tbuckley/cabot-search huggingface dataset:
Comparison of methylation profiles in human blood and lung tissue identifies tissue specific CpG methylation sites
Authors: Denise Daley, Kevin Ushey, Loubna Akhabir, Andrew Sandford, Michael Kobor, Peter Paré
Journal: European Respiratory Journal (2013)

Differences in methylation may contribute to the etiology of asthma, COPD and other lung related traits. As methylation patterns may be tissue specific we evaluated tissue specific methylation (TSM) patterns between blood and lung tissue.  Methods: Using the Illumina Infinium HumanMethylation450K bead chip array, 36 paired samples (blood and lung tissue from the same individual) and 22 lung only samples, methylation levels were assessed using beta values. Correlations between beta values were examined using principal components, heatmaps, and a mixture model.  Results: 49,376 CpG sites demonstrated tissue specific methylation. 31 CpG sites demonstrated extreme differences with complete methylation in lung tissue but no methylation in blood tissue. The remaining 49,345 CpG sites demonstrated more modest differences. Next we examined genes associated with lung related diseases.  At ORMDL3 the patterns vary similar but there is poor concordance at sites within the TSLP gene (figure 1), this can be better seen in figure 2.  Conclusion: We have identified 49,376 CpG sites with tissue specific methyation, including CpG sites within TSLP.
Circulating Ki-67 protein as a biomarker and prognostic indicator of acute lymphoblastic leukemia
Authors: Jean-Marie Bruey, Hagop Kantarjian, Wanlong Ma, Deborah Thomas, Francis Giles, Maher Albitar
Journal: Clinical Cancer Research (2008)

B36  Ki-67 plays an important role in solid tumors and hematological malignancies, and the Ki-67 proliferation index is often correlated with the clinical course of cancer. The prognostic significance of plasma levels of circulating Ki-67 (cKi-67) in patients with cancer remains unknown. We developed a method to measure plasma levels of cKi-67 using a Meso Scale Discovery (MSD) system and demonstrate the assay is highly reproducible and sensitive in detecting low levels in normal individuals. We measured cKi-67 in patients with acute lymphoblastic leukemia (ALL), and then correlated levels with laboratory findings and clinical behavior. All expected quantitative changes in cell lysates were seen; high levels of cKi-67 were detected in cell lysates from cells in cycling stages (G1, S, G2, and mitosis) but not in lysates from cells in the G0 stage after serum starvation. We also show that low levels of cKi-67 can be detected by Immunoblot and by MSD in the plasma of normal controls, confirming the presence of intact Ki-67 protein in plasma. Significantly higher levels of cKi-67 (median, 762 ; range, 0-4574 U/100 µL) were found in newly diagnosed ALL patients (n=27) as compared with normal controls (median, 399; range, 36-2830 U/100 µL) (n=114). Patients with higher plasma levels of cKI-67 had significantly shorter survival that patients with low levels (P=0.05, Figure). Two of the 27 ALL cases were classified as Burkitt’s and showed high levels of cKi-67 (999 and 1623 U/100 µL of plasma). Patient older than 70 years of age with ALL had significantly higher cKi-67 levels (P=0.05). These findings suggest that measuring cKI-67 protein levels in plasma may have a prognostic value in patients with ALL.The value of this biomarker in other diseases will also be discussed.
Specific nasal challenge in the diagnosis of alternaria-induced asthma
Authors: Dimitrios Latsios, Despoina Papakosta, Konstantinos Porpodis, Theodoros Kontakiotis, Chloe Asaridou, Katerina Manika, Dimitrios Gioulekas, Konstantinos Zarogoulidis
Journal: European Respiratory Journal (2011)

