tbuckley/cabot-search huggingface dataset:
Abstract P1-06-09: Engineered model matrix to mimic cancer stem cell microenvironment: Effect of integrin and heparin binding peptides
Authors: E Jabbari, SK Sarvestani
Journal: Cancer Research (2013)

Abstract Introduction: It is critical to understand the mechanism of cancer stem cell (CSC) maintenance and its regulation by the microenvironment to prevent and treat cancer. Since cancer takes many years to grow, it is imperative to develop in vitro models to study the molecular basis of tumorigenesis and progression. In an effort to isolate and investigate the effect of individual physical, mechanical, and biological factors in the tumor microenvironment on the fate of cancer cells and maintenance of CSCs, we have developed novel inert synthetic hydroxy acid-chain-extended polyethylene glycol (PEGXA) hydrogels with defined physical, chemical, mechanical, and biological properties. The objective of this work was to investigate the effect of integrin-binding and heparin-binding peptides conjugated to a matrix with defined physiochemical properties and stiffness on tumorsphere formation and CSC maintenance. Methods: Mouse 4T1, human MCF7, and human MDA-MB-231 breast cancer cells were encapsulated in PEGXA gels conjugated with integrin-binding and heparin-binding peptides. Peptides included laminin-derived IKVAV and YIGSR, collagen-IV derived TAGSCLRKFSTMY and GEFYFDLRLKGDKY, and fibronectin-derived WQPPRARI and RGD. Gels without peptide conjugation and those conjugated with laminin-derived CD44 binding RLVSYNGIGGLK peptide were used as positive (CSC forming) and negative controls, respectively. Tumorsphere size and density, and expression of CSC markers were determined with incubation time in tumor CSC culture medium. For in vivo, cell encapsulated gels were inoculated in syngeneic Balb/C mice and tumor formation was determined with time. Results: All tumor cells types encapsulated in PEGXA gels without peptide formed tumorspheres and maintained CSCs. Gel stiffness had a bimodal effect on tumorsphere formation in the 1-50 kPa compressive modulus range. Tumor cells encapsulated in the gel with 5 kPa compressive modulus had the highest expression of CSC markers. Conjugation of CD44 binding peptide eliminated tumorsphere formation by encapsulated tumor cells. Interestingly, integrin-binding peptides (RGD, IKVAV and YIGSR) conjugated to the gel abolished tumorsphere formation by encapsulated cells whereas heparin-binding peptides (TAGSCLRKFSTMY, GEFYFDLRLKGDKY and WQPPRARI) improved rate of tumorsphere growth and the expression of CSC markers. It should be noted that peptides dissolved in the gel (not chemically attached to the gel) or gels conjugated with mutant peptides did not have a noticeable effect compared to the gels without peptide. Similar results were observed with the cell-encapsulated gels were implanted in Balb/C mice. The expression pattern of EMT markers suggested that enhanced EMT contributed to the increased tumorsphere formation in gels conjugated with heparin-binding peptides. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-09.
Mechanism of killing of Giardia lamblia trophozoites by complement.
Authors: M Deguchi, F D Gillin, I Gigli
Journal: Journal of Clinical Investigation (1987)

Only antibodies of the IgM class support the lytic effect of complement on Giardia lamblia (GL). We sensitized GL trophozoites (SGL) at 4 degrees C with serum containing anti-GL antibodies or IgM purified from this serum, and either normal human serum (NHS), complement 2-deficient human serum (C2d-HS), or C4-deficient guinea pig serum was used as source of complement. SGL were killed by NHS (86%) and by the deficient sera (50 and 40%, respectively), suggesting activation of the alternative pathway. However, the reaction was inhibited by Mg-EGTA. These observations led to studies of the role of C1. The lytic effect of NHS and C2d-HS on SGL was abolished by immunochemically depleting C1 from these sera, and reconstituted by adding purified C1q plus C1r and C1s. Factor B-depleted C2d-HS also lost its capacity to mediate killing, but reconstitution with factor B led to a dose-dependent increase in the killing of SGL. We next investigated the participation of the membrane attack complex in this system. SGL carrying C5b to C7 were lysed when incubated with C8 alone (56%); the addition of C9 further increased killing (98%), while C9 in the absence of C8 had no effect. We concluded that although activation of the classical pathway produces lysis of SGL, lysis may also proceed through a unique pathway of complement activation that requires C1 and factor B, but is independent of C4 and C2. Lysis of SGL can be accomplished by C5b to C8 in the absence of C9.
Optical Mapping in a New Guinea Pig Model of Ventricular Tachycardia Reveals Mechanisms for Multiple Wavelengths in a Single Reentrant Circuit
Authors: Steven D. Girouard, Joseph M. Pastore, Kenneth R. Laurita, Kenton W. Gregory, David S. Rosenbaum
Journal: Circulation (1996)

