tbuckley/cabot-search huggingface dataset:
High Prevalence of Low Bone Turnover and Occurrence of Osteomalacia after Kidney Transplantation
Authors: MARIE-CLAUDE MONIER-FAUGERE, HANNA MAWAD, QUANLE QI, ROBERT M. FRIEDLER, HARTMUT H. MALLUCHE
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Kidney transplantation corrects most of the metabolic abnormalities that cause renal osteodystrophy. However, many transplanted patients develop osteoporosis and other bone lesions that are related, at least in part, to their immunosuppressive regimen. The precise histologic patterns of bone disease after transplantation are not well defined. In a study designed to investigate this issue, 57 adult posttransplant patients agreed to undergo bone biopsies and blood drawings. There were 32 men and 25 women, mean age 45 ± 2 yr, who had received a kidney transplantation 5.6 ± 0.8 yr before biopsy. History of bone pain, fractures, and avascular necrosis was found in 22, 12, and 7 patients, respectively. Serum creatinine was 1.68 ± 0.1 mg/dl, 21% of patients were hypercalcemic, 63.2% had elevated parathyroid hormone (PTH) (&gt;65 pg/ml), and 91.2% had normal calcitriol levels. Cancellous bone volume/tissue volume was below normal compared to age- and gender-matched control subjects in 56.1% of patients. Bone turnover (activation frequency) was low in 45.6%, normal in 28.1%, and elevated in 26.3% of patients. Bone formation rate/bone surface was low in 59.7%, normal in 35%, and elevated in 5.3% of the patients. Erosion surface/bone surface was high in 21.1% of patients. Mineralization was prolonged in 87.5% of patients, including 9 patients with osteomalacia and 12 patients with focal osteomalacia. Cumulative and maintenance doses of prednisone and time elapsed since transplantation correlated negatively with bone volume and bone turnover ( r = -0.32 to -0.59, P &lt; 0.05 to 0.01), whereas cumulative doses of cyclosporine or azathioprine, age, gender, or serum PTH levels did not. Regression analysis identified prednisone as the main factor responsible for low bone volume and bone turnover ( r = 0.54 and r = 0.43, P &lt; 0.01). No factors were found to predict delayed mineralization. The present study shows that low bone volume, low bone turnover, and generalized or focal osteomalacia are frequent histologic features in transplanted patients. The effects of age, gender, PTH, and cyclosporine on bone volume and bone turnover are apparently overridden by the prominent effects of glucocorticoids. The prevalence of mineralization defect in the presence of normal serum levels of calcidiol and calcitriol suggests vitamin D resistance and deserves further study.
Expression and Activation of Signal Regulatory Protein α on Astrocytomas
Authors: Thomas T. Chen, Eric J. Brown, Eric J. Huang, William E. Seaman
Journal: Cancer Research (2004)

Abstract High-grade astrocytomas and glioblastomas are usually unresectable because they extensively invade surrounding brain tissue. Here, we report the expression and function of a receptor on many astrocytomas that may alter both the proliferative and invasive potential of these tumors. Signal regulatory protein (SIRP) α1 is an immunoglobulin superfamily transmembrane glycoprotein that is normally expressed in subsets of myeloid and neuronal cells. Transfection of many cell types with SIRPα1, including glioblastomas, has been shown to inhibit their proliferation in response to a range of growth factors. Furthermore, the expression of a murine SIRPα1 mutant has been shown to enhance cell adhesion and initial cell spreading but to inhibit cell extension and movement. The extracellular portion of SIRPα1 binds CD47 (integrin-associated protein), although this interaction is not required for integrin-mediated activation of SIRPα1. On phosphorylation, SIRPα1 recruits the tyrosine phosphatases SHP-1 and SHP-2, which are important in its functions. Although SHP-1 is uniquely expressed on hematopoietic cells, SHP-2 is ubiquitously expressed, so that SIRPα1 has the potential to function in many cell types, including astrocytomas. Because SIRPα1 regulates cell functions that may contribute to the malignancy of these tumors, we examined the expression of SIRPs in astrocytoma cell lines by flow cytometry using a monoclonal antibody against all SIRPs. Screening of nine cell lines revealed clear cell surface expression of SIRPs on five cell lines, whereas Northern blotting for SIRPα transcripts showed mRNA present in eight of nine cell lines. All nine cell lines expressed the ligand for SIRPα1, CD47. To further examine the expression and function of SIRPs, we studied the SF126 and U373MG astrocytoma cell lines, both of which express SIRPs, in greater detail. SIRP transcripts in these cells are identical in sequence to SIRPα1. The expressed deglycosylated protein is the same size as SIRPα1, but in the astrocytoma cells, it is underglycosylated compared with SIRPα1 produced in transfected Chinese hamster ovary cells. It is nonetheless still capable of binding soluble CD47. Moreover, SIRPα1 in each of the two cell lines recruited SHP-2 on phosphorylation, and SIRPα1 phosphorylation in cultured cells is CD47 dependent. Finally, examination of frozen sections from 10 primary brain tumor biopsies by immunohistochemistry revealed expression of SIRPs on seven of the specimens, some of which expressed high levels of SIRPs. Most of the tumors also expressed CD47. This is the first demonstration that astrocytomas can express SIRPα. Given the known role of SIRPα in regulating cell adhesion and responses to mitogenic growth factors, the expression of SIRPα1 on astrocytomas may be of considerable importance in brain tumor biology, and it offers the potential of a new avenue for therapeutic intervention.
Annexin II Is Present on Renal Epithelial Cells and Binds Calcium Oxalate Monohydrate Crystals
Authors: Vivek Kumar, Gerard Farell, Sergio Deganello, John C Lieske
Journal: Journal of the American Society of Nephrology (2003)

Attachment of newly formed crystals to renal epithelial cells appears to be a critical step in the development of kidney stones. The current study was undertaken to identify potential calcium oxalate monohydrate (COM) crystal-binding proteins on the surface of renal tubular cells. Apical membranes were prepared from confluent monolayers of renal epithelial cells (MDCKI line), and COM crystal affinity was used to isolate crystal-binding proteins that were then subjected to electrophoresis and electroblotting. Microsequencing of the most prominent COM crystal-binding protein (M(r) of 37 kD) identified it as annexin II (Ax-II). When exposed proteins on the surface of intact monolayers were biotinylated and then isolated using streptavidin agarose beads, Ax-II was detected, suggesting that at least a portion is exposed on the apical cell surface. Ax-II was not completely extracted by 0.1 M Na(2)CO(3), suggesting that at least a portion of cellular Ax-II is an intrinsic membrane-bound protein. Using confocal immunofluorescence microscopy, Ax-II was visualized together with Caveolin-1 (Cav-1) on the apical membrane of intact MDCKI cells. Cells pretreated with a monoclonal anti-Ax-II antibody bound significantly fewer COM crystals, whereas anti-LDL receptor antibody did not decrease COM binding, further suggesting a functional role for Ax-II during adhesion of crystals to intact cells. These results suggest that Ax-II avidly binds COM crystals and is present on the apical surface of MDCKI cells. Therefore, in the intact nephron, Ax-II could mediate adhesion of COM crystals to cells, and altered exposure of Ax-II on the surface of renal tubular cells could promote crystal retention and possibly kidney stone formation.
Evidence That the Autoimmune Antigen Myelin Basic Protein (MBP) Ac1-9 Binds Towards One End of the Major Histocompatibility Complex (MHC) Cleft
Authors: Christopher Lee, Michael N. Liang, Keri M. Tate, Joshua D. Rabinowitz, Craig Beeson, Patricia P. Jones, Harden M. McConnell
Journal: The Journal of Experimental Medicine (1998)

