The new small tyrosine-kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs

Tyrosine kinases have been implicated in promoting tumorigenesis of several human cancers. Exploiting these vulnerabilities has been shown to be an effective anti-tumor strategy as demonstrated for example by the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, for treatment of various blood cancers. Here, we characterize a new multiple kinase inhibitor, ARQ531, and evaluate its mechanism of action in preclinical models of acute myeloid leukemia. Treatment with ARQ531, by producing global signaling pathway deregulation, resulted in impaired cell cycle progression and survival in a large panel of leukemia cell lines and patient-derived tumor cells, regardless of the specific genetic background and/or the presence of bone marrow stromal cells. RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1. Finally, ARQ531 treatment was effective in a patient-derived leukemia mouse model with significant impairment of tumor progression and survival, at tolerated doses. These data justify the clinical development of ARQ531 as a promising targeted agent for the treatment of patients with acute myeloid leukemia

Nonthermal Mechanochemical Destruction of POPs

The present chapter is dedicated to all relevant theoretical and application aspects of mechanochemical destruction technology for mineralization of POPs, both stockpiled ones and as contaminants in environmental and waste matrices. It will show that such solid-state technology, realized by high energy milling of POPs with a co-milling solid reagent, can achieve complete mineralization of haloorganics into graphitic/amorphous carbon, carbon oxides, and halides; it takes place at near environmental temperature, thus limiting unintentional formation of dioxins (if treatment conditions are selected carefully); and, in some cases, it can be used to produce useful materials instead of just detoxified waste. The chapter will also give a comprehensive picture of complex mechanochemical destruction mechanism, including mechanochemical activation of the co-milling reagent and the cascade of radical reactions that cause POP molecules mineralization. Finally, technological and economic considerations will be provided, which corroborate the validity and feasibility of the mechanochemical destruction as an effective and safe technology to treat POPs

Synthesis and Regeneration of A MXene-Based Pollutant Adsorbent by Mechanochemical Methods

In the present study, an adsorbent material for removal of organic contaminants in wastewater is synthetized by a green and facile mechanochemical method. It is composed of Ti3C2Tx MXene layers (obtained by mechanochemical etching of MAX phase with concentrated HF) pillared with terephthalate by rapid direct reaction. Such material shows high specific surface area (135.7 m2 g−1) and excellent adsorption capability of methylene blue (209 mg g−1) because of the larger interlayer space among MXene sheets and free carboxylate groups of terephthalate. The spent adsorbent is reutilized (with addition of sole aluminum) to synthetize the MAX phase by mechanochemical procedure, where the terephthalate and the pollutant are carbonized into the carbide. In this way, new MXene-based adsorbent can be re-synthetized for further use

Tailoring the properties of a zero-valent iron-based composite by mechanochemistry for nitrophenols degradation in wastewaters

<p>Zero-valent iron (ZVI) is a valuable material for environmental remediation, because of its safeness, large availability, and inexpensiveness. Moreover, its reactivity can be improved by addition of (nano-) particles of other elements such as noble metals. However, common preparation methods for this kind of iron-based composites involve wet precipitation of noble metal salt precursors, so they are often expensive and not green. Mechanochemical procedures can provide a solvent-free alternative, even at a large scale. The present study demonstrates that it is possible to tailor functional properties of ZVI-based materials, utilizing high-energy ball milling. All main preparation parameters are investigated and discussed. Specifically, a copper-carbon-iron ternary composite was prepared for fast degradation of 4-nitrophenol (utilized as model pollutant) to 4-aminophenol and other phenolic compounds. Copper and carbon are purposely chosen to insert specific properties to the composite: Copper acts as efficient nano-cathode that enhances electron transfer from iron to 4-nitrophenol, while carbon protects the iron surface from fast oxidation in open air. In this way, the reactive material can rapidly reduce high concentration of nitrophenols in water, it does not require acid washing to be activated, and can be stored in open air for one week without any significant activity loss.</p

Resonance frequency evaluation on immediate loading implants with angled abutments: case series

Aim: Immediate loading of implant-supported prosthesis is a predictable and standardised therapy for rehabilitation of partially and totally edentulous patients. The present case series evaluate implant success rates by measuring resonance frequency on immediate loading implants with angled abutments. Materials and Methods: A prospective study was performed on five partially edentulous patients. Twenty-six Neoss ProActive Tapered® (Neoss Ltd. Harrogate, UK) implants were inserted: 22 in the maxillary bone and 4 in the mandibular bone. The Osstell ISQ® (Osstell; Integration Diagnostics, Göteborg, Sweden) was used to evaluate implant stability. Implant Stability Quotient (ISQ) measurements were performed in three stages: at time of implant insertion (t0), after three (t1) and 12 (t2) months. The ISQ values were recorded after implant installation of Access® (Neoss Ltd. Harrogate, UK) during the different stages. Results: A six months follow-up showed implant survival of 96%. Twenty-four implants were osseointegrated, a maxillary implant was lost and one other implant was excluded from the study. The values of ISQ ranged between 53-88 ISQ (average 66 ± 6.1 ISQ, median 67 ISQ) at t0, 51-80 ISQ (average 70 ± 5.8 ISQ, median 70 ISQ) at t1 and 53-80 ISQ (average 70.8 ± 5.7 ISQ, median 72 ISQ) at t2. Conclusions: The 24 out of 25 successful implants in five patients demonstrate how using 4-6 implants guarantees sufficient anchorage for a fixed prosthesis and adequate distribution of the prosthetic load on the maxillary and mandible bones, without causing implants failures