Background Although the relationship between cardiac wavelength (λ) and path length importantly determines the stability of reentrant arrhythmias, the physiological determinants of λ are poorly understood. To investigate the cellular mechanisms that control λ during reentry, we developed an experimental system for continuously monitoring λ within a reentrant circuit with the use of voltage-sensitive dyes and a new guinea pig model of ventricular tachycardia (VT). Methods and Results Action potentials were recorded simultaneously from 128 ventricular sites in Langendorff-perfused hearts (n=15) in which propagation was confined to a two-dimensional rim of epicardium by an endocardial cryoablating procedure. The reentrant path was precisely controlled by creating an epicardial obstacle (2×10 mm) with an argon laser. To control for fiber orientation and rate-dependent membrane properties, λ during reentry was compared with λ during plane wave propagation transverse and longitudinal to cardiac fibers at a stimulus cycle length (CL) comparable to the VT CL. Reentrant VT (CL=97.0±6.2 ms) was reproducibly induced by programmed stimulation in 93% of preparations. λ varied considerably within the reentrant circuit (range, 10.6 to 22.5 mm), because of heterogeneities of conduction rather than action potential duration. λ was significantly shorter during reentrant propagation (ie, with pivoting) parallel to fibers (10.6±4.2 mm) compared with plane wave propagation (ie, without pivoting) parallel to fibers (32.8±6.5 mm, P &lt;.02), indicating that wave-front pivoting was primarily responsible for shortening of λ during reentry. The mechanism of λ shortening was conduction slowing from increased current load experienced by the pivoting wave front. Conclusions We provide direct experimental evidence that multiple wavelengths are present even within a relatively simple reentrant circuit. Abrupt changes in loading during wave-front pivoting, rather than membrane ionic properties or fiber structure, were a major determinant of λ and, therefore, may play an important role in the stability of reentry.
Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China
Authors: Shenjie Tang, Lan Yao, Xiaohui Hao, Xia Zhang, Gang Liu, Xin Liu, Meiying Wu, Linhai Zen, Hua Sun, Yidian Liu, Jin Gu, Feishen Lin, Xiafang Wang, Zhanjun Zhang
Journal: European Respiratory Journal (2014)

Linezolid may be effective in treating multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. We conducted a prospective, multicentre, randomised study to further evaluate the efficacy, safety and tolerability of linezolid in patients with extensively drug-resistant tuberculosis in China. 65 patients who had culture-positive sputum for extensively drug-resistant tuberculosis were randomly assigned to a linezolid therapy group or a control group. Patients in the two groups adopted a 2-year individually based chemotherapy regimen. The linezolid therapy group was given linezolid at a start dose of 1200 mg per day for a period of 4–6 weeks and this was then followed by a dose of 300–600 mg per day. The proportion of sputum culture conversions in the linezolid therapy group was 78.8% by 24 months, significantly higher than that in the control group (37.6%, p&lt;0.001). The treatment success rate in linezolid therapy group was 69.7%, significantly higher than that in the control group (34.4%, p=0.004). 27 (81.8%) patients had clinically significant adverse events in the linezolid group, of whom 25 (93%) patients had events that were possibly or probably related to linezolid. Most adverse events resolved after reducing the dosage of linezolid or temporarily discontinuing linezolid. Linezolid containing chemotherapy for treatment of extensively drug-resistant tuberculosis may significantly promote cavity closure, increase sputum culture-conversion rate and improve treatment success rate.
Nonmurine animal models of food allergy.
Authors: Ricki M Helm, Richard W Ermel, Oscar L Frick
Journal: Environmental Health Perspectives (2003)

