Preclinical pharmacology of RA15127343: In vitro and in vivo activity of a novel ultralong-acting basal insulin.

Aim: To report the in vitro and in vivo preclinical pharmacokinetic (PK) and pharmacodynamic (PD) properties of RA15127343, a novel ultralong-acting insulin analogue targeting once-weekly administration, in female Göttingen minipigs.

Methods: In vitro binding and activation of human insulin receptor isoforms (IR-A/IR-B), glucose uptake in rat myocytes, as well as mitogenic activity of RA15127343 were evaluated. In vivo, the PK and PD activities of RA15127343 were assessed in female, normoglycaemic Göttingen minipigs.

ARAF suppresses ERBB3 expression and metastasis in a subset of lung cancers.

RAF kinases are highly conserved serine/threonine kinases, and among the three RAF isoforms (ARAF, BRAF, and CRAF), the pathophysiological relevance of ARAF is not well defined. Here, we show that patients with lung cancer exhibit low expression of ARAF, which is associated with lymph node metastasis and poor patient survival. We uncover that depletion of ARAF promotes anchorage-independent growth and metastasis through activation of AKT signaling in a subset of lung cancer cells.

Revealing the importance of carrier-cargo association in delivery of insulin and lipidated insulin.

Delivery of therapeutic peptides upon oral administration is highly desired and investigations report that the cell-penetrating peptide (CPP) penetratin and its analogues shuffle and penetramax show potential as carriers to enhance insulin delivery. Exploring this, the specific aim of the present study was to understand the impact that their complexation with a lipidated or non-lipidated therapeutic cargo would have on the delivery, to evaluate the effect of differences in membrane interactions in vitro and in vivo, as well as to deduce the mode of action leading to enhanced delivery. Fundamental biophysical aspects were studied by a range of orthogonal methods.

Insulin Fused to Apolipoprotein A-I Reduces Body Weight and Steatosis in DB/DB Mice.

Targeting long-lasting insulins to the liver may improve metabolic alterations that are not corrected with current insulin replacement therapies. However, insulin is only able to promote lipogenesis but not to block gluconeogenesis in the insulin-resistant liver, exacerbating liver steatosis associated with diabetes. In order to overcome this limitation, we fused a single-chain insulin to apolipoprotein A-I, and we evaluated the pharmacokinetics and pharmacodynamics of this novel fusion protein in wild type mice and in db/db mice using both recombinant proteins and recombinant adenoassociated virus (AAV).

Production of a novel heterodimeric two-chain insulin-Fc fusion protein.

Insulin is a peptide hormone produced by the pancreas. The physiological role of insulin is the regulation of glucose metabolism. Under certain pathological conditions the insulin levels can be reduced leading to the metabolic disorder diabetes mellitus (DM).

Equipotency of insulin glargine 300 and 100 U/mL with intravenous dosing but differential bioavailability with subcutaneous dosing in dogs.

Aims: Insulin glargine 300 U/mL (Gla-300) contains the same units versus glargine 100 U/mL (Gla-100) in three-fold lower volume, and higher subcutaneous (SC) doses are required in people with diabetes. To investigate blood glucose (BG) lowering potency, Gla-300 and Gla-100 were compared after intravenous (IV, for 4 h) and SC (for 24 h) injection in healthy Beagle dogs.

Materials And Methods: The dose of 0.

Linking Complement C3 and B Cells in Nasal Polyposis.

Nasal polyposis often is characterized by a persistent inflammation of the sinonasal mucosa, disease recurrence after medical or surgical intervention, and asthma comorbidity. Dysregulated complement activation may contribute to immunologic alterations and disease. To date, there is only scattered knowledge on the source and regulation of the central complement factors in the pathogenesis of nasal polyps.

Long-term stability of insulin glulisine loaded nanoparticles formulated using an amphiphilic cyclodextrin and designed for intestinal delivery.

Long-term stability is one of the main challenges for translation of therapeutic proteins into commercially viable biopharmaceutical products. During processing and storage, proteins are susceptible to denaturation. The aim of this work was to evaluate the stability of amphiphilic cyclodextrin-based nanoparticles (NPs) containing insulin glulisine.

Silica-Coated Nanoparticles with a Core of Zinc, l-Arginine, and a Peptide Designed for Oral Delivery.

Nanoparticle constructs for oral peptide delivery at a minimum must protect and present the peptide at the small intestinal epithelium in order to achieve oral bioavailability. In a reproducible, scalable, surfactant-free process, a core was formed with insulin in ratios with two established excipients and stabilizers, zinc chloride and l-arginine. Cross-linking was achieved with silica, which formed an outer shell.

Zearalenone and ß-Zearalenol But Not Their Glucosides Inhibit Heat Shock Protein 90 ATPase Activity.

The mycotoxin zearalenone (ZEN) is produced by many plant pathogenic species. It is well known for its estrogenic activity in humans and animals, but whether ZEN has a role in plant-pathogen interaction and which process it is targeting was so far unclear. We found that treatment of seedlings with ZEN induced transcription of the gene.

Evaluation of the Performance of AmpliSeq and SureSelect Exome Sequencing Libraries for Ion Proton.

