tbuckley/cabot-search huggingface dataset:
Sharps injuries in the community: lower risk than in healthcare settings
Authors: Joshua Osowicki, Nigel Curtis
Journal: BMJ (2015)

Riddell and colleagues highlight the importance of risk assessment in the management of healthcare related sharps injuries.1 The relatively high risks in the healthcare setting are often misapplied to community acquired sharps injuries, which are most common in young children. This causes unnecessary anxiety in families and doctors, compounded by further …
Novel Molecular and Nanosensors for In Vivo Sensing
Authors: Mark A. Eckert, Priscilla Q. Vu, Kaixiang Zhang, Dongku Kang, M. Monsur Ali, Chenjie Xu, Weian Zhao
Journal: Theranostics (2013)

In vivo sensors are an emerging field with the potential to revolutionize our understanding of basic biology and our treatment of disease.In this review, we highlight recent advances in the fields of in vivo electrochemical, optical, and magnetic resonance biosensors with a focus on recent developments that have been validated in rodent models or human subjects.In addition, we discuss major challenges in the development and translation of in vivo biosensors and present potential solutions to these problems.The field of nanotechnology, in particular, has recently been instrumental in driving the field of in vivo sensors forward.We conclude with a discussion of emerging paradigms and techniques for the development of future biosensors.
A Gene-Expression Signature as a Predictor of Survival in Breast Cancer
Authors: Marc J. van de Vijver, Yudong D. He, Laura J. van 't Veer, Hongyue Dai, Augustinus A.M. Hart, Dorien W. Voskuil, George J. Schreiber, Johannes L. Peterse, Chris Roberts, Matthew J. Marton, Mark Parrish, Douwe Atsma, Anke Witteveen, Annuska Glas, Leonie Delahaye, Tony van der Velde, Harry Bartelink, Sjoerd Rodenhuis, Emiel T. Rutgers, Stephen H. Friend, René Bernards
Journal: New England Journal of Medicine (2002)

A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy.
Coordinate expression of heme and globin is essential for effective erythropoiesis
Authors: Raymond T. Doty, Susan R. Phelps, Christina Shadle, Marilyn Sanchez-Bonilla, Siobán B. Keel, Janis L. Abkowitz
Journal: Journal of Clinical Investigation (2015)

Erythropoiesis requires rapid and extensive hemoglobin production. Heme activates globin transcription and translation; therefore, heme synthesis must precede globin synthesis. As free heme is a potent inducer of oxidative damage, its levels within cellular compartments require stringent regulation. Mice lacking the heme exporter FLVCR1 have a severe macrocytic anemia; however, the mechanisms that underlie erythropoiesis dysfunction in these animals are unclear. Here, we determined that erythropoiesis failure occurs in these animals at the CFU-E/proerythroblast stage, a point at which the transferrin receptor (CD71) is upregulated, iron is imported, and heme is synthesized--before ample globin is produced. From the CFU-E/proerythroblast (CD71(+) Ter119(-) cells) stage onward, erythroid progenitors exhibited excess heme content, increased cytoplasmic ROS, and increased apoptosis. Reducing heme synthesis in FLVCR1-defient animals via genetic and biochemical approaches improved the anemia, implying that heme excess causes, and is not just associated with, the erythroid marrow failure. Expression of the cell surface FLVCR1 isoform, but not the mitochondrial FLVCR1 isoform, restored normal rbc production, demonstrating that cellular heme export is essential. Together, these studies provide insight into how heme is regulated to allow effective erythropoiesis, show that erythropoiesis fails when heme is excessive, and emphasize the importance of evaluating Ter119(-) erythroid cells when studying erythroid marrow failure in murine models.
Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation
Authors: S. Allahverdian, P. S. Pannu, G. A. Francis
Journal: Cardiovascular Research (2012)

Smooth muscle cells (SMCs) are the main cell type in intimal thickenings and some stages of human atherosclerosis. Like monocyte-derived macrophages, SMCs accumulate excess lipids and contribute to the total intimal foam cell population. In contrast, apolipoprotein (Apo)E-deficient and LDL receptor-deficient mice develop atherosclerotic lesions that are macrophage- as opposed to SMC-rich. The lesser contribution of SMCs to lesion development in these mouse models has distracted attention away from the importance of SMC cholesterol homeostasis in the artery wall. Intimal SMCs accumulate excess amounts of cholesteryl esters when compared with medial layer SMCs, possibly explained by reduced ATP-binding cassette transporter A1 expression and ApoA-I binding to intimal-type SMCs. The aim of this review is to compare the relative contribution of monocyte-derived macrophages and SMCs to human vs. mouse atherosclerosis, and describe what is known about lipid uptake and removal mechanisms contributing to arterial macrophage and SMC foam cell formation. An increased understanding of the contribution of these cell types to lesion development will help to delineate their relative importance in atherogenesis and as potential therapeutic targets.
Protein Kinase D
Authors: Sharon A. Matthews, Enrique Rozengurt, Doreen Cantrell
Journal: The Journal of Experimental Medicine (2000)

