tbuckley/cabot-search huggingface dataset:
Deregulated Syk inhibits differentiation and induces growth factor–independent proliferation of pre–B cells
Authors: Thomas Wossning, Sebastian Herzog, Fabian Köhler, Sonja Meixlsperger, Yogesh Kulathu, Gerhard Mittler, Akihiro Abe, Uta Fuchs, Arndt Borkhardt, Hassan Jumaa
Journal: The Journal of Experimental Medicine (2006)

The nonreceptor protein spleen tyrosine kinase (Syk) is a key mediator of signal transduction in a variety of cell types, including B lymphocytes. We show that deregulated Syk activity allows growth factor–independent proliferation and transforms bone marrow–derived pre–B cells that are then able to induce leukemia in mice. Syk-transformed pre–B cells show a characteristic pattern of tyrosine phosphorylation, increased c-Myc expression, and defective differentiation. Treatment of Syk-transformed pre–B cells with a novel Syk-specific inhibitor (R406) reduces tyrosine phosphorylation and c-Myc expression. In addition, R406 treatment removes the developmental block and allows the differentiation of the Syk-transformed pre–B cells into immature B cells. Because R406 treatment also prevents the proliferation of c-Myc–transformed pre–B cells, our data indicate that endogenous Syk kinase activity may be required for the survival of pre–B cells transformed by other oncogenes. Collectively, our data suggest that Syk is a protooncogene involved in the transformation of lymphocytes, thus making Syk a potential target for the treatment of leukemia.
EFFECTS OF STRIKING STRATEGY ON LOWER EXTREMITY LOADING DURING RUNNING
Authors: Juha-Pekka Kulmala, Janne Avela, Kati Pasanen, Jari Parkkari
Journal: British Journal of Sports Medicine (2013)

Backround It is expected that every second runner has a running-related overuse injury each year. The knee joint and Achilles tendon are the most commonly injured sites covering both about one fifth of all running related injuries. 1 Runners can be categorized into rearfoot strikers, mid-foot strikers or forefoot strikers based on the landing strategy at the instant of initial ground contact. Forefoot or mid-foot striking has been shown to reduce impact peak and loading rate of the ground reaction force during early stance phase. 2 Furthermore, the finding of the recent study suggest that forefoot striking may potentially decrease the risk of running-related injuries. 3 However, the effect of runner's foot striking pattern on the ankle and especially on the knee loading is poorly understood. Therefore, the purpose of this study was to examine whether runners with forefoot striking exhibit different lower limb loading profile than runners who use rearfoot strike pattern. Methods Nineteen female athletes with natural forefoot strike pattern and pair-matched females with rearfoot strike pattern (n=19) performed running analysis at 4 m/s. Kinematic (300Hz) and kinetic (1500Hz) data was recorded using Vicon motion analysis system. Inverse dynamics was used to calculate knee and ankle moments during stance phase of running and biomechanical model was then utilized to estimate patellofemoral stress and Achilles tendon force. Results Forefoot strikers demonstrated lower patellofemoral stress compared to heel strikers (11.1±2.9 vs. 13.0±2.8 Mpa; P=0.04). In addition, the knee frontal plane moment was lower in the forefoot strikers compared heel strikers (1.49±0.51 vs. 1.97±0.66 Nm/kg; P=0.015). At the ankle level, forefoot strikers exhibited higher Achilles tendon force (6.3±0.8 vs. 5.1±1.3 BW; P=0.002) compared to rearfoot strikers. Discussion Forefoot strikers demonstrate lower patellofemoral stress and frontal plane moment compared to runners with rearfoot strike pattern. This suggests that runners with forefoot strike pattern may have reduced risk of running-related knee injuries. However, parallel increase in Achilles tendon loading may alter forefoot striker into higher risk of ankle and foot injuries.
From hepatitis to hepatocellular carcinoma: a proposed model for cross-talk between inflammation and epigenetic mechanisms
Authors: Marion Martin, Zdenko Herceg
Journal: Genome Medicine (2012)