Background:  Allergic sensitization to Alternaria has been identified as a risk factor for the development and persistence of asthma and is associated with severe and life-threatening episodes. The interaction between upper and lower airways has not been investigated for Alternaria.   Aims and objectives:  To investigate whether specific nasal challenge with Alternaria allergen can be used as a diagnostic tool for Alternaria-induced asthma.   Patients and methods:  The study included 15 adults patients with mild, allergic asthma sensitive to Alternaria and two control groups: 1) 8 patients with mild, allergic asthma non-attributed to Alternaria and 2) 7 healthy controls. Diagnosis of asthma was already established by positive both reversibility and methacholine test. Two nasal provocation tests were performed, one with normal saline (placebo) and another with Alternaria antigen (specific nasal challenge, SNC) performed at two different days. FEV 1  was measured during a 12-hour period, at 18 time points (10, 20, 30, 40, 50, 60, 90, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720 minutes) after nasal provocation.   Results:  A significant FEV 1  decline >20% from baseline (26.02±2.38%) was recorded after SNC (p   Conclusions:  Specific nasal challenge could be a reliable and specific tool for the diagnosis of Alternaria-induced asthma, alternatively to bronchial challenge, in case confirmation of mould implication is necessary.
Protective effect of lecithinized superoxide dismutase (PC-SOD) againast elastase-induced pulmonary emphysema in mice
Authors: Ken-Ichiro Tanaka, Tohru Mizushima
Journal: European Respiratory Journal (2011)

No medication exists that clearly improves mortality of chronic obstructive pulmonary disease (COPD). Oxidative molecules, in particular superoxide anions would play important roles in the abnormal inflammatory response and in pulmonary emphysema, which arises due to an imbalance in proteases and antiproteases and increased levels of apoptosis. Superoxide dismutase (SOD) catalyses the dismutation of a superoxide anion to hydrogen peroxide. Lecithinized SOD (PC-SOD) has overcome a number of the clinical limitations of SOD, including low tissue affinity and low stability in plasma. In this study, we examine the effect of PC-SOD on elastase-induced pulmonary emphysema.  The severity of the pulmonary inflammatory response and emphysema in mice was assessed by various criteria, such as enlargement of airspace.  Inhalation of PC-SOD suppressed elastase-induced pulmonary inflammation, emphysema and dysfunction. Inhalation of PC-SOD also suppressed the elastase-induced increase in the pulmonary level of superoxide anions, cell death, activation of proteases and expression of pro-inflammatory cytokines and chemokines. We also found that inhalation of PC-SOD suppressed cigarette smoke-induced pulmonary inflammation.  The results suggest that PC-SOD protects against pulmonary emphysema by inhibition of inflammation and cell death and amelioration of the protease/antiprotease imbalance. We propose that inhalation of PC-SOD would be therapeutically beneficial for COPD.
Enhancement of Tumorigenesis in the Urinary Bladder of Rats by Neonatal Administration of 2-Acetylaminofluorene<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref>
Authors: Ryoichi Oyasu, Hector A. Battifora, Reuben Eisenstein, James H. McDonald, George M. Hass
Journal: JNCI Journal of the National Cancer Institute (1968)
Quantitative Studies on the Induction of Tolerance of Skin Homografts and on Runt Disease in Neonatal Rats&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: R. E. Billingham, V. Defendi, W. K. Silvers, D. Steinmuller
Journal: JNCI Journal of the National Cancer Institute (1962)

Two highly inbred but unrelated strains of rat, Lewis and B.N., were used in quantitative studies to determine the influence of dose, histological origin, and time of intravenous injection after birth of living homologous cell inocula on the induction of 1) tolerance of subsequent skin homografts and 2) runt disease in this species. Cell dose was an important factor in induction of tolerance and must be considered in any definition of the tolerance-responsive period. Evidence is presented that cell suspensions derived from different components of the lympho-hematopoietic system differ in their capacity to confer tolerance in respect to skin. F1 hybrid bone marrow cells were as effective in conferring tolerance as parental-strain marrow cells, but spleen cells, node cells, and leukocytes from adult hybrid donors gave significantly inferior results. However, spleen cells from infant donors were as effective as adult marrow cells. Parental-strain thymocytes were just perceptibly effective. The evidence suggests that tolerance may be induced by cells of some types in respect to themselves which does not extend to skin homografts of similar genetic origin. Thus, there may be differences between the spectra of transplantation antigens expressed by different types of tissue cells from the same individual. Depending on the dose administered, cellular inocula derived from adult spleens, lymph nodes, thoracic-duct lymphocytes, and leukocytes all caused runt disease, though thymocytes were relatively harmless even at high dose levels. Induction of a demonstrable level of tolerance is not necessary for development of this condition. The clinical history and pathology of runt disease was analyzed. In young rats, this disease is characterized by the arrest of body growth, diffuse dermatitis, enlargement of spleen and lymph nodes, with follicular atrophy, atrophy of the thymus, dyscrasia of bone marrow and blood, and hypothermia. Development of these symptoms follows a definite sequence, and death occurs within 15 to 22 days after inoculation of the homologous, immunologically competent cells. Possible pathogenesis of runt disease is discussed, though no completely satisfactory interpretation of the syndrome can be given. An attempt is made to differentiate primary symptoms, resulting from the immunological reaction of the grafted tissue against the host, from secondary ones.
Immunologic injury of cultured cells infected with measles virus. I. role of IfG antibody and the alternative complement pathway.
Authors: B S Joseph, N R Cooper, M B Oldstone
Journal: The Journal of Experimental Medicine (1975)

