tbuckley/cabot-search huggingface dataset:
Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene.
Authors: D Wofsy, E D Murphy, J B Roths, M J Dauphinée, S B Kipper, N Talal
Journal: The Journal of Experimental Medicine (1981)

Spleen cells from MRL-lpr and B6-lpr mice have a marked defect in the ability to produce interleukin 2 (IL-2) in response to concanavalin A stimulation. This defect precedes the onset of clinical illness, increases with age, and eventually becomes virtually absolute. It is not due to cellular suppression of IL-2 production, nor does it reflect the presence of a soluble inhibitor of IL-2 activity. Failure to restore IL-2 production with macrophage-replacing factors, such as interleukin 1 and phorbol myristic acetate, suggests that IL-2 deficiency reflects a primary T cell defect rather than a macrophage defect. MRL-lpr and B6-lpr spleen cells also have an age-dependent reduction in IL-2 response that apparently results from a deficiency of cell surface receptors for IL-2. Congenic MRL-+/+ and B6-+/+ mice, which lack the lpr gene responsible for accelerated autoimmunity and lymphoproliferation, have normal IL-2 activity. These findings suggest that a defect in IL-2 activity may contribute to impaired immunoregulation in mice bearing the lpr gene. The absence of such a defect in MRL-+/+ and B6-+/+ mice further suggests that a single autosomal recessive gene is responsible for IL-2 deficiency.
Association of RASSF1A and p63 with Poor Recurrence-Free Survival in Node-Negative Stage I–II Non–Small Cell Lung Cancer
Authors: Eunkyung Ko, Bo Bin Lee, Yujin Kim, Eun Ju Lee, Eun Yoon Cho, Jungho Han, Young Mog Shim, Joobae Park, Duk-Hwan Kim
Journal: Clinical Cancer Research (2013)

Abstract Purpose: This study was aimed at analyzing the recurrence-related prognostic significance of 12 candidate molecular biomarkers in node-negative stage I–II non–small cell lung cancer (NSCLC). Experimental Design: We retrospectively analyzed promoter methylation of eight genes using methylation-specific PCR in formalin-fixed and paraffin-embedded tissues from 328 node-negative stage I–II NSCLCs. The expression of Bcl-2, E-cadherin, p53, and p63 proteins was also assessed by immunohistochemistry. Results: Recurrence was found in 145 (44%) of 328 node-negative stage I–II NSCLCs with a median follow-up period of 6.2 years. No association was found between recurrence and alteration of individual biomarker in univariate analysis. We defined recurrently divergent groups on the basis of recursive partitioning analyses for 12 biomarkers and found a significant association of co-alteration of RASSF1A and p63 with poor recurrence-free survival (RFS). Cox proportional hazards analysis showed that hypermethylation of RASSF1A and negative expression of p63 was associated with poor RFS [HR, 1.93; 95% confidence interval (CI), 1.13–5.47; P = 0.009] compared with those without co-alteration of RASSF1A and p63, after adjusting for age, adjuvant therapy, histology, and tumor size. Random forest classifier including RASSF1A and p63 showed best performance in the prediction of recurrence in node-negative stage I–II NSCLCs: area under receiver operator characteristic curve for random forest was 0.91 and error rate for the model was 17%. Conclusion: The present study suggests that RASSF1A and p63 may be independent prognostic indicators for RFS in node-negative stage I–II NSCLCs. Clin Cancer Res; 19(5); 1204–12. ©2012 AACR.
The function of Ia+ dendritic cells and Ia- dendritic cell precursors in thymocyte mitogenesis to lectin and lectin plus interleukin 1.
Authors: K Inaba, M D Witmer-Pack, M Inaba, S Muramatsu, R M Steinman
Journal: The Journal of Experimental Medicine (1988)

