tbuckley/cabot-search huggingface dataset:
Detection of Low Molecular Weight Derivatives of Cyclin E1 Is a Function of Cyclin E1 Protein Levels in Breast Cancer
Authors: Charles Spruck, Dahui Sun, Heidi Fiegl, Christian Marth, Elisabeth Mueller-Holzner, Georg Goebel, Martin Widschwendter, Steven I. Reed
Journal: Cancer Research (2006)

Abstract Cyclin E1 regulates the initiation of the S phase program in the mammalian cell division cycle. In normal cells, cyclin E1 protein expression is tightly controlled through a combination of transcriptional and proteolytic regulatory processes. However, in many types of human tumor, cyclin E1 expression is frequently dysregulated, including overexpression, nonperiodic expression relative to cell division, and generation of low molecular weight (LMW) derivatives. LMW derivatives of cyclin E1 have been proposed to be generated by the in vivo proteolytic cleavage of the full-length cyclin E1 protein by a yet to be identified tumor-specific protease. Recently, it was suggested that overexpression of full-length or LMW derivatives of cyclin E1 are independent variables associated with poor outcome in patients with breast cancer. However, we have extensively analyzed cyclin E1 protein expression in primary breast tumors and breast tumor-derived cell lines and found that the ability to detect LMW derivatives of cyclin E1 correlates only with the level of cyclin E1 protein. When cyclin E1 levels on Western blots are normalized, LMW derivatives of cyclin E1 were observed at roughly equal levels in all primary breast tumors, breast tumor-derived cell lines, immortalized nontransformed human mammary epithelial cells, and normal breast tissue. Therefore, the detection of LMW derivatives of cyclin E1 is likely a function of cyclin E1 protein levels, and the activity of the proteolytic machinery responsible for their generation is not a tumor-specific property. (Cancer Res 2006; 66(14): 7355-60)
High density lipoprotein cholesterol is not a major risk factor for ischaemic heart disease in British men.
Authors: S J Pocock, A G Shaper, A N Phillips, M Walker, T P Whitehead
Journal: BMJ (1986)

The concentration of high density lipoprotein cholesterol (HDL cholesterol) in serum was measured at initial examination in a large prospective study of men aged 40-59 drawn from general practices in 24 British towns. After an average follow up of 4.2 years 193 cases of major ischaemic heart disease had been registered in 7415 men in whom both HDL cholesterol and total cholesterol values had been measured. The mean HDL cholesterol concentration was lower in the men with ischaemic heart disease ("cases") compared with other men, but the difference became small and non-significant after adjustment for age, body mass index, blood pressure, cigarette smoking, and concentration of non-HDL cholesterol. The higher mean concentration of non-HDL cholesterol in "cases" remained highly significant after adjustment for other factors. Men in the highest fifth of non-HDL cholesterol values had over three times the risk of major ischaemic heart disease compared with men in the lowest fifth. Multivariate analysis showed that non-HDL cholesterol was a more powerful predictor of risk than the HDL to total cholesterol ratio. These British findings were compared with six other prospective studies. All the larger studies showed similar results, suggesting that HDL cholesterol is not a major risk factor in the aetiology of ischaemic heart disease.
Inverse Association between Raf Kinase Inhibitory Protein and Signal Transducers and Activators of Transcription 3 Expression in Gastric Adenocarcinoma Patients: Implications for Clinical Outcome
Authors: Devasis Chatterjee, Edmond Sabo, Rosemarie Tavares, Murray B. Resnick
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Raf Kinase Inhibitory Protein (RKIP) plays a pivotal role in cancer by regulating apoptosis induced by chemotherapeutic agents, or immune-mediated stimuli and is a metastasis suppressor protein. The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is frequently activated in gastric adenocarcinomas, thereby promoting tumor growth. We examined the expression patterns of RKIP and STAT3 with regard to human gastric cancer, predicting that elevated RKIP status may favor clinical outcome. Experimental Design: Tissue microarrays were created from samples from 143 patients with gastric adenocarcinomas. The microarrays were immunohistochemically stained for RKIP and STAT3, and the intensity and extent of the staining was semiquantitatively scored. Results: In intestinal-type gastric adenocarcinomas, RKIP and STAT3, expression were inversely associated. Cytoplasmic RKIP expression directly correlated with patient survival. Nuclear STAT3 expression inversely correlated with survival. In the diffuse tumor type, no significant correlation was found between RKIP and patient outcome. In the intestinal-type gastric adenocarcinoma, multivariate analysis adjusted for treatment types revealed RKIP and tumor stage to be significant independent predictors of survival. In the diffuse tumor type, stage was the only significant predictor of survival. Conclusion: These results indicate the predictive and protective role of cytoplasmic RKIP expression in gastric adenocarcinoma of the intestinal subtype. In contrast, nuclear STAT3 expression is associated with poor patient prognosis in the intestinal subtype. Significantly, we show an inverse association between RKIP and STAT3 and a positive correlation between RKIP and patient survival.
Thrombogenic potential of human coronary atherosclerotic plaques
Authors: Diego Ardissino, Piera Angelica Merlini, Kenneth A. Bauer, Ezio Bramucci, Maurizio Ferrario, Raffaella Coppola, Raffaela Fetiveau, Stefano Lucreziotti, Robert D. Rosenberg, Pier Mannuccio Mannucci
Journal: Blood (2001)
Diagnosis of airway obstruction: A comparison between the GLI 2012 reference equations, the NHANES III reference equations and the fixed cut-off for FEV1/FVC
Authors: Barbara Chomé, Jan Vandevoorde
Journal: European Respiratory Journal (2013)

