tbuckley/cabot-search huggingface dataset:
Letter: Schonlein versus Henoch.
Authors: J V Jones
Journal: BMJ (1973)

Mechanism of Gouty Inflammation SIR,-In your leading article on this subject (20 October, p. 125) you emphasize the occurrence of leucotaxis after ingestion of sodium urate crvstals by lucocytes.You might also have mentioned the elegant work of Naff and his colleagues,3 2 which showed that sodium urate cystals (but not calcium pyrophosphate) are capable of activating compl-ment with release of chemotactic factors directly, without ingestion by cells.This mechanism may operate in acute gouty arthropathy as well, and contribute to the exuda-e.Complement depletion in animals inhibiPs uric acid crystal-induced inflamma- tion.3I am, etc.,
Characterization of cholinergic receptors in Madin-Darby canine kidney cells.
Authors: D Mohuczy-Dominiak, L C Garg
Journal: Journal of the American Society of Nephrology (1992)

Muscarinic-type cholinergic receptors coupled to the phosphoinositide (PI) second messenger system are reported to be present in the inner medullary collecting duct cells. Madin-Darby canine kidney (MDCK) cells have several characteristics of collecting duct cells and have been shown to respond to muscarinic agonists. To determine if MDCK cells have PI-coupled muscarinic receptors, the radioligand binding and the effects of cholinergic agonists and antagonists on PI hydrolysis in MDCK cells were studied. The specific binding of [3H]1-quinuclidinyl benzilate ([3H]QNB), a muscarinic antagonist, to MDCK cell membranes had a Kd = 88 +/- 7 pM and a Bmax = 1464 +/- 88 fmol/mg of protein. The displacement of [3H]QNB from MDCK cell membranes by various cholinergic antagonists and agonists showed the order of potency: atropine greater than 4-diphenylacetoxy N-methylpiperidine (4-DAMP) greater than p-fluorohexahydrosiladifenidol greater than pirenzepine greater than metoctramine greater than arecoline greater than carbachol. The cholinergic agonists carbachol and arecoline stimulated PI hydrolysis in a concentration-dependent manner with an EC50 of 3.7 and 1.3 microM, respectively. Muscarinic antagonists abolished carbachol-stimulated PI hydrolysis in the following order of potency: atropine greater than 4-DAMP greater than pirenzepine much greater than methoctramine. The order of potency of muscarinic antagonists is consistent with the characteristics of the M3 subtype of muscarinic receptors. It is concluded that: (1) muscarinic receptor density in MDCK cells is 50 times higher than that in inner medullary collecting duct cells; (2) muscarinic receptors in MDCK cells are putative M3 subtype; and (3) muscarinic receptors in MDCK cells are functionally coupled to the PI second messenger system. This intracellular messenger system may, at least, be partially responsible for the action of cholinergic agonists in these cells and in the kidney.
Inducible Resistance of Tumor Cells to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor 2–Mediated Apoptosis by Generation of a Blockade at the Death Domain Function
Authors: Yang Li, Hong Wang, Zheng Wang, Sharmila Makhija, Donald Buchsbaum, Albert LoBuglio, Robert Kimberly, Tong Zhou
Journal: Cancer Research (2006)

Abstract Induction of tumor cell resistance to therapeutics has been a major obstacle in cancer therapy. Targeting of the death receptors by a natural ligand, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), or agonistic monoclonal antibodies against TRAIL receptor 1 (TRAIL-R1) or TRAIL receptor 2 (TRAIL-R2) has been thought to be a promising cancer therapy. To determine whether tumor cells are able to generate a resistance to apoptosis induced by an anti-TRAIL-R2 antibody, TRA-8, we examined the apoptotic response of human breast and ovarian cancer cell lines after treatment with TRA-8. Our results show that tumor cell resistance to TRA-8 can be induced by repeated treatment of tumor cells with low, non-apoptosis-inducing doses of TRA-8. Interestingly, the induced resistance to apoptosis was not due to a global apoptotic defect in tumor cells but rather a selective defect in the TRAIL-R2 signaling pathway. Whereas TRA-8-treated tumor cells developed a selective resistance to TRAIL-R2-mediated apoptosis, the apoptotic responses induced by TRAIL, an anti-TRAIL-R1 antibody (2E12), and other apoptotic stimuli were not impaired. The expression levels of cell surface TRAIL-R2 were not altered and mutations of TRAIL-R2 were not found in the resistant cells. The induced TRA-8 resistance was due to a selective blockade at the level of the death domain and could be reversed by a wide array of chemotherapeutic agents. Proteomic analysis of death-inducing signaling complex formation during TRA-8 treatment shows that the translocation of TRAIL-R2-associated apoptotic proteins was significantly altered. Our results suggest that the prevention of tumor cell resistance to therapeutic agents that target the death receptors must be taken into consideration. (Cancer Res 2006; 66(17): 8520-8)
Infectious Mononucleosis and Cold Urticaria
Authors: J. Wesley Mesko
Journal: JAMA (1982)

