Clinical application of common inflammatory and nutritional indicators before treatment in prognosis evaluation of non-small cell lung cancer: a retrospective real-world study.

Objective: To evaluate the prognostic value of common clinical inflammatory and nutritional indicators before treatment in patients with non-small cell lung cancer in the real world. Method: A total of 5,239 patients with pathologically confirmed non-small cell lung cancer from 2011 to 2018 in the Affiliated Cancer Hospital of Xinjiang Medical University were selected. Their inflammatory and nutritional indicators (RDW, PDW, NLR, LMR, NMR, PLR, SII, PNI, TP, ALB, CYRFA21-1, CEA, CA125, NSE, α1-globulin, α2-globulin, ß1-globulin, ß2-globulin, and γ-globulin) before treatment were collected. From the total number, 1,049 patients were randomly sampled (18 to 20% of patients each year) and used as the validation set; the remaining 4,190 patients were used as the training set. According to the eighth edition of the guidelines for the diagnosis, treatment, and stage risk stratification of lung cancer, the patients were divided into four groups: stage I/II operable, stage III operable, stage III inoperable, and stage IV. We used the X-tile software to intercept and classify the cut-off values of each index in the validation set. Univariate and multivariate Cox proportional-hazard regression were used to screen the independent risk factors affecting the prognosis of non-small cell lung cancer and establish a prognostic model for 1, 3, and 5 years. The validation set was used to verify its performance. Finally, the Kaplan-Meier curve was used to assess the survival rate, and the corresponding nomogram was established for clinical use. Results: After screening, no effective indicators were found in the stage I/II operable group. RDW and CA125 were effective indicators for the stage III operable group (cut-off values were 14.1 and 9.21, respectively, compared with the low-value group; univariate HR was 2.145 and 1.612, and multivariate HR was 1.491 and 1.691, respectively). CYRFA21-1 and CA125 were effective prognostic indicators for the stage III inoperable group (cut-off values were 10.62 and 44.10, respectively, compared with the low-value group; univariate HR was 1.744 and 1.342, and multivariate HR was 1.284 and 1.304, respectively). CYRFA21-1, CA125, NLR, and α1-globulin were effective indicators of prognosis in stage IV (cut-off values were 3.07, 69.60, 4.08, and 5.30, respectively, compared with the low-value group; univariate HR was 1.713, 1.339, 1.388, and 1.539; and multivariate HR was 1.407, 1.119, 1.191, and 1.110, respectively). The model was constructed with the best validation power in stage IV patients (C-index = 0.733, 0.749, and 0.75 at 1, 3, and 5 years, respectively). Conclusion: For patients with stage III and IV non-small cell lung cancer, some inflammatory markers, serum tumor markers, and nutritional indicators are independent prognostic factors. Combined with the general data of patients, the constructed prognostic evaluation model has the best efficacy in patients with stage IV and can be widely used in clinical practice.

Bifunctional scaffolds of hydroxyapatite/poly(dopamine)/carboxymethyl chitosan with osteogenesis and anti-osteosarcoma effect.

The bifunctional tissue engineering scaffold with anti-tumor and bone repair properties is promising for the therapy of bone tumor where large bone defects often occur. In this study, hydroxyapatite (HA), poly(dopamine) (PDA), and carboxymethyl chitosan (CMCS) composite scaffolds were prepared by the 3D-printing technology. PDA significantly improved the rheological properties of the slurry for molding, mechanical properties, surface relative potential, and water absorption of composite scaffolds. The osteogenic properties of HA/PDA/CMCS composite scaffolds were evaluated by the cell experiment in vitro. The photothermal properties and anti-tumor effects of the scaffolds in vivo were assessed by the tumor model in nude mice. HA/PDA/CMCS composite scaffolds could promote more osteogenic differentiation of mouse bone marrow stromal cells (mBMSCs) than scaffolds without PDA in vitro and the effect was not hindered by the photothermal process. The PDA-modified composite scaffold had excellent photothermal properties. Cell experiments showed that scaffolds with PDA under irradiation could suppress the tumor effectively. In vivo anti-tumor effects in nude mice indicated that the HA/PDA/CMCS composite scaffold promoted cell apoptosis/necrosis by the direct photothermal effect. Vascular injury was developed subsequently, which lead to the suppression of tumor cell proliferation due to hypoxia-ischemia. HA/PDA/CMCS composite scaffolds with multiple effects have great potential application in bone tumor therapy.

Biodegradable 3D printed HA/CMCS/PDA scaffold for repairing lacunar bone defect.