Inflammation represents the body's natural response to tissue damage; however, chronic inflammation may activate cell proliferation and induce deregulation of cell death in affected tissues. Chronic inflammation is an important factor in the development of hepatocellular carcinoma (HCC), although the precise underlying mechanism remains unknown. Epigenetic events, which are considered key mechanisms in the regulation of gene activity states, are also commonly deregulated in HCC. Here, we review the evidence that chronic inflammation might deregulate epigenetic processes, thus promoting oncogenic transformation, and we propose a working hypothesis that epigenetic deregulation is an underlying mechanism by which inflammation might promote HCC development. In this scenario, different components of the inflammatory response might directly and indirectly induce changes in epigenetic machineries ('epigenetic switch'), including those involved in setting and propagating normal patterns of DNA methylation, histone modifications and non-coding RNAs in hepatocytes. We discuss the possibility that self-reinforcing cross-talk between inflammation and epigenetic mechanisms might amplify inflammatory signals and maintain a chronic state of inflammation culminating in cancer development. The potential role of inflammation-epigenome interactions in the emergence and maintenance of cancer stem cells is also discussed.
Dedifferentiated Liposarcoma With Unusual Kaposiform Morphology and Whorl Formation Masquerading As Kaposi's Sarcoma: Diagnostically Challenging Case Confirmed by Cytogenetic and <i>TP53</i> Mutation Analysis
Authors: Manish Mani Subramaniam, Jason Yongsheng Chan, Pay-Chin Leow, Kotamma Venkateswaran, Saminathan Suresh Nathan, Richie Soong, Victor Kwan Min Lee
Journal: Journal of Clinical Oncology (2013)
Toll-Like Receptor-7 Modulates Immune Complex Glomerulonephritis
Authors: Rahul D. Pawar, Prashant S. Patole, Daniel Zecher, Stephan Segerer, Matthias Kretzler, Detlef Schlöndorff, Hans-Joachim Anders
Journal: Journal of the American Society of Nephrology (2005)

Viral infections may trigger immune complex glomerulonephritis via Toll-like receptors (TLR), as certain TLR trigger immunity upon recognition of viral nucleic acids. On the basis of previous findings regarding viral double-stranded RNA and TLR3 in experimental lupus erythematosus, a similar role for TLR7 that recognizes viral single-stranded RNA was hypothesized. Immunostaining of kidney sections of nephritic MRLlpr/lpr mice revealed TLR7 expression in infiltrating ER-HR3-positive macrophages and few CD11c-positive dendritic cells but not in glomerular mesangial cells as observed for TLR3. This finding was consistent with the distribution pattern of intravenously injected single-stranded RNA in nephritic MRLlpr/lpr mice. TLR7 ligation activated monocytes and dendritic cells, both isolated from MRLlpr/lpr mice, to secrete IFN-alpha, IL-12p70, IL-6, and CCL2. In vivo, a single injection of the TLR7 ligand imiquimod increased serum levels of IL-12p70, IFN-alpha, and IL-6. A course of 25 microg of imiquimod given every other day from week 16 to 18 of age aggravated lupus nephritis in MRLlpr/lpr mice. This was associated with increased glomerular immune complex deposits as well as interstitial expression of CCL2 in imiquimod-treated MRLlpr/lpr mice. Different types of viral nucleic acids seem to modulate systemic autoimmunity through specific interactions with their respective TLR. Different TLR expression profiles on immune cell subsets and nonimmune parenchymal cell types determine the molecular mechanisms involved in viral infection-associated exacerbation of lupus nephritis and possibly other types of immune complex glomerulonephritis.
Pharmacologic Modulation of Glycogen Synthase Kinase-3β Promotes p53-Dependent Apoptosis through a Direct Bax-Mediated Mitochondrial Pathway in Colorectal Cancer Cells
Authors: Jing Tan, Li Zhuang, Hui-Sun Leong, N. Gopalakrishna Iyer, Edison T. Liu, Qiang Yu
Journal: Cancer Research (2005)

Abstract Activation of p53 tumor suppressor induces either cell cycle arrest or apoptosis through transcription-dependent and independent pathways; however, their relative roles in apoptosis induction and how these pathways are regulated remains elusive. Here, we report a unique role for glycogen synthesis kinase-3β (GSK-3β) in regulating p53 functions in human colorectal cancer cells. Pharmacologic modulation of GSK-3β markedly impaired p53-dependent transactivation of targets including p21 and Puma but promoted p53-dependent conformational activation of Bax, resulting in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 processing. Thus, p53-mediated damage response is converted from cell cycle arrest to apoptosis following exposure to a variety of chemotherapeutic agents. We found that this effect is associated with the modulation of inhibitory Ser9 phosphorylation of GSK-3β but not with the activating tyrosine phosphorylation. We further show that the induction of apoptosis is through a direct mitochondrial pathway that requires Bax but not Puma. Our results underscore the importance of transcription-independent mechanism in p53-induced apoptosis and indicate that GSK-3β plays distinct dual roles in regulating p53 pathways: promoting p53 transcriptional activity in the nucleus but suppressing p53-mediated direct apoptotic function at the mitochondria. Importantly, our data suggest that small-molecule inhibition of GSK-3β might represent a novel approach for modulating chemotherapy.
Optimization of Radioimmunotherapy of Solid Tumors: Biological Impediments and Their Modulation
Authors: Maneesh Jain, Ganesh Venkatraman, Surinder K. Batra
Journal: Clinical Cancer Research (2007)

