tbuckley/cabot-search huggingface dataset:
Collagen-induced arthritis is not impaired in mast cell-deficient mice
Authors: Nick Pitman, Darren L Asquith, Grace Murphy, Foo Y Liew, Iain B McInnes
Journal: Annals of the Rheumatic Diseases (2010)

Mast cells are recognised as important effectors in allergic disease. However, it is increasingly clear that mast cells may fulfil more diverse roles within the immune system and may be pathogenic in a number of diseases not typically associated with T-helper type 2 immune responses.1 Indeed, studies have described the presence of degranulated mast cells within inflamed rheumatoid arthritis (RA) synovium and as such implicate mast cells as potential mediators in the pathogenesis of RA.2 Consistent with these observations, the severity of arthritis, induced by antibody transfer, is reduced in mast cell-deficient strains of mice, W/Wv and Sl/Sld, and can be restored by adoptive transfer of mast cells.3 4

Murine collagen-induced arthritis is a well-characterised model of RA that combines adaptive and innate immune effector components. When complete Freund's adjuvant/collagen …
Soliciting the Patient's Agenda
Authors: M. Kim Marvel, Ronald M. Epstein, Kristine Flowers, Howard B. Beckman
Journal: JAMA (1999)

Context Previous research indicates physicians frequently choose a patient problem to explore before determining the patient's full spectrum of concerns.Objective To examine the extent to which experienced family physicians in various practice settings elicit the agenda of concerns patients bring to the office.Design A cross-sectional survey using linguistic analysis of a convenience sample of 264 patient-physician interviews. Setting and ParticipantsPrimary care offices of 29 board-certified family physicians practicing in rural Washington (n = 1; 3%), semirural Colorado (n = 20; 69%), and urban settings in the United States and Canada (n = 8; 27%).Nine participants had fellowship training in communication skills and family counseling.Main Outcome Measures Patient-physician verbal interactions, including physician solicitations of patient concerns, rate of completion of patient responses, length of time for patient responses, and frequency of late-arising patient concerns. ResultsPhysicians solicited patient concerns in 199 interviews (75.4%).Patients' initial statements of concerns were completed in 74 interviews (28.0%).Physicians redirected the patient's opening statement after a mean of 23.1 seconds.Patients allowed to complete their statement of concerns used only 6 seconds more on average than those who were redirected before completion of concerns.Late-arising concerns were more common when physicians did not solicit patient concerns during the interview (34.9% vs 14.9%).Fellowship-trained physicians were more likely to solicit patient concerns and allow patients to complete their initial statement of concerns (44% vs 22%).Conclusions Physicians often redirect patients' initial descriptions of their concerns.Once redirected, the descriptions are rarely completed.Consequences of incomplete initial descriptions include late-arising concerns and missed opportunities to gather potentially important patient data.Soliciting the patient's agenda takes little time and can improve interview efficiency and yield increased data.
Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer
Authors: Carol J. Fabian, Bruce F. Kimler
Journal: Journal of Clinical Oncology (2005)

Selective estrogen receptor modulators (SERMs) impact a variety of biologic processes regulated by activated estrogen receptor (ER). Depending on the target tissue, physiologic conditions, and their structure, SERMs may exhibit either estrogen antagonist or estrogen agonist effects. SERMs have a long history in the treatment of breast cancer, based on estrogen antagonist activity in ER-positive breast cancer cells. Beginning with tamoxifen, SERMs have moved to the prevention arena, where their partial estrogen effects may provide other organ benefits, particularly for postmenopausal women. It is because of these partial estrogen agonist effects on organs such as the bone, vagina, CNS, and cardiovascular system that SERMs are likely to remain preferable to pure antiestrogens as primary breast cancer prevention agents in the context of total women’s health. The ideal SERM should function as an antiestrogen in the breast and uterus and a partial estrogen agonist in skeletal, cardiovascular, CNS, gastrointestinal tract, and vagina. Further, this ideal SERM should be devoid of procoagulant effects and should not be associated with an increase in perimenopausal symptoms. Although several generations of SERMs have been developed, the ideal SERM for prevention remains elusive. We will review progress to date for SERMs as single agents and potential for combination therapy in the future. BIOLOGY BEHIND THE MULTIFACETED ACTION OF SERMs
Role of oxidants in DNA damage. Hydroxyl radical mediates the synergistic DNA damaging effects of asbestos and cigarette smoke.
Authors: J H Jackson, I U Schraufstatter, P A Hyslop, K Vosbeck, R Sauerheber, S A Weitzman, C G Cochrane
Journal: Journal of Clinical Investigation (1987)

