Construction and validation of a nomogram to predict the overall survival of small cell lung cancer: a multicenter retrospective study in Shandong province, China.

BACKGROUND: Patients diagnosed with small cell lung cancer (SCLC) typically experience a poor prognosis, and it is essential to predict overall survival (OS) and stratify patients based on distinct prognostic risks. METHODS: Totally 2309 SCLC patients from the hospitals in 15 cities of Shandong from 2010 - 2014 were included in this multicenter, population-based retrospective study. The data of SCLC patients during 2010-2013 and in 2014 SCLC were used for model development and validation, respectively. OS served as the primary outcome. Univariate and multivariate Cox regression were applied to identify the independent prognostic factors of SCLC, and a prognostic model was developed based on these factors. The discrimination and calibration of this model were assessed by the time-dependent C-index, time-dependent receiver operator characteristic curves (ROC), and calibration curves. Additionally, Decision Curve Analysis (DCA) curves, Net Reclassification Improvement (NRI), and Integrated Discriminant Improvement (IDI) were used to assess the enhanced clinical utility and predictive accuracy of the model compared to TNM staging systems. RESULTS: Multivariate analysis showed that region (Southern/Eastern, hazard ratio [HR] = 1.305 [1.046 - 1.629]; Western/Eastern, HR = 0.727 [0.617 - 0.856]; Northern/Eastern, HR = 0.927 [0.800 - 1.074]), sex (female/male, HR = 0.838 [0.737 - 0.952]), age (46-60/≤45, HR = 1.401 [1.104 - 1.778]; 61-75/≤45, HR = 1.500 [1.182 - 1.902]; >75/≤45, HR = 1.869 [1.382 - 2.523]), TNM stage (II/I, HR = 1.119[0.800 - 1.565]; III/I, HR = 1.478 [1.100 - 1.985]; IV/I, HR = 1.986 [1.477 - 2.670], surgery (yes/no, HR = 0.677 [0.521 - 0.881]), chemotherapy (yes/no, HR = 0.708 [0.616 - 0.813]), and radiotherapy (yes/no, HR = 0.802 [0.702 - 0.917]) were independent prognostic factors of SCLC patients and were included in the nomogram. The time-dependent AUCs of this model in the training set were 0.699, 0.683, and 0.683 for predicting 1-, 3-, and 5-year OS, and 0.698, 0.698, and 0.639 in the validation set, respectively. The predicted calibration curves aligned with the ideal curves, and the DCA curves, the IDI, and the NRI collectively demonstrated that the prognostic model had a superior net benefit than the TNM staging system. CONCLUSION: The nomogram using SCLC patients in Shandong surpassed the TNM staging system in survival prediction accuracy and enabled the stratification of patients with distinct prognostic risks based on nomogram scores.

Preparation and functionalization of acetylsalicylic acid loaded chitosan/gelatin membranes from ethanol-based suspensions via electrophoretic deposition.

Acetylsalicylic acid (Aspirin, ASP), a frequently used analgesic and antipyretic drug, has prevailed for decades due to its multiple functions. To increase its solubility and maintain the topical and low-dose application, ethanol with electrophoretic deposition (EPD) was introduced. It was initially investigated to fabricate acetylsalicylic acid loaded chitosan/gelatin (CS/G) membranes via simple electrophoretic deposition under mild conditions. The spectrophotometry, SEM, FTIR and XRD results confirmed the entrapment of acetylsalicylic acid. FTIR spectra also indicated that new bonds were formed between acetylsalicylic acid and the CS/G membranes. The contact angle study confirmed the good hydrophilicity of the samples' surfaces. The mechanical strengths of membranes were promoted due to the introduction of ethanol. The in vitro cellular study revealed the capacity of promoting osteogenic differentiation and little influence on the cell viability for BMSCs. All these results suggested that acetylsalicylic acid loaded CS/G membranes could be successfully fabricated via EPD and used for functionalizing the titanium substrate. These membranes loaded with other functional reagents, hydrosoluble or liposoluble, may also be promising for use in medical applications.

Evaluation of antibacterial, angiogenic, and osteogenic activities of green synthesized gap-bridging copper-doped nanocomposite coatings.