In contrast to the overwhelming success of radiolabeled antibodies in treating hematologic malignancies, only modest success has been achieved in the radioimmunotherapy of solid tumors. One of the major limitations in successful application of radioimmunotherapy is the large molecular size of the intact immunoglobulin that results in prolonged serum half-life and poor tumor penetration and uptake. With the advent of antibody engineering, small molecular weight antibody fragments exhibiting improved pharmacokinetics and tumor penetration have been generated. However, their clinical application has been limited by suboptimal tumor uptake and short tumor residence time. There is a greater realization that optimization of the molecular size of the antibodies alone is not sufficient for clinical success of radioimmunotherapy. In addition to their size, radiolabeled antibodies encounter other impediments before reaching their target antigens expressed on the cell surface of solid tumors. Some of the barriers include poor blood flow in large tumors, permeability of vascular endothelium, elevated interstitial fluid pressure of tumor stroma, and heterogeneous antigen expression. Recent research has considerably improved our understanding and appreciation of these forces, and the new wave of optimization strategies involves the use of biological modifiers to modulate the impediments posed by solid tumors. In combination with radiolabeled antibodies, various agents are being used to improve the tumor blood flow, enhance vascular permeability, lower tumor interstitial fluid pressure by modulating stromal cells and extracellular matrix components, up-regulate the expression of target antigens, and improve the penetration and retention of the radiopharmaceuticals. This review outlines ongoing research efforts involving biological modifiers to optimize the uptake and efficacy of radiolabeled antibodies for the treatment of solid tumors.
No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia.
Authors: C Stein, M Pflüger, A Yassouridis, J Hoelzl, K Lehrberger, C Welte, A H Hassan
Journal: Journal of Clinical Investigation (1996)

Pain treatment with centrally acting opiates is limited by tolerance. Tolerance is a decreasing effect of a drug with prolonged administration of that drug or of a related (e.g., endogenous) compound acting at the same receptor. This is often associated with a downregulation of receptors. In peripheral inflamed tissue, both locally expressed opioid peptides and morphine can produce powerful analgesia mediated by similar populations of opioid receptors. We hypothesized that the chronic presence of endogenous opioids in inflamed joints might convey downregulation of peripheral opioid receptors and tolerance to the analgesic effects of intraarticular morphine. We assessed these effects after arthroscopic surgery in patients with and without histologically verified synovial cellular infiltration, and we examined synovial opioid peptides and opioid receptors by immunocytochemistry and autoradiography, respectively. We found that, despite an abundance of opioid-containing cells in pronounced synovitis, morphine is at least as effective as in patients without such cellular infiltrations, and there is no major downregulation of peripheral opioid receptors. Thus, opioids expressed in inflamed tissue do not produce tolerance to peripheral morphine analgesia. Tolerance may be less pronounced for peripherally than for centrally acting opioids, which provides a promising perspective for the treatment of chronic pain in arthritis and other inflammatory conditions.
Smoking and diabetes.
Authors: D Haire-Joshu, R E Glasgow, T L Tibbs
Journal: Diabetes Care (1999)

The objective of this review is to summarize the literature on diabetes and smoking related to epidemiological risks, efficacy and cost-effectiveness of different cessation approaches, and implications for clinical practice. Over 200 studies were reviewed, with special emphasis placed on publications within the past 10 years. Intervention studies that included patients with diabetes but did not report results separately by disease are included. Diabetes-specific studies are highlighted. There are consistent results from both cross-sectional and prospective studies showing enhanced risk for micro- and macrovascular disease, as well as premature mortality from the combination of smoking and diabetes. The general cessation literature is extensive, generally well-designed, and encouraging regarding the impact of cost-effective practical office-based interventions. In particular, system-based approaches that make smoking a routine part of office contacts and provide multiple prompts, advice, assistance, and follow-up support are effective. Although there is minimal information on the effectiveness of cessation interventions specifically for people with diabetes, there is no reason to assume that cessation intervention would be more or less effective in this population. There is a clear need to increase the frequency of smoking cessation advice and counseling for patients with diabetes given the strong and consistent data on smoking prevalence; combined risks of smoking and diabetes for morbidity, mortality, and several complications; and the proven efficacy and cost-effectiveness of cessation strategies.
Case-Mix Adjustment for an Expanded Renal Prospective Payment System
Authors: Richard A. Hirth, Marc N. Turenne, John R.C. Wheeler, Alyssa S. Pozniak, Philip Tedeschi, Chien-Chia Chuang, Qing Pan, Kathryn Slish, Joseph M. Messana
Journal: Journal of the American Society of Nephrology (2007)

