tbuckley/cabot-search huggingface dataset:
The Role of Hypoxia in Vascular Injury and Repair
Authors: Tony E. Walshe, Patricia A. D'Amore
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Although the terms ischemia and hypoxia are often used interchangeably, they represent distinct processes that result in different modulatory effects at the cellular level. Hypoxia is a reduction in oxygen delivery below tissue demand, whereas ischemia is a lack of perfusion, characterized not only by hypoxia but also by insufficient nutrient supply. Hypoxia can be either acute or chronic, and both are centrally regulated by hypoxia-inducible factor, a transcription factor that governs the expression of key response genes such as vascular endothelial growth factor and erythropoietin. Whereas severe chronic hypoxia can cause cell death, less-severe hypoxia can protect against subsequent damage, a phenomenon known as hypoxic conditioning. Several important processes are characterized by hypoxia, including ischemia-reperfusion, tumor growth and progression, inflammation, myocardial ischemia, and a number of ocular pathologies.
Prenatal negative life events increases cord blood <scp>I</scp>g<scp>E</scp>: interactions with dust mite allergen and maternal atopy
Authors: J. L. Peters, S. Cohen, J. Staudenmayer, J. Hosen, T. A. E. Platts‐Mills, R. J. Wright
Journal: Allergy (2012)

Abstract Background Prenatal exposure to both stress and aeroallergens (dust mite) may modulate the fetal immune system. These exposures may interact to affect the newborn immune response. We examined associations between prenatal maternal stress and cord blood total IgE in 403 predominately low‐income minority infants enrolled in the A sthma C oalition on C ommunity, E nvironment, and S ocial S tress ( ACCESS ) project. We also examined potential modifying effects of maternal atopy and maternal dust mite exposure. Methods The C risis in F amily S ystems survey was administered to mothers prenatally, and a negative life event domain score was derived to characterize stress. Dust mite allergen was quantified in dust from pregnant mothers' bedrooms. Cord blood was analyzed for total I g E . Using linear regression, we modeled the relationship of stress with cord blood I g E and interactions of stress with dust mite and/or maternal atopy, adjusting for potential confounders. Results Higher prenatal maternal stress (β = 0.09; P = 0.01) was associated with increased cord blood I g E . The interactive effects between stress and dust mite groups (high vs low) were significantly different for children of atopic vs nonatopic mothers ( P for three‐way interaction = 0.005). Among children of atopic mothers, the positive association between stress and I g E was stronger in the high dust mite group. In children of mothers without a history of atopy, the positive association between stress and I g E was most evident in the low allergen group. Conclusions Prenatal stress was independently associated with elevated cord blood I g E . Mechanisms underlying stress effects on fetal immunomodulation may differ based on maternal atopic status.
Schisandrin B Prevents Doxorubicin-Induced Cardiotoxicity via Enhancing Glutathione Redox Cycling
Authors: Ling Li, Qiangrong Pan, Weidong Han, Zhen Liu, Ling Li, Xun Hu
Journal: Clinical Cancer Research (2007)

The dose-cumulative cardiotoxicities and the emerging cancerous apoptotic/drug resistance are two major obstacles limiting the efficacy of anthracycline antibiotics, notably doxorubicin. We attempted to prove if schisandrin B (Sch B), a dual inhibitor of P-glycoprotein and multidrug resistance-associated protein 1, could protect against doxorubicin-induced cardiotoxicity, on the premise that Sch B is an enhancer of glutathione redox cycling that may attenuate doxorubicin-induced oxidative stress in the cardiomyocytes.Mice or rat were dosed with a single injection of doxorubicin (25 mg/kg, i.p.) with or without pretreatment of Sch B. The protective roles of Sch B against doxorubicin-induced cardiac damage were evaluated on the aspects of the release of cardiac enzymes into serum, the formation of malondialdehyde, the activation of matrix metalloproteinase, the structural damage in the left ventricles, the mortality rates, and the cardiac functions.Pretreatment of Sch B significantly attenuated doxorubicin-induced cardiotoxicities on all the aspects listed above. The underlying mechanism was associated with the effect of Sch B on maintaining the cardiomyocytic glutathione and the activities of superoxide dismutase, and the key enzymes (glutathione peroxidase, glutathione reductase, and glutathione transferase) responsible for glutathione redox cycling, which neutralized doxorubicin-induced oxidative stress.To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a dual inhibitor of P-glycoprotein and multidrug resistance-associated protein 1, which is potentially applicable to treat cancers, especially the multidrug-resistant cancers involving doxorubicin or its kin.
Reply to H.E. Eve et al
Authors: Peter Martin, John P. Leonard
Journal: Journal of Clinical Oncology (2009)

