tbuckley/cabot-search huggingface dataset:
Abstract 4654: Docosahexaenoic acid induces autophagy through reactive oxygen species /mTOR pathway in p53 mutant cancer cells
Authors: Soyeon Shin, Kaipeng Jing, Nayeong Kim, Soyeon Jeong, Hye-Rim Oh, Eun Ah Cho, Jun-Young Heo, Ji-Hoon Park, Kang-Sik Seo, Jeongsu Han, Jong-Il Park, Gi-Ryang Kweon, Seung-Kiel Park, Seung-Kiel Park, Wan-Hee Yoon, Byung-Doo Hwang, Kyu Lim
Journal: Cancer Research (2012)

Abstract Our previous studies reported that docosahexaenoic acid (DHA) induces autophagy through p53 inhibition in the wild-type p53 cancer cells. This study attempts to elucidate the molecular mechanism underlying DHA-induced autophagy in PC3 and DU145 prostate cancer cells harboring mutant p53. DHA increased both the level of microtubule-associated protein light-chain 3 (LC3) and the number of autophagic vacuoles. Autophagic flux assay confirmed that DHA-induced increase in LC3-II and autophagic vesicles was an outcome of autophagic process activation, indicating that DHA also induces autophagy in p53 mutant cancer cells. DHA treatment also increased the level of reactive oxygen species (ROS) as measured by dihydroethidine staining, and pretreatment of an antioxidant, N-acetylcysteine (NAC), significantly inhibited the ROS production as well as autophagy induced by DHA, suggesting that ROS regulates the autophagic process triggered by DHA. Further experiments showed that the mechanism of DHA-induced autophagy associated with ROS production was related to a decrease in the activity of mammalian target of rapamycin (mTOR). NAC remarkably restored the decreases in the levels of phospho-mTOR and 4EBP, an mTOR downstream molecule, induced by DHA as analyzed by the Western blot assay. Furthermore, the level of phospho-AMPK, which negatively regulates mTOR was increased, while phospho-Akt was reduced during the DHA-induced autophagy, indicating the involvement of AMPK and Akt signalings. Collectively, our results demonstrate that DHA induces autophagy through the ROS-mediated mTOR inactivation in p53 mutant prostate cancer cells. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0006232]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4654. doi:1538-7445.AM2012-4654
Subarachnoid Hemorrhage and Hormonal Factors in Women: A Population-Based Case-Control Study
Authors: W. T. Longstreth
Journal: Annals of Internal Medicine (1994)

Objective: To determine the degree to which endogenous and exogenous hormonal factors influence the risk for subarachnoid hemorrhage in women. Design: A population-based case–control study. Setting: King County, Washington. Participants: 103 women with an incident, spontaneous subarachnoid hemorrhage and 2 age- and sex-matched controls per case-patient who were identified through random-digit dialing. Measurements: Information on exposures was collected during in-person interviews of case-patients, controls, and their surrogates. Results: Premenopausal women, especially those without a history of smoking or hypertension, were at a reduced risk for subarachnoid hemorrhage compared with age-matched postmenopausal women (odds ratio, 0.24; 95% CI, 0.09 to 0.68). The use of hormone replacement therapy was associated with a reduced risk (odds ratio, 0.47; CI, 0.26 to 0.86); the reduction was significantly greater in women who had smoked than in those that had never smoked. Of the 23 premenopausal case-patients, 74% were either menstruating when hemorrhaging occurred or had had their last menstrual period 21 or more days before hemorrhaging compared with the expected 43% (difference, 31%; CI, 4% to 58%). Conclusions: Premenopausal women are at reduced risk for subarachnoid hemorrhage, especially those without a history of smoking or hypertension. Hormone replacement therapy reduced the risk only in postmenopausal women who had ever smoked. Among women still menstruating, the risk for hemorrhage was greatest in the perimenstrual period.
Vital Dust: Life as a Cosmic Imperative
Authors: John M. Clark
Journal: JAMA (1995)

