Quantification of preexisting lung ground glass opacities on CT for predicting checkpoint inhibitor pneumonitis in advanced non-small cell lung cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can lead to life-threatening pneumonitis, and pre-existing interstitial lung abnormalities (ILAs) are a risk factor for checkpoint inhibitor pneumonitis (CIP). However, the subjective assessment of ILA and the lack of standardized methods restrict its clinical utility as a predictive factor. This study aims to identify non-small cell lung cancer (NSCLC) patients at high risk of CIP using quantitative imaging. METHODS: This cohort study involved 206 cases in the training set and 111 cases in the validation set. It included locally advanced or metastatic NSCLC patients who underwent ICI therapy. A deep learning algorithm labeled the interstitial lesions and computed their volume. Two predictive models were developed to predict the probability of grade ≥ 2 CIP or severe CIP (grade ≥ 3). Cox proportional hazard models were employed to analyze predictors of progression-free survival (PFS). RESULTS: In a training cohort of 206 patients, 21.4% experienced CIP. Two models were developed to predict the probability of CIP based on different predictors. Model 1 utilized age, histology, and preexisting ground glass opacity (GGO) percentage of the whole lung to predict grade ≥ 2 CIP, while Model 2 used histology and GGO percentage in the right lower lung to predict grade ≥ 3 CIP. These models were validated, and their accuracy was assessed. In another exploratory analysis, the presence of GGOs involving more than one lobe on pretreatment CT scans was identified as a risk factor for progression-free survival. CONCLUSIONS: The assessment of GGO volume and distribution on pre-treatment CT scans could assist in monitoring and manage the risk of CIP in NSCLC patients receiving ICI therapy. CLINICAL RELEVANCE STATEMENT: This study's quantitative imaging and computational analysis can help identify NSCLC patients at high risk of CIP, allowing for better risk management and potentially improved outcomes in those receivingICI treatment.

Fabrication of self-assembled micelles based on amphiphilic oxidized sodium alginate grafted oleoamine derivatives via Schiff base reduction amination reaction for delivery of hydrophobic food active ingredients.

The application of hydrophobic ß-carotene in the food industry are limited due to its susceptibility to light, high temperature, pH value, and other factors, leading to poor stability and low bioavailability. To address this problem, we adopt a more green and environmentally friendly reducing agent, 2-methylpyridine borane complex (pic-BH3), instead of traditional sodium borohydride, to achieve the simple green and efficient synthesis of amphiphilic oxidized sodium alginate grafted oleoamine derivatives (OSAOLA) through the reduction amination reaction of Schiff base. The resultant OSAOLA with the degree of substitution (DS) of 7.2 %, 23.6 %, and 38.8 % were synthesized, and their CMC values ranged from 0.0095 to 0.062 mg/mL, indicating excellent self-assembly capability in aqueous solution. Meanwhile, OSAOLA showed no obvious cytotoxicity to RAW 264.7 cells, thus revealing good biocompatibility. Furthermore, ß-carotene, as the hydrophobic active ingredients in foods was successfully encapsulated in the OSAOLA micelles by ultrasonic-dialysis method. The prepared drug-loaded OSAOLA micelles could maintain good stability when stored at room temperature for 7 d. Additionally, they were able to continuously release ß-carotene and exert long-term effects in pH 7.4 PBS at 37 °C, effectively improving the bioavailability of ß-carotene, which exhibited tremendous application potential in functional food and biomedical fields.

Construction and Evaluation of Alginate Dialdehyde Grafted RGD Derivatives/Polyvinyl Alcohol/Cellulose Nanocrystals IPN Composite Hydrogels.

