Platelet lysate and adipose mesenchymal stromal cells on silk fibroin nonwoven mats for wound healing

In this work platelet lysate (PL) and adipose‐derived mesenchymal stromal cells (ASCs) seeded on nonwoven fibroin mats were in vitro and in vivo evaluated for tissue regenerative applications. Nonwoven mats obtained by a large scale water entanglement technique were characterized for their physico‐chemical properties. Results indicated a high purity of fibroin fibers, their stability after sterilization process and appropriate technological properties suitable for tissue engineering. Moreover, the scaffolds in vitro supported adhesion and migration of ASCs and the presence of PL improved the cell proliferation. The products were then applied on epithelial/dermal wounds carried out on the dorsal surface of rabbit: the skin reparative process was solved in 9 days, with a completely restitutio ad integrum of the epithelium in animals treated with PL alone; ASCs did not further improve the wound healing. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42942.     

Cold Spray Deposition of Freestanding Inconel Samples and Comparative Analysis with Selective Laser Melting

Cold spray offers the possibility of obtaining almost zero-porosity buildups with no theoretical limit to the thickness. Moreover, cold spray can eliminate particle melting, evaporation, crystallization, grain growth, unwanted oxidation, undesirable phases and thermally induced tensile residual stresses. Such characteristics can boost its potential to be used as an additive manufacturing technique. Indeed, deposition via cold spray is recently finding its path toward fabrication of freeform components since it can address the common challenges of powder-bed additive manufacturing techniques including major size constraints, deposition rate limitations and high process temperature. Herein, we prepared nickel-based superalloy Inconel 718 samples with cold spray technique and compared them with similar samples fabricated by selective laser melting method. The samples fabricated using both methods were characterized in terms of mechanical strength, microstructural and porosity characteristics, Vickers microhardness and residual stresses distribution. Different heat treatment cycles were applied to the cold-sprayed samples in order to enhance their mechanical characteristics. The obtained data confirm that cold spray technique can be used as a complementary additive manufacturing method for fabrication of high-quality freestanding components where higher deposition rate, larger final size and lower fabrication temperatures are desired.     

GPU-accelerated minimum distance and clearance queries

We present practical algorithms for accelerating distance queries on models made of trimmed NURBS surfaces using programmable Graphics Processing Units (GPUs). We provide a generalized framework for using GPUs as coprocessors in accelerating CAD operations. By supplementing surface data with a surface bounding-box hierarchy on the GPU, we answer distance queries such as finding the closest point on a curved NURBS surface given any point in space and evaluating the clearance between two solid models constructed using multiple NURBS surfaces. We simultaneously output the parameter values corresponding to the solution of these queries along with the model space values. Though our algorithms make use of the programmable fragment processor, the accuracy is based on the model space precision, unlike earlier graphics algorithms that were based only on image space precision. In addition, we provide theoretical bounds for both the computed minimum distance values as well as the location of the closest point. Our algorithms are at least an order of magnitude faster and about two orders of magnitude more accurate than the commercial solid modeling kernel ACIS.     

Altered Accumbal Dopamine Terminal Dynamics Following Chronic Heroin Self-Administration

Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-h, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats exhibited reduced stimulated dopamine release during tonic-like, single-pulse stimulations, but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5–100 Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor agonist responsivity were increased following heroin self-administration. These results reveal a marked low dopamine state following heroin exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.     

Pharmacogenetics Biomarkers and Their Specific Role in Neoadjuvant Chemoradiotherapy Treatments: An Exploratory Study on Rectal Cancer Patients

Background: Pathological complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is still ascribed to a minority of patients. A pathway based-approach could highlight the predictive role of germline single nucleotide polymorphisms (SNPs). The primary aim of this study was to define new predictive biomarkers considering treatment specificities. Secondary aim was to determine new potential predictive biomarkers independent from radiotherapy (RT) dosage and cotreatment with oxaliplatin. Methods: Thirty germ-line SNPs in twenty-one genes were selected according to a pathway-based approach. Genetic analyses were performed on 280 LARC patients who underwent fluoropyrimidine-based CRT. The potential predictive role of these SNPs in determining pathological tumor response was tested in Group 1 (94 patients undergoing also oxaliplatin), Group 2 (73 patients treated with high RT dosage), Group 3 (113 patients treated with standard RT dosage), and in the pooled population (280 patients). Results: Nine new predictive biomarkers were identified in the three groups. The most promising one was rs3136228-MSH6 (p = 0.004) arising from Group 3. In the pooled population, rs1801133-MTHFR showed only a trend (p = 0.073). Conclusion: This exploratory study highlighted new potential predictive biomarkers of neoadjuvant CRT and underlined the importance to strictly define treatment peculiarities in pharmacogenetic analyses.     