When did life begin? When carbon joined hydrogen and oxygen from sea water to form organic molecules? When lipoidal membranes formed vacuoles? With the replication of RNA? With formation of cells? Christian de Duve, Nobel Prize-winning biochemist, who has apparently devoted his career to the study of life, has produced an important book that is almost autobiographical and is a splendid answer. De Duve leads the reader through the complexities of evolution, from simple ocean chemistry to humans and their unique capacity for speech and self-consciousness. The author applies Darwin's theory to evolving organic molecules and concurrent replication accidents that produce mutations. These mutant molecules then compete with each other for available resources—the limited quantity of nucleotides usable for replication. The winners are those that multiply fastest and monopolize the environment. "Natural selection operates blindly on material offered to it by chance." The author's immaculate syntax explains membrane formation so
Reply to M.J. Molina-Garrido et al
Authors: Cristina Falci, Antonella Brunello, Silvio Monfardini
Journal: Journal of Clinical Oncology (2011)

We appreciate the opportunity to reply to the letter by MolinaGarrido and Guillen-Ponce in relation to our letter, in which we commented on the study by Luciani et al, comparing the vulnerable elders survey–13 and the standard comprehensive geriatric assessment (CGA). We fully agree with the contents of their letter and we thank them for highlighting the two main critical points of geriatric oncology. On the one hand, in the last decades consistent data showed the importance of integrating some form of CGA in the process of therapeutic decision in elderly patients with cancer. Beyond its ability to uncover multiple problems in the older population, CGA is per se prognostic in patients with cancer, independently of stage of disease and treatment. This has been confirmed by a large cohort of more than 900 patients prospectively evaluated by means of a full CGA at our institution. On the other hand, the world of geriatric oncology is a constellation of local realities, each one with its own version of geriatric assessment. The first priority of international societies coordinating clinical research in the appealing field of geriatric oncology should therefore be to establish a unique, universally accepted model for CGA. As underlined by Molina-Garrido and Guillen-Ponce, the need for a shorter screening tool with satisfactory predicting values is strongly felt. Recently, the European Organisation for Research and Treatment of Cancer has suggested a minimal data set of elderly patients to include the G-8 as the screening questionnaire. Yet, there are concerns regarding the choice of the optimal rapid questionnaire as a result of the high heterogeneity of study populations in which these screening tools were tested and regarding the inevitable inaccuracy of any attempt at interstudy comparison. In addition, as we stated in our letter, apparently minor differences in research methodology may lead to misinterpretation of results. For all of these reasons, the next step after establishing the reference CGA model would be to test screening tools against this standard CGA model in large, prospective studies. We strongly believe that multicenter cooperation will be essential for the success of such trials, which we hope will lead to prompt implementation of geriatric tools in clinical practice.
Comparison of immune modulation by TLR8 agonist vtx-2337 (motolimod) in cancer patients and healthy volunteers
Authors: Greg Dietsch, Sam Whiting, Donald Northfelt, Ramesh Ramanathan, Peter Cohen, Kristi Manjarrez, Mona Newkirk, James Bryan, Robert Hershberg
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts The potential benefits of stimulating a patient's immune system to fight cancer are profound. Historically, immunotherapy has been a successful treatment approach for some cancer patients, and recent advances in immunotherapy highlight that the immune system can generate durable
Intratumoral Anti-CTLA-4 Therapy: Enhancing Efficacy While Avoiding Toxicity
Authors: Aurélien Marabelle, Holbrook Kohrt, Ronald Levy
Journal: Clinical Cancer Research (2013)

Abstract Systemic administration of the checkpoint blockade antibody anti-CTLA4 results in severe autoimmune toxicity, limiting its clinical efficacy. Fransen and colleagues show here that peritumoral delivery of low doses of this immunomodulatory drug can trigger a systemic antitumor immune response while preventing the toxicity against other organs. Clin Cancer Res; 19(19); 5261–3. ©2013 AACR.
The UK's Research Excellence Framework 2014
Authors: G. Watt
Journal: BMJ (2012)