Food allergy can present as immediate hypersensitivity [manifestations mediated by immunoglobulin (Ig)E], delayed-type hypersensitivity (reactions associated with specific T lymphocytes), and inflammatory reactions caused by immune complexes. For reasons of ethics and efficacy, investigations in humans to determine sensitization and allergic responses of IgE production to innocuous food proteins are not feasible. Therefore, animal models are used a) to bypass the innate tendency to develop tolerance to food proteins and induce specific IgE antibody of sufficient avidity/affinity to cause sensitization and upon reexposure to induce an allergic response, b) to predict allergenicity of novel proteins using characteristics of known food allergens, and c) to treat food allergy by using immunotherapeutic strategies to alleviate life-threatening reactions. The predominant hypothesis for IgE-mediated food allergy is that there is an adverse reaction to exogenous food proteins or food protein fragments, which escape lumen hydrolysis, and in a polarized helper T cell subset 2 (Th2) environment, immunoglobulin class switching to allergen-specific IgE is generated in the immune system of the gastrointestinal-associated lymphoid tissues. Traditionally, the immunologic characterization and toxicologic studies of small laboratory animals have provided the basis for development of animal models of food allergy; however, the natural allergic response in large animals, which closely mimic allergic diseases in humans, can also be useful as models for investigations involving food allergy.
MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma
Authors: Julia von Frowein, Philipp Pagel, Roland Kappler, Dietrich von Schweinitz, Adelbert Roscher, Irene Schmid
Journal: Hepatology (2010)

MicroRNAs (miRNAs) are well-known regulators of proliferation, apoptosis, and differentiation and are recognized to play an important role in the development of cancers. Here we aimed to identify the functional contribution of miRNAs to the biology of hepatoblastoma (HB), the most common malignant liver tumor in childhood. As overexpression of the oncogene PLAG1 (pleomorphic adenoma gene 1) is a characteristic phenomenon in HB, we used RNA interference and subsequent miRNA array analysis to identify miR-492 as most strongly influenced by PLAG1. We provide novel experimental evidence that miR-492 can originate from the coding sequence of the HB marker gene keratin 19 (KRT19). In agreement with these in vitro observations, significantly elevated levels of coexpressed KRT19 and miR-492 were particularly found in metastatic HB tumor samples. Stable overexpression of miR-492 in HB cell clones served to identify a broad range of differentially expressed transcripts, including several candidate targets of miR-492 predicted by computational algorithms. Among those the liver enzyme BAAT showed significant association with miR-492 expression in HB tumor samples. A close functional relationship between KRT19 and miR-492 was identified that may play an important role in the progression of malignant embryonal liver tumors. Additionally, miR-492 and its associated targets might serve as new HB biomarkers of clinical utility and could assist to explore targeted therapies, especially in metastatic HB with a poor prognosis.
Overgrowth of human synovial cells driven by the human T cell leukemia virus type I tax gene.
Authors: T Nakajima, H Aono, T Hasunuma, K Yamamoto, I Maruyama, T Nosaka, M Hatanaka, K Nishioka
Journal: Journal of Clinical Investigation (1993)

