Clinical Influences in the Multidisciplinary Management of Small Renal Masses at a Tertiary Referral Center

Introduction We designed a multidisciplinary Small Renal Mass Center to help patients decide among treatment options and individualize therapy for small renal masses. In this model physicians and support staff from multiple specialties work as a team to evaluate and devise a treatment plan for patients at the same organized visit. Methods We retrospectively reviewed the records of 263 patients seen from 2009 to 2014. Monitored patient characteristics included age, Charlson comorbidity index, body mass index, nephrometry score, tumor size and estimated glomerular filtration rate. Univariate and multivariate analyses were performed to identify patient characteristics associated with each treatment choice. Results Of the cohort 88 patients elected active surveillance, 64 underwent ablation and 111 were treated with surgery, including partial and radical nephrectomy in 74 and 37, respectively. There were significant associations between treatment modality and age, Charlson comorbidity index, tumor size and estimated glomerular filtration rate. Mean patient age at presentation was 61.1 years. Patients with a high Charlson comorbidity index score (greater than 5) or a decreased estimated glomerular filtration rate (less than 60 ml/minute/1.73 m2) were more likely to undergo active surveillance (41.6% and 35%) and ablative therapy (29.6% and 34%) vs partial nephrectomy (10.6% and 9%, respectively, each p \u3c0.001). On multivariable analysis age, tumor size and estimated glomerular filtration rate remained significantly associated with modality after adjustment for all other factors (each p \u3c0.001). Conclusions The Small Renal Mass Center enables patients to assess the various treatment modalities for a small renal mass in a single setting. By providing simultaneous access to the various specialists it provides an invaluable opportunity for informed patient decision making. © 2016 American Urological Association Education and Research, Inc

Dissecting the supramolecular dispersion of fullerenes by proteins/peptides: Amino acid ranking and driving forces for binding to c60

Molecular dynamics simulations were used to quantitatively investigate the interactions between the twenty proteinogenic amino acids and C60. The conserved amino acid backbone gave a constant energetic interaction ~5.4 kcal mol−1, while the contribution to the binding due to the amino acid side chains was found to be up to ~5 kcal mol−1 for tryptophan but lower, to a point where it was slightly destabilizing, for glutamic acid. The effects of the interplay between van der Waals, hydrophobic, and polar solvation interactions on the various aspects of the binding of the amino acids, which were grouped as aromatic, charged, polar and hydrophobic, are discussed. Although π–π interactions were dominant, surfactant‐like and hydrophobic effects were also observed. In the molecular dynamics simulations, the interacting residues displayed a tendency to visit configura-tions (i.e., regions of the Ramachandran plot) that were absent when C60 was not present. The amino acid backbone assumed a “tepee‐like” geometrical structure to maximize interactions with the fullerene cage. Well‐defined conformations of the most interactive amino acids (Trp, Arg, Met) side chains were identified upon C60 binding

Dissecting the Interactions between Chlorin e6 and Human Serum Albumin

Chlorin e6 (Ce6) is among the most used sensitizers in photodynamic (PDT) and sonodynamic (SDT) therapy; its low solubility in water, however, hampers its clinical exploitation. Ce6 has a strong tendency to aggregate in physiological environments, reducing its performance as a photo/sono-sensitizer, as well as yielding poor pharmacokinetic and pharmacodynamic properties. The interaction of Ce6 with human serum albumin (HSA) (i) governs its biodistribution and (ii) can be used to improve its water solubility by encapsulation. Here, using ensemble docking and microsecond molecular dynamics simulations, we identified the two Ce6 binding pockets in HSA, i.e., the Sudlow I site and the heme binding pocket, providing an atomistic description of the binding. Comparing the photophysical and photosensitizing properties of Ce6@HSA with respect to the same properties regarding the free Ce6, it was observed that (i) a red-shift occurred in both the absorption and emission spectra, (ii) a maintaining of the fluorescence quantum yield and an increase of the excited state lifetime was detected, and (iii) a switch from the type II to the type I mechanism in a reactive oxygen species (ROS) production, upon irradiation, took place

A multidisciplinary study of chemico-physical properties of different classes of 2-aryl-5(or 6)-nitrobenzimidazoles: NMR, electrochemical behavior, ESR, and DFT calculations

