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Background Colorectal cancer (CRC) treatment in patients with peritoneal metastases is complex. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are under debate. The aim of this study was to assess the consensus among international experts for decision-making regarding CRS/HIPEC in CRC patients. Materials and methods Twelve of 15 experts provided their decision algorithms for CRS/HIPEC for patients with or at high risk for peritoneal metastases from CRC. Based on the objective consensus methodology, the results were transformed into decision trees, which then provided information on the consensus and discordance. Results There was only one scenario in which the consensus on performing HIPEC reached 100%, which was when treating young patients with complete cytoreduction and a peritoneal carcinomatosis index (PCI) of less than 16 in the presence of certain risk factors (RFs). Five major decision criteria were identified and displayed: age, PCI, completeness of cytoreduction (CC), extent of extraperitoneal metastases (EoM) and, in the case of nonverified extraperitoneal metastases, further RFs. There was consensus to refrain from using HIPEC in older patients with a high PCI, and the consensus further increased when addressing incomplete cytoreduction and extensive EoM. Conclusion A definite consensus concerning the use of HIPEC was only determined for very selected scenarios. These findings can be used for general guidance, but due to the heterogeneity of each individual situation and the impracticality to present this information through decision trees, as well as the unclear future of the role of HIPEC in the adjuvant setting, a one-on-one transfer to daily clinical practice cannot be achieved. more...

The concept of iontophoresis is often applied to increase the transdermal transport of drugs and other bioactive agents into the skin or other tissues. It is a non-invasive drug delivery method which involves electromigration and electroosmosis in addition to diffusion and is shown to be a viable alternative to conventional administration routs such as oral, hypodermic and intravenous injection. In this study we investigated, experimentally and numerically, in vitro drug delivery of dexamethasone sodium phosphate to porcine skin. Different current densities, delivery durations and drug loads were investigated experimentally and introduced as boundary conditions for numerical simulations. Nernst-Planck equation was used for calculation of active substance flux through equivalent model of homogeneous hydrogel and skin layers. The obtained numerical results were in good agreement with experimental observations. A comprehensive in-silico platform, which includes appropriate numerical tools for fitting, could contribute to iontophoretic drug-delivery devices design and correct dosage and drug clearance profiles as well as to perform much faster in-silico experiments to better determine parameters and performance criteria of iontophoretic drug delivery. more...

The treatment of peritoneal metastases (PM) from colorectal cancer (CRC) has been revolutionized by the availability of cytoreductive surgery (CRS), traditionally coupled with Hyperthermic Intraperitoneal Peroperative Chemotherapy (HIPEC). The impact of HIPEC itself, over the effect of surgery is poorly understood and the presence of various HIPEC regimens for CRC PM complicates objective evaluation. A recent randomized controlled trial (RCT) evaluating one of the CRC HIPEC regimens (30 min of intraperitoneal (IP) oxaliplatin) showed no increase in survival compared to CRS alone. There is uncertainty regarding the current and future use of HIPEC in CRC PM. A reevaluation of existing and the publication of new preclinical work is needed, to analyze potential efficacy of alterantive HIPEC regimens. New advanced phase clinical trials should not be started without convincing preclinical and early phase data on new IP chemotherapy regimens. This review is a critical appraisal of the available preclinical and clinical data to support the design of an alternative HIPEC regimen for CRC focusing on CRC PM specific data. We find that current evidence supports several regimens that have not been tested in prospective clinical trials while the one tested in the PRODIGE-7 RCT has little supportive evidence. more...

Cracked endodontically treated molars (ETMs) are commonly treated with full crowns. Less invasive techniques could include fiber-reinforced composite (FRC) base and adhesively bonded endocrowns. The purpose of this study was to assess the fatigue resistance of ETMs restored with CAD/CAM resin composite endocrowns and reinforced with different FRC bases. Cracks were simulated in fifty mandibular molars by cutting the teeth longitudinally and reassembling the two parts. After performing endodontic treatments and preparing cavities, teeth were restored in one of the following methods (n = 10). In Group 1, cavity floors were lined with 0.5 mm of flowable composite (Universal Injectable; GUI, shade A2). In Groups 2 and 3, the cavity floors were covered with one and three layers of FRC-net (ES Net) respectively, whereas in Groups 4 and 5 with 1 mm and 2 mm of flowable FRC-resin (EverX Flow Dentin; EXFD) respectively. Endocrowns (Cerasmart 270; CE, A2 HT) with 5 mm thickness were adhesively luted with preheated composite and all specimens were subjected to cyclic loading in water at 5 Hz, starting with a load of 600 N (5000 cycles), followed by stages of 1000, 1300, 1600, 1900, 2200 and 2500 at a maximum of 20 000 cycles each. Results were analyzed using Kaplan-Meier survival analysis and the Log-Rank test (p = 0.05). The fatigue failure load of ES Net applied in three layers (1617 N ± 371) or in one layer (1499 N ± 306), as well as EXFD applied in 2 mm (1496 N ± 264) or in 1 mm (1434 N ± 372) did not differ significantly (p > 0.05). Control teeth fractured at 1255 N ± 350 (p > 0.05). In the fiber-reinforced groups, restorable fractures were observed in 50%-80%, with only 30% deemed restorable in the control group. The fractures originated mainly at the occlusal contact points and the main crack propagated in the corono-apical direction. No crack origin (primary or secondary) starting from the artificial pre-existing crack was observed in fractured specimens. FRC bases did not improve the fatigue resistance of cracked ETMs, but favorably influenced the failure mode. more...