To enhance the mechanical strength and cell adhesion of alginate hydrogel, making it satisfy the requirements of an ideal tissue engineering scaffold, the grafting of Arg-Gly-Asp (RGD) polypeptide sequence onto the alginate molecular chain was conducted by oxidation of sodium periodate and subsequent reduction amination of 2-methylpyridine borane complex (2-PBC) to synthesize alginate dialdehyde grafted RGD derivatives (ADA-RGD) with good cellular affinity. The interpenetrating network (IPN) composite hydrogels of alginate/polyvinyl alcohol/cellulose nanocrystals (ALG/PVA/CNCs) were fabricated through a physical mixture of ion cross-linking of sodium alginate (SA) with hydroxyapatite/D-glucono-δ-lactone (HAP/GDL), and physical cross-linking of polyvinyl alcohol (PVA) by a freezing/thawing method, using cellulose nanocrystals (CNCs) as the reinforcement agent. The effects of the addition of CNCs and different contents of PVA on the morphology, thermal stability, mechanical properties, swelling, biodegradability, and cell compatibility of the IPN composite hydrogels were investigated, and the effect of RGD grafting on the biological properties of the IPN composite hydrogels was also studied. The resultant IPN ALG/PVA/CNCs composite hydrogels exhibited good pore structure and regular 3D morphology, whose pore size and porosity could be regulated by adjusting PVA content and the addition of CNCs. By increasing the PVA content, the number of physical cross-linking points in PVA increased, resulting in greater stress support for the IPN composite hydrogels of ALG/PVA/CNCs and consequently improving their mechanical characteristics. The creation of the IPN ALG/PVA/CNCs composite hydrogels' physical cross-linking network through intramolecular or intermolecular hydrogen bonding led to improved thermal resistance and reduced swelling and biodegradation rate. Conversely, the ADA-RGD/PVA/CNCs IPN composite hydrogels exhibited a quicker degradation rate, attributed to the elimination of ADA-RGD by alkali. The results of the in vitro cytocompatibility showed that ALG/0.5PVA/0.3%CNCs and ADA-RGD/PVA/0.3%CNCs composite hydrogels showed better proliferative activity in comparison with other composite hydrogels, while ALG/PVA/0.3%CNCs and ADA-RGD/PVA/0.3%CNCs composite hydrogels displayed obvious proliferation effects, indicating that PVA, CNCs, and ADA-RGD with good biocompatibility were conducive to cell proliferation and differentiation for the IPN composite hydrogels.

Nano-SiO2 reinforced alginate-chitosan-gelatin nanocomposite hydrogels with improved physicochemical properties and biological activity.

Alginate (Alg) hydrogels possess desirable advantages for application in tissue engineering; however, they are limited by their weak mechanical properties, poor chronical stability in phosphate buffered saline, and absence of mammalian cell recognition sites, severely restricting their biomedical applications. To overcome these limitations, we integrated Alg hydrogels with nano-silica (SiO2) to produce nano-SiO2 reinforced Alg-chitosan-gelatin nanocomposite hydrogels (Alg/SiO2-CHI-GA NCH) for biomedical purposes, utilizing Chitosan (CHI) and gelatin (GA) in an alternate electrostatic adsorption. Specifically, we investigated the regulatory and promotional effects of the nano-SiO2 on the morphological structure, mechanical properties, thermal stability, rheological properties, swelling, biodegradability, biomineralization and cytocompatibility of the resultant Alg/SiO2-CHI-GA NCH. The experimental findings demonstrate that the constructed Alg/SiO2-CHI-GA NCH exhibited uniform morphology and a regular structure. Upon freeze-drying, the internal cross-sections of the NCH exhibited a honeycomb porous structure. Furthermore, the physicochemical properties and biological activities of the prepared Alg/SiO2-CHI-GA NCH were regulated to some extent by nano-SiO2 content. Notably, nano-SiO2 inclusion enhanced the attachment and viability of MG63 and MC3T3-E1 cells and induced three-dimensional cell growth in ALG/SiO2-CHI-GA NCH. Among the fabricated NCH, Alg/SiO2-CHI-GA NCH with 0.5% and 1.0% (w/v) nano-SiO2 exhibited significant proliferative activity, which is attributable to their high porosity and uniform cell adhesion. Furthermore, the alkaline phosphatase activity in the cells gradually increased with increasing of nano-SiO2 amount, indicating the favorable effect of nano-SiO2 on the osteogenic differentiation of MG63 and MC3T3-E1 cells. Our study findings provide a comprehensive foundation for the structural- and property-related limitations of Alg hydrogels in biomedicine, thereby expanding their potential applications in tissue engineering.

Investigation and verification of GIMAP6 as a robust biomarker for prognosis and tumor immunity in lung adenocarcinoma.

