EML4-ALK fusion protein in Lung cancer cells enhances venous thrombogenicity through the pERK1/2-AP-1-tissue factor axis.

BACKGROUND: Accumulating evidence links the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement to venous thromboembolism (VTE) in non-small cell lung cancer (NSCLC) patients. However, the corresponding mechanisms remain unclear. METHOD: High-throughput sequencing analysis of H3122 human ALK-positive NSCLC cells treated with ALK inhibitor/ dimethyl sulfoxide (DMSO) was performed to identify coagulation-associated differential genes between EML4-ALK fusion protein inhibited cells and control cells. Sequentially, we confirmed its expression in NSCLC patients' tissues and in the plasma of a subcutaneous xenograft mouse model. An inferior vena cava (IVC) ligation model was used to assess clot formation potential. Additionally, pathways involved in tissue factor (TF) regulation were explored in ALK-positive cell lines H3122 and H2228. Statistical significance was determined by Student t-test and one-way ANOVA using SPSS. RESULTS: Sequencing analysis identified a significant downregulation of TF after inhibiting EML4-ALK fusion protein activity in H3122 cells. In clinical NSCLC cases, TF expression was increased especially in ALK-positive NSCLC tissues. Meanwhile, H3122 and H2228 with high TF expression exhibited shorter plasma clotting time and higher TF activity versus ALK-negative H1299 and A549 in cell culture supernatant. Mice bearing H2228 tumor showed a higher concentration of tumor-derived TF and TF activity in plasma and the highest adjusted IVC clot weights. Limiting EML4-ALK protein phosphorylation downregulated extracellular regulated protein kinases 1/2 (ERK1/2)-activating the protein-1(AP-1) signaling pathway and thus attenuated TF expression. CONCLUSION: EML4-ALK fusion protein may enhance venous thrombogenicity by regulating coagulation factor TF expression. There was potential involvement of the pERK1/2-AP-1 pathway in this process.

Development and Validation of a Dual-Energy CT-Based Model for Predicting the Number of Central Lymph Node Metastases in Clinically Node-Negative Papillary Thyroid Carcinoma.

RATIONALE AND OBJECTIVES: This study aimed to develop and validate a dual-energy CT (DECT)-based model for preoperative prediction of the number of central lymph node metastases (CLNMs) in clinically node-negative (cN0) papillary thyroid carcinoma (PTC) patients. MATERIALS AND METHODS: Between January 2016 and January 2021, 490 patients who underwent lobectomy or thyroidectomy, CLN dissection, and preoperative DECT examinations were enrolled and randomly allocated into the training (N = 345) and validation cohorts (N = 145). The patients' clinical characteristics and quantitative DECT parameters obtained on primary tumors were collected. Independent predictors of> 5 CLNMs were identified and integrated to construct a DECT-based prediction model, for which the area under the curve (AUC), calibration, and clinical usefulness were assessed. Risk group stratification was performed to distinguish patients with different recurrence risks. RESULTS: More than 5 CLNMs were found in 75 (15.3%) cN0 PTC patients. Age, tumor size, normalized iodine concentration (NIC), normalized effective atomic number (nZeff) and the slope of the spectral Hounsfield unit curve (λHu) in the arterial phase were independently associated with> 5 CLNMs. The DECT-based nomogram that incorporated predictors demonstrated favorable performance in both cohorts (AUC: 0.842 and 0.848) and significantly outperformed the clinical model (AUC: 0.688 and 0.694). The nomogram showed good calibration and added clinical benefit for predicting> 5 CLNMs. The KaplanMeier curves for recurrence-free survival showed that the high- and low-risk groups stratified by the nomogram were significantly different. CONCLUSION: The nomogram based on DECT parameters and clinical factors could facilitate preoperative prediction of the number of CLNMs in cN0 PTC patients.

The association of chest computed tomography-defined visual emphysema and prognosis in patients with nonsmall cell lung cancer.

Background: Although computed tomography (CT)-defined emphysema is considered a predictor of lung cancer risk, it is not fully clear whether CT-defined emphysema is associated with the prognosis of lung cancer. We aimed to assess the clinical impact of CT-defined emphysema on the survival of lung cancer. Methods: In the prospective cohort study of nonsmall cell lung cancer (NSCLC), the correlation between CT-defined emphysema and clinical variables was analysed. A multivariable Cox regression model was built to assess the association between CT-defined emphysema and overall survival (OS) for up to 8.8 years. The differences in survival analyses were derived by Kaplan-Meier analysis and log-rank testing. Low attenuation area (LAA%) was defined as the per cent of voxels below -950 HU. Results: 854 patients were included and CT-defined emphysema was present in 300 (35.1%) at diagnosis. Epidermal growth factor receptor (EGFR) wild-type (OR 1.998; p<0.001) and anaplastic lymphoma kinase (ALK) wild-type (OR 2.277; p=0.004) were associated with CT-defined emphysema. CT-defined emphysema remained a significant predictor of prognosis adjusting for age, sex, smoking history, tumour histology and Eastern Cooperative Oncology Group Performance Status (ECOG PS), whether in I-IIIA stage (adjusted hazard ratio (HR) 1.745; p=0.017) or in IIIB-IV stage (adjusted HR 1.291; p=0.022). Stratified analyses showed that OS rate among the driver oncogene groups with different CT-defined emphysema status differed significantly (log-rank p<0.001). Furthermore, patients with centrilobular emphysema (CLE) with LAA% >17% displayed poorer survival than those with LAA% ≤17% (median 432 versus 670 days; HR 1.564; p=0.020). Conclusions: CT-defined emphysema, especially CLE with LAA%>17%, is an independent predictor of NSCLC prognosis. Moreover, prospective studies are needed to further explore this association.