Supramolecular Bioconjugates for Protein and Small Drug Delivery

Supramolecular conjugation techniques have been developed to produce novel nanosized systems by assembling materials with diverse physicochemical and biological features. These techniques have been adapted to obtain innovative bioconjugates to deliver drugs with poor biopharmaceutical properties and nano-devices with potential “theranostic” activity. Supramolecular drug delivery systems include polymer therapeutics such as drug–polymer bioconjugates, and colloidal carriers such as micelles, liposomes, polyplexes, and organic and inorganic nanoparticles. By virtue of their wide array of chemical composition and properties, polymers represent key elements for the construction of novel supramoelcular formulations. Polymer bioconjugation is a fledged technique for fabrication of protein–polymer conjugates. PEGylation, in particular, produces derivatives with enhanced pharmacokinetic, immunological, and stability properties as compared to the parent protein. Over the years, new methods have been set up to obtain site-directed polymer conjugation. In this review we report few grafting to and growing from PEGylation examples for the preparation of therapeutically effective protein bioconjugates. Supramolecular formulations with unique properties can be also obtained by assembling functional polymers, targeting agents, physicochemical modifiers, and biomodulators. These systems may be designed for disease tissue disposition and cell recognition/penetration. Cyclodextrins, for example, have been functionalized with polyethylene glycol and folic acid to produce tumor-targeted drug carriers. Interesting results have been obtained with this novel class of drug delivery systems. In addition, responsive polymers have been conjugated to gold nanoparticles to endow a new colloidal platform with triggerable cell disposition properties, which can be exploited either in biomedicine or diagnosis.     

Engineering Cardiac Tissues from Pluripotent Stem Cells for Drug Screening and Studies of Cell Maturation

Using cardiomyocytes derived from human pluripotent stem cells (hPSC-CMs), it is now possible to develop models of human cardiac diseases and to screen novel pharmaceutical agents on human cardiac cells and tissues. However, since hPSC-CMs display an immature phenotype, significant focus has turned to cardiac tissue engineering to deliver a means to mature these cells. In this review we discuss the maturation state of currently available hPSC-CMs and provide an overview of the processes involved in cardiomyocyte maturation. We then explore the differences between pathological and physiological hypertrophy and discuss how tissue engineering techniques that rely on the combined use of biomaterials and bioreactors can be utilized to enhance and study the hypertrophic response.     

Physicochemical Study of Glycerol Hydrogenolysis Over a Ni–Cu/Al2O3 Catalyst Using Formic Acid as the Hydrogen Source

Glycerol hydrogenolysis to propanediols requires the use of hydrogen as reactant. One interesting option is to directly generate this hydrogen in active sites of the support using hydrogen donors, such as formic acid. The effect that the reacting pressure has on glycerol conversion and product selectivity over a Ni–Cu/Al₂O₃ catalyst was studied. The negative effect of decreasing the pressure was much more significant when the source of hydrogen was dissolved molecular hydrogen than when it was formic acid. X-ray photoelectron spectroscopy and temperature programmed reduction measurements were performed to understand the effect of Ni–Cu/Al₂O₃ reduction procedure on the catalytic activity. Semi-batch reactor studies with the Ni–Cu/Al₂O₃ catalyst were carried out with continuous addition of the hydrogen donor to obtain kinetic data. Langmuir–Hinshelwood type models were developed to describe the direct conversion of glycerol into propanediol, and propanediol further hydrogenolysis to 1-propanol. The model included the competitive adsorption between both glycols. These models were used to obtain valuable data for the optimization of the process.     

Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer.