tbuckley/cabot-search huggingface dataset:
A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis
Authors: Lin Zhang, Martin Orban, Michael Lorenz, Verena Barocke, Daniel Braun, Nicole Urtz, Christian Schulz, Marie-Luise von Brühl, Anca Tirniceriu, Florian Gaertner, Richard L. Proia, Thomas Graf, Steffen-Sebastian Bolz, Eloi Montanez, Marco Prinz, Alexandra Müller, Louisa von Baumgarten, Andreas Billich, Michael Sixt, Reinhard Fässler, Ulrich H. von Andrian, Tobias Junt, Steffen Massberg
Journal: The Journal of Experimental Medicine (2012)

Millions of platelets are produced each hour by bone marrow (BM) megakaryocytes (MKs). MKs extend transendothelial proplatelet (PP) extensions into BM sinusoids and shed new platelets into the blood. The mechanisms that control platelet generation remain incompletely understood. Using conditional mutants and intravital multiphoton microscopy, we show here that the lipid mediator sphingosine 1-phosphate (S1P) serves as a critical directional cue guiding the elongation of megakaryocytic PP extensions from the interstitium into BM sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. Collectively, our findings uncover a novel function of the S1P–S1pr1 axis as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia.
Tuberculosis Morbidity—United States, 1994
Authors: Tuberculosis Morbidity
Journal: JAMA (1995)

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Mechanisms of multistep carcinogenesis and carcinogen risk assessment.
Authors: J C Barrett
Journal: Environmental Health Perspectives (1993)

Many different types of chemical exposures can increase the incidence of tumors in animals and humans, but usually a long period of time is required before the carcinogenic risk of an exposure is manifested. Both of these observations can be explained by a multistep/multigene model of carcinogenesis. In this model, a normal cell evolves into a cancer cell as the result of heritable changes in multiple, independent genes. The two-stage model of initiation and promotion for chemical carcinogenesis has provided a paradigm by which chemicals can act by qualitatively different mechanisms, but the process of carcinogenesis is now recognized as more complex than simply initiation and promotion. Even a three-stage model of initiation, promotion, and progression, which can be operationally defined, is not adequate to describe the carcinogenic process. The number of genes altered in a cancer cell compared to a normal cell is not known; recent evidence suggests that 3-10 genetic events are involved in common adult malignancies in humans. Two distinct classes of genes, protooncogenes and tumor-suppressor genes, are involved in the cancer process. Multiple oncogenes may be activated in a tumor, while multiple tumor-suppressor genes may be inactivated. Identification of the genes involved in carcinogenesis and elucidation of the mechanisms of their activation or inactivation allows a better understanding of how chemical carcinogens influence the process of neoplastic evolution. The findings of multiple genetic changes (including point mutations, chromosomal translocations, deletions, gene amplification, and numerical chromosome changes) in activated protooncogenes and inactivated tumor-suppressor genes provide experimental support for Boveri's somatic mutation theory of carcinogenesis. In addition to mutagenic mechanisms, chemicals may heritably alter cells by epigenetic mechanisms and enhance the clonal expansion of altered cells. Most chemical carcinogens operate via a combination of mechanisms, and even their primary mechanism of action may vary depending on the target tissues. The classification of chemicals by mechanism of action or by nongenotoxic or genotoxic activity has certain inherent difficulties because no classification of chemicals is exhaustive or definitive.
Evolution of antibody structure during the immune response. The differentiative potential of a single B lymphocyte.
Authors: T Manser
Journal: The Journal of Experimental Medicine (1989)

Changes in the structure and function of antibodies occur during the course of an immune response due to variable (V) region gene somatic mutation and isotype switch recombination. While the end products of both these processes are now well documented, their mechanisms, timing, and regulation during clonal expansion remain unclear. Here I describe the characterization of antibodies expressed by a large number of hybridomas derived from single B cell clones at an intermediate stage of an immune response. These data provide new insights into the mechanism, relative timing, and potential of V gene mutation and isotype switching. The data suggest that somatic mutation and isotype switching are completely independent processes that may, but need not, occur simultaneously during clonal expansion. In addition, the results of this analysis demonstrate that individual B cell clones are far more efficient than previously imagined at generating and fixing particular V region somatic mutations that result in increased affinity for the eliciting epitope. Models to account for this high efficiency are discussed. Taken together with previous data, the results of this analysis also suggest that the "somatic evolution" of V region structure to a single epitope takes place in two stages; the first in which particular mutations are sustained and fixed by antigen selection in the CDR regions of the V region genes expressed in a clone over a short period of clonal expansion, and the second in which these selected CDR mutations are maintained in the growing clone, deleterious mutations are lost, and selectively neutral mutations accumulate throughout the length of V genes over long periods of clonal expansion.
Mechanisms of adenosine triphosphate-, thrombin-, and trypsin-induced relaxation of rat thoracic aorta.
Authors: R M Rapoport, M B Draznin, F Murad
Journal: Circulation Research (1984)