The response of thymocytes to lectin is a standard tissue culture model for identifying cytokines such as IL-1 that are required for thymocyte mitogenesis. To study accessory cell requirements for these responses, it was necessary to deplete endogenous accessory cells with two techniques: anti-Ia and complement, and passage over nylon wool. Proliferation to Con A was then restored with 0.1-0.3% exogenous splenic dendritic cells, or 30-fold higher levels of peritoneal macrophages. The "costimulatory" action of IL-1, whereby responses to lectin were enhanced 3-10-fold, required the presence of dendritic cells. This effect of IL-1 could be reproduced by culturing the dendritic cells for 12 h in 1 U/ml human or murine rIL-1 alpha before addition to the thymocyte proliferation assay. The function of IL-1-treated dendritic cells was not blocked by a neutralizing anti-IL-1 antibody. The endogenous population of thymic accessory cells was partially characterized. A trace (0.1-0.3%) fraction of Ia+, Ig-, plastic nonadherent dendritic cells was visualized and enriched to a level of 1-10% by depleting CD4+,CD8+, and Ig+ lymphocytes. When this double-negative population was cultured with IL-1 and washed, the treated thymic dendritic cells were 10-fold more active as accessory cells. When the CD4-,CD8-, Ig- populations were depleted of dendritic cells with anti-Ia and complement, the subsequent addition of IL-1 had a second effect. Ia+ dendritic cells redeveloped over a 2-d interval, and they exhibited the same properties as resident dendritic cells in thymus and spleen. The majority were lysed by 33D1 anti-dendritic cell mAb and complement, lacked Fc receptors, and acted as powerful stimulators of the MLR and Con A mitogenesis. The development of dendritic cells did not occur with IL-2, -3, -4 or granulocyte/macrophage colony-stimulating factor or in nylon-nonadherent populations. The IL-1-dependent, Ia- precursor was not detectable in bone marrow. These results begin to analyze the endogenous accessory function of the thymus in culture. Dendritic cells actively stimulate thymocyte mitogenesis. The mitogenic action of IL-1 involves effects on resident Ia+ dendritic cells as well as a new population of thymic, Ia- precursors.
Visualization of Calcium Dynamics in Kidney Proximal Tubules
Authors: Kornélia Szebényi, András Füredi, Orsolya Kolacsek, Rózsa Csohány, Ágnes Prókai, Katalin Kis-Petik, Attila Szabó, Zsuzsanna Bősze, Balázs Bender, József Tóvári, Ágnes Enyedi, Tamás I. Orbán, Ágota Apáti, Balázs Sarkadi
Journal: Journal of the American Society of Nephrology (2015)

Intrarenal changes in cytoplasmic calcium levels have a key role in determining pathologic and pharmacologic responses in major kidney diseases. However, cell-specific delivery of calcium-sensitive probes in vivo remains problematic. We generated a transgenic rat stably expressing the green fluorescent protein-calmodulin-based genetically encoded calcium indicator (GCaMP2) predominantly in the kidney proximal tubules. The transposon-based method used allowed the generation of homozygous transgenic rats containing one copy of the transgene per allele with a defined insertion pattern, without genetic or phenotypic alterations. We applied in vitro confocal and in vivo two-photon microscopy to examine basal calcium levels and ligand- and drug-induced alterations in these levels in proximal tubular epithelial cells. Notably, renal ischemia induced a transient increase in cellular calcium, and reperfusion resulted in a secondary calcium load, which was significantly decreased by systemic administration of specific blockers of the angiotensin receptor and the Na-Ca exchanger. The parallel examination of in vivo cellular calcium dynamics and renal circulation by fluorescent probes opens new possibilities for physiologic and pharmacologic investigations.
Tonic B cell antigen receptor signals supply an NF-κB substrate for prosurvival BLyS signaling
Authors: Jason E Stadanlick, Mary Kaileh, Fredrick G Karnell, Jean L Scholz, Juli P Miller, William J Quinn III, Randall J Brezski, Laura S Treml, Kimberly A Jordan, John G Monroe, Ranjan Sen, Michael P Cancro
Journal: Nature Immunology (2008)
COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial
Authors: Li-Yan Khor, Kyounghwa Bae, Alan Pollack, M Elizabeth H Hammond, David J Grignon, Varagur M Venkatesan, Seth A Rosenthal, Mark A Ritter, Howard M Sandler, Gerald E Hanks, William U Shipley, Adam P Dicker
Journal: The Lancet Oncology (2007)
Interaction between Adiponectin and Leptin Influences the Risk of Colorectal Adenoma
Authors: Taiki Yamaji, Motoki Iwasaki, Shizuka Sasazuki, Shoichiro Tsugane
Journal: Cancer Research (2010)

