Costimulatory molecule expression profile as a biomarker to predict prognosis and chemotherapy response for patients with small cell lung cancer.

Owing to the paucity of specimens, progress in identifying prognostic and therapeutic biomarkers for small cell lung cancer (SCLC) has been stagnant for decades. Considering that the costimulatory molecules are essential elements in modulating immune responses and determining therapeutic response, we systematically revealed the expression landscape and identified a costimulatory molecule-based signature (CMS) to predict prognosis and chemotherapy response for SCLCs for the first time. We found T cell activation was restrained in SCLCs, and costimulatory molecules exhibited widespread abnormal genetic alterations and expression. Using a LASSO Cox regression model, the CMS was built with a training cohort of 77 cases, which successfully divided patients into high- or low-risk groups with significantly different prognosis and chemotherapy benefit (both P < 0.001). The CMS was well validated in an independent cohort containing 131 samples with qPCR data. ROC and C-index analysis confirmed the superior predictive performance of the CMS in comparison with other clinicopathological parameters from different cohorts. Importantly, the CMS was confirmed as a significantly independent prognosticator for clinical outcomes and chemotherapy response in SCLCs through multivariate Cox analysis. Further analysis revealed that low-risk patients were characteristic by an activated immune phenotype with distinct expression of immune checkpoints. In summary, we firstly uncovered the expression heterogeneity of costimulatory molecules in SCLC and successfully constructed a novel predictive CMS. The identified signature contributed to more accurate patient stratification and provided robust prognostic value in estimating survival and the clinical response to chemotherapy, allowing optimization of treatment and prognosis management for patients with SCLC.

Efficient Adsorption of Tebuconazole in Aqueous Solution by Calcium Modified Water Hyacinth-Based Biochar: Adsorption Kinetics, Mechanism, and Feasibility.

The application of fungicides (such as tebuconazole) can impose harmful impacts on the ecosystem and humans. In this study, a new calcium modified water hyacinth-based biochar (WHCBC) was prepared and its effectiveness for removing tebuconazole (TE) via adsorption from water was tested. The results showed that Ca was loaded chemically (CaC2O4) onto the surface of WHCBC. The adsorption capacity of the modified biochar increased by 2.5 times in comparison to that of the unmodified water hyacinth biochar. The enhanced adsorption was attributed to the improved chemical adsorption capacity of the biochar through calcium modification. The adsorption data were better fitted to the pseudo-second-order kinetics and the Langmuir isotherm model, indicating that the adsorption process was dominated by monolayer adsorption. It was found that liquid film diffusion was the main rate-limiting step in the adsorption process. The maximum adsorption capacity of WHCBC was 40.5 mg/g for TE. The results indicate that the absorption mechanisms involved surface complexation, hydrogen bonding, and π-π interactions. The inhibitory rate of Cu2+ and Ca2+ on the adsorption of TE by WHCBC were at 4.05-22.8%. In contrast, the presence of other coexisting cations (Cr6+, K+, Mg2+, Pb2+), as well as natural organic matter (humic acid), could promote the adsorption of TE by 4.45-20.9%. In addition, the regeneration rate of WHCBC was able to reach up to 83.3% after five regeneration cycles by desorption stirring with 0.2 mol/L HCl (t = 360 min). The results suggest that WHCBC has a potential in application for removing TE from water.

Comprehensive analyses of N6 -methyladenosine-related long noncoding RNA profiles with prognosis, chemotherapy response, and immune landscape in small cell lung cancer.

