tbuckley/cabot-search huggingface dataset:
Abstract 3629: Balance shift between error-free and error prone DNA double-strand break repair as a novel mechanism of radiosensitization by nucleoside analogs
Authors: George Iliakis, Simon Magin
Journal: Cancer Research (2015)

Abstract Nucleoside analogs (NAs) represent a large group of anticancer drugs, several members of which have been shown to sensitize cells to ionizing radiation (IR). Among the lesions induced in cells by IR, the DNA double-strand break (DSB) is considered to be the most detrimental. Therefore we focused on interactions between NAs and pathways of DSB repair. We opted for post-irradiation treatment with NAs to avoid complications arising from redistribution of cells throughout the cycle prior to IR exposure. We compared the effects of 4h treatments post-IR with vidarabine (ara-A), fludarabine (F-ara-A) or gemcitabine (dFdC) on the survival of A549 lung carcinoma cells. We found that post-irradiation treatment with ara-A and F-ara-A, but not dFdC, resulted in cell radiosensitization to killing. Radiosensitization by ara-A was superior to that by F-ara-A. We employed immunofluorescence detection of IR-induced foci and I-SceI-based reporter cell lines to identify the pathways of DSB repair that are inhibited by ara-A and cause the observed radiosensitization. We found that the formation of IR-induced Rad51-foci was compromised by ara-A suggesting inhibition of homologous recombination repair (HRR). Repair of I-SceI-induced DSBs by HRR was also suppressed by ara-A. Furthermore, A549 cells deprived of Rad51 by RNAi could not be efficiently radiosensitized by ara-A. On the other hand, we could not detect impairment by ara-A of non-homologous end-joining (NHEJ), as measured by pulsed-field gel electrophoresis (PFGE) at high doses of IR (20 Gy). Notably, we observed an increase in the frequency of mutagenic NHEJ events in several I-SceI-based repair reporter systems, indicative of processing by error-prone repair pathways such as alternative/backup NHEJ (B-NHEJ). In addition, we could show that treatment with ara-A induces a dramatic increase in B-NHEJ in plateau phase Lig4-/- MEFs. Treatment with F-ara-A also inhibited HRR, but was less proficient in promoting mutagenic NHEJ. We conclude that inhibition of HRR and promotion of B-NHEJ represent two important mechanisms of radiosensitization by NAs. The strong impact of ara-A on both of these repair pathways underpins its superior radiosensitizing potential. Targeting of both HRR and B-NHEJ may provide a promising new strategy for radiosensitization. Citation Format: George Iliakis, Simon Magin. Balance shift between error-free and error prone DNA double-strand break repair as a novel mechanism of radiosensitization by nucleoside analogs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3629. doi:10.1158/1538-7445.AM2015-3629
NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses
Authors: Haitao Guo, Renate König, Meng Deng, Maximilian Riess, Jinyao Mo, Lu Zhang, Alex Petrucelli, Sunnie M. Yoh, Brice Barefoot, Melissa Samo, Gregory D. Sempowski, Aiping Zhang, Anamaris M. Colberg-Poley, Hui Feng, Stanley M. Lemon, Yong Liu, Yanping Zhang, Haitao Wen, Zhigang Zhang, Blossom Damania, Li-Chung Tsao, Qi Wang, Lishan Su, Joseph A. Duncan, Sumit K. Chanda, Jenny P.-Y. Ting
Journal: Cell Host & Microbe (2016)
Advancing the Standard of Cancer Care in 2014
Authors: Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2014)

