tbuckley/cabot-search huggingface dataset:
Immature B cells preferentially switch to IgE with increased direct Sμ to Sε recombination
Authors: Duane R. Wesemann, Jennifer M. Magee, Cristian Boboila, Dinis Pedro Calado, Michael P. Gallagher, Andrew J. Portuguese, John P. Manis, Xiaolong Zhou, Mike Recher, Klaus Rajewsky, Luigi D. Notarangelo, Frederick W. Alt
Journal: The Journal of Experimental Medicine (2011)

Immunoglobulin heavy chain (IgH) class-switch recombination (CSR) replaces initially expressed Cμ (IgM) constant regions (CH) exons with downstream CH exons. Stimulation of B cells with anti-CD40 plus interleukin-4 induces CSR from Cμ to Cγ1 (IgG1) and Cε (IgE), the latter of which contributes to the pathogenesis of atopic diseases. Although Cε CSR can occur directly from Cμ, most mature peripheral B cells undergo CSR to Cε indirectly, namely from Cμ to Cγ1, and subsequently to Cε. Physiological mechanisms that influence CSR to Cγ1 versus Cε are incompletely understood. In this study, we report a role for B cell developmental maturity in IgE CSR. Based in part on a novel flow cytometric IgE CSR assay, we show that immature B cells preferentially switch to IgE versus IgG1 through a mechanism involving increased direct CSR from Cμ to Cε. Our findings suggest that IgE dysregulation in certain immunodeficiencies may be related to impaired B cell maturation.
Quantitative Determination of Factors Contributing to Doxorubicin Resistance in Multidrug-Resistant Cells
Authors: G. J. Schuurhuis, H. J. Broxterman, A. Cervantes, T. H. M. van Heijningen, J. H. M. de Lange, J. P. A. Baak, H. M. Pinedo, J. Lankelma
Journal: JNCI Journal of the National Cancer Institute (1989)

There is a large discrepancy between the changes in drug accumulation and the changes in drug cytotoxicity that accompany development of anthracycline resistance in multidrug-resistant cells. In our study, a quantitative relationship has been established between reversal of multidrug resistance by resistance modifiers and a concomitant decrease in intracellular levels of doxorubicin measured at equitoxic concentrations (IC50) in CHRC5 and 2780AD multidrug-resistant cells. (IC50 = concentration required for 50% growth inhibition.) We have demonstrated that resistance modifiers like verapamil and Ro 11–2933/001 act by increasing the effectiveness of intracellular doxorubicin, apparently by inducing redistribution of the drug from the cytoplasm to the nucleus of a multidrug-resistant cell, as shown by quantitative fluorescence microscopy. At complete reversal of resistance, as measured directly or inferred by extrapolation, the amount of intracellular doxorubicin at the IC50 as well as the ratio of nuclear doxorubicin to cytoplasmic doxorubicin were the same as those in sensitive cells. These results offer an explanation for the frequently observed discrepancies between drug accumulation and cytotoxicity and also show quantitatively that a decrease in drug accumulation and a change in intracellular drug distribution together are the only determinants of doxorubicin resistance in the multidrug-resistant cells studied. [J Natl Cancer Inst 81: 1887–1892, 1989]
Mast cells, cytokines, and metalloproteinases at the rheumatoid lesion: dual immunolocalisation studies.
Authors: L.C Tetlow, D.E Woolley
Journal: Annals of the Rheumatic Diseases (1995)

To examine the distribution and activation of mast cells (MCs) in the rheumatoid lesion (cartilage-pannus junctions demonstrating cartilage erosion), and to determine whether or not their tissue distribution is related to that for tumour necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), stromelysin-1, and collagenase. Immunolocalisation of MC-tryptase was used to identify MCs and their states of degranulation in 35 specimens of cartilage-pannus junctions. Dual immunolocalisation techniques using alkaline phosphatase and peroxidase conjugated antibodies were used to compare the distributions of MCs with the proinflammatory cytokines TNF alpha and IL-1, and the cartilage or matrix degrading enzymes stromelysin-1 and collagenase. Stromelysin-1, TNF alpha, and IL-1 beta were especially prominent at the cartilage-pannus junctions, albeit with patchy distributions. Extracellular MC tryptase, indicative of MC activation/degranulation, was commonly observed at sites of cartilage erosion, and was often associated with the microenvironmental expression of TNF alpha, IL-1 beta, stromelysin-1, and collagenase. Such observations were often associated with localised sites of tissue oedema and stromal disruption. MC activation was frequently associated with proinflammatory cytokine and metalloproteinase expression by neighbouring cells, thereby suggesting an important contributory role for the MC in mediating matrix degradation and oedematous changes within microfoci of the rheumatoid lesion.
Selective Activation of Insulin Receptor Substrate-1 and -2 in Pleural Mesothelioma Cells
Authors: Chuong D. Hoang, Xihong Zhang, Paul D. Scott, Tenner J. Guillaume, Michael A. Maddaus, Douglas Yee, Robert A. Kratzke
Journal: Cancer Research (2004)