In these studies, a number of human cell lines including epithelial, neural, glial, and lymphoid cells infected with several strains of measles virus were found to be lysed upon incubation with fresh sera from humans containing antibody measles virus. In all instances, the cytolytic event was mediated by alternative complement (C) pathway without a significant contribution from classical pathway. In contrast, isolated measles virus in conjunction with antibody was found to selectively activate the classical C pathway. Measles antibodies of the IgG class, but not the IgA class, possessed cytolytic potential against cells infected with measles virus. Human IgG antibodies could directly activate the alternative C pathway. No defect was found in cytolytic measles antibody in sera or cerebrospinal fluid from patients with subacute sclerosing panencephalitis, nor was the alternative C pathway impaired in sera from these patients. Sera from newborn humans exhibited a functional alternative C pathway.
Induction of senescence pathways in Kindler syndrome primary keratinocytes
Authors: E. Piccinni, G. Di Zenzo, R. Maurelli, E. Dellambra, M. Teson, C. Has, G. Zambruno, D. Castiglia
Journal: British Journal of Dermatology (2012)

Background Individuals with Kindler syndrome (KS) have loss‐of‐function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin‐1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. Objectives To investigate how kindlin‐1 deficiency affects the proliferative potential of primary human keratinocytes. Methods We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony‐forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin‐1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. Results We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi‐1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle‐arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin‐1 proved that its deficiency was directly responsible for p63, Bmi‐1 and pRb downregulation and p16 induction. Conclusions Our data directly implicate kindlin‐1 in preventing premature senescence of keratinocytes.
Lymphomas in BALB/c Mice Inoculated With Supernatants From Chemically Induced Sarcomas 2 3
Authors: Miguel Angel Basombrío
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Lymphomas in BALB/c Mice Inoculated With Supernatants From Chemically Induced Sarcomas Get access Miguel Angel Basombrío Miguel Angel Basombrío The Institute for Cancer Research, 7701 Burholme Ave., Fox Chase, Philadelphia, Pa. 19111 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 51, Issue 4, October 1973, Pages 1157–1162, https://doi.org/10.1093/jnci/51.4.1157 Published: 01 October 1973 Article history Received: 16 March 1973 Accepted: 31 May 1973 Published: 01 October 1973
Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts
Authors: Moshi Song, Guohua Gong, Yan Burelle, Åsa B. Gustafsson, Richard N. Kitsis, Scot J. Matkovich, Gerald W. Dorn
Journal: Circulation Research (2015)