Obesity has been associated with an increased risk of colorectal neoplasia, but the mechanisms of this potential association have not been elucidated. We hypothesized that the adipokines adiponectin, leptin, and tumor necrosis factor-alpha (TNF-alpha) may mediate an association between obesity and colorectal cancer. We measured plasma concentrations of total and high-molecular-weight (HMW) adiponectin, leptin, and TNF-alpha in healthy volunteer examinees who underwent total colonoscopy between February 2004 and February 2005, and conducted a case-control study consisting of 778 cases and 735 controls. An inverse association of total and HMW adiponectin was observed with colorectal adenoma (P trend < 0.001 and 0.03, respectively). Further, total adiponectin interacted with leptin, but not TNF-alpha, in relation to colorectal adenoma (P interaction = 0.007). An inverse association of total adiponectin with colorectal adenoma was apparent in the highest two tertiles of leptin, particularly the middle (P trend < 0.001), whereas a positive association of leptin was obvious in the lowest tertile of total adiponectin (P trend = 0.01) after adjusting for potential confounders and body mass index, which is a major determinant of insulin resistance. Adiponectin may exert an anticarcinogenic effect on the large intestine by interfering with leptin, whereas leptin could conversely exert a carcinogenic effect under conditions of a lower abundance of adiponectin. Our findings provide the first epidemiologic evidence for interactive effects of adiponectin and leptin in the early stage of colorectal tumorigenesis, distinct from their involvement in insulin resistance.
AN ANALYSIS OF GRAFT-VERSUS-HOST DISEASE IN SYRIAN HAMSTERS
Authors: J. Wayne Streilein, R. E. Billingham
Journal: The Journal of Experimental Medicine (1970)

The epidermolytic syndrome that can be obtained at will in F1 hybrid hamsters by the cutaneous inoculation of adequate doses of parental strain lymphoid cells has been investigated to determine whether the cutaneous lesions are due to an autoimmune process arising from the severe, initial GVH reactions in the skin. It was amply demonstrated that inoculation of donor cells into the skin was of crucial importance to the development of epidermolysis. Parental strain lymphoid cells in similar doses delivered by any other route into normal F1 hybrids failed absolutely to incite the acute syndrome. If "immune lymphocyte transfer" reactions incited by donor cells in the host's skin were surgically removed at timed intervals after inoculation, only complete excision within 24 hr prevented the appearance of epidermolysis in F1 hybrid hosts, indicating that inoculated donor cells must remain within the confines of the skin for approximately 24 hr in order to evoke the disease, persistence for longer periods of time being unnecessary for the subsequent course of the disease. However, reconstitution experiments involving the intramuscular inoculation of suspensions containing mixtures of donor cells and host lymphoid cells, in the presence or absence of epidermal cells, unequivocally indicated that no intimate exposure of lymphoid cells to putative skin-specific antigens was essential. Similarly, the elicitation of generalized epidermolysis in F1 hybrids irradiated with 300 r and then inoculated intravenously with donor cells casts further doubt on the pathogenic importance of the skin as a source of tissue-specific antigen. The results of subsequent experiments indicated that host leukocytes, rather than parenchymal cells of the dermis or the epidermis, were important contributors of the transplantation antigenic stimulus. Moreover, a series of experiments, using (CB x MHA)F1 hybrid hosts that had been lethally irradiated and reconstituted with bone marrow cells from ALS-treated MHA donors, indicated that from 6 to 10 wk after reconstitution—when direct and immune lymphocyte transfer reactions showed a virtual absence of native F1 leukocytes from the circulation—donor cells obtained from specifically sensitized MHA donors were completely ineffective in inducing epidermolysis, while equivalent lymphoid cell inocula derived from CB donors evoked the cutaneous disease irrespective of the time elapsed since reconstitution. To explain these findings it is postulated that in hamsters, the primary targets in graft-versus-host disease incited by the intracutaneous inoculation of donor cells are leukocytes originating in bone marrow or lymph node, or both.
Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma
Authors: Hitoshi Yoshiji, Shigeki Kuriyama, Junichi Yoshii, Yasuhide Ikenaka, Ryuichi Noguchi, Daniel J. Hicklin, James Huber, Toshiya Nakatani, Hirohisa Tsujinoue, Koji Yanase, Hiroo Imazu, Hiroshi Fukui
Journal: Hepatology (2002)