This study evaluated several fiber- and matrix related factors and investigated different mechanical properties of discontinuous i.e. short fiber-reinforced composite (SFRC) (everX Posterior, eXP). These were compared with three conventional composites, microfilled G-ænial Anterior (GA), nanofilled Supreme XTE (SXTE) and bulk-fill Filtek Bulk-Fill (FBF).Fracture toughness (KIC), flexural strength (FS), flexural modulus (FM), compressive strength (CS), diametral tensile strength (DTS), apparent horizontal shear strength (AHSS) and fracture work (Wf) were determined for each composite (n=8) stored dry or in water. SEM analysis of the fiber diameter (df) (n=6) and orientation (n=6) were performed. The theoretical critical fiber length (lfc) and the aspect ratio (l/d) of SFRC were calculated and the volume fraction of discontinuous fibers (Vf%) and the fiber length (lf) of SFRC were evaluated. The results were statistically analyzed with two-way ANOVA (α=0.05).The mechanical properties of SFRC (eXP) were generally superior (p0.05) compared with conventional composites. GA had the highest FM (p0.05), whereas FBF had the highest AHSS (p0.05). The fiber related properties Vf%, l/d, lf, lfc and df of eXP were 7.2%, 18-112, 0.3-1.9mm, 0.85-1.09mm and 17μm respectively. SEM results suggested an explanation to several toughening mechanisms provided by the discontinuous fibers, which were shown to arrest crack propagation and enable a ductile fracture. Water exposure weakened the mechanical properties regardless of material type. Wf was unaffected by the water storage.The properties of this high aspect ratio SFRC were dependent on the fiber geometry (length and orientation) and matrix ductility.The simultaneous actions of the toughening mechanisms provided by the short fibers accounted for the enhanced toughness of this SFRC, which toughness value matched the toughness of dentin. Hence, it could yield an inherently uniform distribution of stresses to the hard biological tissues. more...

Cycling masticatory loads decrease the strength of particulate filler composites (PFCs) and initiate the failure process by fatigue. The life expectancy of a composite resin restoration under stress remains difficult to predict.The purpose of this study was to determine the fracture resistance and the compressive fatigue limits (CFL) of anterior crown restorations made of a short-fiber reinforced composite resin (SFC), to investigate selected mechanical properties of the material following standard test methods, and to observe their correlation with the CFL.Specimens (n=10) were fabricated either from SFC (everX Posterior, GC Corp) or PFC (G-ænial anterior, GC Corp). The properties investigated were flexural strength (FS), compression strength (CS), diametral-tensile strength (DTS), and single-edge-notched-bend fracture toughness (FT) following ISO standards. Fracture resistance was determined by static load (n=10) and the CFL at 10000 cycles was determined using a staircase approach (n=20), both on anterior composite resin crowns. The results were analyzed with 1-way ANOVA (α=.05) or 2-way ANOVA (α=.05) followed by a Tukey B post hoc test and the Pearson-correlation analysis.The SFC crowns had higher fracture resistance (954 ±121 N) than the PFC crowns (415 ±75 N) (P.001) and higher CFL (267 ±23 N) than the PFC crowns (135 ±64 N) (P.001). SFC revealed also higher FT (2.6 ±0.6 MPa·m(1/2)) than the PFC (1.0 ±0.2 MPa·m(1/2)) (F=69.313, P.001). A significant correlation was observed only between the FT and the CFL (r(2)=0.899; P.001).SFC crowns showed good performance under static and fatigue loading. FT was the only in vitro test method that filtered as a clinically relevant parameter. more...

