tbuckley/cabot-search huggingface dataset:
Abstract 2663: Dual cytoprotective and cytotoxic functions of autophagy in the response ofbreast tumor cells to radiation and in radiosensitization by vitamin D3
Authors: Molly L. Bristol, Xu Di, David A. Gewirtz
Journal: Cancer Research (2011)

Abstract Introduction: While chemotherapy and radiation treatment may be initially effective at suppressing breast cancer growth, disease recurrence and tumor metastasis are major clinical problems. A number of strategies have been developed in an attempt to enhance the response to radiation and prevent tumor cell recovery by interfering with cytoprotective signaling. Autophagy, a cellular process in which the degradation of subcellular organelles generates energy and metabolic precursors, may be cytoprotective or cytotoxic, depending on the cells and the nature of the stressful challenge. Our studies were designed to evaluate the involvement of autophagy in radiosensitization by the hormonally active form of vitamin D3, 1,25D3. Additionally, studies were designed to test the premise that interference with autophagy would influence sensitivity to treatment with 1,25D3 + radiation. Results: Our studies demonstrate radiosensitization of breast tumor cells by vitamin D (1,25D3) through the promotion of autophagy as well as a concurrent cytoprotective function of autophagy in irradiated cells. 1,25D3 promoted autophagy (as well as autophagic flux) in irradiated MCF7 cells and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3 also enhanced radiosensitivity and promoted autophagy in p53 mutant Hs578t breast tumor cells as well as MCF7 cells that overexpress Her-2/neu. In contrast, 1,25D3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D3 was not attenuated by either a pharmacological or genetic block to autophagy due to a shift in the mode of cell death to apoptosis. In contrast to autophagy mediating the cytotoxic impact of the 1,25D3 and radiation combination treatment, radiation alone promoted a low level of autophagy that was cytoprotective. Specifically, pharmacological or genetic interference with autophagy induced by radiation resulted in cell killing (primarily by apoptosis). These studies demonstrate that in the same experimental system, autophagy can function both as a mechanism for evading cell killing by radiation and as a pathway for mediating the killing of breast tumor cells by radiation. Conclusions: Both the suppression of cytoprotective autophagy and the promotion of cytotoxic autophagy represent potential strategies for radiation sensitization in breast cancer. Supported, in part, by American Institute for Cancer Research Grant # 06A058-REV and by DOD predoctoral training grant W81XWH-09-1-0020. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2663. doi:10.1158/1538-7445.AM2011-2663
Refining Case-Mix Adjustment
Authors: Stephen F. Jencks, Allen Dobson
Journal: New England Journal of Medicine (1987)

Abstract We review case-mix adjustment, which is the process of adjusting for differences in the cases treated in different hospitals so that their costs or outcomes can be compared. We examine the Medicare payment system, which rests on case-mix adjustment, and identify areas, including outlier payments, in which payment accuracy might be improved without better measurement of the severity of illness. There is no available measure of severity of illness that would produce a large improvement in the accuracy of Medicare payments if used to supplement or replace the system of diagnosis-related groups. Evidence regarding whether better measurement of severity would substantially change the distribution of payments across hospitals is mixed. Considerable evidence suggests that the intensity of medically appropriate treatment for patients in the same diagnosis-related group varies substantially for reasons other than the severity of illness. Despite great demand for measures of the quality of care, important technical problems must be solved before we can be confident that differences in case-mix-adjusted outcomes reflect differences in the quality of care. (N Engl J Med 1987;317:679–86.)
Effects of PBBs on cattle. III. Target organ modification as shown by renal function and liver biochemistry
Authors: F. L. Schanbacher, L. B. Willett, P. D. Moorhead, H. D. Mercer
Journal: Environmental Health Perspectives (1978)

Efforts were made to more clearly delineate target organs and mechanisms of toxicity for PBBs in cattle. Methods were developed to obtain sequential liver biopsies on bovine heifers which yield 0.5 to 1.0 g of tissue. PBB was fed at a dose of 250 mg/head/day to Holstein heifers for 202 days. This dose produced no clinical signs of toxicity in any of the heifers, yet this produced tissue PBB concentration of greater than 100 times the FDA tolerance in body fat of 0.3 ppm. Liver biopsies (0.5-1.0 g each) were taken at days 0, 90, and 180. The liver tissue was homogenized and microsomes were prepared. Dithionite difference spectra were determined on the carbon monoxide treated microsome suspension and the cytochrome P-450 content determined. Also, the 100,000g supernatant was saved for ornithine decarboxylase analysis as a measure of hepatocyte proliferative activity. Results of the cytochrome P-450 analysis showed a significant (p < 0.05) two-fold elevation (per gram of wet liver) by day 90 and remained significantly (p < 0.05) elevated on day 180. The cytochrome P-450 values of control animals not receiving PBBs showed no such increase with time. The biopsy procedure appeared not to adversely affect the liver cytochrome P-450 concentration in the control heifers. These results show that PBBs at a dose of 250 mg/day induced the drug metabolism system of the liver, of which the cytochrome P-450 is a part, indicating that the liver is a potential target organ for PBBs. However, this has not been shown to cause clear signs of hepatotoxicity in the cow as determined from histopathology or serum enzyme analyses. The observed elevation of gross liver weights of the PBB-treated animals might be an expected consequence of the cytochrome P-450 induction. In contrast to rodents, the kidney has been identified by histopathology as a target organ for PBB toxicity in cattle. However, renal function studies with (131)I-sodium-iodohippurate and (125)I-sodium iodothalamate in PBB treated cows indicated that PBB toxicity to the kidney did not affect glomerular filtration rate or effective renal plasma flow even though nephrotoxic effects were produced. From these studies, both liver (as expected) and kidney (unexpected) were affected by PBBs. For liver this did not result in hepatotoxicity while for kidney nephrotoxicity was produced but could not be mechanistically explained.
In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile
Authors: Michael J Sorich, Nicolas Pottier, Deqing Pei, Wenjian Yang, Leo Kager, Gabriele Stocco, Cheng Cheng, John C Panetta, Ching-Hon Pui, Mary V Relling, Meyling H Cheok, William E Evans
Journal: PLoS Medicine (2008)

Background Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX. Methods and Findings We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial "up-front" in vivo MTX treatment (1 g/m2) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1–18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02). Conclusions Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL. Trial registrations: Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov (NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D).
1049. Serum Free Fedia Is the Best for Cord Blood Hematopoietic Cells Expansion
Authors: Kamran Alimoghaddam, Mitra Khalili, Masoud Soleimani, Lili Moezi, Ardeshir Ghavamzadeh
Journal: Molecular Therapy (2005)

Objectives: to find the best cell culture condition for expansion of cord bloods hematopoietic CD34/CD38- ex vivo expansion and study the role of MIP/a in expansion potential.
Recovery after subarachnoid haemorrhage.
Authors: P. McKenna, J. R. Willison, D. Lowe, G. Neil-Dwyer
Journal: BMJ (1989)

OBJECTIVE--To determine the implications of subarachnoid haemorrhage for quality of life and aftercare. DESIGN--Prospective follow up study of patients surviving subarachnoid haemorrhage over one year (at discharge, three months, and one year) by examination of cognitive functions (a test battery) and changes in everyday life (semistructured interview). SETTING--Regional neurosurgical unit at a tertiary referral centre. PATIENTS--100 Patients with subarachnoid haemorrhage; 17 were lost during the study because of ineligibility (further surgery, previous head injury, relevant psychiatric history, and cultural differences), loss of contact, and non-compliance; a further 13 patients who developed a neurological deficit were considered separately. MAIN OUTCOME MEASURE--Performance on cognitive test battery and reported changes in quality of life. RESULTS--At discharge patients with and without neurological deficit scored below established norms with most tests, but by three months the difference had resolved in patients without deficit. Reduced quality of life attributable to subarachnoid haemorrhage at one year mainly included less energy (seven patients), adverse emotional changes (five), early retirement, affected social life, and domestic tension (three each). None reported reduced capacity for work. CONCLUSIONS--Patients surviving subarachnoid haemorrhage without neurological symptoms have a good prognosis and should be encouraged to return to a normal lifestyle within about three months.
Modeling and Risk Prediction in the Current Era of Interventional Cardiology
Authors: David R. Holmes, Faith Selzer, Janet M. Johnston, Sheryl F. Kelsey, Richard Holubkov, Howard A. Cohen, David O. Williams, Katherine M. Detre
Journal: Circulation (2003)

Validation of in-hospital mortality models after percutaneous coronary interventions using multicenter data remains limited.This study evaluated whether multivariable mortality models developed during the pre-stent era by New York State, American College of Cardiology (ACC)-National Cardiovascular Data Registry, Northern New England Cooperative Group, Cleveland Clinic Foundation, and the University of Michigan are relevant in patients undergoing percutaneous coronary intervention in the 1997 to 1999 National Heart, Lung, and Blood Institute Dynamic Registry. Of 4448 Dynamic Registry patients, 73% received > or =1 stent and 28% received a IIB/IIIA receptor inhibitor. In-hospital mortality occurred in 64 patients (1.4%). The New York state model predicted mortality in 69 patients (1.5%; 95% confidence bounds [CI], 0.89% to 1.70%); Northern New England predicted mortality in 60 patients (1.3%; 95% CI, 1.0% to 1.7%); and Cleveland Clinic predicted mortality in 76 patients (1.7%; 95% CI, 1.3% to 2.1%). Among high-risk subgroups, with these 3 models, observed and predicted in-hospital mortality rates in general were not different. The other 2 models yielded different results. The University of Michigan predicted fewer deaths (n=47; 1.1%; 95% CI, 0.7% to 1.3%), and the ACC Registry model predicted 603 deaths (13.5%; 95% CI, 12.6% to 14.4%). Using the ACC Registry model, predicted mortality was higher than observed in each subgroup.Application of 5 mortality risk models developed from different data sets to patients undergoing percutaneous coronary intervention in the Dynamic Registry predicted, in 3 models, mortality rates that were not significantly different than those observed. In both high and low risk subgroups, the University of Michigan slightly underpredicted mortality, and the ACC Registry predicted significantly higher mortality than that observed.
A 66 year old woman with breathlessness: case outcome
Authors: Douglas Lowdon, Marion McMurdo
Journal: BMJ (2004)

