350 research outputs found
Predicting drug metabolism: experiment and/or computation?
Drug metabolism can produce metabolites with physicochemical and pharmacological properties that differ substantially from those of the parent drug, and consequently has important implications for both drug safety and efficacy. To reduce the risk of costly clinical-stage attrition due to the metabolic characteristics of drug candidates, there is a need for efficient and reliable ways to predict drug metabolism in vitro, in silico and in vivo. In this Perspective, we provide an overview of the state of the art of experimental and computational approaches for investigating drug metabolism. We highlight the scope and limitations of these methods, and indicate strategies to harvest the synergies that result from combining measurement and prediction of drug metabolism.This is the accepted manuscript of a paper published in Nature Reviews Drug Discovery (Kirchmair J, Göller AH, Lang D, Kunze J, Testa B, Wilson ID, Glen RC, Schneider G, Nature Reviews Drug Discovery, 2015, 14, 387â404, doi:10.1038/nrd4581). The final version is available at http://dx.doi.org/10.1038/nrd458
Virtually abelian K\"ahler and projective groups
We characterise the virtually abelian groups which are fundamental groups of
compact K\"ahler manifolds and of smooth projective varieties. We show that a
virtually abelian group is K\"ahler if and only if it is projective. In
particular, this allows to describe the K\"ahler condition for such groups in
terms of integral symplectic representations
PHANGS CO kinematics: disk orientations and rotation curves at 150 pc resolution
We present kinematic orientations and high resolution (150 pc) rotation
curves for 67 main sequence star-forming galaxies surveyed in CO (2-1) emission
by PHANGS-ALMA. Our measurements are based on the application of a new fitting
method tailored to CO velocity fields. Our approach identifies an optimal
global orientation as a way to reduce the impact of non-axisymmetric (bar and
spiral) features and the uneven spatial sampling characteristic of CO emission
in the inner regions of nearby galaxies. The method performs especially well
when applied to the large number of independent lines-of-sight contained in the
PHANGS CO velocity fields mapped at 1'' resolution. The high resolution
rotation curves fitted to these data are sensitive probes of mass distribution
in the inner regions of these galaxies. We use the inner slope as well as the
amplitude of our fitted rotation curves to demonstrate that CO is a reliable
global dynamical mass tracer. From the consistency between photometric
orientations from the literature and kinematic orientations determined with our
method, we infer that the shapes of stellar disks in the mass range of log()=9.0-10.9 probed by our sample are very close to circular
and have uniform thickness.Comment: 19 figures, 36 pages, accepted for publication in ApJ. Table of
PHANGS rotation curves available from http://phangs.org/dat
Anti-seizure medication is not associated with an increased risk to develop cancer in epilepsy patients
Objective
Whether anti-seizure medication (ASM) increases the risk for cancer has been debated for decades. While for some ASM, a carcinoma-promoting effect has been suspected, carcinoma-protective effects have been shown for other ASM. However, the issue remains unresolved as data from preclinical and clinical studies have been inconsistent and contradictory.
Methods
We collected anonymous patient data from practice neurologists throughout Germany between 2009 and 2018 using the IMS Disease Analyzer database (QuintilesIMS, Frankfurt, Germany). People with epilepsy (PWE) with an initial cancer diagnosis and antiepileptic therapy prior to the index date were 1:1 matched with a control group of PWE without cancer according to age, gender, index year, Charlson Comorbidity Index, and treating physician. For both groups, the risk to develop cancer under treatment with different ASMs was analyzed using three different models (ever use vs. never use (I), effect per one (II) and per five therapy years (III).
Results
A total of 3152 PWE were included (each group, nâ=â1,576; ageâ=â67.3â±â14.0 years). The risk to develop cancer was not significantly elevated for any ASM. Carbamazepine was associated with a decreased cancer risk (OR Model I: 0.699, pâ<â.0001, OR Model II: 0.952, pâ=â.4878, OR Model III: 0.758, pâ<â.0004).
Significance
Our findings suggest that ASM use does not increase the risk of cancer in epilepsy patients
Das Tumormikromilieu bei SpeicheldrĂŒsenkarzinomen â mögliche Konsequenzen fĂŒr neue Therapiekonzepte
Hintergrund
SpeicheldrĂŒsenkarzinome (âsalivary gland carcinomasâ, SGC) sind seltene Tumoren, die aufgrund ihrer histologischen Vielfalt und den in AbhĂ€ngigkeit vom Subtyp unterschiedlichen KrankheitsverlĂ€ufen eine Herausforderung fĂŒr Diagnostik und Therapie darstellen. Ăber die Zusammensetzung des Tumormikromilieus (TME) bei SGC ist bislang wenig bekannt. Ein umfassenderes VerstĂ€ndnis der relevanten molekularen VerĂ€nderungen und immunologischen Prozesse des Tumors sowie des umgebenden Stromas könnte dazu beitragen, die therapeutische Effizienz â beispielsweise durch eine adjuvante Immunmodulation â zu verbessern.
Methoden
In diesem Manuskript wurden Ergebnisse aus Studien zusammengefasst, die sich mit der Zusammensetzung des TME bei SGC beschÀftigen.
Ergebnisse
Das Immunzellinfiltrat der verschiedenen TumorentitĂ€ten ist unterschiedlich. Bei einem Drittel der SGC wurde eine Expression des OberflĂ€chenzellrezeptors LAG3 (âlymphocyte activation gene 3â) auf tumorinfiltrierenden Lymphozyten beobachtet. LAG3 inhibiert â Ă€hnlich wie CTLAâ4 (âcytotoxic Tâlymphocyte antigen 4â) und PDâ1 (âprogrammed cell death 1 proteinâ) â die zellulĂ€re Proliferation, Aktivierung und Homöostase von antitumoral wirksamen TâZellen. Höhere Expressionen sind dabei insbesondere bei den prognostisch ungĂŒnstigeren EntitĂ€ten wie den Speichelgangkarzinomen und Adenokarzinomen NOS (ânot otherwise specifiedâ) zu beobachten.
Schlussfolgerungen
LAG3 ist insbesondere bei aggressiven EntitĂ€ten und fortgeschrittenen Tumoren nachzuweisen. Folglich könnte eine Therapie mit LAG3-Inhibitoren eine Therapie bei fortgeschrittenen und metastasierten SGC unterstĂŒtzen
Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2 ) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2 mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability
- âŠ