Rationale: The role of Parkin in hearts is unclear. Germ-line Parkin knockout mice have normal hearts, but Parkin is protective in cardiac ischemia. Parkin-mediated mitophagy is reportedly either irrelevant, or a major factor, in the lethal cardiomyopathy evoked by cardiac myocyte–specific interruption of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Objective: To understand the role of Parkin-mediated mitophagy in normal and mitochondrial fission–defective adult mouse hearts. Methods and Results: Parkin mRNA and protein were present at low levels in normal mouse hearts, but were upregulated after cardiac myocyte–directed Drp1 gene deletion in adult mice. Alone, forced cardiac myocyte Parkin overexpression activated mitophagy without adverse effects. Likewise, cardiac myocyte–specific Parkin deletion evoked no adult cardiac phenotype, revealing no essential function for, and tolerance of, Parkin-mediated mitophagy in normal hearts. Concomitant conditional Parkin deletion with Drp1 ablation in adult mouse hearts prevented Parkin upregulation in mitochondria of fission-defective hearts, also increasing 6-week survival, improving ventricular ejection performance, mitigating adverse cardiac remodeling, and decreasing cardiac myocyte necrosis and replacement fibrosis. Underlying the Parkin knockout rescue was suppression of Drp1-induced hyper-mitophagy, assessed as ubiquitination of mitochondrial proteins and mitochondrial association of autophagosomal p62/sequestosome 1 (SQSTM1) and processed microtubule-associated protein 1 light chain 3 (LC3-II). Consequently, mitochondrial content of Drp1-deficient hearts was preserved. Parkin deletion did not alter characteristic mitochondrial enlargement of Drp1-deficient cardiac myocytes. Conclusions: Parkin is rare in normal hearts and dispensable for constitutive mitophagic quality control. Ablating Drp1 in adult mouse cardiac myocytes not only interrupts mitochondrial fission, but also markedly upregulates Parkin, thus provoking mitophagic mitochondrial depletion that contributes to the lethal cardiomyopathy.
Thymidine Phosphorylase Regulates the Expression of CXCL10 in Rheumatoid Arthritis Fibroblast‐like Synoviocytes
Authors: Yuko Toyoda, Sho Tabata, Jun Kishi, Takuya Kuramoto, Atsushi Mitsuhashi, Atsuro Saijo, Hiroshi Kawano, Hisatsugu Goto, Yoshinori Aono, Masaki Hanibuchi, Hideaki Horikawa, Toshihiro Nakajima, Tatsuhiko Furukawa, Saburo Sone, Shin‐ichi Akiyama, Yasuhiko Nishioka
Journal: Arthritis & Rheumatology (2013)

Thymidine phosphorylase (TP) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) is induced by tumor necrosis factor α (TNFα) and other cytokines that have been reported to be major inflammation mediators in RA. We previously demonstrated that TP plays an important role in angiogenesis and tumor growth, invasion, and metastasis. The aim of this study was to investigate whether the role of TP in the pathogenesis of RA is similar to its role in tumors.In FLS obtained from 2 patients with RA, the expression of TP, interferon-γ (IFNγ)-inducible protein 10 (CXCL10), and other cytokines was measured by quantitative real-time polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assays. Microarray analysis was performed using FLS transfected with TYMP complementary DNA and treated with a TP inhibitor.The expression of TP in FLS was up-regulated by TNFα, interleukin-1β (IL-1β), IL-17, IFNγ, and lipopolysaccharide. Microarray analysis of FLS overexpressing TP identified CXCL10 as a thymidine phosphorylase-related gene. The expression of CXCL10 was induced by TNFα, and this induction was suppressed by TYMP small interfering RNA and TP inhibitor. Furthermore, the combination of TNFα and IFNγ synergistically augmented the expression of TP and CXCL10. TP-induced CXCL10 expression was suppressed by the antioxidant EUK-8. In the synovial tissue of patients with RA, TP levels were significantly correlated with CXCL10 expression.The combination of TNFα and IFNγ strongly induced the expression of thymidine phosphorylase in RA FLS. The induction of thymidine phosphorylase enhanced the expression of CXCL10, which may contribute to the Th1 phenotype and bone destruction observed in RA.
Differential regulation of the dual-specificity protein-tyrosine phosphatases CL100, B23, and PAC1 in mesangial cells.
Authors: D Bokemeyer, A Sorokin, M J Dunn
Journal: Journal of the American Society of Nephrology (1997)