Graphical abstract, Highlights • The PDB was investigated for protein structures with incorporated POMs. • POMs were analyzed with regard to their effects on protein crystallography. • POMs can stabilize and provide crystal contacts which facilitate crystal packing., Polyoxometalates (POMs) are discrete polynuclear metal-oxo anions with a fascinating variety of structures and unique chemical and physical properties. Their application in various fields is well covered in the literature, however little information about their usage in protein crystallization is available. This review summarizes the impact of the vast class of POMs on the formation of protein crystals, a well-known (frustrating) bottleneck in macromolecular crystallography, with the associated structure elucidation and a particular emphasis focused on POM's potential as a powerful crystallization additive for future research. The Protein Data Bank (PDB) was scanned for protein structures with incorporated POMs which were assigned a PDB ligand ID resulting in 30 PDB entries. These structures have been analyzed with regard to (i) the structure of POM itself in the immediate protein environment, (ii) the kind of interaction and position of the POM within the protein structure and (iii) the beneficial effects of POM on protein crystallography apparent so far. more...

The aim of this systematic review is to critically evaluate cytoreductive surgery combined with heated intraoperative intraperitoneal chemotherapy in the treatment of ovarian cancer. A systematic review of all manuscripts published in the English literature that met predetermined inclusion criteria was carried out. Data concerning cytoreductive surgery, method and agents for administration of heated intraoperative intraperitoneal chemotherapy, morbidity, mortality, hospital stay and survival were extracted, critically reviewed and tabulated. Fourteen studies were analyzed. A wide variety of drug doses, methods of intraperitoneal chemotherapy administration and volume of chemotherapy solution were used. Seven studies showed that patients with complete cytoreduction had the greatest benefit. The median overall survival for primary and recurrent disease ranged from 22 to 54 months and the median disease-free survival from 10 to 26 months. The rates of significant morbidity associated with this combined treatment were low, ranging from 5% to 36%. The median mortality was 3% (range 0%-10%). Cytoreductive surgery combined with heated intraoperative intraperitoneal chemotherapy is a treatment option for patients with ovarian cancer that is worthy of further investigation. Selection criteria for patients most likely to benefit need to be defined. more...

This study showed that four factors which stimulate transepithelial fluid secretion and inorganic ion transport across the main segment of the Malpighian tubules of Drosophila melanogaster also stimulate transepithelial secretion of the prototypical organic cation tetraethylammonium (TEA). TEA fluxes across the Malpighian tubules and gut were measured using a TEA-selective self-referencing (TEA-SeR) microelectrode. TEA flux across isolated Malpighian tubules was also measured using a TEA-selective microelectrode positioned in droplets of fluid secreted by tubules set up in a modified Ramsay assay. TEA flux was stimulated by the intracellular second messengers cAMP and cGMP, which increase the lumen-positive transepithelial potential (TEP), and also by tyramine and leucokinin-I (LK-I), which decrease TEP. The largest increase was measured in response to 1 μmol l −1 LK-I which increased transepithelial TEA flux by 72%. TEA flux in the lower tubule was stimulated slightly (13%) by 1 μmol l −1 tyramine but not by any of the other factors. TEA flux across the midgut was unaffected by cAMP, cGMP or tyramine. This is the first study to demonstrate the effects of insect diuretic factors and second messengers on excretion of organic cations. more...

The interfacial properties of a membrane are determinant for interaction among bio-membranes / lipid bilayers, or for establishing contact among layer surfaces and substrates approaching from the bulk. The access to the bilayer and its local structural modifications upon interaction with an adsorbing guest molecule are influenced significantly by the presence of charges, and local changes in surface charge density. Results are being presented on model mono- and bilayers prepared from zwitterionic POPC (DPPC) (1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine) and its cationic sibling lipids E-POPC (E-DPPC) (1-palmitoyl-2-oleoyl-sn-glycero-3-ethyl-phosphocholine/ di-1,2-palmitoyl-sn-glycero-3-ethyl-phosphocholine) that served to inoculate charge densities at different mol percentages. Monolayer compression isotherms obtained for the mixtures are compared with isotherms of pure POPC as a reference system. The presence of layer charges is manifested in an earlier onset of interaction, the range of interaction is increased. POPC bilayers with the same charge densities as the monolayers studied were then investigated by single molecule tracking using the fluorophore DiI-C18 for diffusion tracing. Initial results indicate a linear decrease of the lateral diffusion coefficient with increasing charge density. In the course of the study indications for domain formation in pure POPC layers were observed as novel peculiarities; these will be presented and discussed. Preliminary results about the adsorption of partially charged phospholipid layers onto hydrogel polyelectrolyte cushions on solid supports will be presented. more...