tbuckley/cabot-search huggingface dataset:
Molecular Pathways: Induction of Polyploidy as a Novel Differentiation Therapy for Leukemia
Authors: Diane S. Krause, John D. Crispino
Journal: Clinical Cancer Research (2013)

Abstract Differentiation therapy has emerged as a powerful way to target specific hematologic malignancies. One of the best examples is the use of all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL), which has significantly improved the outcome for patients with this specific form of acute myeloid leukemia (AML). In considering how differentiation therapy could be used in other forms of AML, we predicted that compounds that induce terminal differentiation of megakaryocytes would be effective therapies for the megakaryocytic form of AML, named acute megakaryocytic leukemia (AMKL). We also speculated that such agents would reduce the burden of abnormal hematopoietic cells in primary myelofibrosis and alter the differentiation of megakaryocytes in myelodysplastic syndromes. Using a high-throughput chemical screening approach, we identified small molecules that promoted many features of terminal megakaryocyte differentiation, including the induction of polyploidization, the process by which cells accumulate DNA to 32N or greater. As the induction of polyploidization is an irreversible process, cells that enter this form of the cell cycle do not divide again. Thus, this would be an effective way to reduce the tumor burden. Clinical studies with polyploidy inducers, such as aurora kinase A inhibitors, are under way for a wide variety of malignancies, whereas trials specifically for AMKL and PMF are in development. This novel form of differentiation therapy may be clinically available in the not-too-distant future. Clin Cancer Res; 19(22); 6084–8. ©2013 AACR.
Hearty slices to plan for future health
Authors: B. Russell, J. M. Collins
Journal: Cardiovascular Research (2008)

Clinical trials have shown that heart function can only be moderately improved by injection of stem cells.1,2 Gains to date are most likely the result of increased wall stiffness and angiogenesis rather than generation of new, beating myocytes.3–5 Poor results could be due to the number and kind of cells used, the timing and method of delivery, lack of engraftment in an inhospitable local environment, general immune responses, and many more variables. Thus, although the current approach has been responsive to public pressure to rush to translate new ideas to a cure, the lack of a sound foundation in the basics makes the failure of stem cell therapy to date unsurprising. Working with whole animals is a most difficult way to learn because so much is beyond the control of the experimentalist and assays are limited. It is clear that experimental platforms are required to provide the rational groundwork before future cell therapy trials for cardiovascular disease are carried out.

It is a pleasure to find a simple new platform of an in vitro beating heart model for long-term assessment of experimental therapeutics in this issue by Monville's … 

*Corresponding author. Tel: +1 312 413 0407; fax: +1 312 996 6312. E-mail address : russell{at}uic.edu
Nutrition During Trimodality Treatment in Stage III Non-small Cell Lung Cancer: Not Only Important for Underweight Patients
Authors: Barbara S. van der Meij, Erik C.J. Phernambucq, Geert M. Fieten, Egbert F. Smit, Marinus A. Paul, Paul A.M. van Leeuwen, J. Wolter A. Oosterhuis
Journal: Journal of Thoracic Oncology (2011)
Natural History of Autosomal Dominant Polycystic Kidney Disease
Authors: Godela M. Fick, Patricia A. Gabow
Journal: Annual Review of Medicine (1994)

At least two different genes, which have been mapped to chromosomes 4 and 16, cause autosomal dominant polycystic kidney disease, a disorder with renal and extrarenal manifestations. Although gene-linkage testing is possible, the disease is diagnosed mainly through ultrasonography. Renal disease is characterized clinically by hypertension, acute and chronic pain, and variable progression to end-stage renal disease. Extrarenal manifestations include liver cysts, which may lead to complications; ruptured intracranial aneurysms; cardiac valvular disease; colonic diverticula; and inguinal hernias. Disease management is directed at minimizing and treating the complications of this illness.
Community care for COPD: the good, the bad and the ugly
Authors: D M G Halpin
Journal: Thorax (2008)

It is currently fashionable to believe that patients with chronic diseases can be managed safely, effectively and more cheaply, entirely in the community. In the UK, current commissioning and financial models encourage the development of services to provide continuing care as well as to replace acute care traditionally provided by hospitals. For some patients, this may be appropriate, but there is a danger of taking it too far and for patients to be denied appropriate input from specialists.

In the late 1990s, home care services to manage exacerbations of chronic obstructive pulmonary disease (COPD) were introduced in the UK, largely as a way of reducing the strain on the National Health Service’s (NHS) resources caused by the number of patients admitted during the winter months.1 It is now well recognised that some patients with exacerbations of COPD2 3 can be managed safely at home, and in fact this model of care fits into a model of intermediate care for older patients which has been evolving for several decades.4 Intermediate care has been seen as a way of overcoming the loss of independence and disruption of informal and formal patterns of support in the community that can occur on admission to hospital. In some cases, transferring care to the community also has a political dimension and has been seen as a way of reducing the influence of secondary care in determining priorities within local healthcare communities. Although home care or early assisted discharge may minimise the loss of independence that accompanies hospitalisation, patients at home often struggle because they are frail and they may take longer to recover because they miss out on the reablement services available in hospital.