Objectives  To assess the agreement between three recommended definitions of airflow obstruction,  Methodology  A large existing dataset of spirometric examinations from previous studies was used. Considering the lower limits of normal (LLN) according to the Global Lungs Initiative (GLI) 2012 equations as a gold standard for the diagnosis of obstruction, sensitivity, specificity, positive and negative predictive values were calculated for the LLN according to NHANES III equations, and the fixed cut-off FEV 1 /FVC   Results  Spirometric data from 11,676 Caucasian subjects aged ≥ 20 yrs were studied (60% men).  For the fixed cut-off point relative to the GLI 2012 LLN, sensitivity, specificity, PPV and NPV were 96%, 86%, 81% and 97%, respectively. There was a substantial rate of false positive diagnoses, increasing with age.  For the NHANES III LLN compared to the GLI 2012 LLN, sensitivity, specificity, PPV and NPV were 99%, 98%, 97% and 99%, respectively. There were very few discordant cases.  Analysis of the discordant cases using the fixed cut-off point showed a mean difference of FEV 1 /FVC with the GLI 2012 LLN of 4,2% in the 1030 false-positive cases. In the 192 false-negative cases, the mean difference was – 1,9%. When using the NHANES III LLN, discordant cases were very close to their LLN.  Conclusions  This study showed very good agreement between the GLI 2012 and NHANES III reference equations for the diagnosis of airway obstruction. Using a fixed cutoff for FEV 1 /FVC resulted in a substantial overdiagnosis of obstruction, increasing with age.
Fibrosis and diseases of the eye
Authors: Martin Friedlander
Journal: Journal of Clinical Investigation (2007)

Most diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis and wound healing, often in response to tissue ischemia or inflammation. Disruption of the highly ordered tissue architecture in the eye caused by vascular leakage, hemorrhage, and concomitant fibrosis can lead to mechanical disruption of the visual axis and/or biological malfunctioning. An increased understanding of inflammation, wound healing, and angiogenesis has led to the development of drugs effective in modulating these biological processes and, in certain circumstances, the preservation of vision. Unfortunately, such pharmacological interventions often are too little, too late, and progression of vision loss frequently occurs. The recent development of progenitor and/or stem cell technologies holds promise for the treatment of currently incurable ocular diseases.
History of treated hypertension and diabetes mellitus and risk of renal cell cancer
Authors: A. Zucchetto, L. Dal Maso, A. Tavani, M. Montella, V. Ramazzotti, R. Talamini, V. Canzonieri, A. Garbeglio, E. Negri, S. Franceschi, C. La Vecchia
Journal: Annals of Oncology (2006)