Medicare is considering an expansion of the bundle of dialysis-related services to be paid on a prospective basis. Exploratory models were developed to assess the potential limitations of case-mix adjustment for such an expansion. A broad set of patient characteristics explained 11.8% of the variation in Medicare allowable charges per dialysis session. Although adding recent hematocrit values or prior health care utilization to the model did increase explanatory power, it could also create adverse incentives. Projected gains or losses relative to prevailing fee-for-service payments, assuming no change in practice patterns, were significant for some individual providers. However, systematic gains or losses for different classes of providers were modest.
AZD2171: A Highly Potent, Orally Bioavailable, Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for the Treatment of Cancer
Authors: Stephen R. Wedge, Jane Kendrew, Laurent F. Hennequin, Paula J. Valentine, Simon T. Barry, Sandra R. Brave, Neil R. Smith, Neil H. James, Michael Dukes, Jon O. Curwen, Rosemary Chester, Janet A. Jackson, Sarah J. Boffey, Lyndsey L. Kilburn, Sharon Barnett, Graham H.P. Richmond, Peter F. Wadsworth, Mike Walker, Alison L. Bigley, Sian T. Taylor, Lee Cooper, Sarah Beck, Juliane M. Jürgensmeier, Donald J. Ogilvie
Journal: Cancer Research (2005)

Abstract Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a promising therapeutic approach that aims to stabilize the progression of solid malignancies by abrogating tumor-induced angiogenesis. This may be accomplished by inhibiting the kinase activity of VEGF receptor-2 (KDR), which has a key role in mediating VEGF-induced responses. The novel indole-ether quinazoline AZD2171 is a highly potent (IC50 &amp;lt; 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro. Concordant with this activity, in human umbilical vein endothelial cells, AZD2171 inhibited VEGF-stimulated proliferation and KDR phosphorylation with IC50 values of 0.4 and 0.5 nmol/L, respectively. In a fibroblast/endothelial cell coculture model of vessel sprouting, AZD2171 also reduced vessel area, length, and branching at subnanomolar concentrations. Once-daily oral administration of AZD2171 ablated experimental (VEGF-induced) angiogenesis in vivo and inhibited endochondral ossification in bone or corpora luteal development in ovary; physiologic processes that are highly dependent upon neovascularization. The growth of established human tumor xenografts (colon, lung, prostate, breast, and ovary) in athymic mice was inhibited dose-dependently by AZD2171, with chronic administration of 1.5 mg per kg per day producing statistically significant inhibition in all models. A histologic analysis of Calu-6 lung tumors treated with AZD2171 revealed a reduction in microvessel density within 52 hours that became progressively greater with the duration of treatment. These changes are indicative of vascular regression within tumors. Collectively, the data obtained with AZD2171 are consistent with potent inhibition of VEGF signaling, angiogenesis, neovascular survival, and tumor growth. AZD2171 is being developed clinically as a once-daily oral therapy for the treatment of cancer.
Cross-Presentation of Glycoprotein 96–Associated Antigens on Major Histocompatibility Complex Class I Molecules Requires Receptor-Mediated Endocytosis
Authors: Harpreet Singh-Jasuja, René E.M. Toes, Pieter Spee, Christian Münz, Norbert Hilf, Stephen P. Schoenberger, Paola Ricciardi-Castagnoli, Jacques Neefjes, Hans-Georg Rammensee, Danièle Arnold-Schild, Hansjörg Schild
Journal: The Journal of Experimental Medicine (1999)