Small cell lung cancer (SCLC) is the most devastating subtype of lung cancer with no clinically available prognostic biomarkers. N6 -methyladenosine (m6 A) and noncoding RNAs play critical roles in cancer development and treatment response. However, little is known about m6 A-related long noncoding RNAs (lncRNAs) in SCLC. We used 206 limited-stage SCLC (LS-SCLC) samples from two cohorts to undertake the first and most comprehensive exploration of the m6 A-related lncRNA profile in SCLC and constructed a relevant prognostic signature. In total, 289 m6 A-related lncRNAs were screened out. We then built a seven-lncRNA-based signature in the training cohort with 48 RNA sequencing data using univariate and multivariate Cox regression models. The signature was well validated in an independent cohort containing 158 cases with quantitative PCR data. In both cohorts, the signature divided patients into high- and low-risk groups with significantly different survival rates (both p < 0.001). Our signature predicted chemotherapy survival benefit in patients with LS-SCLC. Receiver operating characteristic and C-index analyses indicated that the signature was better at predicting prognosis and chemotherapy benefit than other clinicopathologic features. Moreover, the signature was identified as an independent predictor of prognosis and chemotherapy response in different cohorts. Furthermore, functional analysis showed that multiple activated immune-related pathways were enriched in the low-risk group. Additionally, the signature was also closely related to various immune checkpoints and inflammatory responses. We generated the first clinically available m6 A-related lncRNA signature to predict prognosis and chemotherapy benefit in patients with LS-SCLC. Our findings could help optimize the clinical management of patients with LS-SCLC and inform future therapeutic targets for SCLC.

m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy-with or without immune checkpoint inhibitors (anti-PDs)-is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N6-methyladenosine (m6A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m6A modification in SCLC remains poorly understood. METHODS: We systematically explored the molecular features and clinical significance of m6A regulators in SCLC. We then constructed an m6A regulator-based prognostic signature (m6A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts-including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m6A score and adjuvant chemotherapy (ACT) benefits and the patients' responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density. RESULTS: We observed abnormal somatic mutations and expressions of m6A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m6A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75-9.77; P < 0.001). The prognostic accuracy of the m6A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m6A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m6A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy. CONCLUSIONS: Our results, for the first time, affirm the significance of m6A regulators in LS-SCLC. Our multicentre analysis found that the m6A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.

An immune-related lncRNA signature predicts prognosis and adjuvant chemotherapeutic response in patients with small-cell lung cancer.

BACKGROUND: Patients with small-cell lung cancer (SCLC) are burdened by limited treatment options and the disease's dismal prognosis. Long non-coding RNAs (lncRNAs) are essential regulators of genetic alteration and are actively involved in tumor immunity. However, few studies have examined interactions between immune genes and lncRNAs in SCLC. METHODS: Immune-related lncRNA (irlncRNA) expression profiles and their clinical significance were explored. We enrolled 227 patients with SCLC, including 79 cases from GSE65002 and 148 cases from a validation cohort with corresponding qPCR data. The least absolute shrinkage and selection operator (LASSO) model was applied to identify prognostic irlncRNAs for an irlncRNA-based SCLC signature. We additionally investigated the potential mechanisms and immune landscape of the signature using bioinformatics methods. RESULTS: An irlncRNA signature including 8 irlncRNAs (ENOX1-AS1, AC005162, LINC00092, RPL34-AS1, AC104135, AC015971, AC126544, AP001189) was established for patients with SCLC in the training cohort. Low-risk patients were more likely to benefit from chemotherapy and achieve a favorable prognosis. The signature was also well-validated in the validation cohort and various clinical subgroups. Compared to other clinical parameters, the irlncRNA signature exhibited superior predictive performance for chemotherapy response and prognosis. The signature was as an independent prognostic factor in the training and validation cohorts. Interestingly, low-risk patients showed an activated immune phenotype. CONCLUSION: We constructed the first irlncRNA-based signature for chemotherapy efficacy and outcome prediction. The irlncRNA signature is a reliable and robust prognostic classifier that could be useful for clinical management and determination of potential chemotherapy benefit for patients with SCLC.

The prognostic value of tumor deposits and the impact on the TNM classification system in esophageal cancer patients.

