Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues.

Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB1 (EC50 = 0.

National trends in alcohol pharmacotherapy: Findings from an Australian claims database.

Background: Although the efficacy of alcohol pharmacotherapy has been widely investigated, little is known about real-world prescription patterns. Population-based dispensing data can provide an understanding of prescription patterns and characteristics of treatment in nonexperimental settings.

Methods: A retrospective cohort study of patients (aged 15-84) treated with acamprosate or naltrexone between July 2009 and June 2013 was conducted using dispensing claims from the Australian Pharmaceutical benefits Scheme Database.

Systematic Review and Meta-Analysis on the Role of Chemotherapy in Advanced and Metastatic Neuroendocrine Tumor (NET).

Background/objectives: In the era of somatostatin analogues and targeted therapies, the role of chemotherapy in NET remains largely undefined. This systematic review aimed to assess the effect of chemotherapy on response rates (RR), progression-free survival (PFS), overall survival (OS) and toxicity compared to other chemotherapies/systemic therapies or best supportive care in patients with advanced or metastatic NET.

Methods: Randomised controlled trials (RCTs) from 1946 to 2015 were identified from MEDLINE, EMBASE, other databases and conference proceedings.

Comparative assessment of phototherapy protocols for reduction of oxidative stress in partially transected spinal cord slices undergoing secondary degeneration.

Background: Red/near-infrared light therapy (R/NIR-LT) has been developed as a treatment for a range of conditions, including injury to the central nervous system (CNS). However, clinical trials have reported variable or sub-optimal outcomes, possibly because there are few optimized treatment protocols for the different target tissues. Moreover, the low absolute, and wavelength dependent, transmission of light by tissues overlying the target site make accurate dosing problematic.

FUT1 genetic variants impact protein glycosylation of porcine intestinal mucosa.

A massive use of antibiotics in industrial pig production is a major cause of the rapidly rising bacterial resistance to antibiotics. An enhanced understanding of infectious diseases and of host-microbe interactions has the potential to explore alternative ways to improve pig health and reduce the need for antibiotics. Host-microbe interactions depend on host-expressed glycans and microbe-carrying lectins.

Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring-The TADE Study.

Purpose: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels.

Experimental Design: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L.

Epigallocatechin-3-gallate induces oxidative phosphorylation by activating cytochrome c oxidase in human cultured neurons and astrocytes.

Mitochondrial dysfunction and resulting energy impairment have been identified as features of many neurodegenerative diseases. Whether this energy impairment is the cause of the disease or the consequence of preceding impairment(s) is still under discussion, however a recovery of cellular bioenergetics would plausibly prevent or improve the pathology. In this study, we screened different natural molecules for their ability to increase intracellular adenine triphosphate purine (ATP).

Central kynurenine pathway shift with age in women.

Age is considered a dominant risk factor in the development of most neurodegenerative disorders. The kynurenine pathway, a major metabolic pathway of tryptophan is altered in the majority of neurodegenerative disorders. In this study, we have analysed CSF samples from 49 healthy women across a wide age range (0-90) for kynurenine pathway metabolites and the inflammatory marker neopterin.

Nonesterified Fatty Acid-Induced Endoplasmic Reticulum Stress in Cattle Cumulus Oocyte Complexes Alters Cell Metabolism and Developmental Competence.

Reduced oocyte quality has been associated with poor fertility of high-performance dairy cows during peak lactation, due to negative energy balance. We examined the role of nonesterified fatty acids (NEFAs), known to accumulate within follicular fluid during under- and overnutrition scenarios, in causing endoplasmic reticulum (ER) stress of in vitro maturated cattle cumulus-oocyte complexes (COCs). NEFA concentrations were: palmitic acid (150 μM), oleic acid (200 μM), and steric acid (75 μM).

Recombinant human heterodimeric IL-15 complex displays extensive and reproducible N- and O-linked glycosylation.

Human interleukin 15 (IL-15) circulates in blood as a stable molecular complex with the soluble IL-15 receptor alpha (sIL-15Rα). This heterodimeric IL-15:sIL-15Rα complex (hetIL-15) shows therapeutic potential by promoting the growth, mobilization and activation of lymphocytes and is currently evaluated in clinical trials. Favorable pharmacokinetic properties are associated with the heterodimeric formation and the glycosylation of hetIL-15, which, however, remains largely uncharacterized.

The Hsp90 inhibitor SNX-7081 is synergistic with fludarabine nucleoside via DNA damage and repair mechanisms in human, p53-negative chronic lymphocytic leukemia.

Clinical trials of heat shock protein 90 (Hsp90) inhibitors have been limited by high toxicity. We previously showed that the Hsp90 inhibitor, SNX-7081, synergizes with and restores sensitivity to fludarabine nucleoside (2-FaraA) in human chronic lymphocytic leukemia (CLL) cells with lesions in the p53 pathway (Best OG, et al., Leukemia Lymphoma 53:1367-75, 2012).

Characterization of red-shifted phycobilisomes isolated from the chlorophyll f-containing cyanobacterium Halomicronema hongdechloris.