Continuing in our researches on the syntheses, reactivity, pharmacological/biological activities of heterocyclic compounds containing one or more nitrogen atoms we have examined some chemico-physical properties (1H and 13C NMR, electrochemical behavior, and ESR) of three series of 2-aryl-5(or 6)-nitrobenzimidazoles (1–3) variously substituted in the 2-aryl ring. The electrochemical behavior of the nitro group on the benzimidazole ring has been studied by cyclic voltammetry. This has allowed to point out both the reversibility, the formal potential, and the number of electrons involved in the electrochemical processes, and to evaluate the effect of the substituents present on the aryl ring. The data collected have been able to furnish a complete picture of electronic distribution and have been supported by DFT calculations

Light-Enhanced Cytotoxicity of Doxorubicin by Photoactivation

The combination of photodynamic therapy with chemotherapy (photochemotherapy, PCT) can lead to additive or synergistic antitumor effects. Usually, two different molecules, a photosensitizer (PS) and a chemotherapeutic drug are used in PCT. Doxorubicin is one of the most successful chemotherapy drugs. Despite its high efficacy, two factors limit its clinical use: severe side effects and the development of chemoresistance. Doxorubicin is a chromophore, able to absorb light in the visible range, making it a potential PS. Here, we exploited the intrinsic photosensitizing properties of doxorubicin to enhance its anticancer activity in leukemia, breast, and epidermoid carcinoma cells, upon irradiation. Light can selectively trigger the local generation of reactive oxygen species (ROS), following photophysical pathways. Doxorubicin showed a concentration-dependent ability to generate peroxides and singlet oxygen upon irradiation. The underlying mechanisms leading to the increase in its cytotoxic activity were intracellular ROS generation and the induction of necrotic cell death. The nuclear localization of doxorubicin represents an added value for its use as a PS. The use of doxorubicin in PCT, simultaneously acting as a chemotherapeutic agent and a PS, may allow (i) an increase in the anticancer effects of the drug, and (ii) a decrease in its dose, and thus, its dose-related adverse effects

Amino acid-driven adsorption of emerging contaminants in water by modified graphene oxide nanosheets

Graphene oxide nanosheets have shown promising adsorption properties toward emerging organic contaminants in drinking water. Here, we report a family of graphene oxide nanosheets covalently modified with amino acids and the study on their adsorption properties toward a mixture of selected contaminants, including pharmaceuticals, additives, and dyes. Graphene oxides modified with l-glutamic acid and l-methionine (GO-Glu and GO-Met) were synthesized and purified with a scalable and fast synthetic and purification procedure, and their structure was studied by combined X-ray photoelectron spectroscopy and elemental analysis. An amino acid loading of about 5% and a slight reduction (from 27% down to 14-20% oxygen) were found and associated with the adsorption selectivity. They were compared to unmodified GO, reduced GO (rGO), GO-lysine, and to the reference sample GO-NaOH. Each type of modified GO possesses a higher adsorption capacity toward bisphenol A (BPA), benzophenone-4 (BP4), and carbamazepine (CBZ) than standard GO and rGO, and the adsorption occurred within the first hour of contact time. The maximum adsorption capacity (estimated from the adsorption isotherms) was strictly related to the amino acid loading. Accordingly, molecular dynamics simulations highlighted higher interaction energies for the modified GOs than unmodified GO, as a result of higher van der Waals and hydrophobic interactions between the contaminants and the amino acid side chains on the nanosheet surface

Adsorption of emerging contaminants by graphene related materials and their alginate composite hydrogels

Graphene nanosheets and nanoplatelets -alginate composite hydrogels were prepared by ionic gelation and the resulting gel beads were exploited for the removal of a mixture of eight selected emerging contaminants (ECs) in tap water, including bisphenol A, ofloxacin and diclofenac. The role of graphene related materials (GRM) on the gel bead structure, adsorption selectivity, kinetic, mechanism, and efficiency was investigated. Combined Scanning Electron Microscopy (SEM) and confocal Raman microscopy mapping showed a porous structure with pore size in the range of 100–200 µm and a homogeneous distribution of graphene nanosheets or nanoplatelets at the pores surface. The adsorption kinetic of GRM was much faster than that of granular activated carbon (GAC), the industrial sorbent benchmark, with removal capacity of ofloxacin from 2.9 to 4.3 times higher. A maximum adsorption capacity of 178 mg/g for rhodamine B was estimated by adsorption isotherm studies for reduced graphene oxide-based beads (a value comparable to that of powered activated carbon). Regeneration test performed on saturated beads by washing with EtOH, and subsequent reiterated reuses, showed no loss of adsorption performance up to the fourth reuse cycle

Core-shell graphene oxide-polymer hollow fibers as water filters with enhanced performance and selectivity