Intermediate care is, however, undoubtedly a suitable way of managing exacerbations for some patients with COPD—but not all. In …
Augmentation of macrophage complement receptor function in vitro. IV. The lymphokine that activates macrophage C3 receptors for phagocytosis binds to a fucose-bearing glycoprotein on the macrophage plasma membrane.
Authors: F M Griffin, P J Mullinax
Journal: The Journal of Experimental Medicine (1984)

Macrophage receptors for the third component of complement (C3) are normally immobilized and unable to diffuse within the cell's plasma membrane and, even though they promote avid particle binding, are unable to promote phagocytosis of C3-coated particles. We have previously identified a lymphokine that activates macrophage C3 receptors for phagocytosis and have found that it acts by freeing the receptors so that they can diffuse within the macrophage plasma membrane. It seemed likely to us that the initial lymphokine-macrophage interaction would occur at the macrophage surface, perhaps via a specific lymphokine receptor. Since the binding of many ligands to cells is mediated by cell surface glycoproteins, we examined the protein and sugar requirements for murine peritoneal macrophages to respond to the lymphokine. Macrophages treated with the neutral protease Dispase lost the ability to respond to the lymphokine, and inclusion of L-fucose in the incubation medium containing lymphokine and macrophages inhibited markedly the macrophages' response to the lymphokine, suggesting that the lymphokine exerts its effects by first binding to fucose residues on a glycoprotein receptor on the macrophage surface. Further evidence for the essential role of macrophage surface fucose was obtained by demonstrating that pretreatment of macrophages with either fucosidase or gorse lectin, a fucose-binding lectin, strikingly disabled the cells from responding to the lymphokine. All treatments that prevented lymphokine activation of macrophage C3 receptors for phagocytosis also prevented lymphokine-induced C3 receptor mobility. These results strongly suggest that the lymphokine binds to a fucose-bearing macrophage surface glycoprotein, perhaps a specific lymphokine receptor. They also strengthen our hypothesis that, for a receptor to be able to promote phagocytosis, it must be able to diffuse within the macrophage plasma membrane.
Endobronchial ultrasound guided transbronchial needle aspiration of mediastinal lymph nodes for lung cancer staging: a projected cost analysis
Authors: M E J Callister, A Gill, W Allott, P K Plant
Journal: Thorax (2008)

Endobronchial ultrasound guided-transbronchial needle aspiration (EBUS-TBNA) of mediastinal lymph nodes provides a safe alternative to mediastinoscopy for staging patients with lung cancer.1–5 Performing TBNA under real time ultrasound visualisation has been shown to significantly improve the yield of TBNA compared with conventional TBNA performed without visualisation.6 In addition to the clinical benefits of this procedure, EBUS-TBNA is likely to offer ongoing cost savings by avoiding the need for mediastinoscopy procedures and positron emission topography (PET) scans in some patients.

At Leeds Teaching Hospitals NHS Trust (LTHT), conventional TBNA is used to assess large subcarinal nodes, but the Trust does not currently offer an EBUS-TBNA service. By reviewing mediastinoscopies performed as staging procedures for lung cancer in LTHT during 2006, we estimated the financial implications of establishing an EBUS-TBNA service.