OBJECTIVE: To explore the prognostic significance of tumor deposits (TDs), isolated tumor foci lacking residual lymph nodes, in esophageal cancer (EC). METHODS: A retrospective review of patients with EC undergoing esophagectomy between 2005 and 2017 was conducted. The prognostic value of TD was evaluated using a Cox regression model. Patients from different sources and periods were split into discovery and validation sets. A propensity score matching model was used in the validation set to reduce the confounding bias. The impact of TD on the TNM classification system was evaluated. RESULTS: The discovery and validation sets included 179 and 2875 patients, respectively. Propensity-matched patients with and without TDs were constructed in the validation set with 132 patients in each group. Overall survival (p < .001 and p = .004, respectively) and disease-free survival (p < .001 and p = .019, respectively) were both decreased in TD positive patients in the discovery set and propensity-matched groups of validation set. Classifying patients with TDs into pN3 stage improved the discriminative power of the current TNM staging system. CONCLUSIONS: TD is an independent prognostic factor for EC. The inclusion of TD in the TNM staging system may upstage appropriate patients to help guide therapy, and future studies are warranted.

Numerical studies on lutetium isotopic selective photoionization based on a three-step ionization scheme.

Numerical studies of lutetium selective photoionization have been carried out based on a three-step photoionization scheme, 5d6s2 2D3/2 â†’ 5d6s6p4Fo5/2 â†’ 5d6s7s4D3/2 → (53,375 cm-1)1/2 → Lu+, by the density matrix theory. Atomic hyperfine structures and magnetic sublevels are considered in our photoionization dynamics model. To examine the effectiveness of this model, the simulated 176Lu ion strengths are compared with the experimental results, and the simulated excitation cross sections of 176Lu excitation channels are compared with the analytical and experimental results. Semi-quantitative agreements are acquired for these two cases. On this basis, selective photoionization processes of two lutetium isotopes are simulated and discussed. Considering the ionization probability and abundance of target isotope, the 8.5-9.5-8.5 two-step excitation channel is optimal for 176Lu enrichment from natural lutetium. The influences of laser parameters and atomic Doppler broadening are presented numerically and optimization excitation conditions are identified. For the co-propagating excitation lasers, extra-narrow laser bandwidth (at the magnitude of 0.1 GHz) and atomic Doppler broadening (smaller than 0.3 GHz) is required. A new time-delayed configuration is proposed to implement multiple counter-propagating laser exposures for high target isotope abundance at the larger atomic Doppler broadening.

[Soil Microbial Community Structure and Functional Diversity Character of Abandoned Farmland in Minqin Oasis].

To clarify the impact of the structure and function of soil microbial communities in the stage of abandoned farmland, three different stages of land abandoned in desert oasis areas were selected as the research objects. We used metagenomic sequencing technology to research soil microbial community structure and functional diversity characteristics of different stages of abandoned farmland. The results showed that there were significant differences in the relative abundance of the dominant phyla Actinobacteria, Proteobacteria, and Gemmatimonadetes in the soil of the three stages of returning farmland. Compared with that in the early stage of abandoned farmland, the later stage of abandoned farmland restoration increased the gene proportion involved in Quorum sensing, porphyrin and chlorophyll metabolism, pantothenate and CoA biosynthesis, and styrene degradation, and there was a significant difference in relative abundance (P<0.05), which indicated that different stages of abandoned farmland had changed the functional potential of the nutrient cycle and energy metabolism in soil microbial communities. The RDA results showed that EC, AK, and TN had a significant impact on the functional composition of soil microbes, and soil EC had the greatest impact on microbial functional composition. The results showed that different stages of abandoned farmland had a significant impact on the soil microbial community structure and functional composition. In the ecological restoration of abandoned farmland in Minqin Oasis, the sensitivity of microbial community structure and functional composition to soil restoration at different stages should be considered using comprehensive relevant indicators.

Bone-patellar tendon-bone autograft versus LARS artificial ligament for anterior cruciate ligament reconstruction.