An increased risk of renal cell cancer (RCC) has been reported in subjects with hypertension. Whether this association may vary according to sex, smoking, obesity, or RCC clinical presentation is unclear. Results on the link between diabetes mellitus and RCC are inconclusive.We conducted an Italian multicenter case-control study, including 767 (494 men, 273 women) incident cases of RCC, under 80 years of age, and 1534 hospital controls, frequency-matched to cases. Multiple logistic regression models, conditioned to center, sex, and age, and adjusted for period of interview, education, smoking, and body mass were used to estimate odds ratios (OR).Compared with subjects never treated, patients with a history of treated hypertension [OR = 1.7, 95% confidence interval (CI) 1.4-2.1] reported an excess risk of RCC. This pattern was confirmed in different strata of sex, education, smoking habits, body mass, tumor histological type, stage, or grade. The attributable risk of RCC for treated hypertension in this population was 16%. A slight, nonsignificant increased risk was found for history of diabetes mellitus (OR = 1.3, 95% CI 0.9-1.7).A possible causal role of hypertension in renal cell carcinogenesis is supported by the consistency of the direct association.
Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective open-label pilot study in five patients
Authors: M.S.Y. Goh, C. McCormack, H.V. Dinh, B. Welsh, P. Foley, H.M. Prince
Journal: British Journal of Dermatology (2007)

Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B lymphocytes. There are reports of its efficacy in the treatment of autoimmune diseases, including pemphigus.Prospectively to evaluate the efficacy of rituximab as adjuvant treatment for pemphigus vulgaris (PV).Patients with PV were treated with intravenous rituximab (375 mg m(-2)) weekly for 4 weeks in this prospective open-label pilot study. Other concurrent immunosuppression was continued.Of five patients, one achieved complete remission and was able to cease all medication, while two achieved clearance of clinical lesions but continued on systemic therapy. Two patients had progressive disease. Time to response was 2-8 months, with a 13- to 18-month response duration. Response was associated with reduction in serum antiepithelial antibodies. Two patients had significant infectious complications (one developed community-acquired pneumonia associated with delayed-onset neutropenia and the other developed cytomegalovirus infection).Rituximab has shown efficacy in the treatment of PV. Patients on multiple immunosuppressives should be closely monitored for infectious complications.
Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity
Authors: Vsevolod Y. Polotsky, Susheel P. Patil, Vladimir Savransky, Alison Laffan, Shannon Fonti, Leigh A. Frame, Kimberly E. Steele, Michael A. Schweizter, Jeanne M. Clark, Michael S. Torbenson, Alan R. Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Obstructive sleep apnea is associated with insulin resistance and liver injury. It is unknown whether apnea contributes to insulin resistance and steatohepatitis in severe obesity.To examine whether sleep apnea and nocturnal hypoxemia predict the severity of insulin resistance, systemic inflammation, and steatohepatitis in severely obese individuals presenting for bariatric surgery.We performed sleep studies and measured fasting blood glucose, serum insulin, C-reactive protein, and liver enzymes in 90 consecutive severely obese individuals, 75 women and 15 men, without concomitant diabetes mellitus or preexistent diagnosis of sleep apnea or liver disease. Liver biopsies (n = 20) were obtained during bariatric surgery.Obstructive sleep apnea with a respiratory disturbance index greater than 5 events/hour was diagnosed in 81.1% of patients. The median respiratory disturbance index was 15 +/- 29 events/hour and the median oxygen desaturation during apneic events was 4.6 +/- 1.8%. All patients exhibited high serum levels of C-reactive protein, regardless of the severity of apnea, whereas liver enzymes were normal. Oxygen desaturation greater than 4.6% was associated with a 1.5-fold increase in insulin resistance, according to the homeostasis model assessment index. Histopathology data suggested that significant nocturnal desaturation might predispose to hepatic inflammation, hepatocyte ballooning, and liver fibrosis. Fasting blood glucose levels and steatosis scores were not affected by nocturnal hypoxia. There was no relationship between the respiratory disturbance index and insulin resistance or liver histopathology.Hypoxic stress of sleep apnea may be implicated in the development of insulin resistance and steatohepatitis in severe obesity.
P117 3D cryo-electron microscopic analysis of the disease mechanism of 1-antitrypsin deficiency
Authors: B. Gooptu, Y. Chaban, J. A. Irving, D. K. Clare, D. A. Lomas, E. Orlova, H. R. Saibil
Journal: Thorax (2011)