The mechanism by which cigarette smoking and asbestos exposure synergistically increase the incidence of lung cancer is unknown. We hypothesized that cigarette smoke and asbestos might synergistically increase DNA damage. To test this hypothesis we exposed isolated bacteriophage PM2 DNA to cigarette smoke and/or asbestos, and assessed DNA strand breaks as an index of DNA damage. Our results supported our hypothesis. 78 +/- 12% of the DNA exposed to both cigarette smoke and asbestos developed strand breaks, while only 9.8 +/- 7.0 or 4.3 +/- 3.3% of the DNA exposed to cigarette smoke or asbestos, respectively, developed strand breaks under the conditions of the experiment. Our experimental evidence suggested that cigarette smoke and asbestos synergistically increased DNA damage by stimulating .OH formation. First, significant amounts of .OH were detected by electron paramagnetic resonance (EPR) in DNA mixtures containing both cigarette smoke and asbestos, but no .OH was detected in mixtures containing cigarette smoke alone or asbestos alone. Second, the .OH scavengers, dimethylsulfoxide (DMSO), mannitol, or Na benzoate decreased both .OH detection by EPR and strand breaks in DNA mixtures exposed to cigarette smoke and asbestos. Third, the H2O2 scavenger, catalase, and the iron chelators, 1,10-phenanthroline and desferrithiocin, decreased both .OH detection and strand breaks in DNA mixtures exposed to cigarette smoke and asbestos. These latter findings suggest that iron contained in asbestos may catalyze the formation of .OH from H2O2 generated by cigarette smoke. In summary, our study indicates that cigarette smoke and asbestos synergistically increase DNA damage and suggests that this synergism may involve .OH production.
Immunoregulation of Carcinogenesis: Past, Present, and Future1
Authors: M. L. Kripke
Journal: JNCI Journal of the National Cancer Institute (1988)

Journal Article Immunoregulation of Carcinogenesis: Past, Present, and Future1 Get access Margaret L. Kripke Margaret L. Kripke 3Department of Immunology, The University of Texas System Cancer Center, M.D.Anderson Hospital and Tumor Institute1515 Holcombe Blvd., Houston, TX 77030 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 10, 20 July 1988, Pages 722–727, https://doi.org/10.1093/jnci/80.10.722 Published: 20 July 1988
Expression of 11<i>HOX</i>Genes Is Deregulated in Esophageal Squamous Cell Carcinoma
Authors: Ke-Neng Chen, Zhen-Dong Gu, Yang Ke, Ji-You Li, Xiao-Tian Shi, Guang-Wei Xu
Journal: Clinical Cancer Research (2005)

HOX genes are vital for all aspects of mammalian growth and differentiation, and recent data have shown that their deregulated expression is related to carcinogenesis. To date, there has been no systemic study on expression of HOX genes in esophageal carcinoma. We investigated the expression pattern of 39 known HOX genes in cancerous and noncancerous tissue from 36 patients with esophageal squamous cell carcinoma to determine whether their expression is altered in esophageal cancer.Thirty-six patients with resectable esophageal squamous cell carcinoma (ESCC) were enrolled in this study. Specific primers were designed for each of 39 HOX genes, and reverse transcription-PCR was done in cancerous and noncancerous samples of these 36 patients. Furthermore, the expression of HOXA9 protein was subjected to Western blot analysis in all 36 paired tissue samples.Eight of 39 HOX genes were expressed in cancerous but not in noncancerous tissue. Five of 39 HOX genes were expressed both in cancerous and noncancerous tissue. Of the latter, expression of HOXA7, HOXA9, and HOXC6 was significantly higher in cancerous tissue (P < 0.05). The remaining 26 HOX genes were not detected in either types of tissue. HOXA9 protein was expressed in both kinds of tissue (cancer tissue versus noncancerous mucosa: 0.34 +/- 0.32 versus 0.24 +/- 0.27, P = 0.121).This is the first comprehensive survey of 39 HOX gene expression in ESCC and noncancerous mucosa. Five of the 39 HOX genes were expressed in both types of tissue indicating their possible role in maintaining normal structure and function of adult esophageal mucosa. Eleven of the 39 HOX genes were deregulated in cancer tissue. These genes possibly participate in the carcinogenesis of ESCC.
Nuclear factor κB: a potential therapeutic target in atherosclerosis and thrombosis
Authors: C Monaco
Journal: Cardiovascular Research (2004)

