tbuckley/cabot-search huggingface dataset:
Cross-talk between EphA2 and BRaf/CRaf Is a Key Determinant of Response to Dasatinib
Authors: Jie Huang, Wei Hu, Justin Bottsford-Miller, Tao Liu, Hee Dong Han, Behrouz Zand, Sunila Pradeep, Ju-Won Roh, Duangmani Thanapprapasr, Heather J. Dalton, Chad V. Pecot, Rajesh Rupaimoole, Chunhua Lu, Bryan Fellman, Diana Urbauer, Yu Kang, Nicholas B. Jennings, Li Huang, Michael T. Deavers, Russell Broaddus, Robert L. Coleman, Anil K. Sood
Journal: Clinical Cancer Research (2014)

EphA2 is an attractive therapeutic target because of its diverse roles in cancer growth and progression. Dasatinib is a multikinase inhibitor that targets EphA2 and other kinases. However, reliable predictive markers and a better understanding of the mechanisms of response to this agent are needed.The effects of dasatinib on human uterine cancer cell lines were examined using a series of in vitro experiments, including MTT, Western blot analysis, and plasmid transfection. In vivo, an orthotopic mouse model of uterine cancer was utilized to identify the biologic effects of dasatinib. Molecular markers for response prediction and the mechanisms relevant to response to dasatinib were identified by using reverse phase protein array (RPPA), immunoprecipitation, and double immunofluorescence staining.We show that high levels of CAV-1, EphA2 phosphorylation at S897, and the status of PTEN are key determinants of dasatinib response in uterine carcinoma. A set of markers essential for dasatinib response was also identified and includes CRaf, pCRaf(S338), pMAPK(T202/Y204) (mitogen-activated protein kinase [MAPK] pathway), pS6(S240/244), p70S6k(T389) (mTOR pathway), and pAKT(S473). A novel mechanism for response was discovered whereby high expression level of CAV-1 at the plasma membrane disrupts the BRaf/CRaf heterodimer and thus inhibits the activation of MAPK pathway during dasatinib treatment.Our in vitro and in vivo results provide a new understanding of EphA2 targeting by dasatinib and identify key predictors of therapeutic response. These findings have implications for ongoing dasatinib-based clinical trials.
Staphylococcal exotoxins exert proinflammatory effects through inhibition of eosinophil apoptosis, increased surface antigen expression (CD11b, CD45, CD54, and CD69), and enhanced cytokine-activated oxidative burst, thereby triggering allergic inflammatory reactions
Authors: Bettina Wedi, Dorothea Wieczorek, Tanja Stünkel, Kristine Breuer, Alexander Kapp
Journal: Journal of Allergy and Clinical Immunology (2002)
Enteral nutrition in inflammatory bowel disease.
Authors: M A Gassull, A Abad, E Cabre, F Gonzalez-Huix, J J Gine, C Dolz
Journal: Gut (1986)

To assess the effect of the addition of enteral tube feeding with polymeric diets to the standard treatment of acute attacks of inflammatory bowel disease a total of 43 patients admitted to hospital (23 with Crohn's disease and 20 with ulcerative colitis) were studied retrospectively. Total enteral nutrition was given to 26 as the sole nutritional supply and to 17 in conjunction with a normal ward diet, when appropriate, according to the severity of attack (control group). Nutritional state was assessed and classified in all patients at admission and at the end of the study, by measuring the triceps skinfold thickness, mid arm muscle circumference, and serum albumin concentration as representative of body fat, muscle protein, and visceral protein, respectively. At admission the three nutritional variables were not statistically different between the groups. There was a significantly positive effect on mid arm muscle circumference in patients on total enteral nutrition compared with the control group, but there was no effect on either triceps skinfold thickness or serum albumin concentration. The percentage of subjects requiring intravenous albumin infusion, however, was significantly less in the group fed enterally than in the control group. In addition, fewer patients in the group fed enterally required surgical treatment compared with the control group, despite the fact that one of the criteria for starting enteral nutritional support was the expectancy that surgery would be needed. Total enteral nutrition was well tolerated and no major side effects arose during its use in patients with acute exacerbations of inflammatory bowel disease.
Changes in xylosyltransferase activity and in proteoglycan deposition in bleomycin-induced lung injury in rat
Authors: R. Koslowski, U. Pfeil, H. Fehrenbach, M. Kasper, E. Skutelsky, K-W. Wenzel
Journal: European Respiratory Journal (2001)