The extracellular-signal-regulated kinase (ERK), the best described MAP kinase cascade, is a major signaling system by which cells transduce extracellular cues into intracellular responses. ERK is activated by phosphorylation both on tyrosine and threonine residues. Therefore, a new clas of protein-tyrosine phosphatases (PTPases) that exhibit dual catalytic activity toward both regulatory sites on ERK is of special interest in the control of intracellular signaling. This study examined the expression and regulation of the dual-specificity PTPases CL100, B23, and PAC1. Findings included differential expression of these phosphatases in diverse cell lines and an expression of all three dual-specificity PTPases in human mesangial cells (HMC), thereby allowing investigation of their regulation in a single cell line. The MEK antagonist PD 098059 and selective extracellular agonists of ERK were used to demonstrate the induction of CL100, PAC1, and B23 in response to activation of the ERK cascade. In contrast, anisomycin, an agonist of the recently described MAP kinases stress-activated protein kinase (SAPK) and p38 MAP kinase, stimulated CL100 gene expression but had little effect on PAC1 and B23. This effect of anisomycin was partly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. This study suggests a potential mechanism to regulate ERK activity through feedback inhibition by demonstrating the ERK cascade's induction of the dual-specificity PTPases CL100, PAC1, and B23. Moreover, this study suggests an ERK-independent induction of CL100 following stimulation of SAPK and p38 MAP kinase. This mode of induction of a phosphatase capable of inactivating ERK may play an important role in the cellular stress response.
Malignant Lymphomas of Extrathymic Origin Induced in Rats by Murine Erythroblastosis Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: W. H. Kirsten, L. A. Mayer
Journal: JNCI Journal of the National Cancer Institute (1969)

Two patterns of morphologic responses were observed in W/Fu, August, and Long-Evans rats following inoculation of rat-adapted murine erythroblastosis virus (MEV). An early response developed after potent virus doses were given to rats between 3 and 14 days of age. Morphologically, the early response included erythroblastosis, sarcomas, osteolytic lesions, and brain hemorrhages. Deaths from the early response occurred between 11 and 40 days after inoculation. The late response was observed when either low doses of rat-adapted MEV were inoculated into 3- to 5-day-old rats or when high virus doses were given intraperitoneally or intravenously to adult rats. Undifferentiated malignant lymphomas were the single morphologic entity which characterized the late response. The lymphomas did not arise in, or involve, the thymus. Cells from lymphomas were transplantable to adult rats of the same strain.
Abstract 704: Comparison of Salmonella typhimurium A1-R and VNP20009 on the Lewis Lung carcinoma
Authors: Yong Zhang, Nan Zhang, Robert M. Hoffman, Ming Zhao
Journal: Cancer Research (2014)

Abstract Salmonella typhimurium A1-R (A1-R) is auxotrophic for arg and leu, which attenuates growth in normal tissue but allows high tumor virulence. A1-R is effective against metastatic human prostate, breast, and pancreatic cancer as well as osteosarcoma, fibrosarcoma, and glioma in clinically-relevant mouse models. VNP20009 is also a genetically-modified strain of Salmonella typhimurium that has been tested in a Phase I clinical trial, but has more attenuation mutations than A1-R. Lewis-lung mouse lung cancer-bearing mice were treated with A1-R and VNP20009 in nude mice. A1-R and VNP20009 were both eliminated from the liver and spleen approximately 3-5 days after administration via tail vein, however A1-R showed higher tumor targeting and increased mouse survival than VNP20009 with less body weight loss. The mice tolerated A1-R at least 2-fold higher than NVP20009 when bacteria were administered iv. The results of the present study suggest that A1-R has greater clinical potential than VNP20009. Citation Format: Yong Zhang, Nan Zhang, Robert M. Hoffman, Ming Zhao. Comparison of Salmonella typhimurium A1-R and VNP20009 on the Lewis Lung carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 704. doi:10.1158/1538-7445.AM2014-704
Violence in the workplace
Authors: S. MacHale
Journal: BMJ (2002)

Successful leadership requires range of stylesEditor-Treasure's views and comments after the NHS Confederation's leadership conference make interesting reading. 1 The leadership style of consultants covers a broad spectrum that could be described as ranging from "huggy touchy feely" all the way up to "Attila the Hun meets Genghis Khan."A similar spectrum exists in managers.The British government's own Cabinet Office expert report on public service leadership indicates that successful leaders need to adopt a range of styles depending on the situation. 2That may include having to resort at times to coercive, browbeating styles.Many consultants would perhaps choose to operate in the lower or middle range of the style spectrum.At times when managers do not listen to consultants' reasonable concerns about the delivery of safe, effective, high quality services there may be no option but reluctantly to wheel out Attila and Genghis to protect both patients and consultants.Treasure is very fortunate to be in a specialty that is comparatively rich in resources and having its concerns addressed by major