A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy.

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.

Extending the Affinity Range of Weak Affinity Chromatography for the Identification of Weak Ligands Targeting Membrane Proteins.

The identification of weak-affinity ligands targeting membrane proteins is of great interest in Fragment-Based Drug Design (FBDD). Recently, miniaturized weak affinity chromatography (WAC) has been proposed as a valuable tool to study interactions between small ligands and wild-type membrane proteins embedded in so-called nanodisc biomimetic membranes immobilized on GMA-co-EDMA monoliths in situ-synthesized in capillary columns (less than one microliter in volume). In this proof-of-concept study, the achievable affinity range was limited to medium affinity (low micromolar range). The present work investigates different strategies to extend the affinity range towards low affinities, either by increasing the density of membrane proteins on the chromatographic support or by reducing non-specific interactions with the monolith. The combination of the use of a new and more hydrophilic monolithic support (poly(DHPMA-co-MBA)) and a multilayer nanodisc grafting process (up to three layers) allows a significant increase in the membrane protein density by a more than three-fold factor (up to 5.4 pmol cm-1). Such an increase in protein density associated with reduced non-specific interactions makes it possible to extend the range of detectable affinity, as demonstrated by the identification and characterization of affinities of very low-affinity ligands (Kd values of several hundred micromolar) for the adenosine receptor AA2AR used as a model protein, which was not possible before. The affinity was confirmed by competition experiments.

Influence of Test Specimen Geometry and Water Soaking on the In Vitro Cytotoxicity of Orthocryl®, Orthocryl® LC, Loctite® EA 9483 and Polypropylene.

Depending on their composition, plastics have a cytotoxic potential that needs to be evaluated before they are used in dentistry, e.g., as orthodontic removable appliances. Relevant guidelines set out requirements that a potential new resin in the medical field must meet, with a wide scope for experimental design. In the present study, test specimens of different geometries consisting of varying polymers (Orthocryl®, Orthocryl® LC, Loctite® EA 9483, Polypropylene) were soaked for different periods of time, then transferred to cell culture medium for 24 h, which was subsequently used for 24-h cultivation of A549 cells, followed by cytotoxicity assays (WST-1, Annexin V-FITC-propidium iodide (PI) flow cytometry). In this context, a reduction in the cytotoxic effect of the eluates of test specimens prepared from Orthocryl® LC and Loctite® EA 9483 was particularly evident in the Annexin V-FITC-PI assay when the soaking time was extended to 48 h and 168 h, respectively. Consistent with this, a reduced release of potentially toxic monomers into the cell culture medium, as measured by gas chromatography-mass spectrometry, was observed when the prior soaking time of test specimens of all geometries was extended. Remarkably, a significant increase in cytotoxic effect was observed in the WST-1 assay, which was accompanied by a higher release of monomers when the thickness of the test sample was increased from 0.5 to 1.0 mm, although an elution volume adapted to the surface area was used. However, further increasing the thickness to 3.0 mm did not lead to an increase in the observed cytotoxicity or monomer release. Test specimens made of polypropylene showed no toxicity under all test specimen sizes and soaking time conditions. Overall, it is recommended to perform toxicity studies of test specimens using different geometries and soaking times. Thereby, the influence of the different specimen thicknesses should also be considered. Finally, an extension of the test protocols proposed in ISO 10993-5:2009 should be considered, e.g., by flow cytometry or monomer analysis as well as fixed soaking times.

Hierarchically Porous Osteoinductive Poly(hydroxyethyl methacrylate-co-methyl methacrylate) Scaffold with Sustained Doxorubicin Delivery for Consolidated Osteosarcoma Treatment and Bone Defect Repair.