We hypothesised that patients found to have …
Does Sustained-Release Lithium Reduce Impulsive Gambling and Affective Instability Versus Placebo in Pathological Gamblers With Bipolar Spectrum Disorders?
Authors: Eric Hollander, Stefano Pallanti, Andrea Allen, Erica Sood, Nicolo Baldini Rossi
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Selective serotonin reuptake inhibitors may be effective for some patients with pathological gambling, but those with comorbid conditions, such as bipolar spectrum disorders, may relapse during treatment. To the authors’ knowledge, this is the first placebo-controlled treatment study in pathological gamblers with bipolar spectrum disorders; it compares sustained-release lithium carbonate to placebo. METHOD: Forty pathological gambling patients with bipolar spectrum disorders entered a 10-week randomized, double-blind, placebo-controlled treatment study of sustained-release lithium carbonate. Outcome measures included gambling severity, mood, anxiety, and impulsivity scales. RESULTS: Pathological gambling patients with bipolar spectrum disorders significantly improved while taking sustained-release lithium carbonate compared to placebo on total pathological gambling scores on the Yale-Brown Obsessive Compulsive Scale, including both thoughts/urges and behavior, as well as on the Clinical Global Impression severity of pathological gambling scale. Affective instability (the Clinician-Administered Rating Scale for Mania score) was also lower in the group treated with sustained-release lithium carbonate compared to placebo. Ten (83%) of 12 completers were rated as responders in the sustained-release lithium group versus five (29%) of 17 in the placebo group. Of note, improvement in gambling severity was significantly correlated with improvement in mania ratings. CONCLUSIONS: Sustained-released lithium may be an effective treatment in reducing both gambling behavior and affective instability in pathological gamblers with bipolar spectrum disorder. This study highlights the need to identify subgroups of pathological gambling patients with bipolar spectrum conditions because this may have important treatment implications.
Epidemiology of antituberculosis drug resistance (the Global Project on Anti-tuberculosis Drug Resistance Surveillance): an updated analysis
Authors: Mohamed Abdel Aziz, Abigail Wright, Adalbert Laszlo, Aimé De Muynck, Françoise Portaels, Armand Van Deun, Charles Wells, Paul Nunn, Leopold Blanc, Mario Raviglione
Journal: The Lancet (2006)
Changes in myofibrillar content and Mg-ATPase activity in ventricular tissues from patients with heart failure caused by coronary artery disease, cardiomyopathy, or mitral valve insufficiency.
Authors: E D Pagani, A A Alousi, A M Grant, T M Older, S W Dziuban, P D Allen
Journal: Circulation Research (1988)

Force development and shortening by cardiac muscle occur as a result of the interaction between actin and myosin within the myofibrillar lattice. This interaction is dependent upon intracellular ionized calcium and is controlled by the troponin-tropomyosin regulatory proteins situated along the actin filament. In this study, we compared the myofibrillar content and myofibrillar Mg-ATPase activity of normal human ventricular muscle with that of ventricular muscle from patients in end-stage failure caused by coronary artery disease or cardiomyopathy and ventricular muscle from patients with heart failure due to mitral valve insufficiency. The results show that the amount of myofibrillar protein (mg/g wet wt ventricle) in hearts in end-stage failure (coronary artery disease and cardiomyopathy) is significantly lower compared with normal hearts and hearts in failure due to mitral valve insufficiency. However, the Mg-ATPase activity of myofibrils from hearts in both end-stage failure and failure due to mitral valve insufficiency is significantly lower compared with myofibrils from normal hearts. The data suggest that the reduction in the amount of myofibrillar protein in ventricular tissue is a pivotal event that may be responsible for the progression of heart disease to the point of end-stage failure.
Accumulation of diabetic rat peripheral nerve myelin by macrophages increases with the presence of advanced glycosylation endproducts.
Authors: H Vlassara, M Brownlee, A Cerami
Journal: The Journal of Experimental Medicine (1984)