The mechanisms by which adenosine triphosphate, thrombin, and trypsin cause relaxation of vascular smooth muscle were investigated. Relaxation of the rat thoracic aorta with adenosine triphosphate, thrombin, and/or trypsin was associated with increased levels of cyclic guanosine monophosphate in both time- and concentration-dependent manners. Thrombin and trypsin did not alter cyclic adenosine monophosphate levels, whereas adenosine triphosphate increased cyclic adenosine monophosphate levels after significant relaxation occurred. Removal of the endothelium abolished adenosine triphosphate-, thrombin-, and trypsin-induced relaxation and the associated increased levels of cyclic nucleotides. Relaxation due to these agents was also inhibited by exposure to nordihydroguaiaretic acid, a lipoxygenase inhibitor, and eicosatetraynoic acid, a lipoxygenase and cyclooxygenase inhibitor. Indomethacin, a cyclooxygenase inhibitor, potentiated relaxation to these agents, whereas the increased levels of cyclic nucleotides due to adenosine triphosphate were unaltered. Bromophenacyl bromide, a phospholipase A2 inhibitor, decreased relaxation due to adenosine triphosphate, thrombin, and trypsin and the associated increased levels of cyclic nucleotides. Removal of extracellular calcium, which also presumably inhibits phospholipase A2, prevented the elevated levels of cyclic nucleotides and the inhibitory effects of adenosine triphosphate and trypsin on contraction. In contrast, sodium nitroprusside-induced relaxation and/or increased levels of cyclic guanosine monophosphate were unaltered by nordihydroguaiaretic acid, eicosatetraynoic acid, bromophenacyl bromide, and removal of extracellular calcium. After incubation of intact tissue with 32P-orthophosphate, the patterns of protein phosphorylation caused by adenosine triphosphate, thrombin, and trypsin were indistinguishable from those of acetylcholine, sodium nitroprusside and 8-bromo cyclic guanosine monophosphate. All these agents dephosphorylated myosin light chain. Thus, the present study supports the hypothesis that relaxation induced by adenosine triphosphate, thrombin, and trypsin is mediated through the formation of an endothelial factor which elevates cyclic guanosine monophosphate levels and causes cyclic guanosine monophosphate-dependent protein phosphorylation and dephosphorylation of myosin light chain.
Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity
Authors: K Haugbro
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> The presence of "anti-DNA antibodies in abnormal titres" is a well established criterion for SLE classification, but there is no agreement on the performance of this test. <b>Objective:</b> To study the correlation between clinical findings and five different solid and solution phase anti-DNA antibody assays. <b>Methods:</b> 158 consecutively collected ANA positive sera were studied in a double blind fashion. Anti-DNA antibodies were determined by different solid phase assays (ssDNA-, dsDNA- specific ELISA, EliA anti-dsDNA assay, <i>Crithidia luciliae</i> assay), and by an experimental solution phase anti-DNA assay using biotinylated pUC18 plasmid, human, calf thymus, and <i>E coli</i> DNA. Antibody affinity was determined by surface plasmon resonance. Clinical data were obtained independently of the laboratory analyses and later related to the anti-dsDNA findings. <b>Results:</b> Anti-dsDNA antibodies were most frequently detected by ELISA, but were not specific for SLE as they were present in up to 30% of other disease groups. Those detected by the <i>Crithidia luciliae</i> assay were predictive for SLE, while antibodies binding in solution phase ELISA using the pUC18 correlated strongly with the <i>Crithidia luciliae</i> assay. Surface plasmon resonance analysis showed that antibody binding to pUC18 was not due to higher relative affinity for dsDNA in general, but apparently to specificity for that plasmid DNA. Serum samples from three patients with lupus nephritis were positive in both pUC18 solution phase and <i>Crithidia luciliae</i> assays. <b>Conclusions:</b> Assay principle selection is decisive for the detection of clinically significant anti-DNA antibodies. Revision of the anti-DNA antibody criterion in the SLE classification may be needed.
HOSPITAL TREATMENT OF PATIENTS WITH PSYCHONEUROTIC DISORDERS
Authors: DONALD M. HAMILTON, JAMES H. WALL
Journal: American Journal of Psychiatry (1942)