BACKGROUND AND AIM: According to previous reports, GTPase of immunity-associated protein 6 (GIMAP6) is essential for autophagy. However, it is unclear how GIMAP6 affects the development and tumor immunity of lung adenocarcinoma (LUAD). METHODS: In the present study, the role of GIMAP6 in vivo and in vitro was examined using reverse transcription-quantitative PCR, western blotting, and Cell Counting Kit-8, colony formation and Transwell assays. Datasets from The Cancer Genome Atlas and Genotype-Tissue Expression databases were thoroughly analyzed using R software. A nomogram was created using GIMAP6 and prognostic characteristics. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were applied to explore the potential mechanism of GIMAP6 in lung cancer. The link between GIMAP6 and the immunological landscape was studied using single-cell RNA sequencing datasets from Tumor Immune Estimation Resource (TIMER) 2.0 and Tumor Immune Single-cell Hub. RESULTS: Patients with high GIMAP6 expression had improved overall and disease-specific survival compared with those patients with low GIMAP6 expression. According to the receiver operating characteristic and calibration curve, the nomogram based on T stage, N stage and GIMAP6 had predictive value for prognosis. According to functional enrichment analysis, GIMAP6 was primarily involved in T-cell receptor signaling pathway, chemokine signaling pathway, cytokine and cytokine receptor interaction. GIMAP6 was shown to be favorably linked with the infiltration of immune cells and immune-related molecules, including cytotoxic T-lymphocyte associated protein 4, programmed death-ligand 1, and T cell immunoreceptor with Ig and ITIM domains, by single-cell sequencing and TIMER2.0 analysis. The role of GIMAP6 in lung cancer cell proliferation, invasion, migration and immunity was experimentally verified. CONCLUSION: These findings confirmed that GIMAP6 was an effective prognostic molecule that was involved in the regulation of the immune microenvironment of LUAD, and may become a predictor for the efficacy of immunotherapy.

KRASG12C mutation-induced TOPK overexpression contributes to tumour progression in non-small cell lung cancer.

KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRASG12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRASG12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRASG12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRASG12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics.

Hypothyroidism induced by immune checkpoint inhibitors combined with antiangiogenic agents is associated with higher body mass index.

Background: Recent studies have reported that the combination of immune checkpoint inhibitors (ICIs) and antiangiogenic agents could be a promising therapeutic strategy for advanced non-small cell lung cancer (NSCLC). However, both ICIs and antiangiogenic agents are associated with endocrine dysfunctions, mainly hypothyroidism. The risk of hypothyroidism is potentially increased with the combination of ICIs and antiangiogenic agents. This study aimed to investigate the incidence and risk factors of hypothyroidism in patients receiving combination therapy. Methods: We performed a retrospective cohort study of advanced NSCLC patients treated with ICIs and antiangiogenic agents at Tianjin Medical University Cancer Institute & Hospital from July 1, 2019, to December 31, 2021. Patients with normal thyroid function at baseline were enrolled, and information on the patients' characteristics before receiving combination therapy, including body mass index (BMI) and laboratory data, was obtained. Results: Among the 137 enrolled patients, 39 (28.5%) developed new-onset hypothyroidism, and 20 (14.6%) developed overt hypothyroidism. The incidence of hypothyroidism was significantly higher in obese patients than in patients with a low to normal BMI (P<0.001). Obese patients also had a higher incidence of overt hypothyroidism (P=0.016). Univariate logistic regression showed that BMI as a continuous variable was a significant risk factor for hypothyroidism [odds ratio (OR) 1.24, 95% confidence interval (CI): 1.10-1.42, P<0.001] and overt hypothyroidism (OR 1.17, 95% CI: 1.01-1.38, P=0.039). Multivariate logistic regression revealed that only BMI (OR 1.36, 95% CI: 1.16-1.61, P<0.001) and age (OR 1.08, 95% CI: 1.02-1.14, P=0.006) were significant risk factors for treatment-related hypothyroidism. Conclusions: The risk of hypothyroidism in patients receiving a combination of ICIs and antiangiogenic therapy is manageable, and a higher BMI is associated with a significantly increased risk of hypothyroidism. Therefore, clinicians should be aware of the development of hypothyroidism in obese advanced NSCLC patients during the administration of ICIs combined with antiangiogenic agents.

A novel pyroptosis-related prognostic signature for lung adenocarcinoma: Identification and multi-angle verification.