The optimized graft for use in anterior cruciate ligament (ACL) reconstruction is still in controversy. The bone-patellar tendon-bone (BPTB) autograft has been accepted as the gold standard for ACL reconstruction. However, donor site morbidities cannot be avoided after this treatment. The artificial ligament of ligament advanced reinforcement system (LARS) has been recommended for ACL reconstruction. The purpose of this study is to compare the midterm outcome of ACL reconstruction using BPTB autografts or LARS ligaments. Between July 2004 and March 2006, the ACL reconstruction using BPTB autografts in 30 patients and LARS ligaments in 32 patients was performed. All patients were followed up for at least 4 years and evaluated using the Lysholm knee score, Tegner score, International Knee Documentation Committee (IKDC) score, and KT-1000 arthrometer test. There were no significant differences between the two groups with respect to the data of Lysholm scores, Tegner scores, IKDC scores, and KT-1000 arthrometer test at the latest follow-up. Our study demonstrates that the similarly good clinical results are obtained after ACL reconstruction using BPTB autografts or LARS ligaments at midterm follow-up. In addition to BPTB autografts, the LARS ligament may be a satisfactory treatment option for ACL rupture.

High versus standard radiation dose of definitive concurrent chemoradiotherapy for esophageal cancer: A systematic review and meta-analysis of randomized clinical trials.

OBJECTIVES: Compare the efficacy and safety of high vs standard radiation dose of definitive concurrent chemoradiotherapy (dCCRT) for esophageal cancer (EC). METHODS AND MATERIALS: This meta-analysis is registered in PROSPERO, and it was followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Eligible randomized clinical trials (RCTs) comparing high dose (HD;≥59.4 Gy/1.8 Gy) and standard doses (SD; 50 Gy/2Gy or 50.4 Gy/1.8 Gy) were identified on electronic databases. STATA16.0 was used for statistical analysis. A meta-analysis was performed to compare treatment effect and toxicity. RESULTS: Four articles with a total of 1014 patients were finally included. The results showed that the two groups had similar 1-, 2-, and 3-year OS rates (RR = 1.08, 95 % CI = 0.90-1.30, P = 0.395; RR = 1.07, 95 % CI = 0.95-1.20, P = 0.272; RR = 1.06, 95 % CI = 0.97-1.17, P = 0.184; respectively) and 2-, and 3-year locoregional progression-free survival (LRPFS) (RR = 0.95, 95 % CI = 0.81-1.10, P = 0.478; RR = 0.97, 95 % CI = 0.85-1.11, P = 0.674; respectively). The HD-RT group had higher grade ≥ 3 treatment-related toxicities (OR = 1.35, 95 % CI = 1.03-1.77, P = 0.029) and treatment-related deaths rates (OR = 1.85, 95 % CI = 1.04-3.28, P = 0.036) compared with the SD-RT group. Results of subgroup analysis also indicated that HD could not bring benefit compared to SD, even with modern radiotherapy techniques. CONCLUSION: SD-RT had similar treatment effect but lower Grade ≥ 3 treatment-related toxicities rates compared with the HD-RT. Therefore, SD (50 Gy/2Gy or 50.4 Gy/1.8 Gy) should be considered as the recommended dose in dCCRT for EC. Further RCTs are needed to verify our conclusions.

Biodegradable porous polymeric drug as a drug delivery system: alleviation of doxorubicin-induced cardiotoxicity via passive targeted release.

Doxorubicin (DOX) is an effective chemotherapeutic drug developed against a broad range of cancers, and its clinical applications are greatly restricted by the side effects of severe cardiotoxicity during tumour treatment. Herein, the DOX-loaded biodegradable porous polymeric drug, namely, Fc-Ma-DOX, which was stable in the circulation, but easy to compose in the acidic medium, was used as the drug delivery system avoiding the indiscriminate release of DOX. Fc-Ma was constructed via the copolymerization of 1,1'-ferrocenecarbaldehyde with d-mannitol (Ma) through the pH-sensitive acetal bonds. Echocardiography, biochemical parameters, pathological examination, and western blot results showed that DOX treatment caused increased myocardial injury and oxidative stress damage. In contrast, treatment with Fc-Ma-DOX significantly reduced myocardial injury and oxidative stress by DOX treatment. Notably, in the Fc-Ma-DOX treatment group, we observed a significant decrease in the uptake of DOX by H9C2 cells and a significant decrease in reactive oxygen species (ROS) production.