1. A study of 100 psychoneurotic men patients admitted to the New York Hospital, Westchester Division, between 1927 and 1937 has been made. 2. Review of the family background revealed that these individuals predominantly came from close-knit, small families, where the father was a weak individual and the mother was aggressive and dominated the home. (Father was weak in 64 cases, mother aggressive and dominating in 67 cases.) 3. An analysis of the life histories revealed a high incidence of serious and prolonged physical illness in infancy and that this was one factor in fixing attention on the body in later life. Such patients responded unfavorably as a group to treatment. 4. The study of the present illness revealed that psychoneuroses tend to be of long duration before hospital treatment is instituted. 5. Identification with relatives suffering from serious physical or mental illness was an etiological factor in the illness of one-fourth of the patients. 6. Outstanding mental symptoms in their order of frequency were tenseness, depression, anxiety, sexual preoccupation, hypochondriasis, obsessions and compulsions, fear of insanity, and weakness. Patients with depression and anxiety as outstanding symptoms responded best to treatment, while fewer recoveries were found in the group displaying hypochondriasis, weakness or fear of insanity, than in the total group. The compulsive and obsessive patients responded least well to treatment. 7. The value of a full and varied program of activities supervised by the physicians and fitted to the patients' needs and capacities, together with frequent psychotherapeutic interviews, was substantiated by this study. 8. The average length of hospitalization was eight and a half months. 9. Follow-up studies of 100 men with psychoneurotic disorders, 4 to 14 years after discharge, revealed that 46 patients were then recovered, 5 much improved, 17 improved, making a total of 68 who had benefited by treatment.
Lys184 deletion in troponin I impairs relaxation kinetics and induces hypercontractility in murine cardiac myofibrils
Authors: Bogdan Iorga, Natascha Blaudeck, Johannes Solzin, Axel Neulen, Ina Stehle, Alfredo J. Lopez Davila, Gabriele Pfitzer, Robert Stehle
Journal: Cardiovascular Research (2007)

AimsTo understand the functional consequences of the Lys184 deletion in murine cardiac troponin I (mcTnIΔK184), we have studied the primary effects of this mutation linked to familial hypertrophic cardiomyopathy (FHC) at the sarcomeric level.
Effects of Persantin (RA8), A New Coronary Vasodilator, on Coronary Blood Flow and Cardiac Dynamics in the Dog
Authors: James W. West, Samuel Bellet, Ugo C. Manzoli, Ottto F. Müller
Journal: Circulation Research (1962)

The effect of a new coronary vasodilator (Persantin), which produces a marked increase in coronary blood flow (up to 159 per cent in normal animals) without increasing cardiac contractility or cardiac work, has been studied in the experimental animal. This is associated with a marked decrease in coronary resistance. There is an increase in the coronary venous oxygen content and a decrease in the coronary A-V oxygen difference; the cardiac output is only slightly affected. Increase in the coronary blood flow has also been observed in dogs in which coronary in sufficiency has been produced by coronary ligation and by narrowing of the lumen of the coronary artery by the application of casein rings. This was accompanied by no significant increase in cardiac work.
Failed Adoptive Immunotherapy with Tumor-Specific T Cells
Authors: Sameek Roychowdhury, Kenneth F. May, Katherine S. Tzou, Teresa Lin, Darshna Bhatt, Aharon G. Freud, Martin Guimond, Amy K. Ferketich, Yang Liu, Michael A. Caligiuri
Journal: Cancer Research (2004)

Abstract Adoptive immunotherapy with tumor-specific T cells has emerged as a valid approach for prevention or treatment of diseases, such as melanoma and EBV-associated lymphoma. As interleukin (IL) 15 promotes survival of CD8+ memory CTLs, we hypothesized that it could be used to enhance antitumor immunity in vivo through the maintenance of adoptively transferred memory CTL. To test this, we treated mice bearing P1A+ tumors with adoptively transferred T cells possessing a transgenic Vα8+ T-cell receptor specific for the P1A tumor antigen (called P1CTL). Mice were then randomized to receive daily low-dose IL-15 (0.5 μg/day) or PBS. Mice receiving the transgenic P1CTL and IL-15 experienced a significantly delayed tumor relapse or complete tumor regression (P &amp;lt; 0.002 compared with PBS), with a striking persistence of the CD8+ Vα8+ P1CTL compared with mice receiving the CD8+ Vα8+ P1CTL and PBS vehicle (26.3 versus 5.1% P &amp;lt; 10−5). Animals exhibiting complete tumor regression had a significant population of CD8+ Vα8+ P1CTL (46%) that persisted with IL-15 treatment until 140 days after adoptive transfer and successfully defended them against tumor rechallenge without IL-15. Low-dose IL-2 afforded no protection over vehicle and resulted in lower percentages of T cells with an activated memory phenotype, lower Bcl-2 expression, and lower ex vivo antitumor cytotoxicity compared with mice treated with IL-15. Collectively, the data support the notion that exogenous low-dose IL-15 therapy can enhance and even reverse the limited efficacy of adoptively transferred tumor-specific T-cell therapy and may do so in a fashion that is superior and distinct from exogenous IL-2 therapy.
Activation of Robo1 Signaling of Breast Cancer Cells by Slit2 from Stromal Fibroblast Restrains Tumorigenesis via Blocking PI3K/Akt/β-Catenin Pathway
Authors: Po-Hao Chang, Wendy W. Hwang-Verslues, Yi-Cheng Chang, Chun-Chin Chen, Michael Hsiao, Yung-Ming Jeng, King-Jen Chang, Eva Y.-H.P. Lee, Jin-Yuh Shew, Wen-Hwa Lee
Journal: Cancer Research (2012)

Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-catenin into nucleus, leading to downregulation of c-myc and cyclin D1 via the phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in patients with breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and show that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes.
Epithelial mesenchymal transition (EMT) in small airways of COPD patients
Authors: Sukhwinder Singh Sohal, Eugene Haydn Walters
Journal: Thorax (2013)

We congratulate Milara et al 1 for getting a paper suggesting that epithelial mesenchymal transition (EMT) is important in the pathogenesis of chronic obstructive pulmonary disease (COPD) into a top respiratory journal. This is quite a breakthrough.

In the discussion, Milara et al were somewhat dismissive of our findings on EMT markers in large airways of COPD patients;2 commenting that our study was limited by the mesenchymal protein expressions analysed (MMP-9, S100A4, vimentin) being potentially expressed by inflammatory cells. In a follow-up paper3 we excluded such confounding. Further, our study illustrated that cells in the basal epithelium, and reticular basement membrane (Rbm) in smokers/COPD double-stain for cytokeratin-(s) and the ‘EMT marker’ S100A4, confirming a likely epithelial …
Left Atrial Volume Monitoring and Cardiovascular Risk in Patients with End-Stage Renal Disease
Authors: Giovanni Tripepi, Francesco Antonio Benedetto, Francesca Mallamaci, Rocco Tripepi, Lorenzo Malatino, Carmine Zoccali
Journal: Journal of the American Society of Nephrology (2007)

Left atrial volume (LAV), as indexed by height(2.7), has recently emerged as an useful echocardiographic measurement to refine the estimate of cardiovascular (CV) risk in ESRD. Whether progression or regression in LAV has prognostic value in patients with ESRD is still unknown. The prognostic value for CV events of changes in LAV was tested in a cohort of 191 dialysis patients. Echocardiography was performed twice, 17 +/- 2 mo apart. Changes in LAV that occurred between the second and the first echocardiographic studies were used to predict CV events during the ensuing 27 +/- 13 mo. During the follow-up, there was a significant increase in LAV (from 10.5 +/- 5.0 to 11.6 +/- 5.6 ml/m(2.7); P < 0.001). After the second echocardiographic study, 76 patients died (52 [68%] of CV causes) and 33 had nonfatal CV events. The independent association between changes in LAV and CV events was analyzed in a multiple Cox regression model taking into account a series of potential confounders, including baseline LAV and left ventricular mass and geometry. In these models, a 1-ml/m(2.7) per yr increase in LAV was associated with a 12% increase in the relative risk for fatal and nonfatal CV events (P < 0.001). Changes in LAV predict incident CV events in dialysis patients independent of the corresponding baseline measurement and of left ventricular mass. Monitoring LA size by echocardiography is useful for monitoring CV risk in patients with ESRD.
Immunoselection of tumor cell variants by mice suppressed with ultraviolet radiation.
Authors: J L Urban, J M Holland, M L Kripke, H Schreiber
Journal: The Journal of Experimental Medicine (1982)

It has previously been shown that mice exposed to ultraviolet radiation (UV) fail to reject highly immunogenic UV-induced tumors, which are regularly rejected by normal mice. The present study shows, however, that this immunosuppresion is incomplete, as UV-treated mice can still mount certain tumor-specific immune responses and reject smaller inocula of tumor cells that regularly grow progressively in athymic nude mice. Furthermore, all tumor cell lines that were reisolated from the tumor mass resulting from one tumor passage through UV-treated recipients heritably lost a tumor-specific determinant present on the parental tumor cells used for transplantation, and a large percentage of these reisolated variant tumors had changed to progressively growing tumors, in that they were no longer rejected by normal mice. In contrast, none of the tumors reisolated from passage through athymic nude mice or anti-idiotypically suppressed mice showed this change in antigenicity and progressive growth behavior. Thus, it appears that the phenotypic change in tumors reisolated from UV-treated mice was caused by immunoselection, and that the tumor-specific immunity in these mice apparently restrained the outgrowth of the parental tumor cells despite the partial immunosuppression. Because of the regularity at which tumor variants arose in the UV-treated mice after tumor transplantation, it appears that the partial immunosuppression caused by UV-treatment may have favored the outgrowth of antigenic variants from the parental tumor cell population, possibly by allowing more time for the generation of tumor variants. A similar immunoselection process might be part of tumor progression during tumor development and preferentially occur in cancer-bearing individuals showing concomitant tumor immunity.