32 research outputs found

    The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection

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    The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell–mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation

    Nonvirally Modified Autologous Primary Hepatocytes Correct Diabetes and Prevent Target Organ Injury in a Large Preclinical Model

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    BACKGROUND: Current gene- and cell-based therapies have significant limitations which impede widespread clinical application. Taking diabetes mellitus as a paradigm, we have sought to overcome these limitations by ex vivo electrotransfer of a nonviral insulin expression vector into primary hepatocytes followed by immediate autologous reimplantation in a preclinical model of diabetes. METHODS AND RESULTS: In a single 3-hour procedure, hepatocytes were isolated from a surgically resected liver wedge, electroporated with an insulin expression plasmid ex vivo and reimplanted intraparenchymally under ultrasonic guidance into the liver in each of 10 streptozotocin-induced diabetic Yorkshire pigs. The vector was comprised of a bifunctional, glucose-responsive promoter linked to human insulin cDNA. Ambient glucose concentrations appropriately altered human insulin mRNA expression and C-peptide secretion within minutes in vitro and in vivo. Treated swine showed correction of hyperglycemia, glucose intolerance, dyslipidemia and other metabolic abnormalities for > or = 47 weeks. Metabolic correction correlated significantly with the number of hepatocytes implanted. Importantly, we observed no hypoglycemia even under fasting conditions. Direct intrahepatic implantation of hepatocytes did not alter biochemical indices of liver function or induce abnormal hepatic lobular architecture. About 70% of implanted hepatocytes functionally engrafted, appeared histologically normal, retained vector DNA and expressed human insulin for > or = 47 weeks. Based on structural tissue analyses and transcriptome data, we showed that early correction of diabetes attenuated and even prevented pathological changes in the eye, kidney, liver and aorta. CONCLUSIONS: We demonstrate that autologous hepatocytes can be efficiently, simply and safely modified by electroporation of a nonviral vector to express, process and secrete insulin durably. This strategy, which achieved significant and sustained therapeutic efficacy in a large preclinical model without adverse effects, warrants consideration for clinical development especially as it could have broader future applications for the treatment of other acquired and inherited diseases for which systemic reconstitution of a specific protein deficiency is critical

    Observation of gravitational waves from the coalescence of a 2.5−4.5 M⊙ compact object and a neutron star

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    Combinatorial algebra syntax and semantics

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    Combinatorial Algebra: Syntax and Semantics provides a comprehensive account of many areas of combinatorial algebra. It contains self-contained proofs of  more than 20 fundamental results, both classical and modern. This includes Golod–Shafarevich and Olshanskii's solutions of Burnside problems, Shirshov's solution of Kurosh's problem for PI rings, Belov's solution of Specht's problem for varieties of rings, Grigorchuk's solution of Milnor's problem, Bass–Guivarc'h theorem about the growth of nilpotent groups, Kleiman's solution of Hanna Neumann's problem for varieties of groups, Adian's solution of von Neumann-Day's problem, Trahtman's solution of the road coloring problem of Adler, Goodwyn and Weiss. The book emphasize several ``universal" tools, such as trees, subshifts, uniformly recurrent words, diagrams and automata.   With over 350 exercises at various levels of difficulty and with hints for the more difficult problems, this book can be used as a textbook, and aims to reach a wide and diversified audience.  No prerequisites beyond standard courses in linear and abstract algebra are required. The broad appeal of this book extends to a variety of student levels: from advanced high-schoolers to undergraduates and graduate students, including those in search of a Ph.D. thesis who will benefit from the  “Further reading and open problems” sections at the end of Chapters 2 –5.   The book can be used in a classroom and for self-study, engaging anyone who wishes to learn and better understand this important area of mathematics

    Quasi-identities of Finite Semigroups and Symbolic Dynamics

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    An algebra is inherently non-finitely (Q-)based if it is not a member of any locally finite (quasi-)variety, whose (quasi-)identities are finitely based. We prove that no finite semigroup is inherently non-finitely Qbased. This is in marked contrast to the case of varieties, where there are many inherently non-finitely based finite semigroups which have all been described by the second author. 1 Introduction Let us first recall some basic facts and definitions from universal algebra (see [Malcev], [Cohn]). A variety is a class of universal algebras given by identities, i.e. formulas of the type (8x 1 ; : : : ; x n ) u = v where u = u(x 1 ; : : : ; x n ) and v = v(x 1 ; : : : ; x n ) are terms. For example, the class of all abelian groups is a variety of groups given by the identity (8x; y) xy = yx. A quasi-variety is a class of universal algebras given by quasi-identities, i.e. formulas of the type (8x 1 ; : : : ; x n ) u 1 = v 1 & : : : &um = v m ! u = v Research of both autho..
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