We present these Highlights as a synopsis of the proceedings in this special issue of JNCCN-Journal of the National Comprehensive Cancer Network.The 3 days of the NCCN 19th Annual Conference included a variety of educational activities.The latest updates in clinical practice decision-making were presented, including updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).Attendees participated in presentations on more than 15 disease types, including breast, non-small cell lung, and prostate cancers, chronic myelogenous leukemia, and melanoma, as well as patient management and supportive care topics.For example, this special edition includes a presentation on "Genetic Counseling in Patients with Familial Risk for Colorectal Cancer," a topic that was translated into new NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal in February 2014.Another interesting discussion centered on "Early Detection of Prostate Cancer: Do the Benefits Outweigh the Consequences?"During this point/counterpoint presentation, Peter R. Carroll, MD, MPH, and Andrew J. Vickers, PhD, discussed the controversy of over-screening in prostate cancer, emphasizing the importance of selective early detection and selective treatment based on patient and risk factors.In addition, Drs.Carroll and Vickers explained that, while prostate cancer screening remains controversial, the NCCN Guidelines for Prostate Cancer Early Detection limit overdetection and overtreatment.This year's Highlights also include summaries of 2 of the now-seminal NCCN Roundtables.The first, titled, "The Child's Experience When a Parent has Cancer" was moderated by Lillie D. Shockney, RN, BS, MAS.It is often recognized that cancer in an individual is a family and a community disease, and no person in the family and community is impacted more than the children, especially when young.This roundtable focused on these children-their challenges and what the health care team can do to support them through their experience.It included notables such as
Chemotherapy of Metastatic Liver Cancer by Prolonged Hepatic-Artery Infusion
Authors: Robert D. Sullivan, John W. Norcross, Elton Watkins
Journal: New England Journal of Medicine (1964)

No conventional form of therapy is of practical value in the management of patients with diffuse primary or secondary liver tumors. This is also true in most cases of cancer of the gallbladder or bile ducts. Approximately 20 to 30 per cent of patients with cancer of the colon or rectum die as a result of progressive liver metastasis although the primary lesion in the bowel has been or may be susceptible of control by surgical resection. Since these forms of cancer are often localized to the distribution of the hepatic artery it is important to evaluate the effects of . . .
A SARC global collaborative phase II trial of R1507, a recombinant human monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R) in patients with recurrent or refractory sarcomas
Authors: S. Patel, A. Pappo, J. Crowley, D. Reinke, J. Eid, S. Ritland, S. Chawla, A. Staddon, R. Maki, G. Vassal, L. Helman
Journal: Journal of Clinical Oncology (2009)

10503 Background: The IGF1 system has been implicated in sarcoma development and inhibition of IGF1R function has been shown to induce clinical responses in select sarcomas. Methods: Objectives included response rate (RR) and progression-free survival (PFS) to R1507 in patients with recurrent or refractory Ewing's (ES, 2 cohorts- primary refractory vs. others) osteo (OS), synovial (SS), rhabdomyosarcoma (RMS), and other sarcomas. Eligibility included recurrent/refractory measurable disease, age ≥ 12 yrs, life expectancy ≥ 6 weeks, Karnofsky PS ≥ 70, adequate renal, hepatic and bone marrow function. R1507 was administered i.v. at 9 mg/kg over one hour weekly. Response was assessed by WHO criteria every 6 wks X 4 and every 12 wks thereafter. A two-stage design (Green and Dahlberg) was used. The endpoint for the primary refractory ES cohort was PFS at week 18 (planned n=65). RR was the primary endpoint for the remaining cohorts (planned n=240). Results: From 12/07–12/08, 203 eligible patients from 29 centers across the US, Europe and Australia were enrolled. Age ranged from 12–85 yrs (median=27 yrs) and 126 were male. Verified histologic subtypes were ES (n=71), OS (n=43), RMS (n=28), SS (n=25), and others (n=25). 15 severe adverse events were reported in 9 patients, the most common being fatigue (n=2), thrombocytopenia (n=2), dehydration (n=2), and hyperglycemia (n=2). Clinically significant activity has been observed in ES, RMS and OS with several dramatic responses seen in ES and RMS. Independent radiologic review is currently ongoing and updated data will be presented. Conclusions: The rapid accrual amongst many centers in diverse geographical locations demonstrates the feasibility of collaborative research in sarcomas. R1507 is well tolerated and a promising new agent for the treatment of various sarcomas. SARC and Roche are collaborating in additional clinical trials to better define the role of R1507 in the treatment of selected sarcomas. [Table: see text]
Family Chronicles of Missed Opportunities
Authors: Anath A. Flugelman, Henry T. Lynch
Journal: JAMA Oncology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Hematopoietic Growth Factors
Authors: Jerome E. Groopman, Jean-Michel Molina, David T. Scadden
Journal: New England Journal of Medicine (1989)