We read with interest the letter submitted by Eve et al in response to our recent report in Journal of Clinical Oncology. Their observations are consistent with our experience that up to one third of patients diagnosed with mantle-cell lymphoma may defer treatment (in the absence of symptoms or other indications for therapy) with no apparent detriment to their long-term outcome. The thoughtful comments made by Eve et al highlight the role of clinical assessment by the hematologist/oncologist in determining the potential need for therapy, with a particular eye toward preservation of quality of life. We strongly agree with their point that biologic and clinical markers need to be additionally developed to predict outcome for patient subsets and direct specific management of such groups on the basis of prospective comparative data. Clearly, cooperative clinical studies of such tools should be a priority for those involved in the care of such patients. We await data that can be used to best define therapy selection. In the meantime, we remain convinced that the clinical judgment of the treating physician, developed through careful monitoring over a period of observation when feasible, is a valuable tool in making management decisions. This information, in conjunction with collaborative discussions with patients regarding their individual goals for therapy, can contribute vital information to optimizing outcome in mantle-cell lymphoma.
Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells
Authors: Anni Laine, Jukka Westermarck
Journal: Clinical Cancer Research (2014)

Abstract Induction of terminal proliferation arrest, senescence, is important for in vivo tumor-suppressive function of p53. Moreover, p53-mutant cells are highly resistant to senescence induction by either oncogenic signaling during cellular transformation or in response to different therapies. Senescence resistance in p53-mutant cells has been attributed mostly to inhibition of the checkpoint function of p53 in response to senescence-inducing stress signals. Here, we review very recent evidence that offers an alternative explanation for senescence resistance in p53-defective cancer cells: p21-mediated E2F1 expression. We discuss the potential relevance of these findings for senescence-inducing therapies and highlight cyclin-dependent kinases (CDK) and mechanisms downstream of retinoblastoma protein (RB) as prospective prosenescence therapeutic targets. In particular, we discuss recent findings indicating an important role for the E2F1–CIP2A feedback loop in causing senescence resistance in p53-compromised cancer cells. We further propose that targeting of the E2F1–CIP2A feedback loop could provide a prosenescence therapeutic approach that is effective in both p53-deficient and RB-deficient cancer cells, which together constitute the great majority of all cancer cells. Diagnostic evaluation of the described senescence resistance mechanisms in human tumors might also be informative for patient stratification for already existing therapies. Clin Cancer Res; 20(14); 3644–50. ©2014 AACR.
Rapid Donor Liver Nutritional Enhancement in A Large Animal Model
Authors: Robert Cywes, Paul D. Greig, Glynn R. Morgan, Juan R. Sanabria, Pierre-Alain Clavien, Robert P.C. Harvey, Steven M. Strasberg
Journal: Hepatology (1992)

Organ donors are typically subject to acute hyponutrition that might affect postpreservation liver function. Livers from nutritionally supplemented rats function better after preservation than livers from fasted rats. We have developed a method to glycogenate the liver of large animals in the temporal context of a human donor liver operation and have studied the fate of glycogen stores during preservation. Starved anesthetized pigs were infused with a hexose solution (glucose, fructose or galactose) by way of the superior mesenteric vein for 3 hr. Regular porcine insulin was infused to maintain a hyperglycemic hyperinsulinemic arterial glucose clamp at 12 to 16 mmol/L. Liver biopsy specimens and blood samples were taken before infusion and hourly. At 3 hr the liver was excised, stored for 24 hr at 1 degrees C in University of Wisconsin solution and biopsied. It was then placed at 20 degrees C for 1 hr to simulate the reimplantation stage of transplantation. Glycogen and nucleotide levels were measured, and results were corrected for starch in the University of Wisconsin solution. A 20% glucose infusion produced rapid hepatic glycogenation without side effects. Greater glycogenation was obtained with 20% fructose but at the cost of lactic acidosis and a fall in pH. A combination of 15% glucose and 5% fructose produced intermediary glycogenation without significant side effects. Galactose (20%) was less efficient than glucose alone. The addition of alanine and glutamine (20 mmol/L) did not significantly improve glycogenation. Metabolism of glycogen at 1 degree C did occur. Glycogen content fell 0.15% +/- 0.05% dry weight liver per hour during cold preservation and 5.49% +/- 2.15% per hour during ischemic rewarming.(ABSTRACT TRUNCATED AT 250 WORDS)
Facemasks for the prevention of infection in healthcare and community settings
Authors: C. R. MacIntyre, A. A. Chughtai
Journal: BMJ (2015)

