Antigen-Drug Conjugates as a Novel Therapeutic Class for the Treatment of Antigen-Specific Autoimmune Disorders

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see doi.org/10.1021/acs.molpharmaceut.9b00063.Multiple sclerosis represents the world’s most common cause of neurological disability in young people and is attributed to a loss of immune tolerance toward proteins of the myelin sheath. Typical treatment options for MS patients involve immunomodulatory drugs, which act non-specifically, resulting in global immunosuppression. The study discussed herein aims to demonstrate the efficacy of antigen-specific immunotherapies involving conjugation of disease causing auto-antigen, PLP139–151, and a potent immunosuppressant, dexamethasone. Antigen-drug conjugates (AgDCs) were formed using copper-catalyzed azide-alkyne cycloaddition chemistry with the inclusion of a hydrolyzable linker to maintain activity of released dexamethasone. Subcutaneous administration of this antigen-drug conjugate to SJL mice induced with experimental autoimmune encephalomyelitis protected the mice from symptom onset throughout the 25-day study, demonstrating enhanced efficacy in comparison to dexamethasone treatment. These results highlight the benefits of co-delivery of auto-antigens with immunosuppressant drugs as AgDCs for the treatment of autoimmune diseases.National Institutes of Health Graduate Training Program in Dynamic Aspects of Chemical Biology Grant (T32 GM008545)Howard Rytting pre-doctoral fellowship from the Department of Pharmaceutical Chemistry at the University of KansasNational Institutes of Health Biotechnology Training Grant (NIH0073415)NIH Shared Instrumentation Grant # S10RR024664NSF Major Research Instrumentation Award # 162592

AllenRV: an Extensible Monitor for Multiple Complex Specifications with High Reactivity

International audienceAllenRV is a tool for monitoring temporal specifications, designed for ensuring good scalability in terms of size and number of formulae, and high reactivity. Its features reflect this design goal. For ensuring scalability in the number of formulae, it can simultaneously monitor a set of formulae written in past and future, next-free LTL, with some metric extensions; their efficient simultaneous monitoring is supported by a let construct allowing to share computations between formulae. For ensuring scalability in the size of formulae, it allows defining new abstractions as user-defined operators, which take discrete time boolean signals as arguments, but also constant parameters such as delays. For ensuring high reactivity, its monitoring algorithm does not require clock tick events, unlike many other tools. This is achieved by recomputing output signals both upon input signals changes and upon internally generated timeout events relative to such changes. As a consequence, monitoring remains efficient on arbitrarily fine-grained time domains. AllenRV is implemented by extending the existing Allen language and compiler, initially targeting ubiquitous applications using binary sensors, with temporal logic operators and a comprehensive library of user-defined operators on top of them. The most complex of these operators, including a complete adaptation of Allen-logic relations as selection operators, are proven correct with respect to their defined semantics. Thus, AllenRV offers an open platform for cooperatively developing increasingly complex libraries of high level, general or domain-specific, temporal operators and abstractions, without compromising correctness

Evaluasi Pemberian Anastesi Infiltrasi Lokal (LIA) pada Pasien Pasca Operasi Total Knee Arthroplasty di RS Ortopedi Prof. Dr. Dr. R. Soeharso Surakarta

Latar Belakang. Operasi arthroplasti lutut memerlukan penanganan nyeri yang tepat untuk mengurangi ketidaknyamanan pasien dan mempercepat pemulihan. Local infiltration analgesia (LIA) merupakan salah satu modalitas untuk penanganan nyeri dimana diberikan kombinasi berbagai macam obat anti nyeri pada ruang intraartikular dan jaringan sekitar sendi. Tujuan. Mengetahui perbedaan nilai Visual Analog Scale (VAS), perbedaan lama rawat inap, perbedaan nilai Knee Society Score (KSS) pada pasien post operasi TKA yang diberikan LIA dan yang tidak diberikan LIA. Metode. Metode penelitian ini adalah eksperimental dengan uji acak terkontrol (Randomized Controled Trial), post test only group design. Sample berupa total sampling dari pasien osteoartritis lutut dengan status fisik American Society of Anesthesiologis (ASA) I-II, usia 50 - 75 tahun yang menjalani operasi TKA satu sisi dengan satu operator dan anastesi regional dalam kurun waktu Agustus 2016 – Desember 2016. Sample terbagi menjadi 2 kelompok, dimana satu kelompok coba diberikan LIA dengan Levobupivacain, dan kelompok kontrol. Variabel independen pada kelompok coba adalah pasien OA knee yang dilakukan TKA diberikan LIA dengan Buvipacain 100 mg sesaat sebelum penjahitan luka operasi. Variable independen pada kelompok kontrol adalah pasien OA knee yang dilakukan TKA yang tidak diberikan LIA sesaat sebelum penjahitan luka operasi. Variabel dependennya berupa skala nyeri diniliai menggunakan Visible Analog Scale (VAS) yang dinilai pada interval waktu 12 jam, 24 jam, 36 jam, dan 48 jam setelah dilakukan injeksi Anestesi Infiltrasi Lokal, lama perawatan di rumah sakit (Length of Stay) yang dihitung sejak pasien dilakukan operasi TKA hingga pasien dibolehkan pulang dan skor fungsional yang dihitung dengan Knee Society Score (KSS) setelah 3 bulan pasca operasi. Hasil: Sebanyak 64 pasien telah dilakukan analisa, didapatkan 14 pasien pria dan 50 pasien wanita. Usia rata-rata adalah 60,87 tahun. Terdapat perbedaan secara signifikan (p = 0,00) pada kelompok yang diberikan LIA untuk nilai nyeri pasca operasi dibandingkan dengan kelompok kontrol, dimana nilai VAS yang lebih rendah pada kelompok yang diberikan LIA. Kesimpulan: Pada penelitian ini dapat disimpulkan bahwa LIA dengan Levobupivakain berpengaruh dalam menurunkan nyeri pasca operasi, mempersingkat lama rawat inap di Rumah Sakit serta mempunyai functional outcome yang lebih baik pada pasien dengan osteoartritis lutut yang dilakukan operasi TKA di RS Ortopedi Prof. Dr. R. Soeharso Surakarta