α<sub>1</sub>-antitrypsin deficiency is characterised by predispositions to liver disease and severe, early-onset emphysema. It is caused by point mutations that destabilise the molecular structure of α<sub>1</sub>-antitrypsin, leading it to self-associate into chains known as polymers. Polymerisation abolishes the antiprotease activity of α<sub>1</sub>-antitrypsin and causes circulating deficiency of the protein. These loss-of-function effects result in dysregulated elastase activity within the lung parenchyma. In addition, polymerisation has pro-inflammatory gain-of-function effects that must be mediated through the structural characteristics of the polymer itself. It is therefore important to understand the structure of the α<sub>1</sub>-antitrypsin polymer to identify targets for drug design. We have used cryo-electron microscopy, single particle reconstruction techniques to study α<sub>1</sub>-antitrypsin polymers. Analysis of the 3D arrangement of α<sub>1</sub>-antitrypsin molecules within the directly observed polymer chain allows us to evaluate current competing models of polymer assembly.
Stem cells for repair of cartilage and bone: the next challenge in osteoarthritis and rheumatoid arthritis
Authors: C Jorgensen
Journal: Annals of the Rheumatic Diseases (2001)

Over the last few years, immunotherapy targeting proinflammatory cytokines has been the main goal of research into rheumatoid arthritis (RA), and recently the new anti-(tumour necrosis factor) blocking agents have dramatically improved the course of the disease by stabilising the symptoms.1 However, this treatment has no effect on regeneration of articular cartilage damaged during the inflammatory process. The next challenge is thus to ensure cartilage repair through cell therapy and tissue engineering (fig 1). Tissue in the body is replaced by two main mechanisms. One is self repair by fully differentiated cells (healing), and the second is replacement with newly differentiated cells derived from stem cells. Recently, the regenerative potential of mesenchymal stem cells (MSCs) has been under intense investigation because of their ability for self renewal and differentiation to reconstitute muscle, cartilage, or bone.2



Figure 1 
Different strategies for cartilage repair.



Articular cartilage is a complex tissue consisting of cartilage matrix and the chondrocytes that have produced the matrix during development. The matrix is composed of collagens and proteoglycan aggregates (aggrecan) which provide the architectural structure and biomechanical strength of the tissue. During RA pathogenesis, proinflammatory cytokines present in the rheumatoid synovial fluid activate metalloproteinase (MMP) secretion by chondrocytes and increase pericellular matrix degradation of these cells. Some of them (interleukin 1β and 6 (IL1β and IL6)) even display the synergistic ability to decrease aggregan chondral synthesis and hyaluronan/aggregan ratio in the extracellular matrix.3 4 However, proteoglycan depletion may be partially inhibited by IL1 receptor antagonist.5 Cartilage and bone degeneration in RA is also the result of the action of MMPs secreted into the synovial fluid by the synoviocytes. MMPs constitute a family of 18 endopeptidases, the secretion of which is stimulated by cytokines of the IL6 family (IL11, IL6, oncostatin M) through a protein called the …
End Point Assessment in Gliomas: Novel Treatments Limit Usefulness of Classical Macdonald's Criteria
Authors: Martin J. van den Bent, Michael A. Vogelbaum, Patrick Y. Wen, David R. Macdonald, Susan M. Chang
Journal: Journal of Clinical Oncology (2009)

Recent trials in glioma have revealed significant limitations in the end points used. This requires a critical and comprehensive review of how brain tumor trials are conducted, particularly of which end points are defined and how response and progression are defined.
RESULTS OBTAINED BY THE INJECTION OF PLACENTA INTO ANIMALS OF THE SAME AND OF DIFFERENT SPECIES
Authors: Robert T. Frank
Journal: The Journal of Experimental Medicine (1907)

The injection of rabbits' placenta into rabbits produces no isoprecipitins. From the incomplete experiments performed it would appear that placental injections into animals of the same species cause no changes in the generative organs. Further research into this question will be pursued. The injection of human placental nucleo-proteid, prepared from placental tissue made nearly blood free, does not produce an antiserum. This result confirms the conclusions of Pearce and Jackson, that nucleo-proteids act merely as mild toxic agents, without specific qualities. The injection, into rabbits, of human placental tissue, rendered practically blood-free, fails to produce any specific reaction. This confirms the view that the serum reaction following the injection of cells into a foreign organism is largely due to the blood contained in the injected tissues. The injection into rabbits, of the human placenta, made nearly blood-free, produces a weak " human reaction " which can be demonstrated by the reactions for precipitin, deflection of complement, agglutinin, and hemolysis. No specific placental reaction can be shown. This is in strict accord with the view that cytotoxines are not specific; that there is no morphological specificity. The anti-sera obtained showed no cytolytic action; therefore no specific syncytiolytic action could be demonstrated. If the information obtained in this investigation is applied to the theory of Halban, it will be noted that no experimental proof of the specific action of placental tissue upon the female generative organs could be demonstrated. The number of experiments performed, bearing upon this one point, were however too few to permit of a definite and final opinion. The work dealing with Veit's ingenious hypothesis was more complete and carried out by many methods, which would necessarily act as a check upon one another. As the results of all these experiments were in complete harmony, I feel justified in making a positive statement that no experimental proof of a specific placental immune reaction can be demonstrated by our present biological methods. Whether Veit's hypothesis, thus deprived of its biological proof, must in consequence be discarded, is a question which I do not consider myself competent to answer.
Steely Eyes and Pain
Authors: E. L. Cohen
Journal: BMJ (1960)