The growth of any solid tumor depends on angiogenesis. Among the known angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), are potent and representative factors involved in tumor development. It has been reported that bFGF and VEGF showed a synergistic effect in both in vitro and in vivo angiogenesis. However, the interaction of these factors on tumor development and angiogenesis, including hepatocellular carcinoma (HCC), has not yet been elucidated. In this study, we examined the combined effect of bFGF and VEGF overexpression by means of a combination of a retroviral tetracycline (tet)–regulated (Retro-Tet) gene expression system, which can manipulate the gene expression in vivo by providing tet in the drinking water, and a conventional plasmid gene expression system. In an allograft study, bFGF and VEGF overexpression synergistically increased tumor growth and angiogenesis in the murine HCC cells. This synergistic effect also was found in established tumors. VEGF messenger RNA (mRNA) expression in the tumor was increased 3.1-fold by bFGF-overexpression, and the bFGF-induced tumor development was significantly attenuated by treatment with KDR/Flk-1 neutralizing monoclonal antibody. In conclusion, these results suggest that bFGF synergistically augments VEGF-mediated HCC development and angiogenesis at least partly by induction of VEGF through KDR/Flk-1.
CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation
Authors: Liuyang Wang, Stefan H. Oehlers, Scott T. Espenschied, John F. Rawls, David M. Tobin, Dennis C. Ko
Journal: Genome biology (2015)

Meta-analyses of genome-wide association studies (GWAS) have demonstrated that the same genetic variants can be associated with multiple diseases and other complex traits. We present software called CPAG (Cross-Phenotype Analysis of GWAS) to look for similarities between 700 traits, build trees with informative clusters, and highlight underlying pathways. Clusters are consistent with pre-defined groups and literature-based validation but also reveal novel connections. We report similarity between plasma palmitoleic acid and Crohn's disease and find that specific fatty acids exacerbate enterocolitis in zebrafish. CPAG will become increasingly powerful as more genetic variants are uncovered, leading to a deeper understanding of complex traits. CPAG is freely available at www.sourceforge.net/projects/CPAG/ .
DEMYELINIZATION INDUCED IN LIVING RABBITS BY MEANS OF A LIPOLYTIC ENZYME PREPARATION
Authors: F. Stephen Vogel
Journal: The Journal of Experimental Medicine (1951)