THE hematopoietic growth factors are glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells and the function of mature blood cells.1 2 3 The recognition that circulating factors regulate red-cell production was derived from the work of Carnot and Deflandre, who in 1906 induced erythrocytosis in normal rabbits by infusing them with plasma from anemic animals.4 Sixty years later, Pluznik and Sachs5 and Bradley and Metcalf6 developed the necessary semisolid culture systems to grow bone marrow progenitor cells in vitro. This led to the identification of hematopoietic growth factors, originally termed "colony-stimulating factors" because they stimulated the formation of . . .
S131 Deficiency mutations of α1-antitrypsin differentially affect folding, function and polymerisation
Authors: I Haq, JA Irving, AD Saleh, L Dron, GL Regan-Mochrie, N Motamedi-Shad, JR Hurst, DA Lomas, B Gooptu
Journal: Thorax (2015)

<h3></h3> Misfolding, polymerisation and defective secretion of functional α<sub>1</sub>-antitrypsin underlie the predispositions to severe liver and lung disease in α<sub>1</sub>-antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterised it relative to the wild-type (M) and common severe Z (Glu342Lys) variant. The index case is a homozygous individual of consangineous parentage. Absolute levels of circulating α<sub>1</sub>-antitrypsin were in the moderate deficiency range but the biochemical phenotype could not be clearly classified by standard methods. Moreover the majority was polymerised, i.e. functionally inactive, and the purified monomer was only 37% active relative to the wild-type ‘M’ variant. Together these resulted in 85–95% loss-of-function, a similarly severe functional deficiency to that of ZZ homozygotes. Biochemical, biophysical and computational studies further defined the molecular basis of this functional deficiency. These demonstrated that native Ala336Pro α<sub>1</sub>-antitrypsin could adopt the polymerogenic intermediate conformation and polymerised more readily not only than M α<sub>1</sub>-antitrypsin but also the severe Z variant. Nevertheless folding was far less impaired in Ala336Pro α<sub>1</sub>-antitrypsin than in the Z variant. The data therefore indicate partitions between the contribution of the ‘breach’ (site of Z mutation) and ‘shutter’ (Ala336Pro) regions of strand 5A to folding and to polymerisation mechanisms. Moreover the findings demonstrate that in these variants, folding efficiency does not correlate directly with the tendency to polymerise <i>in vitro</i> or <i>in vivo</i>. They therefore differentiate generalised misfolding from polymerisation tendencies in missense variants of α<sub>1</sub>-antitrypsin. Clinically they further support the need to quantify loss-of-function in α<sub>1</sub>-antitrypsin deficiency to individualise patient care.
Bile Acids: Effects on Absorption of 1,2-Dimethylhydrazine and 7, 12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene in the Colon of the Rat and Guinea Pig&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: R C Rose, D L Nahrwold
Journal: JNCI Journal of the National Cancer Institute (1982)

The specific effects of bile acids as cocarcinogens were investigated. Absorptions of [14C]7,12-dimethylbenz[a]anthracene, [14C]dimethylhydrazine ([14C]DMH), and [3H]inulin from loops of colons from outbred Sprague-Dawley rats and Hartley guinea pigs were determined. In each animal absorption of one carcinogen and inulin was studied in one control loop and in an experimental loop containing either deoxycholic acid (DOC) or chenodeoxycholic acid (CDOC). DOC had a more pronounced effect on increasing loss of carcinogen from the intestinal lumen than did CDOC. This role of bile acids was consistent with their known effect of increasing intestinal permeability. Less carcinogen remained in the colon mucosa when DOC was present in the intestinal lumen. Although [14C]DMH was absorbed more rapidly from the intestinal lumina of guinea pigs than from those of rats, the rat accumulated more of the carcinogen in the intestinal mucosa and liver.
Breakthrough Zygomycosis after Voriconazole Treatment in Recipients of Hematopoietic Stem-Cell Transplants
Authors: Francisco M. Marty, Lisa A. Cosimi, Lindsey R. Baden
Journal: New England Journal of Medicine (2004)

To the Editor: The Food and Drug Administration (FDA) approved voriconazole for the treatment of invasive aspergillosis partly on the basis of data published in a report in the Journal, 1 which sho...
Psychological Stress and Metabolic Control in Patients with Type I Diabetes Mellitus
Authors: Friedrich W. Kemmer, Rolf Bisping, Hans J. Steingrüber, Helmut Baar, Frank Hardtmann, Reiner Schlaghecke, Michael Berger
Journal: New England Journal of Medicine (1986)