<h3>ABSTRACT</h3> FOXO transcription factors have been shown to regulate longevity in model organisms and are associated with longevity in humans. To gain insight into how FOXO functions to increase lifespan, we examined the subcellular localization of DAF-16 in <i>C. elegans.</i> We show that DAF-16 is localized to endosomes and that this endosomal localization is increased by the insulin-IGF signaling (IIS) pathway. Endosomal localization of DAF-16 is also increased by disrupting the Rab GTPase activating protein TBC-2, or decreased by inhibiting the RAB-5 or RAB-7 GTPases, key regulators of early to late endosome maturation. Importantly, the amount of DAF-16 that is localized to endosomes has functional consequences as increasing endosomal localization through mutations in <i>tbc-2</i> decreased the lifespan of long-lived <i>daf-2 IGFR</i> mutants, depleted their fat stores, and DAF-16 target gene expression. Finally, we show that the ability of TBC-2 proteins, TBC1D2 and TBC1D2B, to regulate FOXO protein localization is conserved in human cells. Overall, this work identifies endosomal localization as a mechanism regulating FOXO/DAF-16, which is important for its functions in metabolism and aging.
Immunotherapy of Metastatic Melanoma Using Genetically Engineered GD2-Specific T cells
Authors: Eric Yvon, Michele Del Vecchio, Barbara Savoldo, Valentina Hoyos, Aurélie Dutour, Andrea Anichini, Gianpietro Dotti, Malcolm K. Brenner
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Genetic engineering of human T lymphocytes to express tumor-directed chimeric antigen receptors (CAR) can produce antitumor effector cells that bypass tumor immune escape mechanisms that are due to abnormalities in protein-antigen processing and presentation. Moreover, these transgenic receptors can be directed to tumor-associated antigens that are not protein-derived, such as the ganglioside GD2, which is expressed in a high proportion of melanoma cells. Experimental Design: We generated chimeric T cells specific for the ganglioside GD2 by joining an extracellular antigen-binding domain derived from the GD2-specific antibody sc14.G2a to cytoplasmic signaling domains derived from the T-cell receptor ζ-chain, with the endodomains of the costimulatory molecules CD28 and OX40. We expressed this CAR in human T cells and assessed the targeting of GD2-positive melanoma tumors in vitro and in a murine xenograft. Results: Upon coincubation with GD2-expressing melanoma cells, CAR-GD2 T lymphocytes incorporating the CD28 and OX40 endodomains secreted significant levels of cytokines in a pattern comparable with the cytokine response obtained by engagement of the native CD3 receptor. These CAR-T cells had antimelanoma activity in vitro and in our xenograft model, increasing the survival of tumor-bearing animals. Conclusion: Redirecting human T lymphocytes to the tumor-associated ganglioside GD2 generates effector cells with antimelanoma activity that should be testable in subjects with disease. (Clin Cancer Res 2009;15(18):5852–60)
Knockout Mice for Pharmacological Screening
Authors: Hannes Reuter, Scott A. Henderson, Tieyan Han, Toshio Matsuda, Akemichi Baba, Robert S. Ross, Joshua I. Goldhaber, Kenneth D. Philipson
Journal: Circulation Research (2002)

The role of the Na + -Ca 2+ exchanger as a major determinant of cell Ca 2+ is well defined in cardiac tissue, and there has been much effort to develop specific inhibitors of the exchanger. We use a novel system to test the specificity of two putative specific inhibitors, KB-R7943 and SEA0400. The drugs are applied to electrically stimulated heart tubes from control mouse embryos or embryos with the Na + -Ca 2+ exchanger knocked out. We monitored effects of the drugs on Ca 2+ transients. Both drugs depress the Ca 2+ transients at low concentrations even in the absence of any Na + -Ca 2+ exchanger. KB-R7943 and SEA0400 are not completely specific and should be used with caution as Na + -Ca 2+ exchange inhibitors.