The NH2-terminal peptide of myelin basic protein (MBP) bound to the class II major histocompatibility complex (MHC) protein I-Au is an immunodominant epitope in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. However, the MBP–I-Au complex is very unstable. To investigate this, we performed site-directed mutagenesis of the I-Au MHC protein and the MBP peptide. Biochemical, T cell activation, and molecular modeling studies of mutant complexes demonstrate that the MBP peptide's key residue for MHC binding, lysine 4, is buried in the P6 pocket of I-Au, which is predominantly hydrophobic. This implies that the MBP–I-Au complex differs from more stable complexes in two respects: (a) the peptide leaves the NH2-terminal region of the MHC peptide-binding cleft unoccupied; (b) the peptide is not anchored by typical favorable interactions between peptide side chains and MHC pockets. To test these hypotheses, a modified MBP peptide was designed based on molecular modeling, with the aim of producing strong I-Au binding. Extension of the NH2 terminus of MBP with six amino acids from the ova peptide, and replacement of the lysine side chain in the P6 pocket with an aromatic anchor, results in &amp;gt;1,000-fold increased binding stability. These results provide an explanation for the unusual peptide–MHC-binding kinetics of MBP, and should facilitate an understanding of why mice are not tolerant to this self-peptide– MHC complex.
Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets
Authors: Charles Swanton, James M Larkin, Marco Gerlinger, Aron C Eklund, Michael Howell, Gordon Stamp, Julian Downward, Martin Gore, P Andrew Futreal, Bernard Escudier, Fabrice Andre, Laurence Albiges, Benoit Beuselinck, Stephane Oudard, Jens Hoffmann, Balázs Gyorffy, Chris J Torrance, Karen A Boehme, Hansjuergen Volkmer, Luisella Toschi, Barbara Nicke, Marlene Beck, Zoltan Szallasi
Journal: Genome Medicine (2010)

The European Union multi-disciplinary Personalised RNA interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics (PREDICT) consortium has recently initiated a framework to accelerate the development of predictive biomarkers of individual patient response to anti-cancer agents. The consortium focuses on the identification of reliable predictive biomarkers to approved agents with anti-angiogenic activity for which no reliable predictive biomarkers exist: sunitinib, a multi-targeted tyrosine kinase inhibitor and everolimus, a mammalian target of rapamycin (mTOR) pathway inhibitor. Through the analysis of tumor tissue derived from pre-operative renal cell carcinoma (RCC) clinical trials, the PREDICT consortium will use established and novel methods to integrate comprehensive tumor-derived genomic data with personalized tumor-derived small hairpin RNA and high-throughput small interfering RNA screens to identify and validate functionally important genomic or transcriptomic predictive biomarkers of individual drug response in patients. PREDICT's approach to predictive biomarker discovery differs from conventional associative learning approaches, which can be susceptible to the detection of chance associations that lead to overestimation of true clinical accuracy. These methods will identify molecular pathways important for survival and growth of RCC cells and particular targets suitable for therapeutic development. Importantly, our results may enable individualized treatment of RCC, reducing ineffective therapy in drug-resistant disease, leading to improved quality of life and higher cost efficiency, which in turn should broaden patient access to beneficial therapeutics, thereby enhancing clinical outcome and cancer survival. The consortium will also establish and consolidate a European network providing the technological and clinical platform for large-scale functional genomic biomarker discovery. Here we review our current understanding of molecular mechanisms driving resistance to anti-angiogenesis agents, the current limitations of laboratory and clinical trial strategies and how the PREDICT consortium will endeavor to identify a new generation of predictive biomarkers.
A heterozygous null mutation combined with the G1258A polymorphism of<i>SPINK5</i>causes impaired LEKTI function and abnormal expression of skin barrier proteins
Authors: W-L. Di, R.C. Hennekam, R.E. Callard, J.I. Harper
Journal: British Journal of Dermatology (2009)