Several lines of evidence support the hypothesis of the involvement of altered proteoglycan deposition in the development of lung diseases. UDP-d-xylose: core protein β-d-xylosyltransferase (UDP-xylosyltransferase; EC 2.4.2.26) is a key enzyme for the glycosylation of proteoglycan core proteins. This study examined the catalytic activity of UDP-xylosyltransferase in lung tissue and in isolated fibroblasts, as well as the deposition of the proteoglycans versican, biglycan and decorin in rat lung tissue during bleomycin-induced lung injury. Rats were given, endotracheally, a single dose of bleomycin. Deposition of proteoglycans in lung tissue was assessed by immunohistochemistry and the catalytic activity of xylosyltransferase was determined with an acceptor peptide of the sequence Q-E-E-E-G-S-G-G-G-Q-G-G as a substrate. The results show coincidence of increasing xylosyltransferase activities in lung tissue with accumulation of versican at alveolar entrance rings and in fibrotic regions in close proximity to α-smooth muscle actin-positive cells. In contrast, no changes in biglycan and decorin deposition in fibrotic lungs were observed, except for decorin in alveolar type II pneumocytes and alveolar macrophages. Bleomycin treatment of isolated rat lung fibroblasts resulted in a concentration-dependent increase of xylosyltransferase activity up to 2 mU bleomycin·mL −1 . The data suggest a participation of myofibroblasts with increased xylosyltransferase activities in accumulation of versican in fibrotic foci of injured lung tissue at the early stages of development of lung fibrosis.
Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate
Authors: Jeffrey D Rothstein, Margaret Dykes-Hoberg, Carlos A Pardo, Lynn A Bristol, Lin Jin, Ralph W Kuncl, Yoshikatsu Kanai, Matthias A Hediger, Yanfeng Wang, Jerry P Schielke, Devin F Welty
Journal: Neuron (1996)

Three glutamate transporters have been identified in rat, including astroglial transporters GLAST and GLT-1 and a neuronal transporter EAAC1. Here we demonstrate that inhibition of the synthesis of each glutamate transporter subtype using chronic antisense oligonucleotide administration, in vitro and in vivo, selectively and specifically reduced the protein expression and function of glutamate transporters. The loss of glial glutamate transporters GLAST or GLT-1 produced elevated extracellular glutamate levels, neurodegeneration characteristic of excitotoxicity, and a progressive paralysis. The loss of the neuronal glutamate transporter EAAC1 did not elevate extracellular glutamate in the striatum but did produce mild neurotoxicity and resulted in epilepsy. These studies suggest that glial glutamate transporters provide the majority of functional glutamate transport and are essential for maintaining low extracellular glutamate and for preventing chronic glutamate neurotoxicity.
Cancer and the Dying Patient
Authors: LEONARD J. HERTZBERG
Journal: American Journal of Psychiatry (1972)

The author, who has been the consulting psychiatrist on a cancer ward, outlines the fears and other problems faced by patients and staff on such a ward and describes his activities. He believes the psychiatrist in this setting can be most helpful by developing vehicles to enhance staff understanding so that the staff need not maintain avoidance techniques. Group meetings with patients' families also appear to be a promising approach.
14-3-3σ gene silencing during melanoma progression and its role in cell cycle control and cellular senescence
Authors: Julia Schultz, Saleh M Ibrahim, Julio Vera, Manfred Kunz
Journal: Molecular Cancer (2009)

Abstract Background The family of 14-3-3 proteins plays an important role in cancer biology by interfering with intracellular signalling pathways and cell cycle checkpoints. The 14-3-3σ isoform acts as a tumor suppressor and is often inactivated during tumor development. Results Here, we demonstrate enhanced CpG methylation of the 14-3-3σ gene in lymph node and cutaneous melanoma metastases compared with primary tumors, associated with dramatically reduced mRNA expression. In line with this, treatment of different metastatic melanoma cell lines with 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of cytosine methylation, significantly induces 14-3-3σ protein expression. Additional treatment with histone deacetylase inhibitor 4-phenylbutyric acid (Pba) further enhances 14-3-3σ expression. Induction of 14-3-3σ expression by 5-Aza-CdR/Pba treatment leads to almost complete inhibition of cell proliferation, with cells predominantly arrested in G2-M. The antiproliferative effect of 5-Aza-CdR/Pba was reversed in 14-3-3σ knockdown cells. Similarly, melanoma cell lines stably overexpressing 14-3-3σ show dramatically reduced cell proliferation rates. Moreover, synchronous 14-3-3σ stably overexpressing cells do not progress through cell cycle, but display a permanent increase in the population of 4 n DNA containing cells. Interestingly, overexpression of 14-3-3σ induces senescence of melanoma cells and is involved in melanoma cell senescence under genotoxic stress. Finally, 14-3-3σ knockdown supports migratory capacity of melanoma cells in vitro , while 14-3-3σ overexpression has opposing effects. Conclusion Taken together, the present report indicates that epigenetic silencing of 14-3-3σ might contribute to tumor progression in malignant melanoma via loss of cell cycle control, impaired cellular senescence program and support of migratory capacity.
A STUDY OF FIBRINOGEN PRODUCTION BY HUMAN LIVER SLICES IN VITRO BY AN IMMUNOPRECIPITIN METHOD
Authors: P. Werner Straub
Journal: Journal of Clinical Investigation (1963)