A bifronted cure system for osteosarcoma, a common aggressive bone tumor, is highly in demand to prevail the postsurgical adversities in connection with systemic chemotherapy and repair of critical-size bone defects. The hierarchically porous therapeutic scaffolds presented here are synthesized by free radical-initiated copolymerization of hydroxyethyl methacrylate and methyl methacrylate [HEMA/MMA 80:20 and 90:10 mM, H2O/NaCl porogen], which are further surface-phosphorylated [P-PHM] and transformed to bifunctional by impregnating doxorubicin (DOX) [DOXP-PHM]. The P-PHM scaffolds exhibited porous microarchitecture analogous to native cancellous bone (scanning electron microscopy analysis), while X-ray photoelectron spectroscopy analysis authenticated surface phosphorylation. Based on pore characteristics, swelling attributes and slow-pace degradation, P-PHM9163 and P-PHM8263 (HEMA/MMA 90:10 and 80:20 with H2O/NaCl: 60/3.0 weight %, respectively) were chosen from the series and evaluated for osteoinductive efficacy in vitro. Both P-PHM9163 and P-PHM8263 invoked calcium phosphate mineralization in simulated physiological conditions (day 14) with Ca/P ratios of 1.58 and 1.66 respectively, comparable to human bone (1.67). Early biomineralization (Alizarin Red S and von Kossa staining) was evidenced at day 7, while osteoblast differentiation was verified by time-dependent expression of the typical late marker, osteocalcin, at day 14 and 21 in rat bone marrow mesenchymal cells. DOX-loaded P-PHM9163 (DOXP-PHM9163) exhibited pH-responsive (tumor analogous pH; 6.5) sustained release of DOX for prolonged time (up to 45 days) and invoked cellular alterations by cortical stress fiber formation and DNA fragmentation in human osteosarcoma cells leading to early apoptosis (24 h), validated by annexin V/PI staining (FACS) and immunostaining (F-actin/DAPI). Subsequent to DOX release tenure, the scaffold induced the formation of well-organized, porous post-release Ca-P apatite coating (Ca/P is 1.3) in simulated body fluid (day 14) which further endorses the dual functionality of the system. Altogether, the results accentuate that DOXP-PHM9163 is a potential bifunctional therapeutic scaffold capable of extended localized chemotherapeutic delivery in-line with inherent osteogenesis for efficient bone cancer treatment.

El grafeno en la rehabilitación bucal y su comportamiento biológico: caso clínico / Graphene in oral rehabilitation and its biological behavior: a clinical case

El grafeno y sus derivados son muy utilizados en ciencia y tecnología por los beneficios que otorgan sus propiedades fisicoquímicas. En el área de la salud en particular, se destacan sus propiedades biológicas debido a su elevada biocompatibilidad, interacción celular y su actividad antibacteriana. La incorporación de grafeno en ciertos materiales permite obtener un material combinado con propiedades mejoradas. Un ejemplo de ello es la incorporación industrial de óxido de grafeno en metacrilato de metilo para generar un polímero (PMMA) mejorado, no solo desde el punto de vista mecánico, sino también una notoria ventaja en la respuesta biológica de los tejidos blandos. Este artículo describe el caso clínico de un paciente de 70 años, que concurrió a la consulta buscando alternativas de tratamiento para mejorar la retención y estabilidad de las prótesis para optimizar la función masticatoria, una alternativa que impacte positivamente sobre su calidad de vida. El plan de tratamiento contempló el reemplazo de las prótesis removibles por prótesis híbridas en ambos maxilares, confeccionadas con PMMA modificado industrialmente con óxido de grafeno, previa colocación de cinco implantes en cada arco (AU)

Graphene and its derivatives are widely used in science and technology due to the benefits provided by their physicochemical properties. In the health area, specifically, its biological properties stand out, due to its high biocompatibility, cellular interaction, and its antibacterial activity. The incorporation of graphene in certain materials allows obtaining a combined material with improved properties. An example of this is the industrial incorporation of graphene oxide in methyl methacrylate, to generate an improved polymer (PMMA), not only from a mechanical point of view, but also a notable advantage in the biological response of soft tissues. This article describes the clinical case of a 70-year-old patient, who attended the consultation looking for treatment alternatives to improve the retention and stability of the prostheses to optimize the masticatory function, or an alternative that had a positive impact on their quality of lifetime. The treatment plan contemplated the replacement of removable prostheses with hybrid prostheses in both jaws, made with PMMA industrially modified with graphene oxide, after placing five implants in each arch (AU)

Novel Osteogenic Behaviors around Hydrophilic and Radical-Free 4-META/MMA-TBB: Implications of an Osseointegrating Bone Cement.