Currently, there are no approved pharmacological treatments for the management of patients with idiopathic pulmonary fibrosis (IPF) in the USA or Europe. Pirfenidone is an orally bio-available small molecule that exhibits antifibrotic and anti-inflammatory properties in a variety of <i>in vitro</i> and animal models. Pirfenidone has been evaluated in four randomised, double-blind, placebo-controlled clinical trials conducted in Japan, North America and Europe. The totality of the data from these trials indicates that pirfenidone is able to reduce the rate of decline in lung function, measured as change in per cent predicted forced vital capacity (FVC) or vital capacity. There was also an effect on secondary end-points of progression free survival, categorical change in per cent predicted FVC, and the 6-min walk test. A recent meta-analysis of the three phase III studies in IPF demonstrated that pirfenidone significantly reduced the risk of disease progression by 30%. The efficacy of pirfenidone is associated with an acceptable tolerability and safety profile.
Carcinoma of the breast in women under the age of 30.
Authors: A S Purandare, J Finbow
Journal: BMJ (1978)

Corticotropin-releasing factor (CRF) and urocortin (Ucn I) are endogenous members among a family of CRF-related peptides that activate two different and synaptically localized G-protein-coupled receptors, CRF<sub>1</sub> and CRF<sub>2</sub>. These peptides and their receptors have been implicated in stress responses and stress with cocaine abuse. In this study, we observed significant alterations in excitatory transmission and CRF-related peptide regulation of excitatory transmission in the lateral septum mediolateral nucleus (LSMLN) after chronic cocaine administration. In brain slice recordings from the LSMLN of control (saline-treated) rats, glutamatergic synaptic transmission was facilitated by activation of CRF<sub>1</sub> receptors with CRF but was depressed after activation of CRF<sub>2</sub> receptors with Ucn I. After acute withdrawal from a chronic cocaine administration regimen, CRF<sub>1</sub> activation remained facilitatory, but CRF<sub>2</sub> activation facilitated rather than depressed LSMLN EPSCs. These alterations in CRF<sub>2</sub> effects occurred through both presynaptic and postsynaptic mechanisms. In saline-treated rats, CRF<sub>1</sub> and CRF<sub>2</sub> coupled predominantly to protein kinase A signaling pathways, whereas after cocaine withdrawal, protein kinase C activity was more prominent and likely contributed to the CRF<sub>2</sub>-mediated presynaptic facilitation. Neither CRF nor Ucn I altered monosynaptic GABA<sub>A</sub>-mediated IPSCs before or after chronic cocaine administration, suggesting that loss of GABA<sub>A</sub>-mediated inhibition could not account for the facilitation. This switch in polarity of Ucn I-mediated neuromodulation, from a negative to positive regulation of excitatory glutamatergic transmission after chronic cocaine administration, could generate an imbalance in the brain reward circuitry associated with the LSMLN.
Shingles
Authors: Stephen E. Straus
Journal: JAMA (1993)

<h3>SELECTED CASES</h3><h3>Case 1</h3> A 56-year-old woman with advanced lymphoma presented with numerous coalescing lesions confined to the distributions of the left maxillary and ophthalmic divisions of the fifth cranial nerve. Ulcerations were also apparent on the left hemipalate. She had completed radiotherapy months before, but she continued to receive aggressive, multidrug chemotherapy, with the last course within days of the onset of the rash. Lesions were culture positive for varicella-zoster virus (VZV). Treatment was begun with high-dose intravenous acyclovir and continued for 7 days until new vesicles stopped forming. Nonetheless, existing lesions evolved into a confluent eschar (Fig 1, left). She then experienced an episode of mental confusion and right-sided paresis presumed to be secondary to virus-associated granulomatous angiitis of the left middle cerebral artery. Then all the teeth in her left maxillary arch loosened and were lost. Left maxillary sinusitis developed, necessitating antibiotics and surgical creation of a
Prescription Drug Diversion Control and Medical Practice
Authors: James R. Cooper
Journal: JAMA (1992)