To the Editor.—  The recent article by Lemanske and Bush (1982;247:1604) reported a case of cold urticaria associated with infectious mononucleosis. We would like to support their findings by presenting a similar case.  Report of a Case.—  A 26-year-old man had a week-long history of pruritus, erythema, and urticaria that first appeared after ingesting cold foods and then progressed to occurring after exposure to cold air or after contact with cold surfaces. No respiratory distress was noted. He had a nonproductive cough with myalgias in the week preceding the onset of urticaria. There was no personal or family history of allergies or urticaria. Physical examination disclosed urticaria on forearms, buttocks, and calves. Submaxillary, axillary, and anterior cervical adenopathy were present, but without hepatosplenomegaly. The presence of urticaria was confirmed by a positive response to an ice cube test. Other laboratory data were as follows: WBC count, 10,000/cu mm, with 79%
TEC FAMILY KINASES IN T LYMPHOCYTE DEVELOPMENT AND FUNCTION
Authors: Leslie J. Berg, Lisa D. Finkelstein, Julie A. Lucas, Pamela L. Schwartzberg
Journal: Annual Review of Immunology (2004)

The Tec family tyrosine kinases are now recognized as important mediators of antigen receptor signaling in lymphocytes. Three members of this family, Itk, Rlk, and Tec, are expressed in T cells and activated in response to T cell receptor (TCR) engagement. Although initial studies demonstrated a role for these proteins in TCR-mediated activation of phospholipase C-gamma, recent data indicate that Tec family kinases also regulate actin cytoskeletal reorganization and cellular adhesion following TCR stimulation. In addition, Tec family kinases are activated downstream of G protein-coupled chemokine receptors, where they play parallel roles in the regulation of Rho GTPases, cell polarization, adhesion, and migration. In all these systems, however, Tec family kinases are not essential signaling components, but instead function to modulate or amplify signaling pathways. Although they quantitatively reduce proximal signaling, mutations that eliminate Tec family kinases in T cells nonetheless qualitatively alter T cell development and differentiation.
Genetic and Phenotypic Diversity in Breast Tumor Metastases
Authors: Vanessa Almendro, Hee Jung Kim, Yu-Kang Cheng, Mithat Gönen, Shalev Itzkovitz, Pedram Argani, Alexander van Oudenaarden, Saraswati Sukumar, Franziska Michor, Kornelia Polyak
Journal: Cancer Research (2014)

Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immunoFISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected before systemic therapy. We calculated the Shannon index of intratumor diversity in all cancer cells and within phenotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naïve primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2(+) tumors compared with other subtypes and in metastases of triple-negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples could be used for the improved prognostication of patients with cancer and for the design of more effective therapies for progressive disease.
Functional Diversification of B MADS-Box Homeotic Regulators of Flower Development: Adaptive Evolution in Protein–Protein Interaction Domains after Major Gene Duplication Events
Authors: Tania Hernández-Hernández, León Patricio Martínez-Castilla, Elena R. Alvarez-Buylla
Journal: Molecular Biology and Evolution (2006)