One of the salient pathological features of rheumatoid arthritis is synovial cell proliferation with bone erosion. Despite extensive investigation, the factors essential for synovial cell proliferation remain to be identified. Recent studies suggest that human T cell leukemia virus type I (HTLV-I) may play an important role in synovial overgrowth observed in patients with one type of chronic inflammatory synovitis. In order to confirm and extend these observations, we have established synovial cell clones (SCCs) from three HTLV-I carriers who demonstrated synovial overgrowth but were otherwise asymptomatic. HTLV-I proviral DNA randomly integrated into the cellular genome was present in 20-30% of SCCs. The SCCs carrying HTLV-I proviral DNA and expressing the tax gene exhibited high levels of proliferative potential. HTLV-I was found to function as a transcriptional trans-activator in these SCCs. Moreover, transfection of the tax expression plasmid into SCCs resulted in the same phenotype of increased proliferation and cytokine expression as exhibited by HTLV-I provirus-carrying and tax-expressing SCCs. These data suggest that tax plays a critical role not only in leukemogenesis but also in synovial overgrowth in humans.
Expression of GAD67 and Novel GAD67 Splice Variants During Human Fetal Pancreas Development
Authors: Esther Korpershoek, Aart M. Verwest, Ynske IJzendoorn, Robbert Rottier, Hemmo A. Drexhage, Ronald R. de Krijger
Journal: Endocrine Pathology (2007)

Glutamic acid decarboxylase (GAD) is a major inhibitory neurotransmitter in the brain, which catalyses the reaction of l-glutamate to γ-aminobutyric acid. There are two isoforms of GAD, a 65-kDa form and a 67-kDa form, which are encoded by two different genes. As previous studies suggested a role for GAD67 splice variants during fetal pancreas development, we have investigated the mRNA expression of GAD67 and GAD67 splice variants in a series of 14 human fetal pancreases between 14 weeks gestation and term and in adult control pancreases by RT-PCR. In this study, we demonstrate mRNA expression of GAD67 and four GAD67 splice variants, including GAD25, in human fetal and adult specimens. Some of the splice variants, including various proportions of exon 7 or a new exon between exons 6 and 7, have not been described before in the human pancreas. We speculate that the expression of these GAD67 splice variants might be related to human fetal pancreas development.
EPR and fluorescence depolarization studies on bovine cardiac myosin.
Authors: D B Stone, R A Mendelson, J Botts, P H Cheung
Journal: Circulation Research (1981)

To test for possible differences in local conformation and S1 flexibility, bovine cardiac and rabbit skeletal myosins were labeled with a fluorophore (1,5-IAEDANS) and a spin label having iodoacetamide reactivity. The marked activation of the Ca2+-ATPase (6- to 8-fold) and inhibition of the K+ (EDTA)-ATPase (80-90%) by both labels indicated specific labeling of the fast-reacting thiols (SH1) of both myosins. Fluorescence depolarization studies of 1,5-IAEDANS-labeled cardiac myosin indicated that, like skeletal myosin, the SI moieties of cardiac myosin exhibit considerable segmental flexibility with respect to the rod portion of the molecule. This indicates that segmental flexibility may be a property of all myosins. Cardiac and skeletal myosins immobilized spin labels to approximately the same extent, indicating a similarity in steric restraints around the SH1 thiol of the two myosins. The magnitude of the changes in spin label mobility accompanying binding of MgADP and hydrolysis of MgATP was reduced in cardiac myosin relative to skeletal myosin. This suggests that the lower catalytic center activity of cardiac myosin is associated with more restricted conformational changes accompanying formation of M.ADP and M.ADP.Pi. From measurements of spin label mobility, the affinity of cardiac and skeletal myosin for ADP were similar: Kd (ADP) = 7 microM, n = 1.6. The EPR spectrum of spin labels attached to cardiac and skeletal myosin showed similar saturation effects upon actin binding indicating immobilization of myosin heads occurs with both proteins.
Alexander Borodin, the Scientist, the Musician, the Man
Authors: James C. Cole
Journal: JAMA (1969)

On March 19, 1887, the back pages of<i>Lancet</i>contained a one-paragraph obituary notice which read in part: Dr. Alexander Porphyryevich Borodin died suddenly, probably from highly diseased coronary arteries. His published works were tolerably numerous and included a number of important articles on the estimation of nitrogen. By means of Professor Borodin's process, combined with that of Kjeldahl's, the physician has a means whereby this estimation may be made with a very moderate amount of difficulty and trouble.... In spite of his arduous professional and laboratory work, Professor Borodin found time for cultivation of the art and science of music, in which he was quite adept. He is, indeed, said to have rendered valuable service to the cause of Russian music. Borodin wore the two hats of medicine and music throughout his life. He had composed a polka by the age of 9 and, when he was 13, a
Mast cells in the labial salivary glands of patients with Sjogren's syndrome: a histochemical, immunohistochemical, and electron microscopical study.
Authors: Y T Konttinen, S Tuominen, M Segerberg-Konttinen, P Jungell, M J Malmstrom, M Gronblad, O Guven, S Santavirta, P Panula
Journal: Annals of the Rheumatic Diseases (1990)