Journal Article A heterozygous null mutation combined with the G1258A polymorphism of SPINK5 causes impaired LEKTI function and abnormal expression of skin barrier proteins Get access W‐L. Di, W‐L. Di Immunobiology Unit Correspondence: Wei‐Li Di. E‐mail: w.di@ich.ucl.ac.uk Search for other works by this author on: Oxford Academic Google Scholar R.C. Hennekam, R.C. Hennekam Clinical and Molecular Genetics Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, U.K.Department of Pediatrics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Search for other works by this author on: Oxford Academic Google Scholar R.E. Callard, R.E. Callard Immunobiology Unit Search for other works by this author on: Oxford Academic Google Scholar J.I. Harper J.I. Harper Immunobiology UnitDepartment of Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 161, Issue 2, 1 August 2009, Pages 404–412, https://doi.org/10.1111/j.1365-2133.2009.09231.x Published: 01 August 2009
Some consensus but little evidence: guidelines on management of pleural infection in children
Authors: I M Balfour-Lynn
Journal: Thorax (2005)

A review of the newly published guidelines on the management of pleural infection in children

Commissioned by the British Thoracic Society (BTS) Standards of Care Committee, the BTS guidelines for the management of pleural infection in children are published as a supplement to this month’s issue of Thorax .1 They have also been subject to scrutiny by the Quality of Practice Committee (QPC) of the Royal College of Paediatrics and Child Health (RCPCH) using the AGREE appraisal instrument, and consequently have been endorsed by the RCPCH. So why did we write them and was it worth it? More importantly—should you read them? What follows are my views as chair of the guideline committee and may not represent those of the other members of the committee (listed in the Acknowledgements).

We are not paediatricians for nothing—we understand sibling rivalry—so when the adult respiratory physicians got an empyema guideline,2 we wanted one. However, it was more than just that. There are major differences between adult and paediatric pleural infections. The principal one is that most children are fit and well before they contract pneumonia and develop an empyema, so the outcome is almost always excellent. This is in contrast to the disease in adults where empyema is a cause of significant morbidity and mortality (recent data has revealed a 12% mortality rate even in those without cancer3). Nevertheless, management of childhood empyema can still be a therapeutic challenge. Unfortunately, in the UK there is little consensus over best practice, both among respiratory paediatricians and also thoracic surgeons. It was therefore considered important to synthesise the available evidence and write guidelines, even though they may only point people in the right direction and highlight the unresolved issues. It is hoped that the guidelines will facilitate dissemination of evidence and standardisation …
CD4 <sup>+</sup> CD25 <sup>+</sup> Regulatory T Cell Depletion Improves the Graft-Versus-Tumor Effect of Donor Lymphocytes After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Sébastien Maury, François M. Lemoine, Yosr Hicheri, Michelle Rosenzwajg, Cécile Badoual, Mustapha Cheraï, Jean-Louis Beaumont, Nabih Azar, Nathalie Dhedin, Anne Sirvent, Agnès Buzyn, Marie-Thérèse Rubio, Stéphane Vigouroux, Olivier Montagne, Dominique Bories, Françoise Roudot-Thoraval, Jean-Paul Vernant, Catherine Cordonnier, David Klatzmann, José L. Cohen
Journal: Science Translational Medicine (2010)

Immunological effects of donor lymphocyte infusion for treatment of recurrent malignancy after allogeneic hematopoietic cell transplantation can be enhanced by depleting T regulatory cells in the infused cells and in the recipient.
Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone With or Without Bevacizumab in Men With Metastatic Castration-Resistant Prostate Cancer: CALGB 90401
Authors: William Kevin Kelly, Susan Halabi, Michael Carducci, Daniel George, John F. Mahoney, Walter M. Stadler, Michael Morris, Philip Kantoff, J. Paul Monk, Ellen Kaplan, Nicholas J. Vogelzang, Eric J. Small
Journal: Journal of Clinical Oncology (2012)

A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).
Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation
Authors: Gregory B. Waypa, Jeremy D. Marks, Robert D. Guzy, Paul T. Mungai, Jacqueline M. Schriewer, Danijela Dokic, Molly K. Ball, Paul T. Schumacker
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