Cardiovascular diseases are the leading cause of morbidity and mortality in Western countries. Atherosclerosis, the background for many cardiovascular diseases, is characterized by the accumulation of lipid and fibrotic entities in large arteries and bears many similarities with chronic inflammatory diseases such as rheumatoid arthritis. Common features include extravasation of blood-derived leukocytes, as well as production of cytokines, chemokines and matrix-degrading enzymes. There are also many shared signaling pathways, including activation of the nuclear factor kappaB (NFkappaB) cascade. In the context of atherosclerosis, there are a range of candidate stimuli which can activate NFkappaB, including traditional risk factors, infectious agents, cytokines and cell-cell contact. Many inflammatory genes relevant to the pathogenesis of atherosclerosis are regulated by NFkappaB, the activated form of which is present in atherosclerotic plaques. Thus, it is essential to understand the role of this important signaling cascade in atherosclerosis, in a quest for more specific therapeutic targets.
Mechanisms Linking Obesity, Chronic Kidney Disease, and Fatty Liver Disease
Authors: Joachim H. Ix, Kumar Sharma
Journal: Journal of the American Society of Nephrology (2010)

Obesity is a risk factor for chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD). Recent studies identify mechanisms common to both diseases linked through an interorgan communication orchestrated by fetuin-A and adiponectin. In liver and kidney, the energy sensor 5'-AMP activated protein kinase (AMPK) is pivotal to directing podocytes and hepatocytes to compensatory and potentially deleterious pathways, leading to inflammatory and profibrotic cascades culminating in end-organ damage. Regulation of these early upstream pathways may provide new therapeutic targets for these increasingly common sequelae of obesity.
The Relationship Between Adrenomedullin, Metabolic Factors, and Vascular Function in Individuals With Type 2 Diabetes
Authors: Su Chi Lim, Nils G. Morgenthaler, Tavintharan Subramaniam, Yew Seng Wu, Siew Kheng Goh, Chee Fang Sum
Journal: Diabetes Care (2007)

Subjects with type 2 diabetes are at risk for vascular injury. Several vasoactive factors (e.g., angiotensin) have been implicated. We hypothesize that adrenomedullin, a novel vascoactive factor, is deranged in subjects with type 2 diabetes.Using a new immunoluminometric method, plasma midregional proadrenomedullin (MR-proADM) was measured in four groups of Chinese subjects: healthy (n = 100, fasting plasma glucose [FPG] <5.6 mmol/l), impaired fasting glucose (IFG) (n = 60, FPG 5.6-6.9 mmol/l), and diabetic subjects with (n = 100) and without (n = 100) nephropathy. Resting forearm cutaneous microcirculatory perfusion (RCMP) was quantified in vivo using 2-dimensional laser Doppler flowmetry. We investigated the relationship between plasma MR-proADM concentrations, multiple metabolic factors, and vascular function.We observed a stepwise increase in MR-proADM among the groups: healthy group mean +/- SD 0.27 +/- 0.09, IFG group 0.29 +/- 0.13, diabetic group 0.42 +/- 0.13, and diabetic nephropathy group 0.81 +/- 0.54 nmol/l (diabetic vs. healthy and IFG groups, P = 0.04; and diabetic nephropathy group vs. all, P < 0.01). Statistical adjustment for sex, age, BMI, and blood pressure did not affect the conclusions. Multiple linear regression analysis revealed that highly sensitive C-reactive protein (beta = 0.11; P = 0.01), insulin resistance index (beta = 0.20; P = 0.001), LDL cholesterol (beta = 0.31; P < 0.001), and adiponectin (beta = 0.33; P < 0.001) were significant predictors of plasma MR-proADM concentrations among nondiabetic individuals. Among subjects with diabetes, plasma MR-proADM concentrations correlated significantly with RCMP (r = 0.43, P = 0.002).Plasma MR-proADM concentration was elevated in subjects with type 2 diabetes. This was further accentuated when nephropathy set in. MR-proADM was related to multiple metabolic factors and basal microcirculatory perfusion. Adrenomedullin might play a role in the pathogenesis of diabetic vasculopathy.
Anti-HCV, anti-GOR, and autoimmunity
Authors: Silvio Magrin, Giovambattista Pinzello, Antonio Craxi, Piero Almasio, Luigi Pagliaro, Barbara Hosein, Xinde Fang, Chang Yi Wang, Marco Lenzi, Fabio Cassani, Giorgio Ballardini, FrancescoB Bianchi, Shunji Mishiro, Masashi Unoura, Shuichi Kaneko, Kenichi Kobayashi
Journal: The Lancet (1992)
G-CSF–stimulated Neutrophils Are a Prominent Source of Functional BLyS
Authors: Patrizia Scapini, Bernardetta Nardelli, Gianpaolo Nadali, Federica Calzetti, Giovanni Pizzolo, Cesare Montecucco, Marco A. Cassatella
Journal: The Journal of Experimental Medicine (2003)