Background: Lung adenocarcinoma (LUAD) is an aggressive disease of heterogeneous characteristics with poor prognosis and high mortality. Pyroptosis, a newly uncovered type of programmed cell death with an inflammatory nature, has been determined to hold substantial importance in the progression of tumors. Despite this, the knowledge about pyroptosis-related genes (PRGs) in LUAD is limited. This study aimed to develop and validate a prognostic signature for LUAD based on PRGs. Methods: In this research, gene expression information from The Cancer Genome Atlas (TCGA) served as the training cohort and data from Gene Expression Omnibus (GEO) was utilized as the validation cohort. PRGs list was taken from the Molecular Signatures Database (MSigDB) and previous studies. Univariate Cox regression and Lasso analysis were then conducted to identify prognostic PRGs and develop a LUAD prognostic signature. The Kaplan-Meier method, univariate and multivariate Cox regression models were employed to assess the independent prognostic value and forecasting accuracy of the pyroptosis-related prognostic signature. The correlation between prognostic signature and immune infiltrating was analyzed to examine the role in tumor diagnosis and immunotherapy. Further, RNA-seq as well as quantitative real-time polymerase chain reaction (qRT-PCR) analysis in separate data sets was applied in order to validate the potential biomarkers for LUAD. Results: A novel prognostic signature based on 8 PRGs (BAK1, CHMP2A, CYCS, IL1A, CASP9, NLRC4, NLRP1, and NOD1) was established to predict the survival of LUAD. The prognostic signature proved to be an independent prognostic factor of LUAD with satisfactory sensitivity and specificity in the training and validation sets. High-risk scores subgroups in the prognostic signature were significantly associated with advanced tumor stage, poor prognosis, less immune cell infiltration, and immune function deficiency. RNA sequencing and qRT-PCR analysis confirmed that the expression of CHMP2A and NLRC4 could be used as biomarkers for LUAD. Conclusion: We have successfully developed a prognostic signature consisting of eight PRGs that providing a novel perspective on predicting prognosis, assessing infiltration levels of tumor immune cells, and determining the outcomes of immunotherapy for LUAD.

Recurrent Neural Networks Are Universal Approximators With Stochastic Inputs.

In this article, we investigate the approximation ability of recurrent neural networks (RNNs) with stochastic inputs in state space model form. More explicitly, we prove that open dynamical systems with stochastic inputs can be well-approximated by a special class of RNNs under some natural assumptions, and the asymptotic approximation error has also been delicately analyzed as time goes to infinity. In addition, as an important application of this result, we construct an RNN-based filter and prove that it can well-approximate finite dimensional filters which include Kalman filter (KF) and Benes filter as special cases. The efficiency of RNN-based filter has also been verified by two numerical experiments compared with optimal KF.

Pan-cancer analysis of the prognostic and immunological role of nucleophosmin/nucleoplasmin 3 (NPM3) and its potential significance in lung adenocarcinoma.

Background: Nucleophosmin/nucleoplasmin 3 (NPM3), a member of the NPM protein family, is widely expressed in various human tissues. Although previous studies identified elevated NPM3 expression in several cancers, a systematic pan-cancer analysis remains lacking. In this study, we conducted a comprehensive analysis of NPM3 to determine its role in tumorigenesis and tumor development. Methods: Using data from The Cancer Genome Atlas (TCGA) and various bioinformatics analysis tools, we conducted a pan-cancer analysis of NPM3. Additionally, we collected gene expression and clinical data from 890 patients with lung adenocarcinoma (LUAD) from TCGA and the Gene Expression Omnibus database. We performed Cox regression analyses to explore the independent prognostic value of NPM3 expression in LUAD and plotted a nomogram to predict patient survival. We also used real-time quantitative polymerase chain reaction (RT-qPCR) to examine the expression levels of NPM3 in seven pairs of LUAD and paraneoplastic tissue samples. Results: NPM3 expression was significantly increased in 20 types of cancer and was associated with poor prognosis in five types (P < 0.05). NPM3 expression was negatively correlated with DNA methylation and positively correlated with copy number variation. NPM3 was also significantly associated with immune cell infiltration in various cancers. Cox regression analyses revealed that NPM3 expression could serve as an independent prognostic marker of LUAD. Moreover, our nomogram demonstrated good predictive ability for the prognosis of patients with LUAD. Finally, the high expression of NPM3 in LUAD was verified using RT-qPCR. Conclusion: NPM3 is a promising biomarker for predicting pan-cancer prognosis and immunotherapeutic efficacy.

Identification of prognostic factors and nomogram model for patients with advanced lung cancer receiving immune checkpoint inhibitors.