Protein kinase Cs (PKCs) are activated by antigen receptors in lymphocytes, but little is known about proximal targets for PKCs in antigen receptor–mediated responses. In this report, we define a role for diacylglycerol-regulated PKC isoforms in controlling the activity of the serine/threonine kinase protein kinase D (PKD; also known as PKCμ) in T cells, B cells, and mast cells. Antigen receptor activation of PKD is a rapid and sustained response that can be seen in T cells activated via the T cell antigen receptor, B cells activated via the B cell antigen receptor, and in mast cells triggered via the high-affinity receptor for IgE (FcεR1). Herein, we show that antigen receptor activation of PKD requires the activity of classical/novel PKCs. Moreover, PKC activity is sufficient to bypass the requirement for antigen receptor signals in the induction of PKD activity. These biochemical and genetic studies establish a role for antigen receptor–regulated PKC enzymes in the control of PKD activity. Regulation of PKD activity through upstream PKCs reveals a signaling network that exists between different members of the PKC superfamily of kinases that can operate to amplify and disseminate antigen receptor signals generated at the plasma membrane.
Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis
Authors: Kristen Pollizzi, Izabela Malinowska-Kolodziej, Michael Stumm, Heidi Lane, David Kwiatkowski
Journal: Molecular Cancer (2009)

Tuberous sclerosis (TSC) is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus) leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235.Using ENU to enhance Tsc2+- kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week) and NVP-BEZ235 (45 mg/kg PO QD) had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation.Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.
Relation Between Baseline and On-Treatment Lipid Parameters and First Acute Major Coronary Events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
Authors: Antonio M. Gotto, Edwin Whitney, Evan A. Stein, Deborah R. Shapiro, Michael Clearfield, Stephen Weis, Jesse Y. Jou, Alexandra Langendörfer, Polly A. Beere, Douglas J. Watson, John R. Downs, John S. de Cani
Journal: Circulation (2000)

Background —The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25% reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk for first acute major coronary event (AMCE), defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. This article describes the relation between baseline and on-treatment lipid and apolipoprotein (apo) parameters and subsequent risk for AMCEs. Methods and Results —With all available data from the entire 6605-patient cohort, a prespecified Cox backward stepwise regression model identified outcome predictors, and logistic regression models examined the relation between lipid variables and AMCE risk. Baseline LDL-C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment LDL-C was not. When event rates were examined across tertiles of baseline lipids, a consistent benefit of treatment with lovastatin was observed. Conclusions —Persons with average TC and LDL-C levels and below-average HDL-C may obtain significant clinical benefit from primary-prevention lipid modification. On-treatment apoB, especially when combined with apoAI to form the apoB/AI ratio, may be a more accurate predictor than LDL-C of risk for first AMCE.
Identification of Bona Fide Esophageal Adenocarcinoma Cell Lines
Authors: R. H. Shoemaker
Journal: JNCI Journal of the National Cancer Institute (2010)

Most investigators using human tumor cell lines have not initiated the tumor cell lines, but rather obtained them from colleagues or repositories. Although the latter source would seem to offer some security regarding the authenticity of the cell lines, investigators bear the burden of assuring that the cell lines selected are appropriate to the research and maintained in a way that preserves their identity. In this issue of the Journal, Boonstra et al. ( 1 ) report a survey of available esophageal adenocarcinoma (EAC) tumor cell lines. They show that three very widely used cell lines are, in fact, derived from other tumor types and concluded that the use of these cell lines “threatens the development of treatment strategies for esophageal adenocarcinoma.” Certainly, it is important for this information to be available to the research community and, to the extent that EAC cell lines may refl ect important aspects of biology unique to therapeutic targeting of that tumor type, their conclusion is valid. Misidentifi cation, cross-contamination, and confusion regarding tumor cell lines is not a new problem. Beginning in the 1970s, evidence of widespread contamination by HeLa cells was recognized by Nelson-Rees et al. ( 2 ) based on cytogenetic analyses. This fi nding led to the development of some early recommendations for quality control of cell lines, which also included analysis of isoenzyme expression patterns ( 3 ). Although state-of-the-art at the time, these methods were time consuming and required a high level of expertise. The identifi cation of HeLa marker chromosomes or derivatives by G-banding in highly aneuploid metaphases with many chromosomal rearrangements is no easy task. The advent of spectral karyotyping has added objectivity and resolution to the process and supported identifi cation of instances of contamination in tumor cell lines with extremely abnormal karyotypes ( 4 ). The development of molecular biological techniques, such as DNA fi ngerprinting, has provided for a quantum increase in resolution. Masters et al. ( 5 ) have advocated the use of short terminal repeat (STR) fi ngerprinting, a straightforward standardized method that has gained wide acceptance. Forensic applications of this technology have generated a large commercial market for DNA fi ngerprinting. This, in turn, has led to the marketing of affordably priced kits for STR fi ngerprinting. Moreover, large publicly accessible databases with STR fi ngerprint results provide a useful reference against which investigators can compare data. Boonstra et al. have made a substantial contribution with STR characterization of the available EAC tumor cell lines.
Protocol Information Provides Opportunity for Patient Safety and Quality Improvement
Authors: Thomas J. George, Helen Leather
Journal: Journal of Clinical Oncology (2011)

