Synthesis, structural study and antitumor activity of novel alditol-based imidazophenanthrolines (aldo-IPs)

A series of 1H-imidazo [4,5-f][1,10] phenanthroline derivatives functionalized at 2-position with chiral, and conformationally flexible polyhydroxy alkyl chains derived from carbohydrates (alditol-based imidazophenanthrolines, aldo-IPs) is presented herein. These novel glycomimetics showed relevant and differential cytotoxic activity against several cultured tumor cell lines (PC3, HeLa and HT-29), dependent on the nature and stereochemistry of the polyhydroxy alkyl chain. The mannose-based aldo-IP demonstrated the higher cytotoxicity in the series, substantially better than cisplatin metallo-drug in all cell lines tested, and better than G-quadruplex ligand 360A in HeLa and HT29 cells. Cell cycle experiments and Annexin V-PI assays revealed that aldo-IPs induce apoptosis in HeLa cells. Initial study of DNA interactions by DNA FRET melting assays proved that the aldo-IPs produce only a slight thermal stabilization of DNA secondary structures, more pronounced in the case of quadruplex DNA. Viscosity titrations with CT dsDNA suggest that the compounds behave as DNA groove binders, whereas equilibrium dialysis assays showed that the compounds bind CT with Ka values in the range 104–105 M−1. The aldo-IP derivatives were obtained with synthetically useful yields through a feasible one-pot multistep process, by aerobic oxidative cyclization of 1,10‐phenanthroline‐5,6‐diamine with a selection of unprotected aldoses using (NH4)2SO4 as promoter.Ministerio de Ciencia e InnovaciónMinisterio de Economía, Comercio y EmpresaUniversidad de AlcaláComunidad de Madri

Association between sleep-disordered breathing and breast cancer aggressiveness

Background Sleep-disordered breathing (SDB) has been associated with cancer aggressiveness, but studies focused on specific tumors are lacking. In this pilot study we investigated whether SDB is associated with breast cancer (BC) aggressiveness. Methods 83 consecutive women <65 years diagnosed with primary BC underwent a home respiratory polygraphy. Markers of SDB severity included the apnea-hypopnea index (AHI) and the 4% oxygen desaturation index (ODI4). The Ki67 proliferation index, lack of hormone receptors (HR-), Nottingham Histological Grade (NHG), and tumor stage were used as markers of BC aggressiveness. The association between SDB and molecular subtypes of BC was also assessed. Results The mean (SD) age was 48.8 (8.8) years and body mass index was 27.4 (5.4) Kg/m2. 42 women (50.6%) were post-menopausal. The median (IQR) AHI was 5.1 (2–9.4), and ODI4 was 1.5 (0.5–5.8). The median (IQR) AHI did not differ between the groups with Ki67>28% and Ki6728% and Ki67<29% (51.2% vs 52.3%, p = 0.90), HR- and HR+ (58.3% vs 49.1%, p = 0.47), NHG categories (p = 0.89), different tumor stages (p = 0.71), or molecular subtypes (p = 0.73). These results did not change when the ODI4 was used instead of the AHI. Conclusion Our results do not support an association between the presence or severity of SDB and BC aggressiveness.Asociación de Neumología y Cirugía Torácica del Sur (NEUMOSUR) 1/201

Polyethylene glycol pulsed electrodeposition for the development of antifouling coatings on titanium

Titanium dental implants are widely used for the replacement of damaged teeth. However, bacterial infections at the interface between soft tissues and the implant can impair the functionality of the device and lead to failure. In this work, the preparation of an antifouling coating of polyethylene glycol (PEG) on titanium by pulsed electrodeposition was investigated in order to reduce Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) adhesion while maintaining human fibroblast adhesion. Different pulsed conditions were prepared and characterized by contact angle, Focused Ion Beam (FIB), Fourier Transformed Infrared Spectroscopy in the Attenuated Total Reflectance mode (ATR-FTIR), and X-ray photoelectron spectroscopy (XPS). XPS tested fibronectin adsorption. S. aureus, E. coli and human fibroblast adhesion was tested in vitro in both mono and co-culture settings. Physicochemical characterization proved useful for confirming the presence of PEG and evaluating the efficiency of the coating methods. Fibronectin adsorption decreased for all of the conditions, but an adsorption of 20% when compared to titanium was maintained, which supported fibroblast adhesion on the surfaces. In contrast, S. aureus and E. coli attachment on coated surfaces decreased up to 90% vs. control titanium. Co-culture studies with the two bacterial strains and human fibroblasts showed the efficacy of the coatings to allow for eukaryotic cell adhesion, even in the presence of pre-adhered bacteria.Peer ReviewedPostprint (published version