Poly(methyl methacrylate) (PMMA)-based bone cement, which is widely used to affix orthopedic metallic implants, is considered bio-tolerant but lacks osteoconductivity and is cytotoxic. Implant loosening and toxic complications are significant and recognized problems. Here we devised two strategies to improve PMMA-based bone cement: (1) adding 4-methacryloyloxylethyl trimellitate anhydride (4-META) to MMA monomer to render it hydrophilic; and (2) using tri-n-butyl borane (TBB) as a polymerization initiator instead of benzoyl peroxide (BPO) to reduce free radical production. Rat bone marrow-derived osteoblasts were cultured on PMMA-BPO, common bone cement ingredients, and 4-META/MMA-TBB, newly formulated ingredients. After 24 h of incubation, more cells survived on 4-META/MMA-TBB than on PMMA-BPO. The mineralized area was 20-times greater on 4-META/MMA-TBB than PMMA-BPO at the later culture stage and was accompanied by upregulated osteogenic gene expression. The strength of bone-to-cement integration in rat femurs was 4- and 7-times greater for 4-META/MMA-TBB than PMMA-BPO during early- and late-stage healing, respectively. MicroCT and histomorphometric analyses revealed contact osteogenesis exclusively around 4-META/MMA-TBB, with minimal soft tissue interposition. Hydrophilicity of 4-META/MMA-TBB was sustained for 24 h, particularly under wet conditions, whereas PMMA-BPO was hydrophobic immediately after mixing and was unaffected by time or condition. Electron spin resonance (ESR) spectroscopy revealed that the free radical production for 4-META/MMA-TBB was 1/10 to 1/20 that of PMMA-BPO within 24 h, and the substantial difference persisted for at least 10 days. The compromised ability of PMMA-BPO in recruiting cells was substantially alleviated by adding free radical-scavenging amino-acid N-acetyl cysteine (NAC) into the material, whereas adding NAC did not affect the ability of 4-META/MMA-TBB. These results suggest that 4-META/MMA-TBB shows significantly reduced cytotoxicity compared to PMMA-BPO and induces osteoconductivity due to uniquely created hydrophilic and radical-free interface. Further pre-clinical and clinical validations are warranted.

[Superficial and internal adaptations of a new self-curing composite resin restored class â ¤ cavity].

Objective: To investigate the superficial and internal adaptations of a new self-curing composite resin in Class Ⅴ cavities. Methods: Class Ⅴ cavities were prepared in 56 caries-free human maxillary premolars (collected from Department of Oral and Maxillofacial Surgery, Capital Medical University School of Stomatology) extracted for orthodontic reasons, and these premolars were assigned into two groups (28 specimens each group). Experimental group were restored with a pretreating agent (Tooth primer) and a new self-curing composite resin (Bondfill SB). Control group were restored with a self-etching adhesive (Scotchbond Universal) and a light-curing composite resin (Z100). The restored teeth were subjected to a fatigue test to simulate temperature change and occlusal load in oral environment: mechanical cycles (1 200 000 cycles at 49 N with a frequency of 1 Hz) and thermocycles (3 000 cycles from 5 ℃ to 55 ℃ with a dwelling time of 1 min each). Before and after fatigue test, restored teeth were immersed in an 50% ammoniacal silver nitrate solution and reduced. Superficial perfect margin percentage value and length of silver deposit along the internal interface were quantified by scanning electron microscopy (SEM). Ultrastructure of dentin bonding interface was analyzed by transmission electron microscope (TEM). Results: Before fatigue test, superficial gaps at dentin side in the specimens in experimental group were narrower than those in control group, and length of silver deposit at enamel side [(0.67±0.15) µm] in specimens in the control group was significantly lower than that in the experimental group [(33.54± 10.27) µm] (P<0.05). After the fatigue test, control group showed higher perfect margin percentage value to enamel [(55.08±15.20)%] than experimental group [(25.15±12.47)%] did (P<0.05). After the fatigue test, cohesive failures could be more easily found in experimental group than in control group at surficial and internal interfaces. In TEM results, more silver deposits were found at dentin bonding interface in control group than in experimental group before the fatigue test. After the fatigue test, the deterioration at dentin bonding interface mostly happened at the bottom of the hybrid layer in control group, while in experimental group it could be found at the bottom of the hybrid layer and in the restorative material. Conclusions: When restored in Class Ⅴ cavity, the studied light-curing composite shows better superficial and internal adaptations for enamel than the new self-curing composite resin and the new self-curing composite resin shows good superficial and internal adaptations for dentin.