Acute psychological stress is believed to cause disturbances of metabolic control in patients with Type I diabetes. To examine the validity of this assumption, we subjected nine healthy persons (mean [±SEM] blood glucose level, 74±2 mg per deciliter), nine patients with Type I diabetes who had normoglycemia (130±10 mg per deciliter), and nine diabetic patients with hyperglycemia (444±17 mg per deciliter) to two acute psychological stresses: mental arithmetic and public speaking. Subjects in the three groups were matched for age, weight, sex, and socioeconomic status. For all subjects, the mean increase in heart rate was 20 beats per minute while they were doing mental arithmetic and 25 beats per minute while they were speaking publicly (P<0.001). In all three groups, systolic and diastolic pressure rose markedly, the plasma epinephrine level increased by 50 to 150 pg per milliliter, and the norepinephrine level by 100 to 200 pg per milliliter under both stress conditions (P<0.001). The plasma cortisol level rose significantly after public speaking in all groups. Neither stress induced changes in circulating levels of glucose, ketones, free fatty acids, glucagon, or growth hormone. Thus, sudden, short-lived psychological stimuli causing marked cardiovascular responses and moderate elevations in plasma concentrations of catecholamines and cortisol are unlikely to disturb metabolic control in patients with Type I diabetes. (N Engl J Med 1986; 314: 1078–84.)
Case 18-1979
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Michael J. Bresnan, Edward P. Richardson, G. Richard Dickersin
Journal: New England Journal of Medicine (1979)

Presentation of CaseA 34-year-old right-handed man was admitted to the hospital because of dysphasia.He was in excellent health until nine months earlier, when he noticed difficulty with vision to the far right. One month later his gait became slightly uncertain. Seven months before admission he began to have slight difficulty in finding words and entered another hospital. Examination disclosed a prominent expressive dysphasia, with dyslexia, mild right central facial weakness and a right homonymous hemianopia; double simultaneous stimulation revealed extinction on the right side. Motor function was normal; the Babinski sign was positive on the right side. A . . .
Pharmacokinetic study of paclitaxel and gefitinib in combination
Authors: A. Locatelli, L. Viganã, S. Cresta, A. Perotti, G. Capri, G. Grasselli, L. Gianni
Journal: Journal of Clinical Oncology (2006)

13123 Background: Both gefitinib and paclitaxel are metabolized by CYP3A4, thus co-administration may result in a pharmacokinetic interaction (Miller V.A. et al. JCO 2003, 21:2094–2100). Paclitaxel is formulated in Cremophor EL (crEL), which also has the potential for pharmacokinetic interactions by either altering protein binding or inhibition of P-glycoprotein transporter systems (Gelderblom H. et al. EJC 2001, 37:1590–1598). Gefitinib is a high extraction ratio drug so changes in protein binding are not a concern, but inhibition of P-glycoprotein transporter systems could change gefitinib’s absorption profile. Methods: In a Phase II study, 17 patients (pts) with metastatic breast cancer received paclitaxel (100 mg/m2 on days 8, 15 q21) with gefitinib (250 mg daily, from day 1 to day 15). Blood samples were collected to measure plasma concentrations of gefitinib on days 7, 8, and 15 from six pts at pre-dose and at 3, 7 and 25 hours after gefitinib administration. The AUC at steady-state (AUCss) was calculated by the linear trapezoidal rule using WinNonlin and the minimum concentration at steady-state (Css, min) was taken directly from the data. Results: The effect of paclitaxel or crEL on the exposure to gefitinib was assessed by comparing the AUCss and Css,min on days 8 and 15 in the presence of paclitaxel to those on day 7 when gefitinib was alone. The geometric mean AUCss increased by 30 to 42% and Css,min by 28 to 58% in the presence of paclitaxel. Individual ratios of days 8 and 15 to day 7 also showed a trend to be greater than 1.0, further indicating an increase in exposure to gefitinib in the presence of paclitaxel. Conclusions: Steady state exposure to gefitinib increased by about 30 to 40% in the presence of paclitaxel. As the increase on day 15 was similar to that on day 8, the effect of paclitaxel appears to be transient, and would be unlikely to affect the safety profile of 250 mg gefitinib when in combination with paclitaxel compared to gefitinib monotherapy. [Table: see text]
Ventricular Dysfunction and the Risk of Stroke after Myocardial Infarction
Authors: Evan Loh, Martin St. John Sutton, Chuan-Chuan C. Wun, Jean L. Rouleau, Greg C. Flaker, Stephen S. Gottlieb, Gervasio A. Lamas, Lemuel A. Moyé, Samuel Z. Goldhaber, Marc A. Pfeffer
Journal: New England Journal of Medicine (1997)