Abstract Molecular mechanisms active in transforming human pleural cells remain incompletely understood. Our previous microarray analysis of malignant pleural mesothelioma revealed alterations in components of the insulin-like growth factor (IGF) system, implicating this signaling axis in tumorigenesis. Therefore, in this current study, we characterized the molecular phenotype and investigated the key signaling pathways of the IGF system in malignant pleural mesothelioma specimens. For the major IGF components, we assessed mRNA abundance and total protein levels. We measured IGF-I ligand-dependent activation of signaling pathways downstream of the type I IGF receptor in a subset of malignant pleural mesothelioma cell lines and determined the corresponding biological consequences. At the transcriptional level, we observed consistent changes in IGF components that may contribute to a malignant phenotype. IGF-I stimulation of cells resulted in enhanced activation of type I IGF receptor and IRS adaptor proteins. Differential activation of IRS-1 signaling was associated with cell growth, whereas IRS-2 signaling was associated with cell motility. Thus, these data suggest that multiple mechanisms likely contribute to malignant pleural mesothelioma tumorigenesis. Therefore, IGF system components represent novel malignant pleural mesothelioma therapeutic targets for investigation.
Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study
Authors: Robert K Nam, Patrick Cheung, Sender Herschorn, Refik Saskin, Jiandong Su, Laurence H Klotz, Michelle Chang, Girish S Kulkarni, Yuna Lee, Ronald T Kodama, Steven A Narod
Journal: The Lancet Oncology (2014)
Synthetic Triterpenoids Cooperate with Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand to Induce Apoptosis of Breast Cancer Cells
Authors: Marc L. Hyer, Rhonda Croxton, Maryla Krajewska, Stanislaw Krajewski, Christina L. Kress, Meiling Lu, Nanjoo Suh, Michael B. Sporn, Vincent L. Cryns, Juan M. Zapata, John C. Reed
Journal: Cancer Research (2005)

Abstract Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL or Apo2L) has been shown to induce apoptosis specifically in cancer cells while sparing normal tissues. Unfortunately not all cancer cells respond to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. We have identified synthetic triterpenoids, including 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), which sensitize TRAIL-resistant cancer cells to TRAIL-mediated apoptosis. Here we show that TRAIL-treated T47D and MDA-MB-468 breast cancer cells fail to initiate detectable caspase-8 processing and, consequently, do not initiate TRAIL-mediated apoptosis. Concomitant treatment with CDDO or CDDO-Im reverses the TRAIL-resistant phenotype, promoting robust caspase-8 processing and induction of TRAIL-mediated apoptosis in vitro. The combination of triterpenoids and monoclonal anti-TRAIL receptor-1 (DR4) antibody also induces apoptosis of breast cancer cells in vitro. From a mechanistic standpoint, we show that CDDO and CDDO-Im down-regulate the antiapoptotic protein c-FLIPL, and up-regulate cell surface TRAIL receptors DR4 and DR5. CDDO and CDDO-Im, when used in combination with TRAIL, have no adverse affect on cultured normal human mammary epithelial cells. Moreover, CDDO-Im and TRAIL are well tolerated in mice and the combination of CDDO-Im and TRAIL reduces tumor burden in vivo in an MDA-MB-468 tumor xenograft model. These data suggest that CDDO and CDDO-Im may be useful for selectively reversing the TRAIL-resistant phenotype in cancer but not normal cells.
Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)
Authors: Paola Secchiero, Elisa Barbarotto, Mario Tiribelli, Carlotta Zerbinati, Maria Grazia di Iasio, Arianna Gonelli, Francesco Cavazzini, Diana Campioni, Renato Fanin, Antonio Cuneo, Giorgio Zauli
Journal: Blood (2006)
Prevalence of symptoms of vaginal fistula in 19 sub-Saharan Africa countries: a meta-analysis of national household survey data
Authors: Mathieu Maheu-Giroux, Véronique Filippi, Sékou Samadoulougou, Marcia C Castro, Nathalie Maulet, Nicolas Meda, Fati Kirakoya-Samadoulougou
Journal: The Lancet Global Health (2015)