There have been numerous experiments based on hepatectomy or acute liver intoxication indi- cating that the liver is the organ responsible for the manufacture of blood fibrinogen in dogs (1, 2) and rabbits (3).Perfusion experiments on rats (4) confirmed the role of the liver in the production of fibrinogen as well as of other plasma proteins except gamma globulins.Up to now, however, no demonstration was given that liver tissue could manufacture fibrino- gen in vitro, despite the fact that in vitro tech- niques with liver tissue were used to demonstrate the production of serum proteins in the chicken and in the rat (5-7).These studies were based on immunological methods for the detection and measurement of serum proteins.The demonstration by Gitlin and Borges (8) that immunoprecipitin methods are able to de- tect minute amounts of fibrinogen, as are found in patients with so-called afibrinogenemia, sug-'f li p A. I 4.
Polychemotherapy in advanced non small cell lung cancer: a meta-analysis
Authors: J.P. Bernard, P.J. Souquet, J.P. Boissel, F. Chauvin, R. Cellerino, D. Tumarello, Y. Cormier, P.A. Ganz, S. Kaasa, J.L. Pater, E. Quoix, E. Rapp, J. Williams, B.L. Woods
Journal: The Lancet (1993)
Multiple sclerosis and systemic sclerosis: efficacy of interferon beta on skin lesions
Authors: P B Carrieri, M Petracca, S Montella, M Delfino, C Sepe, A Gattoni
Journal: Annals of the Rheumatic Diseases (2008)

We report the clinical observation of interferon beta-1a effectiveness in the treatment of skin lesions in a patient affected by multiple sclerosis (MS) and systemic sclerosis (SSc),1 suggesting a common pathogenesis.

A 51-year-old woman was admitted to the department of neurology of the “Federico II” University with a 5-day history of muscle weakness and sensory disturbance in her right leg preceded by optic neuritis. Diagnosis of MS, according to the McDonald2 criteria was carried out; the Expanded Examination Rating Scale (EDSS)3 was 3.5.

A trial of intravenous methylprednisolone resulted in relief of the patient’s symptoms. The neurological status improved …
Combination of a Mood Stabilizer With Risperidone or Haloperidol for Treatment of Acute Mania: A Double-Blind, Placebo-Controlled Comparison of Efficacy and Safety
Authors: Gary S. Sachs, Fred Grossman, S. Nassir Ghaemi, Akiko Okamoto, Charles L. Bowden
Journal: American Journal of Psychiatry (2002)

The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania.This 3-week randomized, double-blind, placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer (lithium or divalproex) and placebo, risperidone, or haloperidol. The primary efficacy measure was the Young Mania Rating Scale. Other assessments used the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and safety measures.The trial was discontinued by 25 (49%) of the 51 placebo group patients, 18 (35%) of the 52 risperidone group patients, and 28 (53%) of the 53 haloperidol group patients. Mean modal doses were 3.8 mg/day (SD=1.8) of risperidone and 6.2 mg/day (SD=2.9) of haloperidol. Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group, compared with the placebo group. Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline. Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients. Antiparkinsonian medications were received by 8%, 17%, and 38% of patients in the placebo, risperidone, and haloperidol groups, respectively.Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone, and as efficacious as haloperidol plus a mood stabilizer, for the rapid control of manic symptoms and was well tolerated.
The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial
Authors: Shahneen K Sandhu, William R Schelman, George Wilding, Victor Moreno, Richard D Baird, Susana Miranda, Lucy Hylands, Ruth Riisnaes, Martin Forster, Aurelius Omlin, Nathan Kreischer, Khin Thway, Heidrun Gevensleben, Linda Sun, John Loughney, Manash Chatterjee, Carlo Toniatti, Christopher L Carpenter, Robert Iannone, Stan B Kaye, Johann S de Bono, Robert M Wenham
Journal: The Lancet Oncology (2013)
Soluble CD8, CD25 and CD30 antigens as prognostic markers in patients with untreated Hodgkin's lymphoma
Authors: A. Gause, W. Jung, R. Schmits, A. Tschiersch, R. Scholz, C. Pohl, D. Hasenclever, V. Diehl, M. Pfreundschuh
Journal: Annals of Oncology (1992)
The Controversy Over Radiation Safety
Authors: J. Samuel Walker
Journal: JAMA (1989)