In patients who have had a myocardial infarction, the long-term risk of stroke and its relation to the extent of left ventricular dysfunction have not been determined. We studied whether a reduced left ventricular ejection fraction is associated with an increased risk of stroke after myocardial infarction and whether other factors such as older age and therapy with anticoagulants, thrombolytic agents, or captopril affect long-term rates of stroke.We performed an observational analysis of prospectively collected data on 2231 patients who had left ventricular dysfunction after acute myocardial infarction who were enrolled in the Survival and Ventricular Enlargement trial. The mean follow-up was 42 months. Risk factors for stroke were assessed by both univariate and multivariate Cox proportional-hazards analysis.Among these patients, 103 (4.6 percent) had fatal or nonfatal strokes during the study (rate of stroke per year of follow-up, 1.5 percent). The estimated five-year rate of stroke in all the patients was 8.1 percent. As compared with patients without stroke, patients with stroke were older (mean [+/-SD] age, 63+/-9 years vs. 59+/-11 years; P<0.001) and had lower ejection fractions (29+/-7 percent vs. 31+/-7 percent, P=0.01). Independent risk factors for stroke included a lower ejection fraction (for every decrease of 5 percentage points in the ejection fraction there was an 18 percent increase in the risk of stroke), older age, and the absence of aspirin or anticoagulant therapy. Patients with ejection fractions of < or = 28 percent after myocardial infarction had a relative risk of stroke of 1.86, as compared with patients with ejection fractions of more than 35 percent (P=0.01). The use of thrombolytic agents and captopril had no significant effect on the risk of stroke.During the five years after myocardial infarction, patients have a substantial risk of stroke. A decreased ejection fraction and older age are both independent predictors of an increased risk of stroke. Anticoagulant therapy appears to have a protective effect against stroke after myocardial infarction.
Trapped by an Incidental Finding
Authors: Stephen G. Pauker, Richard I. Kopelman
Journal: New England Journal of Medicine (1992)

The step-by-step process of clinical problem-solving is the subject of this new Journal feature. Information about a real patient is presented to an expert clinician in stages (boldface type), to simulate the way such information emerges in everyday clinical practice. The clinician responds (regular type) as each piece of information is presented, sharing his or her reasoning extemporaneously with the reader. An analysis of the process follows. Our purposes in introducing this new feature are discussed in an editorial on page 60. A 74-year-old retired attorney, when seen in routine follow-up by his primary care physician, mentioned that he had . . .
Left Ventricular Hypertrophy Diagnosed by Echocardiography
Authors: Abdul S. Abbasi, Rex N. MacAlpin, Leslie M. Eber, Morton Lee Pearce
Journal: New England Journal of Medicine (1973)

Echocardiography was used to differentiate left ventricular hypertrophy due to hypertrophic cardiomyopathy (20 cases) from that due to aortic valvular stenosis (10 cases) or systemic hypertension (10 cases). In aortic stenosis or hypertension symmetrical left ventricular hypertrophy was demonstrated with greater than normal thickness of both the ventricular septum and the posterior ventricular wall. The ratio of septal-to-posterior ventricular-wall thickness (mean ± S.D.) was the same as normal (1.2 ± 0.1). In hypertrophic cardiomyopathy, asymmetrical left ventricular hypertrophy was demonstrated with gross septal thickening (22.5 ± 3.4 mm) and a normal or slightly increased thickness of the posterior left ventricular wall (10.4 ± 2.0 mm). The ratio of septal-to-posterior left-ventricular-wall thickness (2.2 ± 0.2) was greater than that in aortic stenosis or systemic hypertension (p<0.005). The ventricular septum was disproportionately hypertrophied in hypertrophie cardiomyopathy regardless of the presence or absence of left ventricular outflow obstruction. (N Engl J Med 289:118–121, 1973)