Patterns and prognostic values of programmed cell death-ligand 1 expression and CD8+ T-cell infiltration in small cell carcinoma of the esophagus: a retrospective analysis of 34 years of National Cancer Center data in China.

BACKGROUND: Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8+ T cell in SCCE for the first time. MATERIALS AND METHODS: Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density. RESULTS: No patients had PD-L1 expressed in their tumor cells. PD-L1+ expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68+ monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression (Ptrend<0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS. CONCLUSION: Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy.

PEG-modified carbon-based nanoparticles as tumor-targeted drug delivery system reducing doxorubicin-induced cardiotoxicity.

Herein, a doxorubicin-loaded carbon-based drug delivery system, denoted as PC-DOX, composed of pH-responsive imine bond was developed for the tumor-targeted treatment. PC-DOX with a uniform particle size around 180 nm was synthesized by coating of as-synthesized hollow carbon-based nanoparticles (NPs) with dialdehyde PEG, which was used as carrier to attach DOX covalently through dynamic covalent bond. The unique structure endowed the advantages of specific tumor targeting and tumor microenvironment (TME) specific drug delivery capacity with PC-DOX. For the one hand, the tumor targeting caused by the enhanced permeability and retention (EPR) effect could significantly improve the tumor cellular uptake. For the other hand, the pH-responsiveness could realize the effective DOX accumulation in tumor tissues, avoiding the unwanted side effect to the normal tissues. As a result, PC-DOX with high DOX loading capacity (70.12%) and excellent biocompatibility, concurrently, presented a significant anti-tumor effect at a low mass concentration (DOX equivalent dose: 20 µg/mL). Another attractive characteristic of PC-DOX was the remarkable protective effect towards DOX-induced cardiotoxicity, which could be clearly observed from in vitro cellular, and animal assays. Compared with free DOX, the cardiomyocyte viability increased by average 30.58%, and the heart function was also significantly improved. This novel drug delivery nanoplatform provides a new method for the future clinical application of DOX in the cancer's therapeutics.

Development and Validation of a Nomogram for Predicting the 1-, 3-, and 5-year Survival in Patients with Acinar-predominant Lung Adenocarcinoma.

OBJECTIVE: This study aimed to develop a nomogram to predict the overall survival (OS) of patients with acinar-predominant adenocarcinoma (APA). METHODS: Data from patients with APA obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2008 and 2016 were used. Significant prognostic factors were incorporated to construct a nomogram for predicting the 1-, 3-, and 5-year OS in these patients. The discrimination and calibration abilities of the nomogram were assessed using a C-index and calibration curves, respectively. RESULTS: A total of 2242 patients with APA were randomly divided into a training cohort (n=1576) and validation cohort (n=666). The independent prognostic factors for OS incorporated into the nomogram included marital status, age, gender, differentiation grade, T stage, N stage, and M stage. The nomogram showed good prediction capability, as indicated by the C-index [0.713, 95% confidence interval (CI): 0.705-0.721 in the training cohort, and 0.662, 95% CI: 0.649-0.775 in the validation cohort]. The calibration curves demonstrated that the 1-, 3-, and 5-year OS probabilities were consistent between the observed and predicted outcome frequencies. Patients were divided into the high-risk and low-risk groups with the former showing significantly worse survival than the latter (P<0.001). CONCLUSION: Using the SEER database, a nomogram was established to predict the 1-, 3-, and 5-year OS of patients with APA and was superior to the tumor size, lymph node, and metastasis staging system in terms of evaluating long-term prognosis.

Utilizing Network Pharmacology and Molecular Docking Integrated Surface Plasmon Resonance Technology to Investigate the Potential Targets and Mechanisms of Tripterygium wilfordii against Pulmonary Artery Hypertension.