Heat shock proteins (HSPs) like glycoprotein (gp)96 (glucose-regulated protein 94 [grp94]) are able to induce specific cytotoxic T lymphocyte (CTL) responses against cells from which they originate. Here, we demonstrate that for CTL activation by gp96-chaperoned peptides, specific receptor-mediated uptake of gp96 by antigen-presenting cells (APCs) is required. Moreover, we show that in both humans and mice, only professional APCs like dendritic cells (DCs), macrophages, and B cells, but not T cells, are able to bind gp96. The binding is saturable and can be inhibited using unlabeled gp96 molecules. Receptor binding by APCs leads to a rapid internalization of gp96, which colocalizes with endocytosed major histocompatibility complex (MHC) class I and class II molecules in endosomal compartments. Incubation of gp96 molecules isolated from cells expressing an adenovirus type 5 E1B epitope with the DC line D1 results in the activation of E1B-specific CTLs. This CTL activation can be specifically inhibited by the addition of irrelevant gp96 molecules not associated with E1B peptides. Our results demonstrate that only receptor-mediated endocytosis of gp96 molecules leads to MHC class I–restricted re-presentation of gp96-associated peptides and CTL activation; non–receptor-mediated, nonspecific endocytosis is not able to do so. Thus, we provide evidence on the mechanisms by which gp96 is participating in the cross-presentation of antigens from cellular origin.
Safety of Coronary Sirolimus-Eluting Stents in Daily Clinical Practice
Authors: Philip Urban, Anthony H. Gershlick, Giulio Guagliumi, Philippe Guyon, Chaim Lotan, Joachim Schofer, Ashok Seth, J. Eduardo Sousa, William Wijns, Claude Berge, Monika Deme, Hans-Peter Stoll
Journal: Circulation (2006)

The expanding indications for sirolimus-eluting stents (SES) include increasingly complex coronary lesions and populations with clinical profiles markedly different from those of early pivotal controlled studies. The e-Cypher registry monitored the safety and efficacy of SES currently implanted worldwide in daily practice.Between April 2002 and September 2005, data were collected on 15,157 patients who underwent implantation of > or =1 SES at 279 medical centers from 41 countries. An independent endpoint review committee adjudicated all reported major adverse cardiovascular events, stent thromboses, and target-vessel revascularizations. Data were managed and analyzed by independent organizations. Predictors of adverse clinical events were identified by regression analysis. The mean age of the sample was 61.7+/-11.4 years; 77.7% were men, and 28.6% were diabetics. A total of 18,295 lesions were treated (20,503 SES) during the index procedure. The cumulative rates of major adverse cardiovascular events were 1.36% at 30 days, 3.38% at 6 months, and 5.80% at 1 year. The rates of acute, subacute, and late stent thrombosis were 0.13%, 0.56%, and 0.19% of patients, respectively, representing a 12-month actuarial incidence of 0.87%. Insulin-dependent diabetes, acute coronary syndrome at presentation, and advanced age were clinical predictors, whereas TIMI flow grade <3 after the index procedure, treatment of multiple lesions, a prominently calcified or totally occluded target lesion, and multivessel disease were the angiographic or procedural predictors of stent thrombosis at 12 months.This analysis of 1-year data collected by the e-Cypher registry suggests a high degree of safety of SES, with a rate of stent thrombosis similar to that observed in randomized trials.
Hypouricaemia and increased renal urate clearance associated with hyperparathyroidism.
Authors: T Gibson, H P Sims, S A Jimenez
Journal: Annals of the Rheumatic Diseases (1976)

A 64-year-old female was found to have hypouricaemia, with serum uric acid ranging from 0.06-0.12 mmol/l (1.1-2.0 mg/100 ml), associated with an increased urate clearance of 48.9 ml/min and hyperparathyroidism. Known causes of increased uric acid clearance were excluded. Pyrazinamide reduced urate clearance dramatically to 2.1 ml/min, suggesting that the tubular defect was either one of increased secretion or a failure of postsecretory reabsorption. No other tubular abnormality was apparent except diminished urine concentrating ability. Hypouricaemia has not been previously reported in association with hyperparathyroidism and a mechanism relating the two disorders could not be readily postulated. The tubular defect shown in this instance resembled that reported in association with Wilson9s disease and Hodgkin9s disease. This case and earlier reports of isolated tubular defects of uric acid handling enhance our understanding of uric acid excretion.
Does genetic regulation of IgE begin in utero? Evidence from TH1/TH2 gene polymorphisms and cord blood total IgE
Authors: Xiumei Hong, Hui-Ju Tsai, Xin Liu, Lester Arguelles, Rajesh Kumar, Guoying Wang, Nataliya Kuptsova-Clarkson, Colleen Pearson, Kathryn Ortiz, Anthony Bonzagni, Stephanie Apollon, Lingling Fu, Jacqueline A. Pongracic, Robert Schleimer, Patrick G. Holt, Howard Bauchner, Xiaobin Wang
Journal: Journal of Allergy and Clinical Immunology (2010)