Titanium (Ti) and its alloys have been widely used in clinics for years. However, their bio-inert surface challenges application in patients with compromised surgical conditions. Numerous studies were conducted to modify the surface topography and chemical composition of Ti substrates, for the purpose of obtaining antibacterial, angiogenic, and osteogenic activities. In this study, using green electrophoretic deposition method, we fabricated gap-bridging chitosan-gelatin (CSG) nanocomposite coatings incorporated with different amounts of copper (Cu; 0.01, 0.1, 1, and 10 mM for Cu I, II, III, and IV groups, respectively) on the Ti substrates. Physicochemical characterization of these coatings confirmed that Cu ions were successfully deposited into the coatings in a metallic status. After rehydration, the coatings swelled by 850% in weight. Mechanical tests verified the excellent tensile bond strength between Ti substrates and deposited coatings. All Cu-containing CSG coatings showed antibacterial property against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. The antibacterial property was positively correlated with the Cu concentration. In vitro cytocompatibility evaluation demonstrated that activities of bone marrow stromal cells were not impaired on Cu-doped coatings except for the Cu IV group. Moreover, enhanced angiogenic and osteogenic activities were observed on Cu II and Cu III groups. Overall, our results suggested that Cu-doped CSG nanocomposite coating is a promising candidate to functionalize Ti materials with antibacterial, angiogenic, and osteogenic properties.

Enhanced antibacterial activity and biocompatibility of zinc-incorporated organic-inorganic nanocomposite coatings via electrophoretic deposition.

Increased use of reconstruction procedures in orthopedics has improved the life of patients undergoing surgery. However, surgical site infection remains a major challenge. Efforts were made to fabricate antibacterial surfaces with good biocompatibility. This present study aimed to fabricate zinc-incorporated chitosan/gelatin (CS/G) nanocomposite coatings on the titanium substrates via electrophoretic deposition (EPD). Physicochemical characterization confirmed that zinc was successfully deposited in a metallic oxide/salt complex status. Transmission electron microscopic (TEM) results observed formation of core-shell nanosized particles released from the coatings. The selected-area electron diffraction (SAED) pattern of the particles presented faces of ZnO with organic background. Mechanical tests showed improved tensile and shear bond strength between substrates and zinc-incorporated coating surfaces. Zinc-incorporated CS/G coatings presented antibacterial abilities against both Gram-negative E. coli and Gram-positive S. aureus in a concentration-dependent manner. The generation of ZnO/Zn2+ complex in the coatings may contribute to bacteria inhibition. In vitro study demonstrated that appropriate concentration of zinc could promote proliferative and osteogenic activities of rat bone marrow stromal cells. The present study suggested that zinc-incorporated CS/G coating was a promising candidate for surface modification of biomedical materials.

The fabrication of double-layered chitosan/gelatin/genipin nanosphere coating for sequential and controlled release of therapeutic proteins.

Bone regeneration is a complicated process and includes a number of distinct and sequential stages of coordinated cellular actions under the regulation of multiple growth factors. Therefore, bone grafting materials in which growth factors can be incorporated and released in a programmed order in line with the bone tissue healing process may lead to desirable clinical outcomes. In the present study, a double-layered chitosan/gelatin/genipin (d-CSG/G) nanosphere coating is developed by using layer-by-layer electrophoretic deposition and genipin crosslinking. The surface morphology, physicochemical and mechanical properties of the coatings are explored. Cytochrome C is used as a therapeutic model protein and is successfully loaded on the inner and outer layers of the coating. The protein release can be controlled by the loading position, genipin concentration and thickness of the outer layer. Furthermore, the cell response to the coatings was evaluated. Real-time polymerase chain reactions, immunofluorescence staining and extracellular matrix mineralization assay confirmed that the functions of the loaded growth factor are fully preserved after fabrication. Overall, the d-CSG/G nanosphere coating could be a promising growth factor delivery system to promote bone tissue regeneration.

A green single-step procedure to synthesize Ag-containing nanocomposite coatings with low cytotoxicity and efficient antibacterial properties.

Implant-associated infections still pose a serious threat leading to several complications. This study reported an environmentally benign Ag-containing nanocomposite coating with efficient antibacterial property fabricated on the metal implant via electrophoretic deposition (EPD). In such coatings, Ag2O/AgCl mixed with chitosan/gelatin (CS/G) polymers work together to exert the antibacterial property which could act as an alternative to traditional Ag nanoparticles. Scanning electron microscopy images showed the shuttle fiber-like morphology distributed lamellarly and some nanoparticles carved uniformly into the cross section. Transmission electron microscopy results revealed a core-shell-like structure of the released nanoparticles in experimental groups. The Ag-containing coatings exhibited strong antibacterial properties against Staphylococcus aureus strains and Escherichia coli strains. Meanwhile, the CCK-8 tests showed that after assembling with chitosan and gelatin polymers, the cytotoxicity of Ag was largely decreased. In addition, such coatings also exhibited strong bond strength with metal substrates and good degradable properties. Therefore, such Ag-containing CS/G coatings fabricated via EPD may be a promising candidate to be administrated in controlling the implant-associated infections.

In Vitro and In Vivo Evaluation of Tetracycline Loaded Chitosan-Gelatin Nanosphere Coatings for Titanium Surface Functionalization.