The hazards of ionizing radiation have aroused concern since a short time after the discovery of x-rays and natural radioactivity in the 1890s. Misuse of x-rays and radium prompted efforts to encourage radiation safety and to set limits on exposure, culminating in the first recommended "tolerance doses" in 1934. After World War II, the problems of radiation protection became more complex because of the growing number of people subjected to radiation injury and the creation of radioactive elements that had never existed before the achievement of atomic fission. Judging the hazards of radiation became a matter of spirited controversy. Major public debates over the dangers of radioactive fallout from atmospheric bomb testing in the 1950s and early 1960s and the risks of nuclear power generation in later periods focused attention on the uncertainties about the consequences of exposure to low-level radiation and the difficulties of resolving them.
Rotterdam Criteria for Sentinel Node (SN) Tumor Burden and the Accuracy of Ultrasound (US) -Guided Fine-Needle Aspiration Cytology (FNAC): Can US-Guided FNAC Replace SN Staging in Patients With Melanoma?
Authors: Christiane A. Voit, Alexander C.J. van Akkooi, Gregor Schäfer-Hesterberg, Alfred Schoengen, Paul I.M. Schmitz, Wolfram Sterry, Alexander M.M. Eggermont
Journal: Journal of Clinical Oncology (2009)

Purpose Sentinel node (SN) status is the most important prognostic factor for overall survival (OS) for patients with stage I/II melanoma, and the role of the SN procedure as a staging procedure has long been established. However, a less invasive procedure, such as ultrasound (US) -guided fine-needle aspiration cytology (FNAC), would be preferred. The aim of this study was to evaluate the accuracy of US-guided FNAC and compare the results with histology after SN surgery was performed in all patients. Patients and Methods Four hundred consecutive patients who underwent lymphoscintigraphy subsequently underwent a US examination before the SN procedure. When the US examination showed a suspicious or malignant pattern, patients underwent an FNAC. Median Breslow thickness was 1.8 mm; mean follow-up was 42 months (range, 4 to 82 months). We considered the US-guided FNAC positive if either US and/or FNAC were positive. If US was suggestive of abnormality, but FNAC was negative, the US-guided FNAC was considered negative. Results US-guided FNAC identified 51 (65%) of 79 SN metastases. Specificity was 99% (317 of 321), with a positive predictive value of 93% and negative predictive value of 92%. SN-positive identification rate by US-guided FNAC increased from 40% in stage pT1a/b disease to 79% in stage pT4a/b disease. US-guided FNAC detected SN tumors more than 1.0 mm in 86% of cases, SN tumors of 0.1 to 1.0 mm in 46% of cases, and SN tumors less than 0.1 mm in 23% of cases. Estimated 5-year OS rates were 92% for patients with negative US-guided FNAC results and 51% for patients with positive results. Conclusion US-guided FNAC of SNs is highly accurate. Up to 65% of the patients with SN-positive results in our institution could have been spared an SN procedure.
Functionality of Androgen Receptor–Based Gene Expression Imaging in Hormone Refractory Prostate Cancer
Authors: Makoto Sato, Mai Johnson, Liqun Zhang, Sanjiv S. Gambhir, Michael Carey, Lily Wu
Journal: Clinical Cancer Research (2005)