We enthusiastically support and applaud the recent decision by the editors of Journal of Clinical Oncology (JCO) to make available for online readers the entire protocol for published randomized phase II and III trials. 1 This landmark event in clinical trial reporting will not only improve the dissemination of medical knowledge, but will likely simultaneously improve the safe translation of clinical trial data to that of practicing hematologists and oncologists.Noting the details of clinical trial protocol design, statistical methodology, and measurable end points has long been recognized as a critical responsibility of the scientific community.Analysis of such detail is imperative to gauge the scientific merit and accuracy of the data and subsequent conclusions.However, it has recently been recognized that the lack of information in trial publications about patient selection, treatment, monitoring, and management may impact the quality of cancer care that is delivered after publication. 2,3The generalizability of published study results to individual patients with any degree of certainty is dependent on many more variables than can possibly be included in an article limited to 3,000 words.Vague exclusion criteria, limited clinical monitoring information, and scarce information on dose modifications for toxicity each create opportunities for disparate outcomes in translating the science to the clinic. 4,5If schedule-dependent treatments are not made explicitly clear, differences in efficacy may result.In our study of 262 oncologybased therapeutic randomized controlled trials published in JCO, Journal of the National Cancer Institute, Blood, Cancer, and New Eng-land Journal of Medicine, only 11% consistently reported essential therapeutic details. 6 By including the complete protocol for readers as a requirement for publication in JCO, a new standard for quality of cancer care in the oncology community has been established.Having immediate and convenient access to the protocol will make it more likely that practicing clinicians will be able and willing to review the study details relevant to the provision of high-quality, safe clinical care.Our hope is that other journals will follow the lead provided by JCO.
A randomized phase II study of irinotecan plus cisplatin versus irinotecan plus capecitabine with or without isosorbide-5-mononitrate in advanced non-small-cell lung cancer
Authors: J.Y. Han, B.H. Nam, H.Y. Kim, S.J. Yoon, H.T. Kim, J.S. Lee
Journal: Annals of Oncology (2012)
Pathogenetic mechanisms of hepatic encephalopathy
Authors: D Haussinger, F Schliess
Journal: Gut (2008)

Hepatic encephalopathy (HE) in liver cirrhosis is a clinical manifestation of a low-grade cerebral oedema, which is exacerbated in response to ammonia and other precipitating factors. This low-grade cerebral oedema is accompanied by an increased production of reactive oxygen and nitrogen oxide species (ROS/RNOS), which trigger multiple protein and RNA modifications, thereby affecting brain function. The action of ammonia, inflammatory cytokines, benzodiazepines and hyponatraemia integrates at the level of astrocyte swelling and oxidative stress. This explains why heterogenous clinical conditions can precipitate HE episodes. Oxidised RNA species, which are formed in response to oxidative stress, also participate in local postsynaptic protein synthesis in neurons, which is required for memory formation. Although the functional consequences of RNA oxidation in this context remain to be established, these findings bear a potential biochemical explanation for the multiple alterations of neurotransmitter receptor systems and of synaptic plasticity. Such changes may in part also underlie the pathologically altered oscillatory networks in the brain of HE patients in vivo, as detected by magnetencephalography. These disturbances of oscillatory networks, which in part are triggered by hypothalamic structures, can explain the motor and cognitive deficits in patients with HE. Current therapeutic strategies aim at the elimination of precipitating factors. The potential of therapies targeting downstream pathophysiological events in HE has not yet been explored, but offers novel potential sites of therapeutic intervention.
Hypertensive Vascular Disease Induced by Heterologous Renin
Authors: Georges M. C. Masson, Chujiro Kashii, Masato Matsunaga, Irvine H. Page
Journal: Circulation Research (1966)