Background and aim: Some patients with lung cancer can benefit from immunotherapy, but the biomarkers that predict immunotherapy response were not well defined. Baseline characteristic of patients may be the most convenient and effective markers. Therefore, our study was designed to explore the association between baseline characteristics of patients with lung cancer and the efficacy of immunotherapy. Methods: A total of 216 lung cancer patients from Tianjin Medical University Cancer Institute & Hospital who received immunotherapy between 2017 and 2021 were included in the retrospective analysis. All baseline characteristic data were collected and then univariate log-rank analysis and multivariate COX regression analysis were performed. Kaplan-Meier analysis was used to evaluate patients' progression-free survival (PFS). A nomogram based on significant biomarkers was constructed to predict PFS rate of patients receiving immunotherapy. We evaluated the prediction accuracy of nomogram using C-indices and calibration curves. Results: Univariate analysis of all collected baseline factors showed that age, clinical stage, white blood cell (WBC), lymphocyte (LYM), monocyte (MON), eosinophils (AEC), hemoglobin (HB), lactate dehydrogenase (LDH), albumin (ALB) and treatment line were significantly associated with PFS after immunotherapy. Then these 10 risk factors were included in a multivariate regression analysis, which indicated that age (HR: 1.95, 95% CI [1.01-3.78], P = 0.048), MON (HR: 1.74, 95% CI [1.07-2.81], P = 0.025), LDH (HR: 0.59, 95% CI [0.36-0.95], P = 0.030), and line (HR: 0.57, 95% CI [0.35-0.94], P = 0.026) were significantly associated with PFS in patients with lung cancer receiving immunotherapy. Patients with higher ALB showed a greater trend of benefit compared with patients with lower ALB (HR: 1.58, 95% CI [0.94-2.66], P = 0.084). Patients aged ≥51 years, with high ALB, low LDH, first-line immunotherapy, and high MON had better response rates and clinical benefits. The nomogram based on age, ALB, MON, LDH, line was established to predict the prognosis of patients treated with immune checkpoint inhibitor (ICI). The C-index of training cohort and validation cohort were close, 0.71 and 0.75, respectively. The fitting degree of calibration curve was high, which confirmed the high prediction value of our nomogram. Conclusion: Age, ALB, MON, LDH, line can be used as reliable predictive biomarkers for PFS, response rate and cancer control in patients with lung cancer receiving immunotherapy. The nomogram based on age, ALB, MON, LDH, line was of great significance for predicting 1-year-PFS, 2-year-PFS and 3-year-PFS in patients with advanced lung cancer treated with immunotherapy.

Comparative Study of Physicochemical Properties of Alginate Composite Hydrogels Prepared by the Physical Blending and Electrostatic Assembly Methods.

Alginate hydrogel commonly suffers from defects, such as weak mechanical properties, the shortage of long-term stability in physiological medium and the lack of mammalian cell adhesivity due to its strong hydrophilicity in biomedical application. For this reason, the homogeneous alginate hydrogels (Alg Gel) were successfully prepared by the D-glucono-δ-lactone/hydroxyapatite (HAP/GDL) cross-linking system, and then, the physical blending and alternating electrostatic assembly technology were proposed to fabricate alginate composite hydrogels (Alg-GT, Alg-CS-GT and ALG/GT-CS). The feasibility of the design methods was verified through the comparative analysis of their physicochemical properties and biological activity. In particular, the effects of physical blending and alternating electrostatic assembly technology on the pore structure, mechanical properties, swelling, degradation, cell adhesion and proliferation of composite hydrogels were also investigated. Experimental results showed that the formation of polyelectrolyte complexes by electrostatic assembly between biological macromolecules and the covalent cross-linking of EDC/NHS to GT improved the vulnerability of ion cross-linking, enhanced the mechanical properties and swelling stability of the composite hydrogels, and regulated their pore structure and in vitro biodegradability properties. Furthermore, MC3T3-E1 cells could exhibit good cell adhesion, cell viability and cell proliferation on the alginate composite hydrogels. Among them, Alg-CS-GT showed the best cell proliferation ability and differentiation effect due to its good cell adhesion. In view of the excellent physicochemical properties and biological activity of Alg-CS-GT, it exhibited great potential in biomedical application for tissue engineering.

CD7 CAR T bridging to allo-HSCT in R/R T-ALL: A case report.

BACKGROUND: Refractory/relapsed T-cell acute lymphoblastic leukemia (R/R T-ALL) is a hematological malignancy with a poor prognosis. The current treatment strategy has not benefited most patients, and the treatment methods are still being explored. CASE PRESENTATION: An 8-year-old boy with R/R T-ALL achieved CR after multiple chemotherapies, followed by the first allo-HSCT. Unfortunately, 1 year and 3 months later, he relapsed. After recurrence, the patient underwent multiple chemotherapies, but the NOTCH1 gene and MRD were still positive. FCM and immunohistochemistry revealed abnormally high expression of CD7, so we considered bridging the second allo-HSCT after CD7 CAR T-cells treatment. The patient has low toxic and side effects and is still in CR, findings from this case report have more important therapeutic significance for R/R T-ALL. CONCLUSION: In conclusion, CD7 CAR T-cells bridging to allo-HSCT is a safe and effective approach for R/R T-ALL, resulting in durable CR and longer survival.