Five weeks ago (20 March, p 698) we described the case of Mrs Dempsey, who was investigated for suspected heart failure. Her symptoms did not improve after initial treatment, and she had further investigation to determine the cause of her bilateral pleural effusions (27 March, p 758). We then suspected an underlying malignancy, and she had computed tomography to assess her chest and extrapulmonary structures (fig 1). This showed large bilateral effusions associated with widespread mediastinal, axillary, …
MAPPING THE GLIOBLASTOMA METABOLOME AFTER BEVACIZUMAB THERAPY BY 13C6-GLUCOSE METABOLOMIC FLUX ANALYSIS.
Authors: R. Bjerkvig, F. Fack, C. Frezza, O. Keunen, D. Stieber, M. Lund-Johansen, H. Miletic, E. Gottlieb, S. P. Niclou
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastomas (GBMs) are highly vascular tumors. Therefore, anti-vascular therapy has been regarded as a promising treatment strategy. Yet, recent results from two double-blind, placebo-controlled phase III trials, (RTOG 0825), and (AVAglio), for first-line treatment of GBM patients did not show any improvement of overall survival. In order to provide new insight into how GBMs adapt to antivascular therapy we have performed a detailed 13C6-glucose metabolomic flux analysis of human GBM xenografts that show strong genotypic and phenotypic similarities to human GBMs in situ. This approach, together with functional MRI and PET imaging show that bevacizumab treatment leads to a significant reduction in intratumoral blood flow accompanied by an induction of hypoxia. METHODS: In order to delineate metabolomic changes iduced by bevacizumab therapy, we infused bevacizumab treated animals with 13C6-glucose 15 min and 120min. before the tumors were removed. We then performed a detailed LC-MS analysis of 13C-labelled metabolites as well as cold metabolites associated with glycolysis and the citric acid cycle (TCA-cycle associated with oxidative respiration). Analyses were performed on both tumors as well as normal adjacent brain tissue. RESULTS: We show that bevacizumab treatment induces an increased influx of glucose into the tumors, which is accompanied by an increase in metabolites associated with the pentose phosphate pathway (PPP). Also, levels of lactate dehydrogenase (LDHA) as well as lactate were increased in the treated tumors. Interestingly, bevacizumab treatment caused a reduction of metabolites associated with the TCA cycle. Moreover, the metabolomics analyses revealed reduced levels of glutamine in treated tumors indicating that alternative pathways fueling the TCA cycle are depleted. CONCLUSIONS: In sum, our results show that GBMs respond to bevacizumab therapy by up-regulating glycolysis, with a down-regulation of oxidative respiration. Importantly, the results indicate that through the PPP-shunt, enough energy is produced to drive tumor progression. How bevacizumab treatment should be combined with inhibitors of glycolysis will be discussed. SECONDARY CATEGORY: Tumor Biology.
WHAT SHOULD THE GENERAL PRACTITIONER DO ABOUT ALLERGY?
Authors: STEARNS S. BULLEN
Journal: JAMA (1949)

There is a growing body of evidence that altered reactivity of the tissues on reexposure to certain substances is the causative factor in the production of several diseases the causation of which has been obscure, such as periarteritis nodosa, dermatomyositis, acute glomerular nephritis and others. However, it is the allergic manifestations which appear on the covering and lining membranes of the body, that is, the skin and the mucous membranes of the respiratory and gastrointestinal tracts, which present the day by day problems in practice. These include the eczemas of the infantile, "atopic" and contact types; urticaria; coryzas of the seasonal and perennial varieties; asthma, and some disturbances of the gastrointestinal tract which are usually functional in nature and in which the tissue changes are generally reversible. In uncomplicated cases, these allergic diseases seldom cause death, but their chronicity and the suffering and disability which they produce demand careful clinical
Perfusion of Isolated Animal Kidneys.
Authors: Nathan W. Levin
Journal: Annals of Internal Medicine (1964)

s1 October 1964Perfusion of Isolated Animal Kidneys.Nathan W. Levin, M.B., F.C.P.(S.A.), James A. Hayashi, Ph.D., Will G. Ryan, M.D., Hermann Mattenheimer, M.D., Robert M. Kark, F.R.C.P., F.A.C.P.Nathan W. Levin, M.B., F.C.P.(S.A.)Search for more papers by this author, James A. Hayashi, Ph.D.Search for more papers by this author, Will G. Ryan, M.D.Search for more papers by this author, Hermann Mattenheimer, M.D.Search for more papers by this author, Robert M. Kark, F.R.C.P., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-61-4-816_3 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptStudy of the isolated perfused kidney sacrifices normality in environment, but attains greater simplicity and a higher degree of experimental control. Although in recent years this preparation has been extensively used to study renal autoregulation, little attention has been paid to its potential usefulness in metabolic studies or in following the processes of renal failure. This presentation discusses the role of the isolated perfused kidney, describes experimental methods, presents serial data on fatty acid and glucose utilization during the course of failure of the kidney and on the enzymatic and histochemical changes that occur.... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: Nathan W. Levin, M.B., F.C.P.(S.A.); James A. Hayashi, Ph.D.; Will G. Ryan, M.D.; Hermann Mattenheimer, M.D.; Robert M. Kark, F.R.C.P., F.A.C.P.Affiliations: Chicago, Ill. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1964Volume 61, Issue 4Page: 816-816KeywordsFatty acidsGlucoseKidneysRenal failure ePublished: 1 December 2008 Issue Published: 1 October 1964 PDF downloadLoading ...
544. Interferon alpha-2b Gene Delivery for Bladder Cancer Demonstrates Feasibility of Repeated Intravesical Dosing with an Adenovirus Vector
Authors: Heidrun Engler, Robert J. Connor, Jennifer M. Anderson, Drake LaFace, Daniel C. Maneval
Journal: Molecular Therapy (2005)