Novel method for delayed primary closure and incisional hernia prevention in open abdomen: COmbined and MOdified Definitive Abdominal wall closure (COMODA).

BACKGROUND: Intended open abdomen is an option in cases of trauma and non-trauma patients. Nevertheless, after primary closure, incisional hernia rate is high. We describe a novel method, called COmbined and MOdified Definitive Abdominal closure (COMODA), a delayed primary closure which prevents incisional hernia. METHODS: A negative pressure wound therapy system is combined with a condensed polytetrafluoroethylene (cPTFE) mesh. TRIAL REGISTRATION: ISRCTN72678033. RESULTS: Ten male patients with a median age of 68.8 (43-87) years were included. Primary closure rate was 100% per protocol. The median number of procedures per patient was 5.7 (5-9). Primary closure was obtained in 20.8 (10-32) days and median hospital stay was 36.3 (18-52) days. Only one patient developed incisional hernia during a median follow-up of 27 (8-60) months. CONCLUSION: COMODA method allows for a high rate of delayed primary closure. It is safe and decreases the risk for developing an incisional hernia. However, a large number of patients are needed to support this conclusion.

Hybrid monoliths with metal-organic frameworks in spin columns for extraction of non-steroidal drugs prior to their quantitation by reversed-phase HPLC.

A (glycidyl methacrylate)-co-(ethylene glycol dimethacrylate) polymer (poly(GMA-co-EDMA)) was functionalized with metal-organic frameworks (MOF) and used as a sorbent for solid-phase extraction (SPE). The polymeric sorbent was prepared in-situ by photopolymerization in a previously wall-modified spin column, and then modified with an amino-modified MOF of type NH2-MIL-101(Cr). The sorbents were used for the extraction of nonsteroidal anti-inflammatory drugs (NSAIDs) from human urine samples. The sorbent was compared with the parent monolith and embedded approach, where the MOF particles are admixed in the polymerization mixture before the in-situ polymerization in the modified spin column. SPE is performed by percolating the sample solutions in a centrifuge, which streamlines the SPE steps. The hybrid composites were characterized by scanning electron microscopy and nitrogen intrusion porosimetry. Three NSAIDs (ketoprofen, flurbiprofen, and ibuprofen) were tested. They were eluted from the sorbent with acidified water-acetonitrile mixtures and subsequently analyzed by reversed-phase HPLC with UV detection. The detection limits varied in the range from 0.1 to 7 µg·L-1, and the precisions (relative standard deviation) were <14% in all the cases. The recoveries were between 71.0 and 78.0% in spiked urine samples. Graphical abstractA hybrid monolith modified with amino-modified MOF [named NH2-MIL-101(Cr)] in wall-modified spin columns was prepared. The resulting micro-extraction device was applied to the extraction and preconcentration of non-steroidal anti-inflammatory drugs.

Biodrug Suppresses Breast and Colorectal Cancer in Murine Models.

