Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor.

Purpose: TAS266 is a novel agonistic tetravalent Nanobody(®) targeting the DR5 receptor. In preclinical studies, TAS266 was more potent than a cross-linked DR5 antibody or TRAIL. This first-in-human study was designed to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of TAS266.

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies.

Experimental Design: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors.

Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma.

Purpose: To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib.

Patients And Methods: Eligibility criteria were advanced solid tumors, 18 years or older, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Exclusion criteria included Type 1 diabetes, active GI disease, leptomeningeal disease, or current evidence/risk of retinal venous occlusion/central serous retinopathy.

A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

Background: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity.

Patients And Methods: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study.

Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma.

The maximum tolerated dose of SAR245409 (voxtalisib), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, was determined in a phase 1 dose-escalation study in advanced solid tumors. We report safety, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409 capsules 50 mg twice daily in an expansion cohort of 16 patients with relapsed/refractory lymphoma. The most common treatment-related adverse events (AEs) were nausea (31.

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

Purpose: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing.

Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma.

Purpose: Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed.

Evaluation of total reducing power of edible oils.

The lipophilicity of untreated edible oils narrows the application of most published methods for the determination of antioxidant activity to hydrophilic extracts of oils. This research addresses the issue of the estimation of the total antioxidant properties of untreated edible oils by modifying two widely applied analytical methods, the Fe-Phenanthroline and the CUPRAC assays, to be used in untreated oils. The modifications pertain to the selection of mixture of solvents (ethanol-butanol in 3:1 v/v ratio), and the optimization of the reaction conditions (reagents concentration and reaction time).

Presurgical orthodontic treatment of patients with complete bilateral cleft lip and palate.

Introduction: Cleft lips and palates are the most common congenital orofacial anomaly. This type of clefts is the most severe from the orthodontic-surgical therapy aspect.

Case Report: A female newborn with a complete cleft of the primary and the secondary palate was admitted to the clinic, where a multiple-role orthodontic device was specially designed and applied to primarily manage the closure of the existing cleft and help to improve the suckling ability of the baby.

Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors.

Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks.

Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma.

Background: Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib.

Methods: Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg(-1) intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib.

Lack of meaningful effect of ridaforolimus on the pharmacokinetics of midazolam in cancer patients: model prediction and clinical confirmation.

Ridaforolimus, a unique non-prodrug analog of rapamycin, is a potent inhibitor of mTOR under development for cancer treatment. In vitro data suggest ridaforolimus is a reversible and time-dependent inhibitor of CYP3A. A model-based evaluation suggested an increase in midazolam area under the curve (AUC(0- ∞)) of between 1.

Social support and depression of adults with visual impairments.

Relatively little research exists with regard to the relationship between social support and depression among adults with visual impairments. Such a gap is noteworthy when one considers that individuals become more dependent on others as they enter middle and late adulthood. The present research will examine the association between social networks, social support and depression among adults with visual impairments.

A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors.

The human monoclonal antibody MNRP1685A targets the VEGF binding domain of neuropilin-1 (NRP1), a multi-domain receptor necessary for neural development and blood vessel maturation. In nonclinical studies, MNRP1685A prevents vascular maturation by keeping blood vessels in an immature, highly VEGF-dependent state. We explored the safety and tolerability of MNRP1685A in patients with advanced solid tumors.

Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors.

Purpose: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors.

Experimental Design: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily.

Filamentous Escherichia coli cells swimming in tapered microcapillaries.

This study analyzed the swimming characteristics of filamentous Escherichia coli cells inside tapered capillaries with a diameter decreasing from 700 μm to 4 μm and a mean body length of 27.8 μm ± 11.9 μm.

Renal injury following intravitreal anti-VEGF administration in diabetic patients with proliferative diabetic retinopathy and chronic kidney disease--a possible side effect?

The use of intravitreal injections of anti-Vascular Endothelial Growth Factor (anti-VEGF) has been used for a broad spectrum of ocular pathologic entities. Although the dose of anti-VEGF agents used for treating eye disease is minute compared with that used intravenously, intraocular administration can lead to systemic absorption and reduce serum VEGF levels. Several systemic side effects, such as hypertension and cardiovascular complications have been rarely reported in the literature.

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening.

Glucose-6-Phosphate Dehydrogenase (G6PD) gene is located at the X-chromosome at Xq28 and the disease is recessively inherited predominantly in males. More than 400 variants have been proposed based on clinical and enzymatic studies. The aim of the current study was to identify C563T mutation in G6PD-deficient newborns and to correlate the enzyme residual activity with the presence of the mutation.

The impact of individual characteristics in self-esteem and locus of control of young adults with visual impairments.

In this study the impact of personal/individual characteristics (gender, vision status, age, age at loss of sight, recency of vision loss, education level, employment status, and ability of independent movement) in locus of control (LOC) and self-esteem were examined. Eighty-four young adults with visual impairments (42 with blindness and 42 with low vision) took part in this study. The significant predictors of self-esteem were vision status, age at loss of sight, recency of vision loss and educational level.

A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours.

Background: LY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis.

Methods: Patients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met.

Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors.

Background: Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies.

Methods: Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.