B-class MADS-box genes have been shown to be the key regulators of petal and stamen specification in several eudicot model species such as Arabidopsis thaliana, Antirrhinum majus, and Petunia hybrida. Orthologs of these genes have been found across angiosperms and gymnosperms, and it is thought that the basic regulatory function of B proteins is conserved in seed plant lineages. The evolution of B genes is characterized by numerous duplications that might represent key elements fostering the functional diversification of duplicates with a deep impact on their role in the evolution of the floral developmental program. To evaluate this, we performed a rigorous statistical analysis with B gene sequences. Using maximum likelihood and Bayesian methods, we estimated molecular substitution rates and determined the selective regimes operating at each residue of B proteins. We implemented tests that rely on phylogenetic hypotheses and codon substitution models to detect significant differences in substitution rates (DSRs) and sites under positive adaptive selection (PS) in specific lineages before and after duplication events. With these methods, we identified several protein residues fixed by PS shortly after the origin of PISTILLATA-like and APETALA3-like lineages in angiosperms and shortly after the origin of the euAP3-like lineage in core eudicots, the 2 main B gene duplications. The residues inferred to have been fixed by positive selection lie mostly within the K domain of the protein, which is key to promote heterodimerization. Additionally, we used a likelihood method that accommodates DSRs among lineages to estimate duplication dates for AP3-PI and euAP3-TM6, calibrating with data from the fossil record. The dates obtained are consistent with angiosperm origins and diversification of core eudicots. Our results strongly suggest that novel multimer formation with other MADS proteins could have been crucial for the functional divergence of B MADS-box genes. We thus propose a mechanism of functional diversification and persistence of gene duplicates by the appearance of novel multimerization capabilities after duplications. Multimer formation in different combinations of regulatory proteins can be a mechanistic basis for the origin of novel regulatory functions and a gene regulatory mechanism for the appearance of morphological innovations.
Isolation and purification of a pemphigus vulgaris antigen from human epidermis.
Authors: L L Peterson, K D Wuepper
Journal: Journal of Clinical Investigation (1984)

Pemphigus vulgaris is an autoimmune disease associated with an autoantibody directed against a keratinocyte membrane antigen. The purpose of this study was to purify the human pemphigus vulgaris antigen, to produce an antibody to this antigen, and to use the antibody to induce pemphigus in newborn mice. Various techniques to extract the membrane-rich pellet from human epidermal homogenate were compared; 1% sodium dodecyl sulfate (SDS) and 1% dimethylsulfoxide proved to be superior to extract the pemphigus vulgaris antigen. This antigen was identified by transfer blotting to nitrocellulose paper, incubated with pemphigus vulgaris serum, or 20 control sera, and detected with fluorescein labeled antisera to human IgG. Since concanavalin A inhibits the binding of pemphigus vulgaris antibody to tissue sections, we studied the binding of the extracted proteins to concanavalin A covalently coupled to Sepharose. Pemphigus vulgaris antigen bound to the concanavalin A column and was released by 0.02 M methyl alpha-D-mannopyranoside. The proteins thus recovered were subjected to AcA 54 gel permeation chromatography, and the pemphigus antigen was detected by the transfer blot assay. The antigen corresponded to a discrete peak at 66,000 D by gel permeation and gave one homogeneous band at 33,000 D in urea-SDS-polyacrylamide gel electrophoresis. Monospecific antibody to the antigen raised in rabbits stained human epidermis in the same manner as the pemphigus vulgaris autoantibody and induced pemphigus vulgaris in newborn mice when injected intraperitoneally. A pemphigus vulgaris antigen has been purified from adult human epidermis. It is a 66,000-D membrane glycoprotein that is composed of two apparently identical subunits of 33,000 D each.
Sprouty 2, an Inhibitor of Mitogen-Activated Protein Kinase Signaling, Is Down-Regulated in Hepatocellular Carcinoma
Authors: Chee Wai Fong, Mei-Sze Chua, Arthur B. McKie, Sharon Hee Ming Ling, Veronica Mason, Rui Li, Permeen Yusoff, Ting Ling Lo, Hing Y. Leung, Samuel K.S. So, Graeme R. Guy
Journal: Cancer Research (2006)