Wound Healing Modulation through the Local Application of Powder Collagen-Derived Treatments in an Excisional Cutaneous Murine Model

15 p.Wound healing includes dynamic processes grouped into three overlapping phases: inflammatory, proliferative, and maturation/remodeling. Collagen is a critical component of a healing wound and, due to its properties, is of great interest in regenerative medicine. This preclinical study was designed to compare the effects of a new collagen-based hydrolysate powder on wound repair to a commercial non-hydrolysate product, in a murine model of cutaneous healing. Circular excisional defects were created on the dorsal skin of Wistar rats (n = 36). Three study groups were established according to the treatment administered. Animals were euthanized after 7 and 18 days. Morphometric and morphological studies were performed to evaluate the healing process. The new collagen treatment led to the smallest open wound area throughout most of the study. After seven days, wound morphometry, contraction, and epithelialization were similar in all groups. Treated animals showed reduced granulation tissue formation and fewer inflammatory cells, and induction of vasculature with respect to untreated animals. After 18 days, animals treated with the new collagen treatment showed accelerated wound closure, significantly increased epithelialization, and more organized repair tissue. Our findings suggest that the new collagen treatment, compared to the untreated control group, produces significantly faster wound closure and, at the same time, promotes a slight progression of the reparative process compared with the rest of the groups.CIBER-BBNViscofan S.A

New insights into the application of 3D-printing technology in hernia repair.

"Publicación presentada para sexenios"Abdominal hernia repair using prosthetic materials is among the surgical interventions most widely performed worldwide. These materials, or meshes, are implanted to close the hernial defect, reinforcing the abdominal muscles and reestablishing mechanical functionality of the wall. Meshes for hernia repair are made of synthetic or biological materials exhibiting multiple shapes and configurations. Despite the myriad of devices currently marketed, the search for the ideal mesh continues as, thus far, no device offers optimal tissue repair and restored mechanical performance while minimizing postoperative complications. Additive manufacturing, or 3D-printing, has great potential for biomedical applications. Over the years, different biomaterials with advanced features have been successfully manufactured via 3D-printing for the repair of hard and soft tissues. This technological improvement is of high clinical relevance and paves the way to produce next-generation devices tailored to suit each individual patient. This review focuses on the state of the art and applications of 3D-printing technology for the manufacture of synthetic meshes. We highlight the latest approaches aimed at developing improved bioactive materials (e.g., optimizing antibacterial performance, drug release, or device opacity for contrast imaging). Challenges, limitations, and future perspectives are discussed, offering a comprehensive scenario for the applicability of 3D-printing in hernia repair.Financial support from the CIBER-BB

Experimental study on the use of a chlorhexidine-loaded carboxymethylcellulose gel as antibacterial coating for hernia repair meshes

