A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells.

The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB).

The IASP classification of chronic pain for ICD-11: chronic neuropathic pain.

The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for ≥3 months.

Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study.

Neuropeptide S (NPS) is a regulatory peptide expressed by limited number of neurons in the brainstem. The simultaneous anxiolytic and arousal-promoting effect of NPS suggests an involvement in mood control and vigilance, making the NPS-NPS receptor system an interesting potential drug target. Here we examined, in detail, the distribution of NPS-immunoreactive (IR) fiber arborizations in brain regions of rat known to be involved in the regulation of sleep and arousal.

Deuterium-substituted L-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson's disease: comparison with the effects produced by L-DOPA and an MAO-B inhibitor.

The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO).

Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial.

Importance: No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles.

Objective: To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS).

Nicotine hapten structure, antibody selectivity and effect relationships: results from a nicotine vaccine screening procedure.

The aim of the present study was to synthesise and screen a set of novel nicotine hapten immunogens used for the treatment of nicotine dependence. In the screening process we studied the amount of antibodies generated and their selectivity, using ELISA techniques, and their effects on nicotine-induced dopamine release in the NAC(shell) of the rat, assessed by in vivo voltammetry. We conclude that even small changes such as the linker attachment on the nicotine molecule as well as the structure of the linker may greatly influence the selectivity of the antibodies and the central neurobiological effects of nicotine that are considered critical for its dependence producing properties.

Asenapine elevates cortical dopamine, noradrenaline and serotonin release. Evidence for activation of cortical and subcortical dopamine systems by different mechanisms.

Rationale: Asenapine, a psychopharmacologic agent developed for schizophrenia and bipolar disorder, has higher affinity for 5-HT(2A/C,6,7) and alpha(2) adrenergic receptors than for D(2) receptors. Asenapine exhibits potent antipsychotic-like effects without inducing catalepsy, increases cortical and subcortical dopamine release, and facilitates cortical glutamatergic transmission in rats. In this study, we further analyzed the effects of asenapine on dopaminergic, noradrenergic, and serotonergic systems in the rat brain.

Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia.

Rationale: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder.

Materials And Methods: The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed.

Active immunisation against nicotine blocks the reward facilitating effects of nicotine and partially prevents nicotine withdrawal in the rat as measured by dopamine output in the nucleus accumbens, brain reward thresholds and somatic signs.

We recently showed that active immunisation with the nicotine immunoconjugate IP18-KLH reduces the nicotine-induced increase in dopamine (DA) output in the nucleus accumbens (NAC) and prevents reinstatement of nicotine-seeking behaviour in rats. These effects are mediated by altered distribution of nicotine, resulting in reduced amounts of nicotine reaching the brain, thereby interfering with the rewarding properties of the drug. The present study was designed to explore the effect of immunisation against nicotine on mecamylamine-precipitated nicotine withdrawal as assessed by the reduction in DA output in the NAC in rats.

Topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride.

Recent clinical studies have shown that the anticonvulsant drug topiramate may improve negative symptoms in schizophrenia when added to a stable regimen of neuroleptic medication. It has also been shown that addition of topiramate to neuroleptics might be beneficial in treatment-resistant schizophrenia. Clinically effective doses of antipsychotic drugs (APDs) have been found to suppress conditioned avoidance response behavior (CAR), a preclinical test of antipsychotic activity with high predictive validity, in rats.

Active immunization against nicotine alters the distribution of nicotine but not the metabolism to cotinine in the rat.

We have previously shown that active immunization with the nicotine immunoconjugate IP18-KLH attenuates the reinforcing effects of nicotine, i.e., suppresses the nicotine-induced brain dopamine release and prevents reinstatement of the nicotine-seeking behavior in rats.

Nitric oxide is involved in nicotine-induced burst firing of rat ventral tegmental area dopamine neurons.

In the present study, using single cell recordings in vivo and intracellular recordings in vitro from midbrain slices, the role of N-methyl-d-aspartate (NMDA) receptor signaling on firing activity in ventral tegmental area dopamine neurons elicited by nicotine was investigated in the rat. In accordance with previous studies, systemic nicotine (0.5 mg/kg s.

Differential recruitment of endogenous pain inhibitory systems in neuropathic pain patients.

Neuronal hyperexcitability is a key finding in patients with neuropathic pain. Contributing to hyperexcitability may be decreased activity in the endogenous pain inhibitory systems. The present study aimed at recruiting descending inhibition, by the use of painful heterotopic stimulation (HTS), in 16 patients with peripheral chronic neuropathic pain and associated brush-evoked allodynia.

Experimental brush-evoked allodynia activates posterior parietal cortex.

Objective: To study the brain activation pattern of coexisting experimental ongoing pain and brush-evoked allodynia (pain evoked by innocuous brush) with the use of PET.

Background: Neuropathic pain usually has two essential phenomena: ongoing pain and brush-evoked allodynia, which coexist and may influence each other. Capsaicin induces both ongoing pain and brush-evoked allodynia.

Repetitive intradermal capsaicin: differential effect on pain and areas of allodynia and punctate hyperalgesia.

This study examined the effect of repeated intradermal capsaicin injections on capsaicin pain intensity and areas of allodynia and punctate hyperalgesia. Seventeen healthy volunteers participated in four sessions separated by at least 5 days. Each session included four intradermal injections of 10 microg of capsaicin.

Intramuscular and intradermal injection of capsaicin: a comparison of local and referred pain.

The present study compared capsaicin-induced muscle and skin pain in humans. Twelve healthy subjects received, in a randomised, balanced order, 3 intramuscular (i.m.

Differential effect of painful heterotopic stimulation on capsaicin-induced pain and allodynia.

Painful heterotopic stimulation (HTS) may inhibit experimental and clinical pain, an effect known as diffuse noxious inhibitory control (DNIC). This study examined the effect of painful HTS on capsaicin-induced pain intensity, brush-evoked pain intensity and area of brush-evoked pain in humans. Immersion of the foot into painful cold water significantly reduced capsaicin-induced pain intensity and brush-evoked pain intensity in the contralateral forearm, but did not change area of brush-evoked pain.