B lymphocyte stimulator (BLyS) is a novel member of the TNF ligand superfamily that is important in B cell maturation and survival. We demonstrate that human neutrophils, after incubation with G-CSF or, less efficiently, IFNγ, express high levels of BLyS mRNA and release elevated amounts of biologically active BLyS. In contrast, surface expression of the membrane-bound BLyS was not detected in activated neutrophils. Indeed, in neutrophils, uniquely among other myeloid cells, soluble BLyS is processed intracellularly by a furin-type convertase. Worthy of note, the absolute capacity of G-CSF–stimulated neutrophils to release BLyS was similar to that of activated monocytes or dendritic cells, suggesting that neutrophils might represent an important source of BLyS. In this regard, we show that BLyS serum levels as well as neutrophil-associated BLyS are significantly enhanced after in vivo administration of G-CSF in patients. In addition, serum obtained from two of these patients induced a remarkable accumulation of neutrophil-associated BLyS in vitro. This effect was neutralized by anti–G-CSF antibodies, indicating that G-CSF, present in the serum, stimulated neutrophils to produce BLyS. Collectively, our findings suggest that neutrophils, through the production of BLyS, might play an unsuspected role in the regulation of B cell homeostasis.
Glutathione enhances fibroblast collagen contraction and protects keratinocytes from apoptosis in hyperglycaemic culture
Authors: Mustafa Deveci, Robert R. Gilmont, W. R. Dunham, B. P. Mudge, D. J. Smith, Cynthia L. Marcelo
Journal: British Journal of Dermatology (2005)

Background Cutaneous wound healing is relatively slow in patients with diabetes. Objectives To test the hypothesis that this defect in healing of wounds in patients with diabetes results from dysfunction of skin fibroblasts and epidermal keratinocytes and that this dysfunction is related to disrupted intracellular glutathione (GSH) homeostasis. Methods We investigated the effects of esterified GSH on the contraction of fibroblasts in a fibroblast-populated collagen lattice and on keratinocyte apoptosis. Results High glucose medium (hyperglycaemia) reduced the contraction ability of fibroblasts (P < 0·05). The normalization of glucose medium concentrations for hyperglycaemic fibroblasts did not restore the contraction capacity. The percentage of apoptotic keratinocytes was statistically higher in hyperglycaemic cells (P < 0·05). GSH media concentrations ranging from 0·1 to 100 µmol L−1 restored the ability of hyperglycaemic fibroblasts to contract the gels in a concentration-dependent manner. Primary human keratinocytes grown in hyperglycaemic medium were more susceptible to apoptosis, and treatment with esterified GSH rescued the keratinocytes from apoptosis. Conclusions These data suggest that intracellular GSH can normalize skin cell functions disrupted by in vitro cell growth under hyperglycaemic conditions.
Limited copy number - high resolution melting (LCN-HRM) enables the detection and identification by sequencing of low level mutations in cancer biopsies
Authors: Hongdo Do, Alexander Dobrovic
Journal: Molecular Cancer (2009)

Mutation detection in clinical tumour samples is challenging when the proportion of tumour cells, and thus mutant alleles, is low. The limited sensitivity of conventional sequencing necessitates the adoption of more sensitive approaches. High resolution melting (HRM) is more sensitive than sequencing but identification of the mutation is desirable, particularly when it is important to discriminate false positives due to PCR errors or template degradation from true mutations. We thus developed limited copy number - high resolution melting (LCN-HRM) which applies limiting dilution to HRM. Multiple replicate reactions with a limited number of target sequences per reaction allow low level mutations to be detected. The dilutions used (based on Ct values) are chosen such that mutations, if present, can be detected by the direct sequencing of amplicons with aberrant melting patterns. Using cell lines heterozygous for mutations, we found that the mutations were not readily detected when they comprised 10% of total alleles (20% tumour cells) by sequencing, whereas they were readily detectable at 5% total alleles by standard HRM. LCN-HRM allowed these mutations to be identified by direct sequencing of those positive reactions. LCN-HRM was then used to review formalin-fixed paraffin-embedded (FFPE) clinical samples showing discordant findings between sequencing and HRM for KRAS exon 2 and EGFR exons 19 and 21. Both true mutations present at low levels and sequence changes due to artefacts were detected by LCN-HRM. The use of high fidelity polymerases showed that the majority of the artefacts were derived from the damaged template rather than replication errors during amplification. LCN-HRM bridges the sensitivity gap between HRM and sequencing and is effective in distinguishing between artefacts and true mutations.
Targeted therapy against EGFR and VEGFR using ZD6474 enhances the therapeutic potential of UV-B phototherapy in breast cancer cells
Authors: Siddik Sarkar, Shashi Rajput, Amit Kumar Tripathi, Mahitosh Mandal
Journal: Molecular Cancer (2013)