Intravesical interferon protein therapy has been utilized as a monotherapy for treatment of superficial bladder cancer with only modest success, likely in part due to the limited exposure of bladder tumors to interferon. To increase exposure of the bladder tumors to interferon, we have utilized an adenoviral delivery system (rAd) to deliver and express the human secreted interferon alpha-2b gene product (rAd-IFN) using a novel polyamide (Syn3) formulation that dramatically enhanced the uptake and expression of adenoviral vectors in the normal urothelium (Connor et al., 2001) and tumor tissue (Yamashita et al., 2002). We evaluated whether rAd-IFN could improve the tissue and urine levels of interferon protein by transducing the urothelium with the secreted human interferon-alpha gene (IFN alpha). We also assessed the possibility of repeated intravesical dosing with an adenovirus vector to mimic clinical need of multiple dosing cycles for cancer therapies.
D-Dimer and Prothrombin Fragment 1 + 2 Predict Venous Thromboembolism in Patients With Cancer: Results From the Vienna Cancer and Thrombosis Study
Authors: Cihan Ay, Rainer Vormittag, Daniela Dunkler, Ralph Simanek, Alexandru-Laurentiu Chiriac, Johannes Drach, Peter Quehenberger, Oswald Wagner, Christoph Zielinski, Ingrid Pabinger
Journal: Journal of Clinical Oncology (2009)

Venous thromboembolism (VTE) is a well-recognized complication of cancer. Laboratory parameters might be useful to assess the VTE risk in patients with cancer. The aim of this study was to investigate D-dimer and prothrombin fragment 1 + 2 (F 1 + 2), which reflect activation of blood coagulation and fibrinolysis, for prediction of cancer-associated VTE.In a prospective, observational, cohort study of 821 patients with newly diagnosed cancer or progression of disease who did not recently receive chemotherapy, radiotherapy, or surgery were enrolled and followed for a median of 501 days (interquartile range, 255 to 731 days). The malignancies in these patients were as follows: breast (n = 132), lung (n = 119), stomach (n = 35), lower gastrointestinal tract (n = 106), pancreas (n = 46), kidney (n = 22), and prostate (n = 101) cancers; high-grade glioma (n = 102); malignant lymphoma (n = 94); multiple myeloma (n = 17); and other tumor types (n = 47). The study end point was occurrence of objectively confirmed symptomatic or fatal VTE.VTE occurred in 62 patients (7.6%). The cutoff level for elevated D-dimer and elevated F 1 + 2 was set at the 75th percentile of the total study population. In multivariable analysis that included elevated D-dimer, elevated F 1 + 2, age, sex, surgery, chemotherapy, and radiotherapy, the hazard ratios (HRs) of VTE in patients with elevated D-dimer (HR, 1.8; 95% CI, 1.0 to 3.2; P = .048) and elevated F 1 + 2 (HR, 2.0; 95% CI, 1.2 to 3.6; P = .015) were statistically significantly increased. The cumulative probability of developing VTE after 6 months was highest in patients with both elevated D-dimer and elevated F 1 + 2 (15.2%) compared with patients with nonelevated D-dimer and nonelevated F 1 + 2 (5.0%; P < .001).High D-dimer and F 1 + 2 levels independently predict occurrence of VTE in patients with cancer.