21 p.Purpose: Biomaterials with an antimicrobial coating could avoid mesh-associated infection following hernia repair. This study assesses the use of a chlorhexidine-loaded carboxymethylcellulose gel in a model of Staphylococcus aureus mesh infection. Methods: A 1% carboxymethylcellulose gel containing 0.05% chlorhexidine was prepared and tested in vitro and in vivo. The in vitro tests were antibacterial activity (S. aureus; agar diffusion test) and gel cytotoxicity compared to aqueous 0.05% chlorhexidine (fibroblasts; alamarBlue). For the in vivo study, partial abdominal wall defects (5 × 2 cm) were created in New Zealand white rabbits (n = 15) and inoculated with 0.25 mL of S. aureus ( 106 CFU/mL). Defects were repaired with a lightweight polypropylene mesh (Optilene) without coating (n = 3) or coated with a carboxymethylcellulose gel (n = 6) or chlorhexidine-loaded carboxymethylcellulose gel (n = 6). Fourteen days after surgery, bacterial adhesion to the implant (sonication, immunohistochemistry), host tissue incorporation (light microscopy) and macrophage reaction (immunohistochemistry) were examined. Results: Carboxymethylcellulose significantly reduced the toxicity of chlorhexidine (p < 0.001) without limiting its antibacterial activity. While control and gel-coated implants were intensely contaminated, the chlorhexidine-gel-coated meses showed a bacteria-free surface, and only one specimen showed infection signs. The macrophage reaction in this last group was reduced compared to the control (p < 0.05) and gel groups. Conclusions: When incorporated in the carboxymethylcellulose gel, chlorhexidine showed reduced toxicity yet maintained its bactericidal effect at the surgery site. Our findings suggest that this antibacterial gel-coated polypropylene meshes for hernia repair prevent bacterial adhesion to the mesh surface and have no detrimental effects on wound repair.Ministerio de Ciencia, Innovación y Universidade

Preclinical bioassay of a novel antibacterial mesh for the repair of abdominal hernia defects

25 p.Background: In hernia surgery, soaking of meshes in antibiotics before implantation is a prophylactic strategy for minimizing the risk of infection while providing minimal, local, drug doses. This study describes the development and application of an antibacterial mesh coating comprising a carboxymethylcellulose gel loaded with rifampicin in a preclinical model of Staphylococcus aureus and S. epidermidis infection in rabbits. Methods: Antibacterial activity and cytocompatibility (with fibroblasts) of unloaded carboxymethylcellulose gel and 0.13 mg/mL rifampicin-carboxymethylcellulose gel were assessed in vitro. Then, partial abdominal wall defects (5 x 2 cm) were created in New Zealand white rabbits (n = 34), the wound inoculated with 0.25 mL of 106 CFU Staphylococcus aureus/ S. epidermidis (n = 17 each), and the defect then repaired with a lightweight, monofilament, large pore polypropylene mesh either uncoated (n = 3) or coated with carboxymethylcellulose gel (n = 7) or rifampicin-carboxymethylcellulose gel (n = 7). By postoperative day 14, coating performance was evaluated by determining bacterial adhesion (via sonication), host tissue incorporation (via histology), macrophage response via immunostaining), and bloodstream drug diffusion (via high-performance liquid chromatography). Results: In vitro, rifampicin-carboxymethylcellulose gel demonstrated great activity against Staphylococcus aureus/S. epidermidis, while being innocuous for fibroblasts. In vivo, rifampicincarboxymethylcellulose gel-coated implants displayed full bacterial clearance and optimal tissue integration, irrespective of the strain of Staphylococcus. In contrast, uncoated and carboxymethylcellulose gel-coated implants exhibited macro/microscopic signs of infection and impaired tissue integration. Macrophage responses were less in rifampicin-carboxymethylcellulose gel implants than in uncoated mesh (Staphylococcus aureus/S. epidermidis; P < .01) and carboxymethylcellulose gel (S. epidermidis; P < .05) implants. Bloodstream levels of rifampicin were undetectable. Conclusion: Soaking meshes in rifampicin-carboxymethylcellulose gel inhibited effectively the bacterial adhesion to the mesh without compromising the tissue repair. This antibiotic gel constitutes an easy-touse and effective prophylactic strategy that potentially reduce the prevalence of postoperative mesh infectionMinisterio de Ciencia, Innovación y Universidade

Mesh fixation using a cyanoacrylate applied as a spray improves abdominal wall tissue repair