Three-dimensional (3D) printing technology has attracted considerable focus for preparing porous bone repair scaffolds to promote bone regeneration. Inspired by organic-inorganic components and the porous structure of natural bone, novel porous degradable scaffolds have been printed using hydroxyapatite (HA), carboxymethyl chitosan (CMCS), and polydopamine (PDA). The well-designed HA/CMCS/PDA scaffolds exhibited a porous structure with 60.5 ± 4.6% porosity and 415 ± 87 µm in mode pore diameter. The weight loss percentage (WL%) of the HA/CMCS/PDA scaffolds reached about 17% during a 10-week degradation in vitro. The degradation process between the CMCS and HA induced the release of calcium ions. Using commercial product as the contrast material, the osteogenic properties of the scaffolds were assessed in vivo. The implantation and degradation of HA/CMCS/PDA scaffolds had no adverse effects on the kidney and liver of rabbits with no inflammatory response in the implantation sites. The micro-CT and histology data suggested that the HA/CMCS/PDA scaffolds could effectively stimulate new bone formation within the femoral lacuna defect region of rabbits versus blank control at 12 weeks after implantation. Surface cortical bone was generated in the defect area in the HA/CMCS/PDA group; the defect in the blank group remained obvious. HA/CMCS/PDA scaffolds had excellent biodegradability matching the formation of new bone during implantation. In conclusion, 3D-printed HA/CMCS/PDA scaffolds have remarkable potential as a new material for repairing bone defects.

Tailorable hierarchical structures of biomimetic hydroxyapatite micro/nano particles promoting endocytosis and osteogenic differentiation of stem cells.

Hydroxyapatite (HA) micro/nano particles show great promise as artificial bone and dental substitutes, or drug carrier systems. However, the precise regulation of hydroxyapatite micro/nano particles with controllable physicochemical properties (such as hierarchical structure, particle size, potential and crystallinity) is still a challenge. Furthermore, the effects of different hierarchical structures on biological responses have been rarely reported. Herein, the HA particles with a precisely tailored micro/nano hierarchical structure have been developed using an elaborate biomimetic synthesis technology. Three representative particles, namely, micro/nano needle-like HA particles, micro/nano rod-like HA particles, and micro/nano flake-like HA particles, were featured to evaluate their biological responses to stem cells. The pore structure facilitated the adsorption of serum adhesive proteins, which together with the unique hierarchical architecture of micro/nano flake-like HA particles remarkably promoted the endocytosis efficiency in a concentration-dependent manner. The qRT-PCR together with RNA-seq and western blot analyses showed that micro/nano flake-like HA particles more significantly up-regulated the expression of genes and production of proteins related to osteogenic differentiation among the three particles through the activated ERK/MAPK signalling pathway. RNA-seq further revealed a complex mechanism of cell interface events, suggesting that the hierarchical architecture of HA particles is of crucial importance for the regulation of actin cytoskeleton involved in the modulation of cell adhesion which positively stimulated osteogenic differentiation of stem cells. Moreover, the endocytosis of particles into lysosomes resulted in an increase in the intracellular Ca2+ levels, which activated possible intracellular Ca2+-mediated signaling cascades (Ras/cAMP/Rap1/MAPK signaling pathways) related to osteogenic differentiation of stem cells. Our findings shed light on the effects of different hierarchical structures of HA particles on stem cell differentiation and contribute to the optimal design of implant materials.

Biomimetic mineralization of carboxymethyl chitosan nanofibers with improved osteogenic activity in vitro and in vivo.

Inspired by the natural extracellular matrix, the organic-inorganic composite nanofibers are promising scaffolds for bone tissue engineering. Chitosan-based nanofibers are widely used as bone tissue engineering scaffolds with good biocompatibility but pungent solvents are frequently used for its processing. Carboxymethyl chitosan (CMCS), a water-soluble derivative of chitosan, has better biodegradability and bioactivity which allows CMCS to chelate Ca2+ and induce the deposition of apatite. Moreover, with water as solvent, CMCS nanofibers avoid the acidic salt removal comparing to electrospun-chitosan. In this study, we successfully prepared uniform CMCS nanofibers with the aid of polyethylene oxide (PEO) and obtained the optimized conditions with a voltage of 25 kV and PEO of molecular weight 1000 kDa. We further prepared hydroxyapatite (HA) coated electrospun CMCS nanofibers by biomimetic mineralization using 5 times simulated body fluid. The promotion of osteogenic differentiation of mouse bone marrow stromal cells (mBMSCs) in vitro was evaluated on the nanofibers scaffolds. Cell experiments revealed that CMCS-HA composite nanofibers increased the ALP activity. The gene expression level of Runx2 and ALP were about 1.6 and 4.3 folds at the 7 days, and 5.1 and 10 folds at the 14 days on CMCS-HA nanofibrous membranes than that on CMCS alone samples. The level of OCN increased by 24 and 1.5 times on the CMCS-HA scaffolds than CMCS scaffolds at the 14 and 21 days. In vivo new bone formation by nanofiber scaffolds was investigated in a critical-size rat calvarial bone defect model. Micro-CT results showed that the whole defect was covered by new bone after CMCS-HA filling the defect for 12 weeks. The results of H&E staining and Masson's trichrome staining on histological sections further confirmed that composite nanofibers promoted new bone formation and maturation.