Concern about the role of prescription drug diversion in drug abuse has led to demands for more stringent regulation and for better ways to detect prescription drug diversion. Advances in technology now allow point-of-sale computer systems to report prescriptions filled by pharmacies to state agencies rapidly and possibly more economically. However, the advantages of more comprehensive control systems must be balanced against their possible effects on medical practice and patient care. Our limited knowledge about prescription drug diversion and the impact of diversion control systems on medical practice is summarized. Needed research is outlined together with the components of a diversion control program that balances reducing drug diversion with minimizing adverse effects on medical practice and patient care. We stress the need for broadly defined practice parameters and peer review by medical experts thoroughly familiar with the complexities of medical practice.
Active Immunotherapy with Corynebacterium parvum and Chemotherapy in Murine Fibrosarcomas
Authors: G. A. Currie, K. D. Bagshawe
Journal: BMJ (1970)

Corynebacterium parvum used alone to enhance immunological reactivity produced transient inhibition of the growth of chemically induced isogenic mouse tumours. Attempts were made to combine C. Parvum with cyclophosphamide to see whether this would increase the latter9s effectiveness in inhibiting early but established tumours. Of the various regimens tested, the administration of the C. parvum 12 days after a single dose of chemotherapy produced dramatic inhibition of tumour growth and resulted in complete and lasting regressions in up to 70% of tumour-bearing animals. The most important variable in this regimen is the time between the chemotherapy and the subsequent immunotherapy. It is possible that non-specific active immunotherapy with agents such as C. parvum may be a valuable adjunct to the conventional cyto-reductive treatments of cancer, but the time of administration of such therapy is probably critical for each tumour and for each chemotherapeutic regimen.
THE PLACE OF MEDICINE IN PUBLIC HEALTH
Authors: WALTER M. DICKIE
Journal: JAMA (1923)

From a theoretical standpoint, the practice of medicine bears the same relationship to public health today that it did twenty years ago. Actually, the changes that have occurred in this relationship are extremely drastic. In recent years a new social point of view has developed, but most practitioners are apparently unaware of the awakening of the nation's social conscience and of the new demands on the profession that must naturally follow. It is my purpose in this paper to outline the more recent development of the demand for public health protection and the general trend of its fulfilment. The advancement of learning in America is the most outstanding achievement of the age in which we live. We are in the midst of an enlightened public opinion. Our educational systems have become so extensive that even our recently arrived immigrants have little or no difficulty in securing at least the rudiments
Glycolysis-Mediated Changes in Acetyl-CoA and Histone Acetylation Control the Early Differentiation of Embryonic Stem Cells
Authors: Arieh Moussaieff, Matthieu Rouleau, Daniel Kitsberg, Merav Cohen, Gahl Levy, Dinorah Barasch, Alina Nemirovski, Shai Shen-Orr, Ilana Laevsky, Michal Amit, David Bomze, Bénédicte Elena-Herrmann, Tali Scherf, Malka Nissim-Rafinia, Stefan Kempa, Joseph Itskovitz-Eldor, Eran Meshorer, Daniel Aberdam, Yaakov Nahmias
Journal: Cell Metabolism (2015)
Anglo-Canadian Exchange in General Practice: Canadian View of British General Practice
Authors: G. P. Sweeny
Journal: BMJ (1971)

Before embarking on this exchange venture in British general practice I had many preconceived impressions of what it might be like to be an English family physician. Early in my five months of group practice it became apparent that many of my attitudes had no real basis and in fact I had to admit many aspects of the British health system were indeed superior. It has been my impression that a group general practice in Great Britain can certainly afford the practising family doctor a stimulating and rewarding professional and social life.
Families in high-rise flats.
Authors: J W Kleevens
Journal: BMJ (1982)

IL-6 mediates numerous immunologic effects relevant to transplant rejection; however, its specific contributions to these processes are not fully understood. To this end, we neutralized IL-6 in settings of acute cardiac allograft rejection associated with either CD8<sup>+</sup> or CD4<sup>+</sup> cell-dominant responses. In a setting of CD8<sup>+</sup> cell-dominant graft rejection, IL-6 neutralization delayed the onset of acute rejection while decreasing graft infiltrate and inverting anti-graft Th1/Th2 priming dominance in recipients. IL-6 neutralization markedly prolonged graft survival in the setting of CD4<sup>+</sup> cell-mediated acute rejection and was associated with decreased graft infiltrate, altered Th1 responses, and reduced serum alloantibody. Furthermore, in CD4<sup>+</sup> cell-dominated rejection, IL-6 neutralization was effective when anti–IL-6 administration was delayed by as many as 6 d posttransplant. Finally, IL-6–deficient graft recipients were protected from CD4<sup>+</sup> cell-dominant responses, suggesting that IL-6 production by graft recipients, rather than grafts, is necessary for this type of rejection. Collectively, these observations define IL-6 as a critical promoter of graft infiltration and a shaper of T cell lineage development in cardiac graft rejection. In light of these findings, the utility of therapeutics targeting IL-6 should be considered for preventing cardiac allograft rejection.
Rockets land around hospital in Haifa
Authors: Judy Siegel-Itzkovich
Journal: BMJ (2006)

Staff at Israel's northern hospitals have remained at work, despite the threat of rocket attack, to treat some 3000 wounded soldiers and civilians.

“We had thought we'd need court restraining orders to keep them working, but they volunteered, even though they are at risk,” said the deputy director general of the health ministry, Yitzhak Berlovich.

Rockets fell in the grounds of the 1000 bed Rambam Medical Centre in Haifa on Tuesday …
An Historical Account of Pharmacology to the 20th Century
Authors: William K. Beatty
Journal: JAMA (1976)

Chauncey Leake has spent half a century discovering, applying, and teaching pharmacological information and knowledge. This book contains a combination of his historical and scientific interests, blended with an enthusiasm that will be evident to any reader. Dr Leake begins his story with "protopharmacology": the early medicinal uses of plant, mineral, and animal substances, and then describes the investigative spirit of the Arabic writers in the Middle Ages. Later, his accounts of Paracelsus, Cesalpino, and Vesalius show the beginnings of modern scientific methods. Each chapter begins with a quotation; Osler's "One should treat as many patients as possible with a new drug while it still has the power to heal" opens the chapter on the 17th and 18th centuries and not only sets the tone for that chapter but also exemplifies the author's healthy skepticism. In the 19th century, Leake draws special attention to Magendie and his pupils, among whom
Stem Cell Tourism: Doctors' Duties to Minors and Other Incompetent Patients
Authors: Jennifer Chandler
Journal: The American Journal of Bioethics (2010)

"Stem Cell Tourism: Doctors' Duties to Minors and Other Incompetent Patients." The American Journal of Bioethics, 10(5), pp. 27–28 Notes 1. It is sensible to focus on this class of patients given that the cases reported as problematic tend to involve children. I raise the possibility of risks to other incompetent patients, such as adults, although these cases may be less common.
Use of cluster analysis to define COPD phenotypes
Authors: M. Weatherall, P. Shirtcliffe, J. Travers, R. Beasley
Journal: European Respiratory Journal (2010)

The current classification of airways disorders is imprecise, with an overlap of phenotypes ( e.g. asthma, chronic bronchitis and emphysema), resulting in difficulties in differentiating the disorders from each other. This has led to considerable diagnostic, management and prognostic uncertainty. The traditional approach has been to present this phenotypic overlap in the Venn diagram format 1; however, this results in ≥15 phenotypes, whose pathogenesis or response to treatment have not been clearly defined 2, 3. More recent work 4–8, including that of Burgel et al. 8 published in the current issue of the European Respiratory Journal , has used cluster analysis to characterise different types of airways disorders. But what is cluster analysis, is it a reasonable approach to take, and how valid are the conclusions?

Cluster analysis is a collection of methods for defining groups of individuals based on measured characteristics, so that they are grouped based on their differences (or similarities), into clusters 9–11. The groupings are constructed such that the degree of association is strong between members of the same cluster and weak between members of different clusters 4.

Cluster analysis is distinct from other ways of trying to understand multivariate data, which include principal component and factor analysis, discriminant analysis and multivariate regression. Principal component (as used by Burgel et al. 8) and factor analysis produce linear combinations of measured variables, in the sense that new derived variables are produced by multiplying each of the original variables by a scaling parameter and adding the resulting numbers. Discriminant analysis (as also used by Moore et al. 5) starts with known groups and finds scaled combinations of the measured variables that best distinguish those known groups. Multivariate regression can have a set of response variables predicted by a set …