A Framework to Predict the Molecular Classification and Prognosis of Breast Cancer Patients and Characterize the Landscape of Immune Cell Infiltration.

It is known that all current cancer therapies can only benefit a limited proportion of patients; thus, molecular classification and prognosis evaluation are critical for correctly classifying breast cancer patients and selecting the best treatment strategy. These processes usually involve the disclosure of molecular information like mutation, expression, and immune microenvironment of a breast cancer patient, which are not been fully studied until now. Therefore, there is an urgent clinical need to identify potential markers to enhance molecular classification, precision prognosis, and therapy stratification for breast cancer patients. In this study, we explored the gene expression profiles of 1,721 breast cancer patients through CIBERSORT and ESTIMATE algorithms; then, we obtained a comprehensive intratumoral immune landscape. The immune cell infiltration (ICI) patterns of breast cancer were classified into 3 separate subtypes according to the infiltration levels of 22 immune cells. The differentially expressed genes between these subtypes were further identified, and ICI scores were calculated to assess the immune landscape of BRCA patients. Importantly, we demonstrated that ICI scores correlate with patients' survival, tumor mutation burden, neoantigens, and sensitivity to specific drugs. Based on these ICI scores, we were able to predict the prognosis of patients and their response to immunotherapy. Together, these findings provide a realistic scenario to stratify breast cancer patients for precision medicine.

A Study on the Correlation between the Oxidation Degree of Oxidized Sodium Alginate on Its Degradability and Gelation.

Oxidized sodium alginate (OSA) is selected as an appropriate material to be extensively applied in regenerative medicine, 3D-printed/composite scaffolds, and tissue engineering for its excellent physicochemical properties and biodegradability. However, few literatures have systematically investigated the structure and properties of the resultant OSA and the effect of the oxidation degree (OD) of alginate on its biodegradability and gelation ability. Herein, we used NaIO4 as the oxidant to oxidize adjacent hydroxyl groups at the C-2 and C-3 positions on alginate uronic acid monomer to obtain OSA with various ODs. The structure and physicochemical properties of OSA were evaluated by Fourier transform infrared spectroscopy (FT-IR), 1H nuclear magnetic resonance (1H NMR), X-ray Photoelectron Spectroscopy (XPS), X-ray Diffraction (XRD), and thermogravimetric analysis (TGA). At the same time, gel permeation chromatography (GPC) and a rheometer were used to determine the hydrogel-forming ability and biodegradation performance of OSA. The results showed that the two adjacent hydroxyl groups of alginate uronic acid units were successfully oxidized to form the aldehyde groups; as the amount of NaIO4 increased, the OD of OSA gradually increased, the molecular weight decreased, the gelation ability continued to weaken, and degradation performance obviously rose. It is shown that OSA with various ODs could be prepared by regulating the molar ratio of NaIO4 and sodium alginate (SA), which could greatly broaden the application of OSA-based hydrogel in tissue engineering, controlled drug release, 3D printing, and the biomedical field.

Association of pre-existing lung interstitial changes with immune-related pneumonitis in patients with non-small lung cancer receiving immunotherapy.

BACKGROUND AND AIM: Many pieces of literature have evaluated the predictive value of pre-existing lung interstitial changes for immunotherapy-related pneumonia in patients with non-small cell lung cancer (NSCLC), but the results of studies are still controversial. The purpose of this article is to explore whether pre-existing lung interstitial changes can predict the occurrence of immunotherapy-related pneumonia. METHODS: PubMed, Web of Science, and Embase were used to search for relevant documents. Two investigators respectively carried out literature screening, quality evaluation, and data extraction strictly according to the inclusion criteria. Odds ratios (ORs) and the corresponding 95% CIs were applied to assess the predictive value of interstitial lung disease (ILD), interstitial lung abnormalities (ILA), and radiation pneumonitis (RP). Stata 12.0 software was used for the statistical analysis of data. RESULTS: Seventeen studies involving 2758 patients were included in the final analysis. NSCLC patients with pulmonary interstitial changes were more likely to develop immune-related pneumonia after immunotherapy (OR = 3.68, 95% CI: 2.49-5.44). Subgroup analysis revealed that ILD (OR = 3.59, 95% CI: 2.22-5.82), RP (OR = 3.63, 95% CI: 1.80-7.30), and ILA (OR = 6.64, 95% CI: 1.78-24.8) were all predictors of immune-related pneumonia. As the preliminary screening of other risk factors, gender, neutrophilic lymphocyte ratio (NLR), actual eosinophil count (AEC), and drug type may have potential predictive value for immunotherapy-related pneumonia. There was no significant statistical heterogeneity and publication bias in our study. Further research is needed to update and validate our results. CONCLUSION: Pulmonary interstitial changes can be considered as a predictive factor of immune-related pneumonia after immunotherapy in NSCLC patients.