Commercial hollow fiber filters for micro-and ultrafiltration are based on size exclusion and do not allow the removal of small molecules such as antibiotics. Here, we demonstrate that a graphene oxide (GO) layer can be firmly immobilized either inside or outside polyethersulfone-polyvinylpyrrolidone hollow fiber (Versatile PES®, hereafter PES) modules and that the resulting core-shell fibers inherits the microfiltration ability of the pristine PES fibers and the adsorption selectivity of GO. GO nanosheets were deposited on the fiber surface by filtration of a GO suspension through a PES cartridge (cut-off 0.1-0.2 μm), then fixed by thermal annealing at 80 °C, rendering the GO coating stably fixed and unsoluble. The filtration cut-off, retention selectivity and efficiency of the resulting inner and outer modified hollow fibers (HF-GO) were tested by performing filtration on water and bovine plasma spiked with bovine serum albumin (BSA, 66 kDa, ≈15 nm size), monodisperse polystyrene nanoparticles (52 nm and 303 nm sizes), with two quinolonic antibiotics (ciprofloxacin and ofloxacin) and rhodamine B (RhB). These tests showed that the microfiltration capability of PES was retained by HF-GO, and in addition the GO coating can capture the molecular contaminants while letting through BSA and smaller polystyrene nanoparticles. Combined XRD, molecular modelling and adsorption experiments show that the separation mechanism does not rely only on physical size exclusion, but involves intercalation of solute molecules between the GO layers

Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds

BACKGROUND: Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation. METHODS: Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroids and after PCFT silencing. Inhibitors of lactate dehydrogenase (LDH-A) were tested in vitro and in vivo. LDH-A expression was determined in tissue microarrays of radically resected malignant pleural mesothelioma (MPM, N = 33) and diffuse peritoneal mesothelioma (DMPM, N = 56) patients. RESULTS: Overexpression of hypoxia marker CAIX was associated with low PCFT expression and decreased MPM cell growth inhibition by pemetrexed. Through integration of PCR arrays in hypoxic cells and spheroids and following PCFT silencing, we identified the upregulation of LDH-A, which correlated with shorter survival of MPM and DMPM patients. Novel LDH-A inhibitors enhanced spheroid disintegration and displayed synergistic effects with pemetrexed in MPM and gemcitabine in DMPM cells. Studies with bioluminescent hypoxic orthotopic and subcutaneous DMPM athymic-mice models revealed the marked antitumour activity of the LDH-A inhibitor NHI-Glc-2, alone or combined with gemcitabine. CONCLUSIONS: This study provides novel insights into hypoxia/PCFT-dependent chemoresistance, unravelling the potential prognostic value of LDH-A, and demonstrating the preclinical activity of LDH-A inhibitors

Protocol for Project FACT: a randomised controlled trial on the effect of a walking program and vitamin B supplementation on the rate of cognitive decline and psychosocial wellbeing in older adults with mild cognitive impairment [ISRCTN19227688]

BACKGROUND: the prevalence of individuals with cognitive decline is increasing since the number of elderly adults is growing considerably. The literature provides promising results on the beneficial effect of exercise and vitamin supplementation on cognitive function both in cognitively healthy as well as in the demented elderly. METHODS/DESIGN: the design is a two-by-two factorial randomised controlled trial. The study population consists of independently living elderly, between 70 and 80 years old, with mild cognitive impairment (MCI). In the RCT the effect of two interventions, a walking program and vitamin supplementation, is examined. The walking program (WP) is a group-based program aimed at improving cardiovascular endurance; frequency two lessons a week; lesson duration one hour; program duration one year. Non-walking groups receive a placebo activity program (PAP) (i.e. low intensive non-aerobic group exercises, like stretching) with the same frequency, lesson and program duration. Vitamin supplementation consists of a single daily vitamin supplement containing 50 mg B6, 5 mg folic acid and 0,4 mg B12 for one year. Subjects not receiving vitamin supplements are daily taking an identically looking placebo pill, also for a year. Participants are randomised to four groups 1) WP and vitamin supplements; 2) WP and placebo supplements; 3) PAP and vitamin supplements; 4) PAP and placebo supplements. Primary outcome measures are measures of cognitive function. Secondary outcomes include psychosocial wellbeing, physical activity, cardiovascular endurance and blood vitamin levels. DISCUSSION: no large intervention study has been conducted yet on the effect of physical activity and vitamin supplementation in a population-based sample of adults with MCI. The objective of the present article is to describe the design of a randomised controlled trial examining the effect of a walking program and vitamin B supplementation on the rate of cognitive decline in older adults with MCI