Chronic treatment with crude hog, or rat, renin administered subcutaneously to uninephrectomized rats elicits hypertension, renal and vascular lesions, hypertrophy of the zona glomerulosa of the adrenals, and renin depletion in the remaining kidney. Semipurified hog renin given in equipressor doses also causes renin depletion and stimulation of the zona glomerulosa, but no hypertension nor vascular disease. However, semipurified hog renin becomes as effective as the crude preparation after addition of retarding substances such as gelatin, oil, or cholesterol. Thus, a prolonged and sustained resorption of renin seems to be a prerequisite for the development of hypertension. Since hypertension takes place only after a latent period during which arterial pressure remains within the normal range, it does not appear that hypertension can be attributed to the acute pressor effect of renin. It is proposed as a working hypothesis that renin, through angiotensin, initiates nervous mechanisms which are responsible for the development of benign hypertension and that the acute pressor effect of angiotensin is more specifically associated with the malignant phase of hypertension.
Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages.
Authors: Y J Geng, G K Hansson
Journal: Journal of Clinical Investigation (1992)

The scavenger receptor (ScR) mediates uptake of chemically modified low density lipoprotein (LDL) by human monocyte-derived macrophages. It is not down-regulated by high intracellular cholesterol levels, and exposure of macrophages to acetylated or oxidized LDL therefore leads to foam cell development. The hypothesis that this represents an important mechanism for intracellular cholesterol accumulation in atherosclerosis is supported by the finding of ScR expression in foam cells of atherosclerotic plaques. T lymphocytes are also present in such plaques and it is known that T cell products regulate macrophage activation. We have therefore studied the effect of interferon-gamma (IFN gamma), a lymphokine secreted by activated T lymphocytes, on the expression of ScR in human monocyte-derived macrophages. Binding and uptake of acetylated LDL were significantly reduced in macrophages exposed to recombinant IFN gamma or IFN gamma-containing lymphocyte-conditioned media. Competition experiments showed that the IFN gamma-regulated binding and uptake of acetylated LDL was mediated via ScR. IFN gamma exerted its effect on the saturable binding of acetylated LDL by reducing the number of cell surface binding sites without significantly affecting the affinity between acetylated LDL and its receptor. Northern analysis revealed that the type I ScR mRNA was significantly reduced in IFN gamma-treated cells. Finally, IFN gamma treatment reduced intracellular cholesteryl ester accumulation and inhibited the development of foam cells in the cultures. In conclusion, our data show that IFN gamma blocks the development of macrophage-derived foam cells by inhibiting expression of ScR. This suggests that macrophage-T lymphocyte interactions may reduce intracellular cholesterol accumulation in the atherosclerotic plaque.
Combination Photoimmunotherapy and Cisplatin: Effects on Human Ovarian Cancer Ex Vivo
Authors: L R Duska, M R Hamblin, J L Miller, T Hasan
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Patients with ovarian cancer that is clinically resistant to cisplatin-based chemotherapy have little hope of a cure of their disease. Photoimmunotherapy, which involves the antibody-targeted delivery of a nontoxic photosensitizer that is activated to a cytotoxic state with visible light, may offer a new treatment option. Photoimmunotherapy may be applied intraperitoneally to target disseminated tumor. We tested the hypothesis that this treatment in combination with cisplatin potentiates cytotoxicity in ovarian cancer cell lines and primary cultures of human tumors. METHODS: Five human cancer cell lines (ovarian and breast) and 19 primary cultures were studied. The primary cultures were from solid and ascites tumor samples obtained from 14 patients with ovarian cancer who were undergoing primary surgery. The photosensitizer chlorin e 6 was conjugated to the F(ab′) 2 fragment of the murine monoclonal antibody OC-125, which is directed against the antigen CA 125. Cytotoxicity was measured by the microculture tetrazolium assay. Treatments consisted of cisplatin alone, photoimmunotherapy alone, and photoimmunotherapy followed by cisplatin. The fractional product method was used to assess synergy in treatment effects. Ex vivo cultured human cells exhibiting 80% or greater survival at cisplatin concentrations of 10 μ M for 24 hours were defined as cisplatin resistant for this study. RESULTS: When all cell types (cisplatin sensitive and cisplatin resistant) were considered together, combination treatment yielded cytotoxicity that was, on average, 6.9 times (95% confidence interval = 1.86-11.94) greater than that of cisplatin alone (two-sided P = .023). Cisplatin-resistant cells showed a synergistic effect of the two treatments (two-sided P = .044), while cisplatin-sensitive cells showed an additive effect. CONCLUSION: These ex vivo data suggest that platinum resistance in human ovarian cancer cells may be reversible by pretreatment with OC-125-targeted photoimmunotherapy. Further studies are required to confirm the efficacy of this approach in vivo.