Vaginal fistula is a serious medical disorder characterised by an abnormal opening between the vagina and the bladder or rectum, which results in continuous leakage of urine or stool. The burden of this disorder in sub-Saharan Africa is uncertain. We estimated the lifetime and point prevalence of symptoms of vaginal fistula in this region using national household surveys based on self-report of symptoms.We considered all Demographic and Health Surveys (DHS) and Multiple Indicators Cluster Surveys (MICS) from sub-Saharan Africa and included data for women of reproductive age (15-49 years). We estimated lifetime prevalence and point prevalence of vaginal fistula with use of Bayesian hierarchical meta-analysis.We included 19 surveys in our analysis, including 262,100 respondents. Lifetime prevalence was 3.0 cases (95% credible interval 1.3-5.5) per 1000 women of reproductive age. After imputation of missing data, point prevalence was 1.0 case (0.3-2.4) per 1000 women of reproductive age. Ethiopia had the largest number of women who presently have symptoms of vaginal fistula.This study is the first to estimate the burden of vaginal fistula in 19 sub-Saharan Africa countries using nationally representative survey data. Point prevalence was slightly lower than previously estimated but these earlier estimates are within the prevalence's credible intervals. Although vaginal fistula is relatively rare, it is still too common in sub-Saharan Africa.None.
Cost-Effectiveness Analysis of Screening for KRAS and BRAF Mutations in Metastatic Colorectal Cancer
Authors: Ajay S. Behl, Katrina A. B. Goddard, Thomas J. Flottemesch, David Veenstra, Richard T. Meenan, Jennifer S. Lin, Michael V. Maciosek
Journal: JNCI Journal of the National Cancer Institute (2012)

In 2009, the American Society of Clinical Oncology recommended that patients with metastatic colorectal cancer (mCRC) who are candidates for anti-epidermal growth factor receptor (EGFR) therapy have their tumors tested for KRAS mutations because tumors with such mutations do not respond to anti-EGFR therapy. Limiting anti-EGFR therapy to those without KRAS mutations will reserve treatment for those likely to benefit while avoiding unnecessary costs and harm to those who would not. Similarly, tumors with BRAF genetic mutations may not respond to anti-EGFR therapy, though this is less clear. Economic analyses of mutation testing have not fully explored the roles of alternative therapies and resection of metastases.This paper is based on a decision analytic framework that forms the basis of a cost-effectiveness analysis of screening for KRAS and BRAF mutations in mCRC in the context of treatment with cetuximab. A cohort of 50 000 patients with mCRC is simulated 10 000 times, with attributes randomly assigned on the basis of distributions from randomized controlled trials.Screening for both KRAS and BRAF mutations compared with the base strategy (of no anti-EGFR therapy) increases expected overall survival by 0.034 years at a cost of $22 033, yielding an incremental cost-effectiveness ratio of approximately $650 000 per additional year of life. Compared with anti-EGFR therapy without screening, adding KRAS testing saves approximately $7500 per patient; adding BRAF testing saves another $1023, with little reduction in expected survival.Screening for KRAS and BFAF mutation improves the cost-effectiveness of anti-EGFR therapy, but the incremental cost effectiveness ratio remains above the generally accepted threshold for acceptable cost effectiveness ratio of $100 000/quality adjusted life year.
A New Approach to Reducing Postsurgical Cancer Recurrence: Perioperative Targeting of Catecholamines and Prostaglandins
Authors: Elad Neeman, Oded Zmora, Shamgar Ben-Eliyahu
Journal: Clinical Cancer Research (2012)

Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases-the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous "immune-resistant" tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous β-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period.
Pharmacology of Cloned P2X Receptors
Authors: R. Alan North, Annmarie Surprenant
Journal: The Annual Review of Pharmacology and Toxicology (2000)

There are seven P2X receptor cDNAs currently known. Six homomeric (P2X 1 , P2X 2 , P2X 3 , P2X 4 , P2X 5 , P2X 7 ) and three heteromeric (P2X 2 /P2X 3 , P2X 4 /P2X 6 , P2X 1 /P2X 5 ) P2X receptor channels have been characterized in heterologous expression systems. Homomeric P2X 1 and P2X 3 receptors are readily distinguishable by their rapid desensitization, the agonist action of αβmethyleneATP, and the block by 2′,3′-O-(2,4,6-trinitrophenyl)-ATP. P2X 2 receptors are unique among homomeric forms in their potentiation by low pH. Homomeric P2X 4 receptors are much less sensitive to antagonism by suramin and pyridoxal 5-phosphate-6-azo-2′,4′-disulfonic acid. Homomeric P2X 7 receptors are the only form in which 2′,3′-O-(4-benzoylbenzoyl)-ATP is more potent than ATP. The heteromeric P2X 2 /P2X 3 receptor resembles P2X 2 in slow desensitization kinetics and potentiation by low pH and is similar to P2X 3 with respect to agonism by αβmethyleneATP and block by 2′,3′-O-(2,4,6-trinitrophenyl)-ATP. Other agonists, antagonists, and ions that can be used to differentiate among the receptors are discussed.
The isolation and maintenance of the human pilosebaceous unit
Authors: D.A. SANDERS, M.P. PHILPOTT, F.V. NICOLLE, T. KEALEY
Journal: British Journal of Dermatology (2006)

Journal Article The isolation and maintenance of the human pilosebaceous unit Get access D.A. SANDERS, D.A. SANDERS Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, U.K. Search for other works by this author on: Oxford Academic Google Scholar M.P. PHILPOTT, M.P. PHILPOTT Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, U.K. Search for other works by this author on: Oxford Academic Google Scholar F.V. NICOLLE, F.V. NICOLLE 30 Harley Street, London WIN 1AB, U.K. Search for other works by this author on: Oxford Academic Google Scholar T. KEALEY T. KEALEY Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 131, Issue 2, 1 August 1994, Pages 166–176, https://doi.org/10.1111/j.1365-2133.1994.tb08487.x Published: 01 August 1994 Article history Accepted: 24 January 1994 Published: 01 August 1994
Abnormal permeability precedes the development of a gluten sensitive enteropathy in Irish setter dogs.
Authors: E J Hall, R M Batt
Journal: Gut (1991)

Intestinal permeability to 51Cr-EDTA was examined during the development of gluten sensitive enteropathy in dogs bred from affected Irish setters and reared on a normal wheat containing diet. Comparisons were made with litter mates reared on a gluten free diet and with a control group of age matched, clinically healthy Irish setters reared on the normal diet. Studies at 4, 6, 8, and 12 months of age were correlated with morphometric and biochemical examinations of peroral jejunal biopsy specimens. Permeability was increased at all ages in the group fed gluten free diet compared with control dogs, although there were no differences in villus height, intraepithelial lymphocyte density, and alkaline phosphatase activity. At four months, permeability in the normal diet group was greater than in controls, although comparable with that in the gluten free diet group. Permeability in the normal diet group increased further in conjunction with the development of partial villus atrophy and reduced alkaline phosphatase activity, and by 12 months permeability was significantly greater than in their gluten free diet litter mates and the control dogs. The findings suggest that an underlying permeability abnormality may be involved in the pathogenesis of gluten sensitive enteropathy in Irish setter dogs.
Pollen polarize dendritic cells
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

![Graphic][1] 

DCs (blue) exposed to pollen lipids polarize T cells (yellow) toward a Th2 phenotype.How do pollen particles provoke allergic reactions? On 

[page 627][2], Traidl-Hoffmann et al. put some of the blame on bioactive lipids that are released from pollen and cause dendritic
The Use of Packed Red Blood Cells
Authors: Jerry W. Staples
Journal: JAMA (1976)