Abstract Purpose: A highly augmented, prostate-specific two-step transcriptional amplification (TSTA) method was developed with the ultimate goal of delivering an effective and safe gene-based treatment to prostate cancer patients. Because very limited treatment options are available for recurrent hormone refractory prostate cancer (HRPC), it is imperative to assess whether the prostate-specific antigen (PSA) promoter-based TSTA gene therapy will be functional in HRPC. Experimental Design: We tested the TSTA-driven adenovirus vector on three androgen-dependent and six HRPC models. Real-time gene expression was monitored by both optical imaging and the combined modality of positron emission tomography (PET) and computed tomography. Results: The TSTA-driven firefly luciferase expressing adenoviral vector was active in all androgen receptor (AR)–expressing HRPC models, but inactive in AR- and PSA-negative lines. Interestingly, the TSTA-mediated gene expression was induced by hydrocortisone in MDA PCa 2b, a cell line with mutated AR that possesses altered ligand specificity. In animal models, the TSTA-mediated optical signal was more robust in the HRPC than androgen-dependent tumors. In a parallel trend, a TSTA vector that expresses the herpes simplex virus thymidine kinase PET reporter gene also displayed more robust PET signal in the HRPC tumor. Conclusions: The activity of TSTA system is AR dependent and it recapitulates the functional status of endogenous AR. These data support the conclusion that AR function is activated in HRPC despite castrated levels of androgen. Together with the fact that majority of recurrent prostate cancers express AR and PSA, we foresee that the TSTA approach can be a promising gene therapy strategy for the advanced stages of prostate cancer.
Prognostic Significance of Exercise-Induced Left Bundle-Branch Block
Authors: Thomas A. Grady
Journal: JAMA (1998)

Context.-Approximately 0.5% of all patients who undergo exercise testing develop a transient left bundle-branch block (LBBB) during exercise, but its prognostic significance is unclear.Objective.-Todetermine whether exercise-induced LBBB is an independent predictor of mortality and cardiac morbidity.Design.-Matched control cohort study.Between September 1990 and February 10, 1994, 17 277 exercise stress tests were performed on patients.Setting.-Tertiary care, academic medical center.Patients.-From the cohort, 70 cases of exercise-induced LBBB were identified.The controls comprised 70 individuals without LBBB at rest or during exercise that matched the 70 cases based on age, test date, sex, prior history of coronary artery disease, hypertension, diabetes, smoking, and ␤-blocker use.Main Outcome Measures.-All-causemortality, percutaneous coronary intervention, open heart surgery, nonfatal myocardial infarction, documented symptomatic or sustained ventricular tachydysrhythmia, or implantation of a permanent pacemaker or an implantable cardiac defibrillator.Results.-A total of 37 events (28 events from the exercise-induced LBBB cases and 9 from the control cohort) occurred in 25 patients (17 exercise-induced LBBB patients and 8 control patients) during a mean follow-up period of 3.7 (0.9 years) (median, 3.8 years [range, 0.9-5.2years]).There were 7 deaths, of which 5 occurred among patients with exercise-induced LBBB.Four-year Kaplan-Meier event rates were 19% among exercise-induced LBBB patients and 10% among controls (logrank 2 , 5.2; P=.02).After further adjusting for small differences in age, exerciseinduced LBBB remained associated with a higher risk of primary events (adjusted relative risk, 2.78; 95% confidence interval, 1.16-6.65;P=.02).Conclusion.-Exercise-induced LBBB independently predicts a higher risk of death and major cardiac events.
Pediatric Cancer Survivorship: Research and Clinical Care
Authors: Anna T. Meadows
Journal: Journal of Clinical Oncology (2006)

Regardless of how one defines survivorship, more than 10 million individuals in the United States have been treated for a malignant disease; about 250,000 were younger than 21 years of age at diagnosis. Thirty years ago, pediatric oncologists recognized that children with cancer might be cured by adding chemotherapy to surgery and radiation. Studies were then begun of complications that could reduce survival or the quality of survival, and that might be associated with previous therapy. The complications were termed late effects, and studies focused on patients who were likely to be cured, or less likely to succumb to the original cancer than they were to experience disabilities. Clinical trials tested whether changes in therapy to reduce complications could maintain the same excellent survival rates. During the last 20 years, articles detailing late effects and the relationship between therapy and outcome have been published. This article reviews the progress made in understanding the outcomes reported and the efforts made to improve the quality of long-term survival for children and adolescents. Several questions remain regarding the long-term complications of therapy. Clinicians need more data regarding the effects of aging to guide them in managing former patients. Caregivers and pediatric cancer survivors who are now adults seek the optimal venue in which to receive care as independent adults. In addition, medical oncologists need to determine whether the models for research and clinical care of survivors created in pediatric oncology can be applied to survivors of adult-onset cancer.