-glycosylation and AIDs. We investigated this by testing variants associated with levels of IgG N-glycosylation for association with rheumatoid arthritis (RA) susceptibility using a Mendelian randomisation study, and testing a subset of these variants in a less well-powered study of treatment response and severity. <h3>Methods</h3> SNPs showing association with IgG N-glycosylation were analysed for association with RA susceptibility in 14 361 RA cases and 43 923 controls. Five SNPs were tested for association with response to anti-tumour necrosis factor (TNF) therapy in 1081 RA patient samples and for association with radiological disease severity in 342 patients. <h3>Results</h3> Only one SNP (rs9296009) associated with N-glycosylation showed an association (p=6.92×10<sup>–266</sup>) with RA susceptibility, although this was due to linkage disequilibrium with causal human leukocyte antigen (HLA) variants. Four regions of the genome harboured SNPs associated with both traits (shared loci); although statistical analysis indicated that the associations observed for the two traits are independent. No SNPs showed association with response to anti-TNF therapy. One SNP rs12342831 was modestly associated with Larsen score (p=0.05). <h3>Conclusions</h3> In a large, well-powered cohort of RA patients, we show SNPs driving levels of N-glycosylation have no association with RA susceptibility, indicating colocalisation of associated SNPs are not necessarily indicative of a shared genetic background or a role for glycosylation in disease susceptibility.
Drug Provocation Tests in the Diagnosis of Hypersensitivity Reactions to Non-Steroidal Anti-Inflamatory Drugs in Children
Authors: Maria Angeles Zambonino, María José Torres, Candelaria Muñoz, Gloria Requena, Cristobalina Mayorga, Teresa Posadas, Antonio Urda, Miguel Blanca, Jose Luis Corzo Higueras
Journal: Journal of Allergy and Clinical Immunology (2013)
Gastrointestinal involvement and multiple lymphomatous polyposis in mantle-zone lymphoma.
Authors: P L Triozzi, M J Borowitz, J P Gockerman
Journal: Journal of Clinical Oncology (1986)

The clinical, histologic, and immunologic features of three cases of lymphoma presenting with gastrointestinal symptoms and involving the gastrointestinal tract were studied. Two of the cases had involvement of long segments of the bowel with polypoid lesions, a rare presentation of gastrointestinal lymphoma referred to as multiple lymphomatous polyposis (MLP). All cases were classified as mantle-zone lymphoma (MZL), a follicular variant of intermediate lymphocytic lymphoma (ILL) characterized by the proliferation of small atypical lymphoid cells as wide mantles surrounding benign-appearing germinal centers. The patients were typical of other patients with MZL in that they were male, middle age or older, and their clinical courses were not aggressive despite the presence of disease at an advanced stage. Our review of the literature suggests that there is an inordinate number of cases of MZL with gastrointestinal involvement. We also note that most reports of cases of MLP have described histologic lesions remarkably similar to what we have observed. We conclude that MZL may have predilection for involvement of the gastrointestinal tract, that this involvement is often in the manner of MLP, and that most cases of MLP probably have MZL or ILL.
Development of chimeric antigen receptor (CAR) T-cell immunotherapy for glioblastoma targeting epidermal growth factor receptor variant III (EGFRvIII)
Authors: Anthony K Park, Saul Priceman, Ethan Gerdts, Wen-Chung Chang, Sarah Wright, Stephen J Forman, Christine E Brown
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Glioblastoma multiforme (GBM) is the most common brain tumor, with a poor prognosis of less than 14 months after initial diagnosis. Gene amplification and mutation of epidermal growth factor receptor (EGFR) are frequently observed in primary GBM. The most common variant of EGFR,
Glomerular (Azotemic) Osteodystrophy
Authors: L H Kyle
Journal: Annual Review of Medicine (1969)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Abstract 19023: Association between Intraplaque Hemorrhage and Two Plaque Burden Measurements: Maximum Wall Thickness and Luminal Stenosis
Authors: Jie Sun, Yan Song, Li Dong, Nan Luo, Min Chen, Cheng Zhou, Daniel Hippe, Yin Yang, Thomas Hatsukami, Chun Yuan
Journal: Circulation (2010)

Background: Intraplaque hemorrhage (IPH) has been shown to be a high risk plaque feature. It is well known that angiography underestimates plaque burden due to expansive remodeling and the unique g...
Tuberculous Abscess
Authors: Thomas Troelsen, Ole Hilberg
Journal: New England Journal of Medicine (2014)

A previously healthy 18-year-old man was admitted to the hospital with a 3-month history of coughing, expectoration of reddish sputum, weight loss, and fever; a small area of swelling had developed on his anterior chest wall in the preceding week. Chest CT revealed a collar-button abscess.
A randomized clinical trial comparing melphalan/prednisone with or without interferon alfa-2b in newly diagnosed patients with multiple myeloma: a Cancer and Leukemia Group B study.
Authors: M R Cooper, K Dear, O R McIntyre, H Ozer, J Ellerton, G Canellos, B Bernhardt, D Duggan, D Faragher, C Schiffer
Journal: Journal of Clinical Oncology (1993)

PURPOSE This clinical trial was designed to compare the effectiveness of the standard melphalan and prednisone regimen to that of melphalan, prednisone, and interferon in patients with untreated multiple myeloma. PATIENTS AND METHODS Between October 1985 and March 1988, 278 patients were accrued to a multi-institutional, randomized clinical trial. Responding patients were treated for 2 years before termination of therapy. RESULTS After a median follow-up of 23 months, the overall remission rate for the melphalan/prednisone treatment group was 44% compared with 33% for the group receiving melphalan/prednisone/interferon alfa-2b. The durations of response and survival were identical for the two treatment groups. Median survival was 3.17 years on melphalan/prednisone treatment and 3.0 years on melphalan/prednisone/interferon alfa-2b treatment. Both hematologic and nonhematologic toxicities were greater in the melphalan/prednisone/interferon alfa-2b treatment group, but were usually of a mild or moderate degree and did not interfere with the completion of therapy. The frequency of deaths in the two treatment groups attributable to the treatment itself was similar. CONCLUSION This study shows no advantage to the concomitant delivery of interferon alfa-2b with standard melphalan and prednisone as initial treatment for patients with multiple myeloma.
IgG SUBCLASS DEFICIENCIES
Authors: H D Ochs, R J Wedgwood
Journal: Annual Review of Medicine (1987)

IgG subclasses represent distinct immunoglobulin types, each defined by unique primary structures of the constant region of the heavy-chain molecule, and each with characteristic biological and functional properties. New methods and reagents to measure serum concentrations have contributed to the study of the ontogeny, antigen restriction, and deficiencies of IgG subclasses. Distinct clinical entities of single or multiple IgG subclass deficiencies have been identified and the efficacy of immunoglobulin replacement therapy has been demonstrated in several instances.