A Constructor-Based Reachability Logic for Rewrite Theories

Reachability logic has been applied to K rewrite-rule-based language definitions as a language-generic logic of programs. It has been proved successful in verifying a wide range of sophisticated programs in conventional languages. Here we study how reachability logic can be made not just language-generic, but rewrite-theory-generic to make it available not just for conventional program verification, but also to verify rewriting-logic-based programs and distributed system designs. A theory-generic reachability logic is presented and proved sound for a wide class of rewrite theories. Particular attention is given to increasing the logic's automation by means of constructor-based semantic unification, matching, and satisfiability procedures. The relationships to Hoare logic and LTL are discussed, new methods for proving invariants of possibly never terminating distributed systems are developed, and experiments with a prototype implementation illustrating the new methods are presented.Partially supported by NSF Grants CNS 13-19109 and CNS 14-09416, and AFOSR Contract FA8750-11-2-0084.Ope

Generalized Rewrite Theories and Coherence Completion

A new notion of generalized rewrite theory suitable for symbolic reasoning and generalizing the standard notion is motivated and defined. Also, new requirements for symbolic executability of generalized rewrite theories that extend those for standard rewrite theories, including a generalized notion of coherence, are given. Finally, symbolic executability, including coherence, is both ensured and made available for a wide class of such theories by automatable theory transformations.Partially supported by by NRL under contract number N00173-17-1-G002.Ope

Sferična kristalizacija zdravilnih učinkovin

Spherical crystallization of drugs is the process of obtaining larger particles by agglomeration during crystallization. The most common techniques used to obtain such particles are spherical agglomeration and quasi-emulsion solvent diffusion. Ammonia diffusion systems and crystallo-co-agglomeration are extensions of these techniques. By controlling process parameters during crystallization, such as temperature, stirring rate, type and amount of solvents, or excipient selection, it is possible to control the formation of agglomerates and obtain spherical particles of the desired size, porosity, or hardness. Researchers have reported that the particles produced have improved micromeritic, physical, and mechanical properties, which make them suitable for direct compression. In some cases, when additional excipients are incorporated during spherical crystallization, biopharmaceutical parameters including the bioavailability of drugs can also be tailored.Sferična kristalizacija je postopek izdelave večjih delcev z aglomeracijo manjših med samo kristalizacijo. Najpogosteje uporabljeni tehniki za izdelavo takšnih delcev sta sferična aglomeracija in kvaziemulzija z difuzijo topila. Sistem z difuzijo amoniaka in kristalo-ko-aglomeracija sta razširitvi teh dveh metod. Z nadzorovanjem procesnih parametrov med kristalizacijo, kot sta temperatura in hitrost mešanja, z izbiro lastnosti in množine topil ter z izbiro pomožnih snovi, lahko vplivamo na nastanek aglomeratov in izdelamo sferične delce želenih velikosti, primerne poroznosti ali trdote. Raziskovalci poročajo, da imajo izdelani delci izboljšane pretočne lastnosti, izboljšane druge fizikalne in mehanske lastnosti zaradi česar so primerni za direktno tabletiranje. V nekaterih primerih lahko ob vgradnji ustreznih pomožnih snovi, ki jih dodamo med procesom sferične kristalizacije, izboljšamo tudi biofarmacevtske lastnosti zdravilnih učinkovin vključno s povečanjem biološke uporabnosti

Comparison of onset and duration of sensory and motor blockade with intrathecal isobaric bupivacaine versus isobaric levobupivacaine for infraumblical surgeries

Background: Spinal anaesthesia remains a popular technique of choice for performing surgeries on abdomen, pelvis and lower limbs. It has fast onset of action and provides effective sensory and motor blockade. Spinal anaesthesia is routinely performed by administration of 0.5% bupivacaine. Aims: Aim of the study was to compare onset and duration of sensory and motor blockade between intrathecal isobaric 0.5% bupivacaine and isobaric 0.5% levobupivacaine. Materials and methods: 80 patients between the age group of 18-65 years of either gender, belonging to ASA Grade I and II scheduled for elective infraumbilical surgeries were enrolled in the study. They were randomised into 2 groups. Group B received intrathecal 3.2 ml of 0.5 % isobaric bupivacaine and Group L received intrathecal 3.2 ml of 0.5% isobaric levobupivacaine. Onset and duration of sensory and motor blockage were compared between the two groups