RNA interference (RNAi) remains one of the most promising and emerging strategies for the effective cancer treatment due to its high target specificity and greater potency. However, it is hindered due to lack of appropriate targeting technologies. Therefore, there is an imminent need to develop specific and robust delivery systems for successful gene silencing. Nanotechnology-based strategies have been in place to combat the shortcomings associated with viral-based delivery systems. Herein we describe protocols for successful in vitro and in vivo delivery of gene-specific nucleic acids such as siRNAs and shRNAs using PEI-PGMA nanoparticles for efficient cancer therapy.

UV-Responsive Multilayers with Multiple Functions for Biofilm Destruction and Tissue Regeneration.

The increasing demands of surgical implantation highlight the significance of anti-infection of medical devices, especially antibiofilm contamination on the surface of implants. The biofilms developed by colonized microbes will largely hinder the adhesion of host cells, leading to failure in long-term applications. In this work, UV-responsive multilayers were fabricated by stepwise assembly of poly(pyrenemethyl acrylate- co-acrylic acid) (P(PA- co-AA)) micelles and chitosan on different types of substrates. Under UV irradiation, the cleavage of pyrene ester bonds in the P(PA- co-AA) molecules resulted in the increase of roughness and hydrophilicity of the multilayers. During this process, reactive oxygen species were generated in situ within 10 s, which destroyed the biofilms of Staphylococcus aureus, leading to the degradation of the bacterial matrix. The antibacterial rate was above 99.999%. The UV-irradiated multilayers allowed the attachment and proliferation of fibroblasts, endothelial cells, and smooth muscle cells, benefiting tissue integration of the implants. When poly(dimethylsiloxane) slices with the multilayers were implanted in vivo and irradiated by UV, the density of bacteria and the inflammatory level (judging from the number of neutrophils) decreased significantly. Moreover, formation of neo blood vessels surrounding the implants was observed after implantation for 7 days. These results reveal that the photoresponsive multilayers endow the implants with multifunctions of simultaneous antibiofilm and tissue integration, shedding light for applications in surface modification of implants in particular for long-term use.

Extrusion of Biocompatible Osteoconductive Polymer (BOP) Causing Cervical Myelopathy.

BACKGROUND: As the prevalence of spinal fusion surgery has increased, reliable and safe bone graft substitutes have been developed in response. Biocompatible osteoconductive polymer (BOP) has been used as a bone graft alternative for spine surgery. We present a case of cervical myelopathy due to extrusion of BOP 23 years after surgery and discuss the pathophysiology in terms of spinal fusion. CASE DESCRIPTION: A 65-year-old man presented with a 3-month history of cervical myelopathic symptoms. Twenty-three years earlier, the patient had undergone cervical surgery for a C6-7 herniated disc with the use of BOP. Imaging studies of the cervical spine showed cord compression due to extruded BOP at C6-7. He underwent corpectomy of the C7 vertebral body and removal of the BOP for the neural decompression, combined with interbody fusion by use of an iliac bone graft and plate fixation. During the operation, crumbly fibers of the BOP were easily removed. His myelopathic symptoms improved immediately after surgery. Postoperative magnetic resonance imaging also showed successful decompression of the spinal cord. Histologically, a foreign body reaction and bony degeneration were found around the synthetic fibers of the BOP. CONCLUSIONS: Spine surgeons should recognize the pathophysiology of the BOP used for spine fusion surgery. Although BOP is not currently used for spinal surgery, patients undergoing previous surgery with the BOP can present with related complications. Revision surgery is recommended to remove the unincorporated BOP and achieve solid spine fusion.

Importance of Three-Dimensional Modeling in Cranioplasty.

Cranioplasty is a reconstruction operation made to protect intracranial structures. It is applied for the closure of bone defects occurring due to causes such as trauma, tumor, infection, and infarct. Many different products changing from autologous bone grafts to synthetic materials are used for cranioplasty. Three-dimensional printers that are among the popular innovations of today are used gradually more in medical area as in every field of life and they make the surgical operation easier. When customizable materials are combined with technology, the authors come across successful results and less complications. The aim of the authors' study was to show a 3-dimensional modeling method in 2 patients the authors applied cranioplasty and the advantages provided by this method for the surgeon and the patient.