<h3>To the Editor.—</h3> In reference to Dr Grindon's commentary on component therapy, especially the use of PRBC, we believe that Dr Grindon neglected to discuss the component that would solve the majority of problems involved in the use of PRBC. The component we are referring to, is, of course, saline-washed RBC. For patients with long-term renal disease and difficulty in handling potassium loads, washed cells are the ideal solution, since the plasma potassium remaining in our washed units is less than 1 mEq/liter. Tests of more than 50 units of saline-washed RBC showed that the average remaining total protein was 45 mg/100 ml, which makes washed cells quite an acceptable component for transfusion of those patients who may have an anaphylactic reaction or febrile reaction to IgA. Washed RBC will also eliminate any reactions caused by other plasma protein antibodies. Our washed cells have 85% of the white blood cells
Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey.
Authors: Z Huang, N L Bodkin, H K Ortmeyer, B C Hansen, A R Shuldiner
Journal: Journal of Clinical Investigation (1994)

The human insulin receptor has two isoforms derived from alternative splicing of exon 11 of the insulin receptor gene. The type B (containing exon 11, or exon 11+) isoform binds insulin with twofold lower affinity than the type A (lacking exon 11, or exon 11-) isoform. In efforts to resolve the controversy over whether altered splicing is involved in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM), the spontaneously obese diabetic rhesus monkey, a unique model that is extraordinarily similar to human NIDDM, was used. Cross-sectional studies of insulin receptor mRNA splicing variants in vastus lateralis muscle were performed on 19 rhesus monkeys. When monkeys were divided into four groups based upon the known stages of progression to NIDDM: normal (normoglycemic/normoinsulinemic), prediabetic (normoglycemic/hyperinsulinemic), early NIDDM (hyperglycemic/hyperinsulinemic), and late NIDDM (hyperglycemic/hypoinsulinemic), both hyperinsulinemic groups had significantly higher percentages of the exon 11- mRNA splicing variant compared to the normal (74.8 +/- 1.7 vs 59.0 +/- 2.3%; P < 0.005) and late NIDDM groups (74.8 +/- 1.7 vs 64.2 +/- 3.9%; P < 0.05). Our findings provide the first direct evidence linking hyperinsulinemia to alterations in insulin receptor mRNA splicing, and suggest that alterations of insulin receptor mRNA splicing in muscle is an early molecular marker that may play an important role in NIDDM.
TUMOUR-INFILTRATING LYMPHOCYTES AND INTERLEUKIN-2 IN TREATMENT OF ADVANCED CANCER
Authors: RichardL. Kradin, DavidS. Lazarus, StevenM. Dubinett, Julie Gifford, Beverly Grove, JamesT. Kurnick, FredericI. Preffer, ClareE. Pinto, Elise Davidson, RonaldJ. Callahan, H.William Strauss
Journal: The Lancet (1989)
THE EFFECTS OF TWENTY DEGREE HEAD-UP TILT UPON THE CEREBRAL CIRCULATION OF PATIENTS WITH ARTERIAL HYPERTENSION BEFORE AND AFTER SYMPATHECTOMY 1
Authors: Joseph H. Hafkenschiel, Charles W. Crumpton, Henry A. Shenkin, John H. Moyer, Harold A. Zintel, Herbert Wendel, William A. Jeffers, Sally Conlin Harned, Nelly J. Keffer, Geraldine Croft
Journal: Journal of Clinical Investigation (1951)

The present study was undertaken in order to measure the effect of a slight elevation of the head and shoulders upon the, cerebral circulation of hypertensive patients following sympathectomy.Twenty degree tilt was chosen because it could be tolerated for 20 minutes, as early as two weeks after the Smithwick sympathectomy.Shenkin and coworkers in 1948 reported that 200 head-up tilt did not alter the cerebral blood flow, cerebral oxygen consumption, and oxygen content of the internal jugular blood in five normal subjects (1).They also reported that, following thoracolumbar sympathectomy, cerebral oxygen uptake and blood flow in hypertensive pa- tients while in the supine position did not differ from the preoperative level (2).We have measured mean arterial pressure, blood flow, and oxygen uptake of the brain, before and after tilt in two groups of patients: (a) 15 pa- tients who had been subjected to bilateral thora- columbar (D6-L3) sympathectomy, and (b) 18 patients with essential hypertension. METHODSPatients with essential hypertension were selected from the medical and surgical wards of the Hospital of the