Library preparation for whole-exome sequencing is a critical step serving the enrichment of the regions of interest. For Ion Proton, there are only two exome library preparation methods available, AmpliSeq and SureSelect. Although of major interest, a comparison of the two methods is missing in the literature.

SEDDS for intestinal absorption of insulin: Application of Caco-2 and Caco-2/HT29 co-culture monolayers and intra-jejunal instillation in rats.

To face the challenges of oral delivery of peptide and protein (P/P) drugs, self-emulsifying drug delivery systems (SEDDSs) containing monoacyl phosphatidylcholine (MAPC), Labrasol (LAB) and medium-chain (MC) monoglycerides as permeation enhancers (PEs) were evaluated for their effect on intestinal absorption of insulin. In this study, insulin was complexed with phosphatidylcholine (SPC) to form an insulin-SPC complex (ins-SPC) with increased lipophilicity. The following three SEDDSs: MCT(MAPC) (MC triglycerides and MAPC included), MCT(RH40) (MC triglycerides and Kolliphor RH40 included) and LCT(MAPC) (long-chain triglycerides and MAPC included) were loading with ins-SPC (4% or 8% w/w of SPC).

Physicochemical, pharmacokinetic and pharmacodynamic analyses of amphiphilic cyclodextrin-based nanoparticles designed to enhance intestinal delivery of insulin.

Due to excellent efficacy, low toxicity, and well-defined selectivity, development of new injectable peptides is increasing. However, the translation of these drugs into products for effective oral delivery has been restricted due to poor oral bioavailability. Nanoparticle (NP) formulations have potential to overcome the barriers to oral peptide delivery through protecting the payload and increasing bioavailability.

IgG4-Associated Adrenalitis-a Case Report.

A 67-year-old man was adrenalectomized due to a tumor measuring 100 mm. Specimens revealed an inflammation with slight fibrosis and moderate infiltrates of lymphocytes and plasmacytes with immunoreactivity for IgG and IgG4 resulting in the diagnosis of an active IgG4-associated adrenalitis. To our knowledge, this is the first reported active adrenalitis of this type.

Impact of quality improvement in tuberculosis laboratories in low- and lower-middle-income countries: a systematic review.

Background: The effect of quality improvement measures on the performance of diagnostic tuberculosis (TB) laboratories in low- and lower-middle-income countries is not known, and is the subject of this review.

Methods: Three databases were searched for quality improvement studies presenting data on performance parameters before and after the implementation of quality improvement interventions.

Results: Twenty-one studies were included in this review.

The sword of Damocles for the splenectomised: death by OPSI.

The overwhelming post splenectomy infection (OPSI) in splenectomised patients is a rare but severe infection mostly caused by encapsulated bacteria. We analyse the case of a 65-year-old female patient who was presented with clinical and laboratory findings indicating gastroenteritis. Two years years before admission, the patient underwent a splenectomy for a two stage splenic rupture following resuscitation for pulmonary embolism.

Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes.

Aims/hypothesis: Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present.

Oral delivery of diabetes peptides - Comparing standard formulations incorporating functional excipients and nanotechnologies in the translational context.

While some orally delivered diabetes peptides are moving to late development with standard formulations incorporating functional excipients, the demonstration of the value of nanotechnology in clinic is still at an early stage. The goal of this review is to compare these two drug delivery approaches from a physico-chemical and a biopharmaceutical standpoint in an attempt to define how nanotechnology-based products can be differentiated from standard oral dosage forms for oral bioavailability of diabetes peptides. Points to consider in a translational approach are outlined to seize the opportunities offered by a better understanding of both the intestinal barrier and of nano-carriers designed for oral delivery.

Validation of "laboratory-supported" criteria for functional (psychogenic) tremor.

Background: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity.

Objectives: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty.

Methods: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.

Methane and nitrous oxide emissions from a subtropical coastal embayment (Moreton Bay, Australia).

Surface water methane (CH4) and nitrous oxide (N2O) concentrations and fluxes were investigated in two subtropical coastal embayments (Bramble Bay and Deception Bay, which are part of the greater Moreton Bay, Australia). Measurements were done at 23 stations in seven campaigns covering different seasons during 2010-2012. Water-air fluxes were estimated using the Thin Boundary Layer approach with a combination of wind and currents-based models for the estimation of the gas transfer velocities.

Sulfide and methane production in sewer sediments.

Recent studies have demonstrated significant sulfide and methane production by sewer biofilms, particularly in rising mains. Sewer sediments in gravity sewers are also biologically active; however, their contribution to biological transformations in sewers is poorly understood at present. In this study, sediments collected from a gravity sewer were cultivated in a laboratory reactor fed with real wastewater for more than one year to obtain intact sediments.

Assessing the spatial and temporal variability of diffusive methane and nitrous oxide emissions from subtropical freshwater reservoirs.

Surface water-methane (CH4) and nitrous oxide (N2O) concentrations were measured and diffusive fluxes were estimated in three subtropical freshwater reservoirs (Little Nerang Dam (LND), Lake Wivenhoe (LW) and Lake Baroon (LB)) in southeast Queensland, Australia, during four seasons in 2011-2012. All reservoirs were strong sources of CH4 in all seasons. Surface water CH4 varied between 1350 and 524,000% saturation, and was overall highest in spring and summer, and lowest in winter, however, with no clear patterns common to all reservoirs.