Construction of Bovine Serum Albumin/AIE-Based Quaternary Complexes for Efficient Gene Transfection.

High transfection efficiency and superior cell imaging are required for cationic polymers-based gene delivery system to afford high therapeutic effect but its high toxicity and unstable cell imaging are easily ignored. In this study, cationic amino poly(glycerol methacrylate) derivative (PGMA-EDA) is used to incorporate bovine serum albumin (BSA) and aggregation-induced emission (AIE) molecular (tetraphenylethylene derivatives, TPE) as an efficient carrier for gene transfection and intracellular imaging. The obtained polymer/pDNA-TPE/BSA (PDTB) quaternary nanoparticles (NPs) not only exhibit efficient gene transfection but also show excellent biocompatibility. After inclusion of TPE/BSA (TB) NPs, BSA promoted dissociation of the complexes upon being protonated and the lipophilic TPE-reduced endosomal membrane stability, which enhanced endosomal escape of pDNA payload, finally resulting in an excellent gene transfection. On the other hand, less positive surface charge of PDTB NPs than that of the binary PD complexes, as well as the addition of biocompatible BSA, both factors contribute to the improved cell viability. Moreover, the AIE feature of TPE compared to aggregation-caused quenching character of conventional fluorophores enables the complex with stably tracking the delivery of pDNA into cancer cells. Therefore, the newly developed PDTB complexes may be a promising candidate vector for traceable, safe, and effective gene delivery.

Site-Selective in Situ Growth-Induced Self-Assembly of Protein-Polymer Conjugates into pH-Responsive Micelles for Tumor Microenvironment Triggered Fluorescence Imaging.

Self-assembly of site-selective protein-polymer conjugates into stimuli-responsive micelles is interesting owing to their potential biomedical applications, ranging from molecular imaging to drug delivery, but remains a significant challenge. Herein we report a method of site-selective in situ growth-induced self-assembly (SIGS) to synthesize site-specific human serum albumin-poly(2-(diisopropylamino)ethyl methacrylate) (HSA-PDPA) conjugates that can in situ self-assemble into pH-responsive micelles with tunable morphologies. Indocyanine green (ICG) was selectively loaded into the core of sphere-like HSA-PDPA micelles to form pH-responsive fluorescence nanoprobes. The nanoprobes rapidly dissociated into protonated individual unimers at a transition pH of around 6.5, that is the extracellular pH of tumors, which resulted in a sharp fluorescence increase and markedly enhanced cellular uptake. In a tumor-bearing mouse model, they exhibited greatly enhanced tumor fluorescence imaging as compared to ICG alone and pH-nonresponsive nanoprobes. These findings suggest that pH-responsive and site-selective protein-polymer conjugate micelles synthesized by SIGS are promising as a new class of tumor microenvironment-responsive nanocarriers for enhanced tumor imaging and therapy.

Carrageenans from Sarcothalia crispata and Gigartina skottsbergii: Structural Analysis and Interpolyelectrolyte Complex Formation for Drug Controlled Release.

The aims of the present study were to characterize for the first time the carrageenan extracted from cystocarpic stage of S. crispata collected in the Patagonian coast of Argentina, and to prepare interpolyelectrolytic complexes (IPECs) between the polysaccharide extracted from cystocarpic stage of Sarcothalia crispata and Gigartina skottsbergii thalli, and basic butylated methacrylate copolymer (Eudragit E), in order to test their potential for the controlled release of ibuprofen as model drug. The structural determination revealed that the polysaccharides extracted from S. crispata and G. skottsbergii were mainly constituted by κ-carrageenan, particularly in the case of G. skottsbergii; however, significant amounts of ι- and ν-carrageenan were also detected in both polygalactans. The differences in diad composition and possibly in their distribution along the polysaccharide chain of both carrageenans would favor a different arrangement in the resulting IPEC structure. The smaller pores observed by scanning electron microscopy in the IPEC of S. crispata suggest that the kinks in the polysaccharide backbone are evenly distributed, resulting in a slower ibuprofen release compared to the IPEC of G. skottsbergii.