Facemasks are recommended for diseases transmitted through droplets and respirators for respiratory aerosols, yet recommendations and terminology vary between guidelines. The concepts of droplet and airborne transmission that are entrenched in clinical practice have recently been shown to be more complex than previously thought. Several randomised clinical trials of facemasks have been conducted in community and healthcare settings, using widely varying interventions, including mixed interventions (such as masks and handwashing), and diverse outcomes. Of the nine trials of facemasks identified in community settings, in all but one, facemasks were used for respiratory protection of well people. They found that facemasks and facemasks plus hand hygiene may prevent infection in community settings, subject to early use and compliance. Two trials in healthcare workers favoured respirators for clinical respiratory illness. The use of reusable cloth masks is widespread globally, particularly in Asia, which is an important region for emerging infections, but there is no clinical research to inform their use and most policies offer no guidance on them. Health economic analyses of facemasks are scarce and the few published cost effectiveness models do not use clinical efficacy data. The lack of research on facemasks and respirators is reflected in varied and sometimes conflicting policies and guidelines. Further research should focus on examining the efficacy of facemasks against specific infectious threats such as influenza and tuberculosis, assessing the efficacy of cloth masks, investigating common practices such as reuse of masks, assessing compliance, filling in policy gaps, and obtaining cost effectiveness data using clinical efficacy estimates.
Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies
Authors: Lindsey N. Micel, John J. Tentler, Peter G. Smith, Gail S. Eckhardt
Journal: Journal of Clinical Oncology (2013)

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.
Oxidative stress injury during cardiac surgery: How important is it?
Authors: David J. Chambers
Journal: Cardiovascular Research (2007)

See article by Milei et al.  [11]  (pages 710–719) in this issue. 

The concept that the reintroduction of oxygen to the ischaemic myocardium causes significant injury has long been known [1], and it is now well-established [2] that oxidative stress is one of the major initiators of myocardial injury during ischaemia and reperfusion. Cardiac surgery for coronary artery bypass generally involves cardiopulmonary bypass with cardioplegic arrest and elective global ischaemia of the heart. It would appear to represent the ideal situation to evaluate the potential injury induced by oxidative stress during ischaemia and subsequent reperfusion, since in this clinical situation (and unusually for most ischaemic conditions) the time of onset and the duration of ischaemia are known as is the time and conditions of reperfusion, and all are under the control of the operating surgeon. This means that studies in patients undergoing surgery are able to be controlled in a similar manner to that of experimental studies involving animal models. In experimental studies on isolated rat hearts, ischaemia and reperfusion are known to generate oxygen-derived free radicals; the use of electron-spin-resonance techniques has allowed the direct detection of reactive oxygen species produced when ischaemic myocardium is reperfused [3] and has also shown that this production can be prevented by various antioxidant or scavenger agents [4]. A large number of experimental studies that simulate this surgical ischaemia and reperfusion have shown that various antioxidant agents can ameliorate the detrimental effects of oxidative stress … 

*Tel.: +44 20 7188 0958; fax: +44 20 7188 3902. Email address: david.chambers{at}kcl.ac.uk david.chambers{at}gstt.nhs.uk
Problems of developing countries.
Authors: F M Shattock
Journal: BMJ (1990)

the agents gave advice on relevant immunisations and malaria prophylaxis.Nineteen agents recog- nised that there was a risk of acquiring HIV infection in Bangkok, but only four of these advised customers of that risk.The Department of Health booklet The Travel- lers Guide to Health contains information on HIV infection and the measures to take to avoid infection.2This booklet was available in 18 of the agencies: for reference only in two, on request in 11, and given to all booking customers in five.We were concerned to discover that two commonly quoted reference sources ABC Guide to Inter- national Travel1 and World Travel Guide' did not mention the risk of HIV infection to travellers.We recommend that the Department of Health book- let should be readily available to all travellers.Though we recognise worldwide distribution of HIV and that the risk of infection relates to particular activities and not to the area per se, perhaps known high risk areas should be identified specifically.Clearly, travel agents already assume some responsibility for providing health informa- tion to travellers.We suggest that this should be extended to include advice about the risks of contracting HIV while abroad and ways to minimise this risk.
Long-Term Clinical and Angiographic Follow-Up After Coronary Stent Placement in Native Coronary Arteries
Authors: Takeshi Kimura, Kenichi Abe, Satoshi Shizuta, Keita Odashiro, Yoshinori Yoshida, Koyu Sakai, Kazuaki Kaitani, Katsumi Inoue, Yoshihisa Nakagawa, Hiroyoshi Yokoi, Masashi Iwabuchi, Naoya Hamasaki, Hideyuki Nosaka, Masakiyo Nobuyoshi
Journal: Circulation (2002)