We have previously shown that increased nonenzymatic glycosylation occurs in peripheral nervous tissue of diabetic humans and animals, primarily on the PO-protein of peripheral nerve myelin. The pathophysiologic mechanism by which this biochemical alteration leads to myelin breakdown and removal is not as yet understood. In the present study we show that advanced glycosylation end-product (AGE) adducts that form during long-term exposure of peripheral nerve myelin proteins to glucose in vitro and in vivo markedly alter the way in which myelin interacts with elicited macrophages. In this interaction, macrophages appear to specifically recognize AGEs on myelin, since AGE-BSA competes nearly as effectively as AGE-myelin, while neither unmodified BSA nor unmodified myelin compete. The failure of yeast mannan to interfere with macrophage recognition of AGE-myelin suggests that the mannose/fucose receptor does not mediate this process. Recognition of AGE-protein by macrophages is associated with endocytosis, as demonstrated by resistance of cell-associated radioactivity to removal by trypsin action, and by low temperature inhibition of ligand accumulation in the cellular fraction. 125I-labeled myelin that had been incubated in vitro with 50 mM glucose for 8 wk reached a steady state accumulation within thioglycolate-elicited macrophages that was five times greater than that of myelin incubated without glucose. Similarly, myelin isolated from rats having diabetes for 1.5-2.0 years duration had a steady state level that was 9 times greater than that of myelin from young rats, and 3.5 times greater than that of myelin from age-matched controls. In contrast, myelin isolated from rats having diabetes for 4-5 wk had the same degree of accumulation observed with myelin of age-matched normal rats. These data suggest that the amount of increased nonenzymatic glycosylation observed in the myelin of short-term diabetic rats had not yet resulted in the significant accumulation of AGE-myelin present both in vitro and in the long-term diabetic rats. The disappearance of acid-insoluble radioactivity from within the cells and the appearance of acid-soluble radioactivity released into the medium were very similar for the two groups, suggesting that the striking difference in accumulation seen between normal myelin and AGE-myelin is due primarily to increased uptake. Formation of irreversible AGE-adducts on myelin appears to promote the recognition and uptake of the modified myelin by macrophages. This interaction between AGE-myelin and macrophages may initiate or contribute to the segmental demyelination associated with diabetes and the normal aging of peripheral nerve.
HDAC6 Expression Is Correlated with Better Survival in Breast Cancer
Authors: Zhenhuan Zhang, Hiroko Yamashita, Tatsuya Toyama, Hiroshi Sugiura, Yoko Omoto, Yoshiaki Ando, Keiko Mita, Maho Hamaguchi, Shin-ichi Hayashi, Hirotaka Iwase
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The structure and function of chromatin can be altered by modifications to histone. Histone acetylation in vivo is a dynamic reversible process governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC6 is a unique isoform among the HDACs, and a gene expression pattern study, with cDNA microarray in MCF-7 cells, showed the HDAC6 gene to be late responsive, estrogen induced, and up-regulated. This led us to hypothesize that there was a link between levels of HDAC6 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients. Experimental Design: In the present study, the level of HDAC6 mRNA expression was analyzed with quantitative real-time reverse transcription-PCR, in 135 female patients with invasive breast cancer. HDAC6 protein expression was also determined by immunohistochemistry. An association was sought between HDAC6 expression and various clinicopathologic factors. Results: HDAC6 mRNA was expressed at significantly higher levels in breast cancer patients with small tumors measuring less than 2 cm, with low histologic grade, and in estrogen receptor α- and progesterone receptor-positive tumors. By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathologic factors, namely, age, menopausal status, and axillary lymph node involvement. Patients expressing high levels of HDAC6 mRNA and protein had a better prognosis than those expressing low levels, in terms of disease-free survival. However, multivariate analysis failed to show that HDAC6 mRNA and protein are an independent prognostic factors for disease-free survival and overall survival. Furthermore, the patients with high levels of HDAC6 mRNA tended to be more responsive to endocrine treatment than those with low levels. Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells. Although postmenopausal patients showed higher HDAC6 protein expression, there were no relationship between protein expression and any other clinicopathologic factors. Conclusions: We conclude that the levels of HDAC6 mRNA expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator in breast cancer. Additional investigations are warranted concerning the relationship between HDAC6 expression and response to endocrine therapy.
The Politics and Promise of Stem-Cell Research
Authors: Robert S. Schwartz
Journal: New England Journal of Medicine (2006)

On July 19, 2006, President George W. Bush exercised his constitutional prerogative to veto a congressional act for the first time in the 6 years he has been in office. The bill, passed by a Republican-controlled Congress, would have allowed a modest extension of embryonic stem-cell research. It called for federal funding to enable the derivation of embryonic stem-cell lines from fertilized eggs that are stored in freezers and already tagged for destruction. In his veto message, the President explained that, "stem cells . . . can be drawn from children, adults, and the blood in umbilical cords with no harm to . . .
Negative-strand RNA viral vectors: intravenous application of sendai virus vectors for the systemic delivery of therapeutic genes
Authors: Michael Bitzer, Guy Ungerechts, Sascha Bossow, Florian Graepler, Reinhard Sedlmeier, Sorin Armeanu, Christian Bernloehr, Martin Spiegel, Christine D Gross, Michael Gregor, Wolfgang J Neubert, Ulrich M Lauer
Journal: Molecular Therapy (2003)

Treatment by gene replacement is critical in the field of gene therapy. Suitable vectors for the delivery of therapeutic genes have to be generated and tested in preclinical settings. Recently, extraordinary features for a local gene delivery by Sendai virus vectors (SeVV) have been reported for different tissues. Here we show that direct intravenous application of SeVV in mice is not only feasible and safe, but it results in the secretion of therapeutic proteins to the circulation, for example, human clotting Factor IX (hFIX). In vitro characterization of first-generation SeVV demonstrated that secreted amounts of hFIX were at least comparable to published results for retroviral or adeno-associated viral vectors. Furthermore, as a consideration for application in humans, SeVV transduction led to efficient hFIX synthesis in primary human hepatocytes, and SeVV-encoded hFIX proteins could be shown to be functionally active in the human clotting cascade. In conclusion, our investigations demonstrate for the first time that intravenous administration of negative-strand RNA viral vectors may become a useful tool for the wide area of gene replacement requirements.
THE DETERMINATION OF THE CONCENTRATION OF THE DYE T-1824 IN NORMAL AND LIPEMIC PLASMAS
Authors: Francis P. Chinard, Howard A. Eder
Journal: The Journal of Experimental Medicine (1948)

A method is presented for estimating the concentration of T-1824 in lipemic plasma. The plasma is mixed with acetone, which precipitates the proteins, dissolves or precipitates the lipids, and yields a clear solution for photometric measurement of the dye. The method is not sensitive to changes in the degree of lipemia and is relatively insensitive to hemolysis.