ASSESSING BONE MINERAL DENSITY IN ITALIAN ADULT CYSTIC FIBROSIS PATIENTS: A CROSS SECTIONAL STUDY.

The purpose of this study was to assess bone mineral density in a cystic fibrosis (CF) outpatient clinic population and to investigate the relationship between BMD and forced expiratory volume in one second (FEV1), DEXA T-scores and 25-hidroxivitamin D (25-OHD) serum levels. We examined a consecutive series of 44 CF patients. Bone mass density was measured by dual-photon X-ray absorptiometry of lumbar spine and femur (total and neck) and lung function was performed in all patients. Medication data were obtained from medical records. A correlation analysis was performed to determine the relationship between BMD and forced expiratory volume in one second (FEV1), DEXA T-scores and 25-hidroxivitamin D (25-OHD) serum levels. In the results, age showed a significant inverse correlation indicating that as the age increases, bone density decreases and we concluded that most CF patients have low BMD and that there is a positive correlation with lung function and an inverse correlation with age

Ultrasound-Assisted Preparation of Chitosan/Nano-Activated Carbon Composite Beads Aminated with (3-Aminopropyl)Triethoxysilane for Adsorption of Acetaminophen from Aqueous Solutions

A composite chitosan/nano-activated carbon (CS-NAC) aminated by (3-aminopropyl) triethoxysilane (APTES) was prepared in the form of beads and applied for the removal of acetaminophen from aqueous solutions. NAC and APTES concentrations were optimized to obtain a suitable adsorbent structure for enhanced removal of the pharmaceutical. The aminated adsorbent (CS-NAC-APTES beads) prepared with 40% w/w NAC and 2% v/v APTES showed higher adsorption capacity (407.83 mg/g) than CS-NAC beads (278.4 mg/g). Brunauer-Emmett-Teller (BET) analysis demonstrated that the surface area of the CS-NAC-APTES beads was larger than that of CS-NAC beads (1.16 times). The adsorption process was well fitted by the Freundlich model (R2 > 0.95), suggesting a multilayer adsorption. The kinetic study also substantiated that the pseudo-second-order model (R2 > 0.98) was in better agreement with the experimental data. Finally, it was proved that the prepared beads can be recycled (by washing with NaOH solution) at least 5 times before detectable performance loss. © 2019 by the authors

VITAMIN D DEFICIENCY IN ADULTS: SEARCHING FOR THE PROPER LOADING DOSE

Vitamin D is the main hormone regulating calcium phosphate homeostasis and mineral bone metabolism. Vitamin D deficiency is indeed extremely frequent in musculoskeletal diseases. Recent studies have shown that the treatment of osteoporosis needs to have an optimal vitamin D and calcium supplementation for its efficacy. Actually no agreement exists on the estabilished dose of vitamin D to administer in deficency states. We conducted a prospective study to develop a practical cholecalciferol loading dose regimen that would enable rapid correction of vitamin D deficiency. Sixty post-menopausal age woman were enrolled secondary to a fragility fracture (hip, vertebral, wrist) and screened for 25-hydroxyvitamin D (25(OH)D), calcium, and PTH at baseline (T0), after one month (T1), two months (T2), three months (T3) and six months (T4). Secondary to initial blood values of vitamin D patients were divided into 2 groups; the first group (group A, n=30) included patients with 25(OH)D values between 10-30 ng/ml and the second group (group B, n=30) with values under 10 ng/ml. Each group was then divided in 3 subgroups secondary to the randomized administered dose of 25(OH)D. By this, patients can alternatively receive 25000 UI two times monthly, 100000 UI monthly, 10000 UI (25 drops) weekly. The highest values of mean increase of 25(OH)D were observed in patients treated with 100000 UI. Patients treated with 10000 UI weekly did never achieve the target value. Additionally, as vitamin levels increased, pain intensity decreased. Vitamin D supplementation of 100000 UI monthly seems to be adequate to ensure that serum 25(OH)D values reach the threshold level; by this, it will confer the expected effects without risks of toxicity