Background — Although coronary stents have been proved effective in reducing clinical cardiac events for up to 3 to 5 years, longer term clinical and angiographic outcomes have not yet been fully clarified. Methods and Results — To evaluate longer term (7 to 11 years) outcome, clinical and angiographic follow-up information was analyzed in 405 patients with successful stenting in native coronary arteries. Primary or secondary stabilization, which was defined as freedom from death, coronary artery bypass grafting, and target lesion-percutaneous coronary intervention (TL-PCI) during the 14 months after the initial procedure or after the last TL-PCI, was achieved in 373 patients (92%) overall. Only 7 patients (1.7%) underwent TL-PCI more than twice. After the initial 14-month period, freedom from TL-PCI reached a plateau at 84.9% to 80.7% over 1 to 8 years. However, quantitative angiographic analysis in 179 lesions revealed a triphasic luminal response characterized by an early restenosis phase until 6 months, an intermediate-term regression phase from 6 months to 3 years, and a late renarrowing phase beyond 4 years. Minimal luminal diameter in 131 patients with complete serial data were 2.62±0.4 mm immediately after stenting, 2.0±0.49 mm at 6 months, 2.19±0.49 mm at 3 years, and 1.85±0.56 mm beyond 4 years ( P &lt;0.0001). Conclusions — The efficacy and safety of coronary stenting seemed to be clinically sustained at 7 to 11 years of follow-up. However, late luminal renarrowing beyond 4 years was common, which demonstrates the need for further follow-up.
Dipeptidyl Peptidase IV and Incident Diabetes
Authors: Vivian C. Luft, Maria Inês Schmidt, James S. Pankow, Ron C. Hoogeveen, David Couper, Gerardo Heiss, Bruce B. Duncan
Journal: Diabetes Care (2010)

OBJECTIVE Dipeptidyl peptidase IV (DPP-IV) is not only important in β-cell function but also has proinflammatory actions. We aimed to investigate whether it could act as a link between low-grade chronic inflammation and diabetes. RESEARCH DESIGN AND METHODS Using a case-cohort design, we followed 546 middle-aged individuals who developed diabetes and 538 who did not over ∼9 years within the Atherosclerosis Risk in Communities study. RESULTS In weighted analyses, the correlation between DPP-IV levels and anthropometric, inflammatory, or metabolic variables was minimal (Spearman correlations &amp;lt;0.11). Those who developed diabetes had mean DPP-IV values similar to those who did not (P = 0.18). Individuals in the highest quartile of DPP-IV were not at greater risk of diabetes (hazard ratio 0.88 [95% CI 0.62–1.24]) in Cox proportional hazards models adjusting for age, sex, race, study center, and multiple additional diabetes risk factors. CONCLUSIONS Fasting DPP-IV levels do not appear to predict incident diabetes.
Somatic Hypermutation Is Limited by CRM1-dependent Nuclear Export of Activation-induced Deaminase
Authors: Kevin M. McBride, Vasco Barreto, Almudena R. Ramiro, Pete Stavropoulos, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2004)

Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated in activated B lymphocytes by activation-induced deaminase (AID). AID is thought to make lesions in DNA by deaminating cytidine residues in single-stranded DNA exposed by RNA polymerase during transcription. Although this must occur in the nucleus, AID is found primarily in the cytoplasm. Here we show that AID is actively excluded from the nucleus by an exportin CRM1-dependent pathway. The AID nuclear export signal (NES) is found at the carboxyl terminus of AID in a region that overlaps a sequence required for CSR but not SHM. We find that AID lacking a functional NES causes more hypermutation of a nonphysiologic target gene in transfected fibroblasts. However, the NES does not impact on the rate of mutation of immunoglobulin genes in B lymphocytes, suggesting that the AID NES does not limit AID activity in these cells.
Guidelines for Improving Breast Health Care in Limited Resource Countries: The Breast Health Global Initiative
Authors: Benjamin O. Anderson, Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2007)

Breast cancer is an increasingly urgent problem in low- and mid-level resource regions of the world. Despite knowing the optimal management strategy based on guidelines developed in wealthy countries, clinicians are forced to provide less-than-optimal care when diagnostic or treatment resources are lacking. For this reason, it is important to identify which resources most effectively fill health care needs in limited-resource regions, where patients commonly present with more advanced disease at diagnosis, and to provide guidance on how new resource allocations should be made to maximize improvement in outcome. Established in 2002, the Breast Health Global Initiative (BHGI) created an international health alliance to develop evidence-based guidelines for countries with limited resources to improve breast health outcomes. The BHGI serves as a program for international guideline development and as a hub for linkage among clinicians, governmental health agencies, and advocacy groups to translate guidelines into policy and practice. The BHGI collaborated with 12 national and international health organizations, cancer societies, and nongovernmental organizations to host 2 BHGI international summits. The evidence-based BHGI guidelines, developed at the 2002 Global Summit, were published in 2003 as a theoretical treatise on international breast health care. These guidelines were then updated and expanded at the 2005 Global Summit into a fully comprehensive and flexible framework to permit incremental improvements in health care delivery, based on outcomes, cost, cost-effectiveness, and use of health care services.