Phycobilisomes are the main light-harvesting protein complexes in cyanobacteria and some algae. It is commonly accepted that these complexes only absorb green and orange light, complementing chlorophyll absorbance. Here, we present a new phycobilisome derived complex that consists only of allophycocyanin core subunits, having red-shifted absorption peaks of 653 and 712 nm.

A Structural Equation Modeling Analysis of the Relationships between Depression, Anxiety, and Sexual Problems over Time.

Sexual dysfunctions are related to depressive and anxiety disorders, but the nature of these relationships remains unclear. This study examined the relationship among symptoms of these disorders over time by comparing (a) a model that included causal relationships, (b) a model that accounted for change over time with a shared underlying factor (or latent liability) among all the disorders, and (c) a model that conceptualized sexual dysfunctions as unrelated to depressive and anxiety disorders over time. Participants (n = 1,012) completed online self-report measures of sexual dysfunctions and depressive and anxiety disorders across six time points at either weekly or monthly intervals.

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.

Background: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.

Methods: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily.

Identification of N-arachidonoyl dopamine as a highly biased ligand at cannabinoid CB1 receptors.

Background And Purpose: N-arachidonyl dopamine (NADA) has been identified as a putative endocannabinoid, but there is little information about which signalling pathways it activates. The purpose of this study was to identify the signalling pathways activated by NADA in vitro.

Experimental Approach: Human or rat cannabinoid CB1 receptors were expressed in AtT20, CHO or HEK 293 cells.

Data from a proteomic baseline study of Assemblage A in Giardia duodenalis.

Eight Assemblage A strains from the protozoan parasite Giardia duodenalis were analysed using label-free quantitative shotgun proteomics, to evaluate inter- and intra-assemblage variation and complement available genetic and transcriptomic data. Isolates were grown in biological triplicate in axenic culture, and protein extracts were subjected to in-solution digest and online fractionation using Gas Phase Fractionation (GPF). Recent reclassification of genome databases for subassemblages was evaluated for database-dependent loss of information, and proteome composition of different isolates was analysed for biologically relevant assemblage-independent variation.

Do MRI findings identify patients with low back pain or sciatica who respond better to particular interventions? A systematic review.

Purpose: Magnetic resonance imaging (MRI) can reveal a range of degenerative findings and anatomical abnormalities; however, the clinical importance of these remains uncertain and controversial. We aimed to investigate if the presence of MRI findings identifies patients with low back pain (LBP) or sciatica who respond better to particular interventions.

Methods: MEDLINE, EMBASE and CENTRAL databases were searched.

Somatostatin in the rat rostral ventrolateral medulla: Origins and mechanism of action.

Somatostatin (SST) or agonists of the SST-2 receptor (sst2 ) in the rostral ventrolateral medulla (RVLM) lower sympathetic nerve activity, arterial pressure, and heart rate, or when administered within the Bötzinger region, evoke apneusis. Our aims were to describe the mechanisms responsible for the sympathoinhibitory effects of SST on bulbospinal neurons and to identify likely sources of RVLM SST release. Patch clamp recordings were made from bulbospinal RVLM neurons (n = 31) in brainstem slices prepared from juvenile rat pups.

Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans.

Unlabelled: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims.

Paucimannosidic glycoepitopes are functionally involved in proliferation of neural progenitor cells in the subventricular zone.

Protein glycosylation has received much attention due to its multiple functional roles in physiological and pathophysiological conditions. Paucimannose is a common mannosidic N-glycoepitope in invertebrates and plants but has only recently been detected in vertebrates. Herein, we demonstrate the presence of paucimannosidic epitopes specifically in early postnatal neural progenitor cells (NPCs) between postnatal day 0 and 7 in mouse brain suggesting a possible role in the development of NPCs.

Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135.

Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of N-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB1) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the in vitro functional activities of SC designer drugs JWH-018, UR-144, PB-22, and APICA, and their respective terminally fluorinated analogues AM-2201, XLR-11, 5F-PB-22, and STS-135 at human CB1 and CB2 receptors using a FLIPR membrane potential assay.

New antimicrobial bromotyrosine analogues from the sponge Pseudoceratina purpurea and its predator Tylodina corticalis.

Bioassay-guided fractionation of extracts from temperate Australian collections of the marine sponge Pseudoceratina purpurea resulted in the isolation and characterisation of two new and six known bromotyrosine-derived alkaloids with antibiotic activity. Surprisingly, a single specimen of the mollusc Tylodina corticalis, which was collected while feeding on P. purpurea, contained only a few of the compounds found in the sponge suggesting selective accumulation and chemical modification of sponge metabolites.

Quantitative proteomic analysis of Giardia duodenalis assemblage A: A baseline for host, assemblage, and isolate variation.

Giardia duodenalis is a gastrointestinal protozoan parasite of vertebrates and is a species complex comprised of eight assemblages, with the zoonotic assemblage A one of two subtypes infective for humans. With increasing genomic and transcriptomic data publicly available through the centralized giardiaDB.org, we have quantitatively analyzed the proteomes of eight G.