The role of reactive oxygen species (ROS) signaling in the O(2) sensing mechanism underlying acute hypoxic pulmonary vasoconstriction (HPV) has been controversial. Although mitochondria are important sources of ROS, studies using chemical inhibitors have yielded conflicting results, whereas cellular models using genetic suppression have precluded in vivo confirmation. Hence, genetic animal models are required to test mechanistic hypotheses.We tested whether mitochondrial Complex III is required for the ROS signaling and vasoconstriction responses to acute hypoxia in pulmonary arteries (PA).A mouse permitting Cre-mediated conditional deletion of the Rieske iron-sulfur protein (RISP) of Complex III was generated. Adenoviral Cre recombinase was used to delete RISP from isolated PA vessels or smooth muscle cells (PASMC).In PASMC, RISP depletion abolished hypoxia-induced increases in ROS signaling in the mitochondrial intermembrane space and cytosol, and it abrogated hypoxia-induced increases in [Ca(2+)](i). In isolated PA vessels, RISP depletion abolished hypoxia-induced ROS signaling in the cytosol. Breeding the RISP mice with transgenic mice expressing tamoxifen-activated Cre in smooth muscle permitted the depletion of RISP in PASMC in vivo. Precision-cut lung slices from those mice revealed that RISP depletion abolished hypoxia-induced increases in [Ca(2+)](i) of the PA. In vivo RISP depletion in smooth muscle attenuated the acute hypoxia-induced increase in right ventricular systolic pressure in anesthetized mice.Acute hypoxia induces superoxide release from Complex III of smooth muscle cells. These oxidant signals diffuse into the cytosol and trigger increases in [Ca(2+)](i) that cause acute hypoxic pulmonary vasoconstriction.
Necrotic, ulcerative bronchitis, the presenting feature of lymphoproliferative disease following heart-lung transplantation.
Authors: J J Egan, P S Hasleton, N Yonan, A N Rahman, A K Deiraniya, K B Carroll, A A Woodcock
Journal: Thorax (1995)

Following heart-lung transplantation two of 21 patients who survived more than 100 days developed post-transplant lymphoproliferative disease. Both presented with localised ulcerative bronchitis documented at flexible bronchoscopy four months after transplantation. Histological examination showed necrosis with acute inflammation and ulceration. Case 2 demonstrated lymphoproliferative disease from biopsies subsequently taken at rigid bronchoscopy. Case 1 later developed lung nodules and a monoclonal high grade B cell non-Hodgkin's lymphoma was confirmed by an open lung biopsy. The bronchoscopic features described should alert clinicians to post-transplant lymphoproliferative disease as an underlying diagnosis and suggest that bronchus associated lymphoid tissue is the initial site for clonal proliferation in the disease.
Approving the Vagus-Nerve Stimulator for Depression
Authors: Miriam Shuchman
Journal: New England Journal of Medicine (2007)

The vagus-nerve stimulator (VNS), a device that is implanted by a neurosurgeon and sends intermittent electrical pulses to the brain, has been marketed in the United States since 1997 as an adjunctive therapy for the control of epilepsy. Debate is ongoing, however, over the use of the device in patients with refractory depression. Though the key clinical questions (Does it work? Is it safe?) seem straightforward, answering them is proving rather complicated. The Food and Drug Administration (FDA) approved the use of the VNS for depression in 2005, but in February 2007, the Centers for Medicare and Medicaid Services issued . . .
Points from letters: Campaign for Independence in Medicine
Authors: M B Carson
Journal: BMJ (1976)

4) Teaching and administrative duties.(5) A "flexibility factor," so dear to the hearts of our junior colleagues, should apply equally to consultants.(6) A "continuity factor" could also be brought in for the fact that consultants, whether officially on or off duty, still carry responsibility for patients in their care and expect to be called in if anything goes wrong.The pension scheme would also need to be revised, but this is perhaps a separate matter.