Mast cells in labial salivary glands obtained from patients with xerostomia with or without focal sialadenitis/Sjögren9s syndrome were studied. There was no significant correlation between the intensity of local lymphocyte infiltration and the morphometrically analysed number of mast cells staining positive with toluidine blue. Histamine staining with heterologous 11C antiserum showed significantly fewer positive cells than staining with toluidine blue (mean (SD) 62 (10) v 138 (30)). This suggests heterogeneity of the mast cell population. Furthermore, there was a correlation between the focus score and the number of mast cells containing histamine. This suggests that the proliferation of mast cells containing histamine may be locally regulated by the immune inflammation, possibly through mediators from macrophages and fibroblasts. In contrast, the number of mast cells staining positive with toluidine blue could not be used as a marker of the degree of local inflammation. Although transmission electron microscopic analysis did not disclose signs of 9en masse9 mast cell degranulation, mast cells may have a role in the local disease process.
T lymphocyte-mediated protection against Pseudomonas aeruginosa infection in granulocytopenic mice.
Authors: W G Powderly, G B Pier, R B Markham
Journal: Journal of Clinical Investigation (1986)

BALB/c mice immunized with Pseudomonas aeruginosa immunotype 1 polysaccharide develop protective T cell immunity to bacterial challenge. In vitro, T cells from immunized mice kill P. aeruginosa by production of a bactericidal lymphokine. The present study demonstrates that adoptive transfer of T cells from immunized BALB/c mice to granulocytopenic mice resulted in 97% survival on challenge with P. aeruginosa, compared with 17% survival with adoptive transfer of T cells from nonimmune BALB/c mice. This protection is specifically elicited by reexposure to the original immunizing antigen; adoptive recipients cannot withstand challenge with immunotype 3 P. aeruginosa. However, the adoptive recipients do survive simultaneous infection with both P. aeruginosa immunotypes 1 and 3. Adoptive transfer of T cells from the congenic CB.20 mice, which are unable to kill P. aeruginosa in vitro, provides only 20% protection to granulocytopenic mice. These studies indicate that transfer of specific immune T lymphocytes can significantly enhance the resistance to P. aeruginosa infection in granulocytopenic mice.
Factor V, tissue factor pathway inhibitor, and east Texas bleeding disorder
Authors: George J. Broze, Thomas J. Girard
Journal: Journal of Clinical Investigation (2013)

In a report reading like a fascinating detective story, Vincent and colleagues crack the mysterious case of east Texas bleeding disorder. They show that affected individuals have a mutation in exon 13 of the coagulation F5 gene that causes increased expression of an alternatively spliced transcript, which encodes a previously unrecognized factor V (FV) isoform they call FV-short. This FV isoform lacks a large portion of the B domain of FV, which is normally released upon the proteolytic activation of FV by thrombin and binds tightly to the coagulation regulator tissue factor pathway inhibitor-α (TFPIα). This interaction leads to an approximately 10-fold increase in the level of TFPIα circulating in plasma and a resultant anticoagulant effect that produces a hemorrhagic diathesis.
Some Diagnostic Problems Surrounding Poliomyelitis
Authors: J. F. Galpine
Journal: BMJ (1959)

In this paper reference is made to three problems in the recognition of poliomyelitis that are topical.Firstly, the diagnosis of non-paralytic poliomyelitis and its relationship to similar syndromes mainly of virus origin and often referred to as " aseptic meningitis "; secondly, the need to distinguish the paresis of so-called " benign myalgic encephalomyelitis" from paralytic poliomyelitis; thirdly, the existence of polioencephalitis unaccompanied by paralysis.