Abstract The Sprouty proteins are increasingly being recognized to be deregulated in various types of cancers. This deregulation is often associated with aberrant signaling of receptor tyrosine kinases and its downstream effectors, leading to the mitogen-activated protein kinase (MAPK) signaling pathway. In human hepatocellular carcinoma, where the MAPK activity is enhanced via multiple hepatocarcinogenic factors, we observed a consistent reduced expression of the sprouty 2 (Spry2) transcript and protein in malignant hepatocytes compared with normal or cirrhotic hepatocytes. The expression pattern of Spry2 in hepatocellular carcinoma resembles that of several potential tumor markers of hepatocellular carcinoma and also that of several angiogenic factors and growth factor receptors. In contrast to previous studies of Spry2 down-regulation in other cancers, we have ruled out loss of heterozygosity or the methylation of promoter sites, two common mechanisms responsible for the silencing of genes with tumor suppressor properties. Functionally, we show that Spry2 inhibits both extracellular signal-regulated kinase signaling as well as proliferation in hepatocellular carcinoma cell lines, whereas knocking down Spry2 levels in NIH3T3 cells causes mild transformation. Our study clearly indicates a role for Spry2 in hepatocellular carcinoma, and an understanding of the regulatory controls of its expression could provide new means of regulating the angiogenic switch in this hypervascular tumor, thereby potentially controlling tumor growth. (Cancer Res 2006; 66(4): 2048-58)
Air Pollution and Markers of Inflammation and Coagulation in Patients with Coronary Heart Disease
Authors: Regina Rückerl, Angela Ibald-Mulli, Wolfgang Koenig, Alexandra Schneider, Gabriele Woelke, Josef Cyrys, Joachim Heinrich, Victor Marder, Mark Frampton, H. Erich Wichmann, Annette Peters
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Ambient air pollution has been shown to be associated with cardiovascular morbidity and mortality.Objectives: A prospective panel study was conducted to study the early physiologic reactions characterized by blood biomarkers of inflammation, endothelial dysfunction, and coagulation in response to daily changes in air pollution in Erfurt, Germany.Methods: Blood parameters were repeatedly measured in 57 male patients with coronary heart disease during the winter of 2000/2001. Fixed-effects linear and logistic regression models were applied, adjusting for trend, weekday, and meteorologic parameters.Measurements: Hourly data on ultrafine particles (UFPs; number concentration of particles from 0.01 to 0.1 μm), mass concentration of particles less than 10 (PM10) and 2.5 μm in diameter, elemental and organic carbon, gaseous pollutants, and meteorologic data were collected at central monitoring sites.Main Results: Increased levels of C-reactive protein above the 90th percentile were observed for an increase in air pollution concentrations of one interquartile range. The effect was strongest for accumulation mode particles, with a delay of 2 d (odds ratio [OR], 3.2; confidence interval [CI], 1.7, 6.0). Results were consistent for UFPs and PM10, which also showed a 2-d delayed response (OR, 2.3; CI, 1.3, 3.8; and OR, 2.2; CI, 1.2, 3.8, respectively). However, not all of the blood markers of endothelial dysfunction and coagulation increased consistently in association with air pollutants.Conclusion: These results suggest that inflammation as well as parts of the coagulation pathway may contribute to the association between particulate air pollution and coronary events.
De Novo Expression of Macrophage Migration Inhibitory Factor in Atherogenesis in Rabbits
Authors: Shu-Guang Lin, Xi-Yong Yu, Yong-Xiong Chen, Xiao R. Huang, Christine Metz, Richard Bucala, Chu-Pak Lau, Hui Y. Lan
Journal: Circulation Research (2000)

Macrophage migration inhibitory factor (MIF) has been shown to play an important role in macrophage-mediated diseases. We investigate the potential role of MIF in atherogenesis using a hypercholesterolemic rabbit model. New Zealand White rabbits fed with a 2% cholesterol diet developed hypercholesterolemia and early fatty streaks at 1 month. The lesions became advanced at 3 months and were associated with de novo MIF expression by vascular endothelial cells (VECs) and smooth muscle cells (SMCs), as demonstrated by immunohistochemistry, reverse transcriptase-polymerase chain reaction, and in situ hybridization. By contrast, there was no increase in MIF levels in rabbits fed a normal diet. In early atherogenesis, marked upregulation of MIF mRNA and protein by VECs and some intimal cells were closely associated with CD68(+) monocyte adhesion onto and subsequent migration into subendothelial space. Of significance, the accumulation of macrophages was exclusively localized to areas of strong MIF expression, which may be associated with the macrophage-rich fatty streak lesion formation. Upregulation of MIF by SMCs is transient during atherogenesis. Importantly, strong MIF expression by activated macrophages may be responsible for the development of foam cell-rich lesions. Finally, the ability of MIF to induce intercellular adhesion molecule-1 expression by VECs implicates its pathogenic role in atherogenesis. In conclusion, the present study provides the first demonstration that MIF is markedly upregulated during atherogenesis. Upregulation of MIF by VECs and SMCs may play a role in macrophage adhesion, transendothelial migration, accumulation, and, importantly, transformation into foam cells. Furthermore, strong MIF expression by macrophages may both initiate and amplify the atherogenesis process.
Nutritional depletion in patients on long-term oxygen therapy and/or home mechanical ventilation
Authors: N.J.M. Cano, H. Roth, I. Court-Fortuné, L. Cynober, M. Gérard-Boncompain, A. Cuvelier, J-P. Laaban, J-C. Melchior, C. Pichard, J-C. Raphaël, C.M. Pison
Journal: European Respiratory Journal (2002)