One-Pot Synthesis of Amphiphilic Biopolymers from Oxidized Alginate and Self-Assembly as a Carrier for Sustained Release of Hydrophobic Drugs.

In this paper, we developed an organic solvent-free, eco-friendly, simple and efficient one-pot approach for the preparation of amphiphilic conjugates (Ugi-OSAOcT) by grafting octylamine (OCA) to oxidized sodium alginate (OSA). The optimum reaction parameters that were obtained based on the degree of substitution (DS) of Ugi-OSAOcT were a reaction time of 12 h, a reaction temperature of 25 °C and a molar ratio of 1:2.4:3:3.3 (OSA:OCA:HAc:TOSMIC), respectively. The chemical structure and composition were characterized by Fourier transform infrared spectroscopy (FTIR), 1H nuclear magnetic resonance (1H NMR), X-ray diffraction (XRD), thermogravimetry analyser (TGA), gel permeation chromatography (GPC) and elemental analysis (EA). It was found that the Ugi-OSAOcT conjugates with a CMC value in the range of 0.30-0.085 mg/mL could self-assemble into stable and spherical micelles with a particle size of 135.7 ± 2.4-196.5 ± 3.8 nm and negative surface potentials of -32.8 ± 0.4--38.2 ± 0.8 mV. Furthermore, ibuprofen (IBU), which served as a model poorly water-soluble drug, was successfully incorporated into the Ugi-OSAOcT micelles by dialysis method. The drug loading capacity (%DL) and encapsulation efficiency (%EE) of the IBU-loaded Ugi-OSAOcT micelles (IBU/Ugi-OSAOcT = 3:10) reached as much as 10.9 ± 0.4-14.6 ± 0.3% and 40.8 ± 1.6-57.2 ± 1.3%, respectively. The in vitro release study demonstrated that the IBU-loaded micelles had a sustained and pH-responsive drug release behavior. In addition, the DS of the hydrophobic segment on an OSA backbone was demonstrated to have an important effect on IBU loading and drug release behavior. Finally, the in vitro cytotoxicity assay demonstrated that the Ugi-OSAOcT conjugates exhibited no significant cytotoxicity against RAW 264.7 cells up to 1000 µg/mL. Therefore, the amphiphilic Ugi-OSAOcT conjugates synthesized by the green method exhibited great potential to load hydrophobic drugs, acting as a promising nanocarrier capable of responding to pH for sustained release of hydrophobic drugs.

Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker for Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

There is increasing evidence to suggest that the neutrophil-to-lymphocyte ratio (NLR) is related to the prognosis of patients with renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs). However, these findings are inconsistent. The present study was performed with the aim of exploring the utility of NLR in patients with RCC treated with ICIs. For this purpose, a comprehensive search of PubMed, Web of Science, and Embase was performed to find studies evaluating the prognostic value of NLR. The overall survival (OS) and progression-free survival (PFS) were the assessed clinical outcomes. All statistical analysis was performed using Stata version 12.0 software. The combined hazard ratios (HRs) and 95% confidence intervals (CIs) of NLR for OS and PFS were calculated using the random-effect models. Heterogeneity was evaluated based on the I 2 value and Cochran's Q test. Egger's and Begg's tests were applied to precisely assess the publication bias. The "trim and fill" method was adopted to perform the sensitivity analysis to determine whether the results were stable. In total, 12 studies encompassing 1,275 patients were included in the final analysis. The results revealed that a high NLR at baseline or pre-therapy was associated with a poor OS (HR, 2.23; 95% CI, 1.84-2.70; p < 0.001) and PFS (HR, 1.78; 95% CI, 1.72-2.09; p < 0.001). During the course of treatment, a decrease in the NLR was associated with a significantly longer OS (HR, 0.34; 95% CI, 0.20-0.56; p < 0.001) and PFS (HR, 0.44; 95% CI, 0.30-0.63; p < 0.001) compared to an increase in NLR. As a preliminary screening of other risk factors, age, sex, race, and IMDC risk may have a certain prognostic value for RCC treated with ICIs. People over 70 years old had better OS compared to people younger than 70 (HR, 0.65; 95% CI, 0.48-0.89). Non-Caucasians treated with immunotherapy had a worse OS (HR, 8.67; 95% CI, 2.87-26.2) and PFS (HR, 2.65; 95% CI, 1.28-5.48) than Caucasians. Males had a worse OS than females (HR, 1.48; 95% CI, 1.14-1.93). Compared with the IMDC favorable risk group, the OS of the IMDC poor risk group was worse (HR, 2.59; 95% CI, 1.56-4.32). There was no significant publication bias or heterogeneity observed in the present study. On the whole, the present study demonstrated that an elevated NLR is associated with an adverse OS and PFS in patients with RCC treated with ICIs. The NLR may thus be used as a readily available prognostic biomarker for these patients. Age, sex, race, and IMDC risk may have potential predictive value for the prognosis of RCC treated with ICIs. However, further investigations are warranted to validate these results.