Owing to the biocompatibility of titanium surface, titanium implants are suitable substrates for microbial colonization and biofilm formation, which is still a serious clinical threat. Current research trends have been focused on the development of antibacterial coatings on titanium substrate or adhesion resistant surface. In our previous study, tetracycline (Tc) loaded chitosan-gelatin (CSG) nanosphere coatings are successfully fabricated on titanium substrates via electrophoretic deposition. These coatings show nanosphere structure, and excellent antibacterial property in vitro. However, further in vitro and in vivo evaluation of the coatings is required for the future application. Therefore, in the present study, the authors investigate the coatings' mechanical, swelling and degradation property, in vitro cellular response to preosteoblast cells, and the antibacterial property in rabbits. Results show that Tc incorporation can improve the tensile bond strength of the coating, decrease the swelling ratio, and accelerate the degradation of the coating. Although high Tc concentration group exhibits cytotoxicity to MC3T3-E1 cells, its in vivo antibacterial property is preferred, and shows better outcome than the prophylactic administration of Tc. Tc loaded CSG nanosphere coatings are suitable antibacterial coatings for titanium surface functionalization.

Surface functionalization with strontium-containing nanocomposite coatings via EPD.

Metal orthopedic implants still face challenges in some compromised conditions, partly due to bio-inertness. The present study aimed to functionalize metallic implants with organic-inorganic nanocomposite (strontium-containing chitosan/gelatin) coatings through a simple single-step electrophoretic deposition under mild conditions. The surface characterization and in vitro cellular response were studied and compared with chitosan/gelatin (CS/G) coatings. SEM images suggested the inorganic nanoparticles may be encapsulated within or mixed with organic polymers. The XRD patterns showed that strontium carbonate was generated in the coatings. The TEM images revealed strontium-containing nanoparticles were released from the coatings in PBS. The continuous release after the initial burst release ensured the enduring effects of the functionalized surface. The tensile bond strength of the coatings to the substrates increased after the addition of strontium. In vitro cellular study confirmed that strontium-containing coatings supported the proliferation of MC3T3-E1 cells and exhibited excellent ability to enhance the differentiation of such pre-osteoblasts. Therefore, such organic-inorganic nanocomposite coatings are a promising candidate to functionalize orthopedic implant surfaces.

Fabrication and characterization of Mg-doped chitosan-gelatin nanocompound coatings for titanium surface functionalization.

Titanium and its alloys have been widely used in clinic and achieved great success. Due to the bio-inertness of titanium surface, challenges still exit in some compromised conditions. The present study aimed to functionalize titanium surface with magnesium (Mg)-doped chitosan/gelatin (CS/G) nanocompound coatings via electrophoretic deposition (EPD). CS/G coatings loaded with different amount of magnesium were successfully prepared on titanium substrate via EPD. Physicochemical characterization of the coatings confirmed that magnesium ions were loaded into the coatings in a dose-dependent manner. XRD results demonstrated that co-deposition of magnesium influenced the crystallinity of the coatings, and a new crystalline substance presented, namely hydrated basic magnesium carbonate. Mechanical tests showed improved tensile and shear bond strength of the magnesium-doped coatings, while the excessively high magnesium concentration could eventually decrease the bonding strength. Sustained release of magnesium ion was detected by ICP-OES within 28 days. TEM images also displayed that nanoparticles could be released from the coatings. In vitro cellular response assays demonstrated that the Mg-doped nanocompound coatings could enhance the proliferation and osteogenic differentiation of MC3T3-E1 cells compared to CS/G coatings. Therefore, it could be concluded that Mg-doped CS/G nanocompound coatings were successfully fabricated on titanium substrates via EPD. It would be a promising candidate to functionalize titanium surface with such organic-inorganic nanocompound coatings.

Osteogenetic property of a biodegradable three-dimensional macroporous hydrogel coating on titanium implants fabricated via EPD.

The potential for a successful integration of implants with surrounding tissue may be jeopardized in a number of compromised conditions. Biochemical surface modification is one of the choices to extend the spectrum of indications. We have previously successfully fabricated chitosan-gelatin (CS/G) coatings on a titanium surface via electrophoretic deposition, which may be promising candidates for further loading of functional agents. In this study, we have identified the microstructure, physicochemical properties and biological performance of CS/G coatings in vitro and in vivo. The in vitro degradation test indicated that CS/G coatings in the presence of lysozyme showed a significant weight loss after 28 days. The results of the cell culture exhibited that CS/G coatings could sustain MC3T3-E1 cell attachment, proliferation and migration. In vivo osteogenetic behavior evaluated by Micro-CT and histomorphometrical analysis revealed significant new bone formation around CS/G implants at 8 and 12 weeks, compared to sandblasted/acid-etched implants. Moreover, histological evaluation suggested the majority of CS/G coatings were degraded at 12 weeks. Therefore, we have concluded that the three-dimensional porous structure of scaffold-like CS/G coatings may facilitate osteogenesis and that such coatings can be biodegraded in the early bone healing process.