Supermolecular drug challenge to overcome drug resistance in cancer cells.

Overcoming multidrug resistance (MDR) of cancer cells can be accomplished using drug delivery systems in large-molecular-weight ATP-binding cassette transporters before entry into phagolysosomes and by particle-cell-surface interactions. However, these hypotheses do not address the intratumoral heterogeneity in cancer. Anti-MDR must be related to alterations of drug targets, expression of detoxification, as well as altered proliferation. In this study, it is shown that the excellent efficacy and sustainability of anti-MDR is due to a stable ES complex because of the allosteric facilities of artificial enzymes when they are used as supermolecular complexes. The allosteric effect of supermolecular drugs can be explained by the induced-fit model and can provide stable feedback control systems through the loop transfer function of the Hill equation.

Outcome of Endodontic Surgery: A Meta-analysis of the Literature-Part 3: Comparison of Endodontic Microsurgical Techniques with 2 Different Root-end Filling Materials.

INTRODUCTION: The aim of the present study was to investigate the influence of root-end preparation and filling material on endodontic surgery outcome. A systematic review and meta-analysis was conducted to determine the outcome of resin-based endodontic surgery (RES, the use of high-magnification preparation of a shallow and concave root-end cavity and bonded resin-based root-end filling material) versus endodontic microsurgery (EMS, the use of high-magnification ultrasonic root-end preparation and root-end filling with SuperEBA [Keystone Industries, Gibbstown, NJ], IRM [Dentsply Sirona, York, PA], mineral trioxide aggregate [MTA], or other calcium silicate cements). METHODS: An exhaustive literature search was conducted to identify prognostic studies on the outcome of root-end surgery. Human studies conducted from 1966 to the end of December 2016 in 5 different languages (ie, English, French, German, Italian, and Spanish) were searched in 4 electronic databases (ie, Medline, Embase, PubMed, and Cochrane Library). Relevant review articles on the subject were scrutinized for cross-references. In addition, 5 dental and medical journals (Journal of Endodontics; International Endodontic Journal; Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics; Journal of Oral and Maxillofacial Surgery; and International Journal of Oral and Maxillofacial Surgery) were hand checked dating back to 1975. All abstracts were screened by 3 independent reviewers (H.B., M.K., and F.S.). Strict inclusion-exclusion criteria were defined to identify relevant articles. Raw data were extracted from the full-text review of these selected articles independently by each of the 3 reviewers. In case of disagreement, an agreement was reached by discussion, and qualifying articles were assigned to group RES. For EMS, the same search strategy was performed for the time frame October 2009 to December 2016, whereas up to October 2009 the data were obtained from a previous systematic review with identical criteria and search strategy. Weighted pooled success rates and a relative risk assessment between RES and EMS were calculated. To make a comparison between groups, a random effects model was used. RESULTS: Sixty-eight articles were eligible for full-text review. Of these, per strict inclusion exclusion criteria, 14 studies qualified, 3 for RES (n = 862) and 11 for EMS (n = 915). Weighted pooled success rates for RES were 82.20% (95% confidence interval [CI], 0.7965-0.8476) and 94.42% for EMS (95% CI, 0.9295-0.9590). This difference was statistically significant (P < .0005). CONCLUSIONS: The probability for success for EMS proved to be significantly greater than the probability for success for RES, providing best available evidence on the influence of cavity preparation with ultrasonic tips and/or SuperEBA (Keystone Industries, Gibbstown, NJ), IRM (Dentsply Sirona, York, PA), MTA, or silicate cements as root-end filling material instead of a shallow cavity preparation and placement of a resin-based material. Additional large-scale randomized clinical trials are needed to assess other predictors of outcome.