19 p.Background: Tissue adhesives are a feasible option to fix a hernia repair mesh, avoiding tissue trauma of suture fixation. Classically, they are applied in the form of a drop, although novel applications such as spray are emerging. This study compares the use of a new experimental cyanoacrylate (n-butyl) in the form of a spray or drops. Materials and methods: Three study groups of New Zealand White rabbits were established (n ? 6 each) according to the method used to fix a 5 3 cm polypropylene mesh in a partial abdominal wall defect model: control group (polypropylene stitches), adhesive drops group, and adhesive spray group. Morphological, immunohistochemical, and biomechanical strength studies were performed at 14 d postimplant. Collagen 1/3 gene ratio was determined by quantitative reverse transcription polymerase chain reaction. Results: In the drops group, the adhesive obstructed the mesh pores and prevented tissue infiltration at the points of application. When the adhesive was applied as a spray, although more numerous, adhesive deposits were smaller and allowed for better host tissue infiltration into the mesh. The inflammatory response was similar in the adhesive groups and more intense than in the control group. Collagen 1/3 mRNA ratio was significantly higher in the spray than the control group. The mechanical resistance of the meshes was similar in all three groups. * Corresponding author. Department of Surgery, Medical and Social Sciences. Faculty of Medicine and Health Sciences, University of Alcala, Ctra. Madrid-Barcelona, Km 33,600, Alcala de Henares, 28871 Madrid, Spain. Tel.: þ34 91 8854540; fax: þ34 91 8854885. E-mail address: [email protected] (J.M. Bellon). 1 These authors contributed equally to this work. 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.08.020 Conclusions: The application of the cyanoacrylate adhesive in the form of spray to fix polypropylene meshes in an animal model had a similar inflammatory response compared with droplet application. Neither application impacted the mechanical strength of the repaired area. An increased in collagen 1/3 ratio was found with cyanoacrylate spray compared with suture, and future studies should focus on this pathway.Ministerio de Economía y Competitivida

Behaviour at the peritoneal interface of next generation prosthetic materials for hernia repair

22 p.Background When using a prosthetic material in hernia repair, the behaviour of the mesh at the peritoneal interface is especially important for implant success. Biomaterials developed for their intraperitoneal placement are known as composites and are made up of two different-structure materials, one is responsible for good integration within host tissue and the other is responsible to make contact with the viscera. This study examines the behaviour at the peritoneal level of two composites, the fully degradable Phasix-ST® and the partially degradable Symbotex®. A polypropylene mesh (Optilene®) served as control. Methods Sequential laparoscopy from 3 to 90 days, in a preclinical model in the New Zealand white rabbit, allowed monitoring adhesion formation. Morphological studies were performed to analyse the neoperitoneum formed in the repair process. Total macrophages were identified by immunohistochemical labelling. To identify the different macrophage phenotypes, complementary DNAs were amplified by qRT-PCR using specific primers for M1 (TNF-?/CXCL9) and M2 (MRC1/IL-10) macrophages. Results The percentage of firm and integrated adhesions remained very high in the control group over time. Both composites showed a significant decrease in adhesions at all study times and in qualitative terms were mainly loose. Significant differences were also observed from 7 days onwards between the two composites, increasing the values in Phasix over time. Neoperitoneum thickness for Phasix was significantly greater than those of the other meshes, showing mature and organized neoformed connective tissue. Immunohistochemically, a significantly higher percentage of macrophages was observed in Symbotex. mRNA expression levels for the M2 repair-type macrophages were highest for Phasix but significant differences only emerged for IL-10. Conclusions Fewer adhesions formed to the Symbotex than Phasix implants. Ninety days after implant, total macrophage counts were significantly higher for Symbotex, yet Phasix showed the greater expression of M2 markers related to the tissue repair process.Ministerio de Economía y Competitivida

The Breast Milk Immunoglobulinome

Breast milk components contribute to the infant's immune development and protection, and among other immune factors, immunoglobulins (Igs) are the most studied. The presence of IgA in milk has been known for a long time; however, less information is available about the presence of other Igs such as IgM, IgG, and their subtypes (IgG1, IgG2, IgG3, and IgG4) or even IgE or IgD. The total Ig concentration and profile will change during the course of lactation; however, there is a great variability among studies due to several variables that limit establishing a clear pattern. In this context, the aim of this review was firstly to shed light on the Ig concentration in breast milk based on scientific evidence and secondly to study the main factors contributing to such variability. A search strategy provided only 75 studies with the prespecified eligibility criteria. The concentrations and proportions found have been established based on the intrinsic factors of the study¿such as the sampling time and quantification technique¿as well as participant-dependent factors, such as lifestyle and environment. All these factors contribute to the variability of the immunoglobulinome described in the literature and should be carefully addressed for further well-designed studies and data interpretation