Background: Pulmonary artery hypertension (PAH) is a rare, life-limiting cardiopulmonary disorder characterized by the progressive and remodeling of pulmonary vasculature. Although the development of the technology brings us many approaches for the treatment of PAH, the effect of treatment is unsatisfactory. Tripterygium wilfordii (TW), as a traditional Chinese medicine (TCM), has been widely used in anti-inflammation, anticancer, and other fields. However, the potential of TW in treating PAH is currently unclear. Methods: Active ingredients and their corresponding genes were harvested from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP), CTD, and STITCH. Meanwhile, genes associated with PAH were adopted from OMIM and GeneCards databases. Through Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses, potential targeting KEGG pathways and functions were further collected. Then, STRING was used to generate the protein-protein interaction (PPI) network. The "ingredients-targets-pathway" network was built by Cystoscope. Finally, the binding between active ingredients of TW and corresponding targets of PAH was identified via molecular docking technology and surface plasmon resonance (SPR) experiments. Results: The network pharmacology analysis revealed 36 active ingredients in TW and 150 potential targets related to the treatment of PAH with TW. Moreover, GO enrichment analysis showed that the key function in molecular function (MF) was related to enzyme binding, the key function in biological process (BP) was related to cellular response to organic substance, and the key function in cellular component (CC) was related to KEGG enrichment analysis and found that it was closely related to the IL-17 signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and apoptosis. At last, molecular docking results revealed that the main active ingredients of TW had a strong binding ability with the PAH target protein. In addition, the SPR experiment revealed that kaempferol was combined with the CASP3 protein rather than PARP1, while triptolide was combined with PARP1 rather than the CASP3 protein. Conclusion: TW may have therapeutic effects on PAH through multitargets and multimethods, which provide a scientific basis for further elaborating the mechanism of Tripterygium wilfordii in the treatment of PAH.

Tumor Necrosis Factor Family Member Profile Predicts Prognosis and Adjuvant Chemotherapy Benefit for Patients With Small-Cell Lung Cancer.

Tumor necrosis factor (TNF) family members participate in the body's antitumor immunity response and influence tumor prognosis and treatment response. However, little is known about the roles of TNF family members in small cell lung cancer (SCLC). Therefore, we conducted the first comprehensive investigation of TNF family members in patients with SCLC, with the goal of using them to predict prognosis and chemotherapy benefit. Abnormal genetic alterations and expression of TNF family members were found to be widespread in SCLC patients. Using LASSO Cox regression analysis, we constructed a TNF family-based signature that separated SCLC patients in the training set (n=77) into high- and low-risk groups with distinct survival and chemotherapy benefit, and the signature was well-validated in the validation set (n=137) by RT-qPCR. Importantly, the signature exhibited superior predictive performance and was identified as a novel independent prognostic factor. Additionally, different immune phenotypes were found between the low-risk and high-risk groups, and high-risk patients had higher CMTM6 expression, suggesting that these patients could benefit from therapeutic methods targeting CMTM6. We constructed the first clinically applicable TNF family-based signature for predicting prognosis and chemotherapy benefit for patients with SCLC. The findings reported here provide a new method for predicting the prognosis of SCLC patients and optimizing clinical management.

Development and validation of a nomogram for predicting survival in patients with surgically resected lung invasive mucinous adenocarcinoma.

BACKGROUND: Lung invasive mucinous adenocarcinoma (LIMA) is a unique and rare subtype of lung adenocarcinoma. We identified prognostic factors and developed a nomogram for predicting overall survival (OS) in LIMA patients after surgery. METHODS: Patients diagnosed with LIMA between 2008 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database were randomized into training (n=1,254) and test (n=538) cohorts. A nomogram was established using the prognostic signature from the training cohort after multivariable Cox regression analysis. We externally validated the nomogram in a group of 369 patients from China. We separately tested for accuracy and clinical practicability using Harrell's concordance-index (C-index), calibration plots, and decision curve analysis (DCA). RESULTS: We included 2,161 patients in the analysis. Seven factors, all of which significantly affected OS, were incorporated into the final model, including age, sex, differentiation grade, the extent of surgery, lymphadenectomy, and T, N, and M stage. C-indexes for the training, test, and external validation cohorts were 0.735, 0.736, and 0.773, respectively. The areas under the time-dependent receiver operating characteristic curves at five years were 0.747, 0.798, and 0.777, respectively. The nomogram was discriminative and well-calibrated when applied to the test and external validation cohorts. Significant between-group differences in OS were observed when classifying groups by nomogram score (log-rank P<0.001). An online web server for clinical use was developed using the nomogram. CONCLUSIONS: The nomogram facilitates accurate prediction of survival for patients with LIMA and can be used to stratify clinical risk groups for individualized treatment.