The hypoxic environment of tumor region stimulated the up regulation of growth factors responsible for angiogenesis and tumor proliferation. Thus, targeting the tumor vasculature along with the proliferation by dual tyrosine kinase inhibitor may be the efficient way of treating advanced breast cancers, which can be further enhanced by combining with radiotherapy. However, the effectiveness of radiotherapy may be severely compromised by toxicities and tumor resistance due to radiation-induced adaptive response contributing to recurrence and metastases of breast cancer. The rational of using ZD6474 is to evaluate the feasibility and efficacy of combined VEGFR2 and EGFR targeting with concurrent targeted and localized UV-B phototherapy in vitro breast cancer cells with the anticipation to cure skin lesions infiltrated with breast cancer cells.Breast cancer cells were exposed to UV-B and ZD6474 and the cell viability, apoptosis, invasion and motility studies were conducted for the combinatorial effect. Graphs and statistical analyses were performed using Graph Pad Prism 5.0.ZD6474 and UV-B decreased cell viability in breast cancers in combinatorial manner without affecting the normal human mammary epithelial cells. ZD6474 inhibited cyclin E expression and induced p53 expression when combined with UV-B. It activated stress induced mitochondrial pathway by inducing translocation of bax and cytochrome-c. The combination of ZD6474 with UV-B vs. either agent alone also more potently down-regulated the anti-apoptotic bcl-2 protein, up-regulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3 and caspase-7 proteins, and induced poly (ADP-ribose) polymerase resulting in apoptosis. ZD6474 combined with UV-B inhibited invasion of breast cancer cells in vitro as compared to either single agent, indicating a potential involvement of pro-angiogenic growth factors in regulating the altered expression and reorganization of cytoskeletal proteins in combinatorial treated breast cancer cells. Involvement of combination therapy in reducing the expression of matrix metalloprotease was also observed.Collectively, our studies indicate that incorporating an anti-EGFR plus VEGFR strategy (ZD6474) with phototherapy (UV-B), an alternative approach to the ongoing conventional radiotherapy for the treatment of infiltrating metastatic breast cancer cells in the skin and for locally recurrence breast cancer than either approach alone.
Non-steroidal anti-inflammatory drugs in sports medicine: guidelines for practical but sensible use: Table 1
Authors: J A Paoloni, C Milne, J Orchard, B Hamilton
Journal: British Journal of Sports Medicine (2009)

Non-steroidal anti-inflammatory drugs (NSAID) are commonly used in sports medicine. NSAID have known anti-inflammatory, analgesic, antipyretic and antithrombotic effects, although their in-vivo effects in treating musculoskeletal injuries in humans remain largely unknown. NSAID analgesic action is not significantly greater than paracetamol for musculoskeletal injury but they have a higher risk profile, with side-effects including asthma exacerbation, gastrointestinal and renal side-effects, hypertension and other cardiovascular diseases.The authors recommend an approach to NSAID use in sports medicine whereby simple analgesia is preferentially used when analgesia is the primary desired outcome. However, based both on the current pathophysiological understanding of most injury presentations and the frequency that inflammation may actually be a component of the injury complex, it is premature to suppose that NSAID are not useful to the physician managing sports injuries. The prescribing of NSAID should be cautious and both situation and pathology specific. Both dose and duration minimisation should be prioritized and combined with simple principles of protection, rest, ice, compression, elevation (PRICE), which should allow NSAID-sparing. NSAID use should always be coupled with appropriate physical rehabilitation.NSAID are probably most useful for treating nerve and soft-tissue impingements, inflammatory arthropathies and tenosynovitis. They are not generally indicated for isolated chronic tendinopathy, or for fractures. The use of NSAID in treating muscle injury is controversial. Conditions in which NSAID use requires more careful assessment include ligament injury, joint injury, osteoarthritis, haematoma and postoperatively.