The purpose of this study was to estimate the prevalence of malnutrition in outpatients on long-term oxygen therapy or home mechanical ventilation, to determine the relationships between malnutrition and impairment/disability and smoking and also to identify relevant tools for routine nutritional assessment. In 744 patients (M:F 1.68, aged 65±15 yrs) with chronic obstructive pulmonary disease (COPD, 40%), restrictive disorders (27%), mixed respiratory failure (15%), neuromuscular diseases (13%) and bronchiectasis (5%), body mass index (BMI), fat-free mass (FFM), serum albumin, transthyretin, 6-min walking test, forced vital capacity (FVC), forced expiratory volume in one second (FEV 1 ) and blood gases were recorded. FFM was the most sensitive parameter for detecting malnutrition, being abnormal in 53.6% of patients, while BMI was &lt;20 in 23.2%, serum albumin &lt;35 g·L −1 in 20.7 %, and serum transthyretin &lt;200 mg·L −1 in 20%. FFM depletion predominated in neuromuscular, bronchiectasis and restrictive disorders. BMI and FFM were correlated with FEV 1 , FVC and 6-min walking test. In multivariate analysis a BMI&lt;20 was related to FEV 1 and smoking habits, and a low FFM to smoking, FEV 1 and female sex. Malnutrition is highly prevalent in home-assisted respiratory patients and is related to causal disease, forced expiratory volume in one second, smoking and disability. Fat-free mass appeared to be the most sensitive and relevant nutritional parameter according to impairment and disability.
Remember them well
Authors: L. Farrell
Journal: BMJ (1997)

How strong you were, so bright and gay / A prince of love in every way / Ah yes—I remember it well.—Gigi

Africa: the name alone inspires and magicks, a land redolent of spice and wild beasts, where champions stalked and men of rock like Burton and Stanley roamed. And it has its very own guardian angel: high in the plateau above Ngorongoro Crater is a simple stone monument to Michael Grzimek. With his father, Bernard, he was among the first to recognise the precious jewel that the east African reserves represent and the mortal danger they were in; together …
Molecular Requirements for T Cell Recognition by a Major Histocompatibility Complex Class II–restricted T Cell Receptor: The Involvement of the Fourth Hypervariable Loop of the Vα Domain
Authors: Jayant Thatte, Ayub Qadri, Caius Radu, E. Sally Ward
Journal: The Journal of Experimental Medicine (1999)

The role of two central residues (K68, E69) of the fourth hypervariable loop of the Vα domain (HV4α) in antigen recognition by an MHC class II–restricted T cell receptor (TCR) has been analyzed. The TCR recognizes the NH2-terminal peptide of myelin basic protein (Ac1-11, acetylated at NH2 terminus) associated with the class II MHC molecule I-Au. Lysine 68 (K68) and glutamic acid 69 (E69) of HV4α have been mutated both individually and simultaneously to alanine (K68A, E69A). The responsiveness of transfectants bearing wild-type and mutated TCRs to Ac1-11–I-Au complexes has been analyzed in the presence and absence of expression of the coreceptor CD4. The data demonstrate that in the absence of CD4 expression, K68 plays a central role in antigen responsiveness. In contrast, the effect of mutating E69 to alanine is less marked. CD4 coexpression can partially compensate for the loss of activity of the K68A mutant transfectants, resulting in responses that, relative to those of the wild-type transfectants, are highly sensitive to anti-CD4 antibody blockade. The observations support models of T cell activation in which both the affinity of the TCR for cognate ligand and the involvement of coreceptors determine the outcome of the T cell–antigen-presenting cell interaction.