m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer.

Small-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and the outcomes are heterogeneous. Therefore, clinically feasible classification strategies and potential therapeutic targets for overcoming chemotherapy resistance are urgently needed. N6-methyladenosine (m6A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m6A modification in SCLC. Here, we assessed 200 SCLC samples from patients who underwent chemotherapy from three different cohorts, including a validation cohort containing 71 cases with qPCR data and an independent cohort containing 79 cases with immunohistochemistry data (quantified as H-score). We systematically characterized the predictive landscape of m6A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (ZCCHC4, IGF2BP3, ALKBH5, YTHDF3, METTL5, G3BP1, and RBMX) chemotherapy benefit predictive classifier (m6A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m6A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m6A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators-ZCCHC4, G3BP1, and RBMX-may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m6A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m6A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC.

Anterior cruciate ligament reconstruction with LARS artificial ligament: a multicenter study with 3- to 5-year follow-up.

PURPOSE: The aim of this multicenter study was to evaluate the clinical outcome of anterior cruciate ligament (ACL) reconstruction by use of the Ligament Advanced Reinforcement System (LARS) artificial ligament (Surgical Implants and Devices, Arc-sur-Tille, France) with 3- to 5-year follow-up. METHODS: From August 2004 to July 2006, 159 patients with ACL rupture underwent arthroscopic ACL reconstruction with LARS artificial ligament at 4 orthopaedic sports medicine centers in China. They were retrospectively followed up for 50 +/- 6 months (range, 36 to 62 months). Outcome assessment included physical examination, KT-1000 arthrometer testing (MEDmetric, San Diego, CA), magnetic resonance imaging, radiography, Lysholm score, Tegner score, International Knee Documentation Committee score, and subjective satisfaction rate. Quadriceps and hamstring isokinetic strength was evaluated in 68 patients. RESULTS: The side-to-side difference in anterior translation (injured side - uninjured side) measured by KT-1000 arthrometer was 1.5 +/- 1.6 mm (range, -1 to 7 mm) postoperatively, and knee stability was significantly improved compared with preoperative data (P < .0001). Quadriceps and hamstring isokinetic peak torque of the injured limb expressed as a percentage of the contralateral limb was 93.6 +/- 10.7 and 95.8 +/- 12.0, respectively. The Lysholm score improved from 65.1 +/- 12.3 points (range, 30 to 95 points) preoperatively to 94.5 +/- 7.0 points (range, 65 to 100 points) postoperatively (P < .0001). The Tegner score improved from 3.1 +/- 1.6 (range, 0 to 6) preoperatively to 6.1 +/- 1.5 (range, 1 to 9) postoperatively (P < .0001). According to the International Knee Documentation Committee score, 94% of patients were graded A or B at last follow-up. Ninety-three percent of patients were very satisfied or satisfied with their outcome. LARS artificial ligament rupture occurred in 3 patients; knee synovitis developed in 1 of these patients. CONCLUSIONS: ACL reconstruction with LARS artificial ligament used in patients with the ACL stump preserved in the acute and chronic phases has a very good outcome at mean of 50 months' follow-up. The overall complication rate for ACL reconstruction with LARS artificial ligament is 5.7%, and knee synovitis developed in only 1 case. LEVEL OF EVIDENCE: Level IV, therapeutic case series.