Purified lipase, injected intracerebrally and intravasculariy in rabbits, gave rise to focal areas of demyelinization in the central nervous system in 10 of 13 animals so treated. In one instance the lesions became manifest within 48 hours and in another they persisted for 6 months; they were not infrequently accompanied by paresis and by tilting or tremor of the head. They were characterized by a focal loss of myelin and moderate gliosis with little or no neuronal destruction or inflammatory reaction, in these respects resembling the plaques of multiple sclerosis. The intracerebral injection of trypsin and chymotrypsin in control animals failed to produce the characteristic demyelinization, but by contrast caused focal areas of necrosis in which all the cerebral tissues were involved. Furthermore, demyelinization did not result when heat-inactivated pancreatic lipase was injected intracerebrally, and similarly negative results were obtained when an incubated mixture comprised of fatty connective tissue that had been acted upon by the pancreatic preparation and then heated to inactivate the lipase, was injected into the brains of rabbits. In supplementary experiments the pancreatic lipase preparation and fresh rabbit brain, incubated together in vitro, were found to form acid, presumably owing to the breakdown of brain lipids to fatty acids; trypsin and chymotrypsin mixed with brain in control experiments failed to form acid. When incubated with segments of the spinal cord of experimental animals, the lipolytic enzyme brought about a loss of stainable myelin in peripheral areas and in the spinal nerve roots; again trypsin and chymotrypsin had no such effect in control experiments. The findings as a whole show that an enzyme preparation with lipolytic activity has the ability to destroy myelin in living animals, and in vitro as well, and to produce lesions remarkably similar to those of multiple sclerosis. They have additional interest in light of the demonstration that a lipolytic enzyme is regularly present in the reactive histiocytes of guinea pigs with experimental encephalomyelitis (5).
The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis
Authors: Yoshiteru Miyauchi, Ken Ninomiya, Hiroya Miyamoto, Akemi Sakamoto, Ryotaro Iwasaki, Hiroko Hoshi, Kana Miyamoto, Wu Hao, Shigeyuki Yoshida, Hideo Morioka, Kazuhiro Chiba, Shigeaki Kato, Takeshi Tokuhisa, Mitinori Saitou, Yoshiaki Toyama, Toshio Suda, Takeshi Miyamoto
Journal: The Journal of Experimental Medicine (2010)

Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte-induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets 'osteoclastic' molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1-Bcl6-osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.
Protein Kinase D Regulates Cell Migration by Direct Phosphorylation of the Cofilin Phosphatase Slingshot 1 Like
Authors: Philipp Peterburs, Johanna Heering, Gisela Link, Klaus Pfizenmaier, Monilola A. Olayioye, Angelika Hausser
Journal: Cancer Research (2009)

Abstract Protein kinase D (PKD) has been identified as a negative regulator of epithelial cell migration; however, its molecular substrates and downstream signaling pathways that mediate this activity have remained elusive. In this study, we provide evidence that the cofilin phosphatase slingshot 1 like (SSH1L), an important regulator of the complex actin remodeling machinery, is a novel in vivo PKD substrate. PKD-mediated phosphorylation of serines 937 and 978 regulates SSH1L subcellular localization by binding of 14-3-3 proteins and thus impacts the control of local cofilin activation and actin remodeling during cell migration. In line with this, we show that the loss of PKD decreases cofilin phosphorylation, induces a more spread cell morphology, and stimulates chemotactic migration of breast cancer cells in an SSHL1-dependent fashion. Our data thus identify PKD as a central regulator of the cofilin signaling network via direct phosphorylation and regulation of SSH1L. [Cancer Res 2009;69(14):5634–8]
Doctors are only ones to benefit from changes in out of hours care, say MPs
Authors: Adrian O'Dowd
Journal: BMJ (2006)

Changes to the provision for out of hours primary care in England were a costly mess that allowed GPs to “run laughing all the way to the bank,” it has been claimed in a parliamentary inquiry.

MPs on the parliamentary Committee of Public Accounts, which held its inquiry into the provision of out of hours care in England last week, accused government witnesses giving evidence of allowing a change to how out of hours care is delivered that benefited only doctors.

The one-off evidence session for the inquiry was prompted by the publication earlier this month of a report by the government's spending watchdog, the …