Association Between RSK2 and Clinical Indexes of Primary Breast Cancer: A Meta-Analysis Based on mRNA Microarray Data.

Background: Although ribosomal protein S6 kinases, 90 kDa, polypeptide 3 (RSK2, RPS6KA3) has been reported to play an important role in cancer cell proliferation, invasion, and migration, including breast cancer, its clinical implication in primary breast cancer patients is not well understood, and there were not many studies to explore the relationship between RSK2 and breast cancer on a clinical level. Methods: A systematic series matrix file search uploaded from January 1, 2008 to November 31, 2017 was undertaken using ArrayExpress and Gene Expression Omnibus (GEO) databases. Search filters were breast cancer, RNA assay, and array assay. Files eligible for inclusion met the following criteria: a) sample capacity is over 100, b) tumor sample comes from unselected patient's primary breast tumor tissue, and c) expression of RSK2 and any clinical parameters of patients were available from the files. We use median as the cutoff value to assess the association between the expression of RSK2 and the clinical indexes of breast cancer patients. Finding: The meta-analysis identified 13 series matrix files from GEO database involving 3,122 samples that come from patients' primary breast cancer tissue or normal tissue. The expression of RSK2 in tumor tissues is lower than that in normal tissues [odds ratio (OR), 0.54; 95% credible interval (CI), 0.44-0.67; Cochran's Q test p = 0.14; I 2 = 41.7%]. Patients with a high expression of RSK2 showed more favorable overall survival [hazard ratio (HR), 0.71; 95% CI, 0.49-0.94; Cochran's Q test p = 0.95; I 2 = 0.0%] and less potential of distant metastasis (OR, 0.59; 95% CI, 0.41-0.87; Cochran's Q test p = 0.88; I 2 = 0.0%) and lymph node infiltration (OR, 0.81; 95% CI, 0.65-0.998; Cochran's Q test p = 0.09; I 2 = 42.8%). Besides, the expression of RSK2 in luminal breast cancer is lower than Cochran's Q test p = 0.06; I 2 = 63.5%). RSK2 overexpression corresponded with higher histological grade (OR, 1.329; 95% CI, 1.03-1.721; Cochran's Q test p = 0.69; I 2 = 0.0%). RSK2 expression is also associated with estrogen receptor (ER) and age. Conclusion: The meta-analysis provides evidence that RSK2 is a potential biomarker in breast cancer patients. The expression of RSK2 is distinctive in different intrinsic subtypes of breast cancer, indicating that it may play an important role in specific breast cancer. Further study is needed to uncover the mechanism of RSK2 in breast cancer. Systematic Review Registration: (website), identifier (registration number).

Abnormal Network Homogeneity in the Right Superior Medial Frontal Gyrus in Cervical Dystonia.

Background: Increasing evidence from modern neuroimaging has confirmed that cervical dystonia (CD) is caused by network abnormalities. Specific brain networks are known to be crucial in patients suffering from CD. However, changes in network homogeneity (NH) in CD patients have not been characterized. Therefore, the purpose of this study was to investigate the NH of patients with CD. Methods: An automated NH method was used to analyze resting-state functional magnetic resonance (fMRI) data from 19 patients with CD and 21 gender- and age-matched healthy controls (HC). Correlation analysis were conducted between NH, illness duration and symptom severity measured by the Tsui scale. Results: Compared with the HC group, CD patients showed a lower NH in the right superior medial frontal gyrus. No significant correlations were found between abnormal NH values and illness duration or symptom severity. Conclusion: Our findings suggest the existence of abnormal NH in the default mode network (DMN) of CD patients, and thereby highlight the importance of the DMN in the pathophysiology of CD.