Newly diagnosed non-small cell lung cancer with interstitial lung abnormality: Prevalence, characteristics, and prognosis.

BACKGROUND: Along with the improvement of lung cancer screening implementation, the identification of interstitial lung abnormality (ILA) is increasing. Currently, there is a limited description of the oncogenic status and ILA subtypes among newly diagnosed non-small cell lung cancer (NSCLC) patients with ILA in the Chinese population. This study aimed to investigate the prevalence, characteristics, oncogenic status and factors associated with overall survival (OS) among NSCLC patients with ILA. METHODS: A total of 765 newly diagnosed NSCLC cases at our hospital were reviewed and ILA was diagnosed according to the criteria of the Fleischner Society. The characteristics, clinical pathological features and OS of NSCLC patients with ILA were retrospectively analyzed. RESULTS: Of the 765 patients included in the study, 101 (13.2%) cases experienced ILA at the time of NSCLC diagnosis. Multivariate analysis revealed that ILA was more likely to be detected in NSCLC patients who were age ≥60 (OR 2.404, p = 0.001), male gender (OR 2.476, p = 0.004), and EGFR wild-type (OR 2.035, p = 0.007). Additionally, according to the multivariate Cox model, the presence of ILA in NSCLC patients was significantly associated with a shorter OS period than those without ILA (751 days vs. 445 days, HR 0.6, p = 0.001). Following analysis, it was determined that OS in patients with usual interstitial pneumonia (UIP) was shorter than in those without UIP (HR 1.82, p = 0.037). CONCLUSION: ILA is a common comorbidity among newly diagnosed NSCLC patients. We found that patients with EGFR wild-type NSCLC were more likely to develop ILA. The presence of ILA, especially UIP, was significantly associated with poor NSCLC prognosis.

Establishment and optimization of an in vitro guinea pig oocyte maturation system.

Guinea pigs are a valuable animal model for studying various diseases, including reproductive diseases. However, techniques for generating embryos via embryo engineering in guinea pigs are limited; for instance, in vitro maturation (IVM) technique is preliminary for guinea pig oocytes. In this study, we aimed to establish and optimize an IVM method for guinea pig oocytes by investigating various factors, such as superovulation induced by different hormones, culture supplementation (e.g., amino acids, hormone, and inhibitors), culture conditions (e.g., oocyte type, culture medium type, and treatment time), and in vivo hCG stimulation. We found that oocytes collected from guinea pigs with superovulation induced by hMG have a higher IVM rate compared to those collected from natural cycling individuals. Moreover, we found that addition of L-cysteine, cystine, and ROS in the culture medium can increase the IVM rate. In addition, we demonstrated that in vivo stimulation with hCG for 3-8 h can further increase the IVM rate. As a result, the overall IVM rate of guinea pig oocytes under our optimized conditions can reach ~69%, and the mature oocytes have high GSH levels and normal morphology. In summary, we established an effective IVM method for guinea pig oocytes by optimizing various factors and conditions, which provides a basis for embryo engineering using guinea pigs as a model.

Precise prediction of the sensitivity of platinum chemotherapy in SCLC: Establishing and verifying the feasibility of a CT-based radiomics nomogram.

Objectives: To develop and validate a CT-based radiomics nomogram that can provide individualized pretreatment prediction of the response to platinum treatment in small cell lung cancer (SCLC). Materials: A total of 134 SCLC patients who were treated with platinum as a first-line therapy were eligible for this study, including 51 patients with platinum resistance (PR) and 83 patients with platinum sensitivity (PS). The variance threshold, SelectKBest, and least absolute shrinkage and selection operator (LASSO) were applied for feature selection and model construction. The selected texture features were calculated to obtain the radiomics score (Rad-score), and the predictive nomogram model was composed of the Rad-score and the clinical features selected by multivariate analysis. Receiver operating characteristic (ROC) curves, calibration curves, and decision curves were used to assess the performance of the nomogram. Results: The Rad-score was calculated using 10 radiomic features, and the resulting radiomics signature demonstrated good discrimination in both the training set (area under the curve [AUC], 0.727; 95% confidence interval [CI], 0.627-0.809) and the validation set (AUC, 0.723; 95% CI, 0.562-0.799). To improve diagnostic effectiveness, the Rad-score created a novel prediction nomogram by combining CA125 and CA72-4. The radiomics nomogram showed good calibration and discrimination in the training set (AUC, 0.900; 95% CI, 0.844-0.947) and the validation set (AUC, 0.838; 95% CI, 0.534-0.735). The radiomics nomogram proved to be clinically beneficial based on decision curve analysis. Conclusion: We developed and validated a radiomics nomogram model for predicting the response to platinum in SCLC patients. The outcomes of this model can provide useful suggestions for the development of tailored and customized second-line chemotherapy regimens.

Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway.

Liver cancer is a kind of malignant tumor with poor sensitivity to chemotherapy. It is urgent to investigate approaches to improve the outcome of chemotherapy. KDM5A has been reported to be an oncogene in various cancers and is associated with drug resistance. However, the functions of KDM5A in chemotherapeutic sensitivity of liver cancer not been well illustrated. In this study, we found that KDM5A was upregulated in liver cancer tissue and cell lines. KDM5A knockdown using a gene interference strategy suppressed the growth of liver cancer in vitro and in vivo. CPI-455, a pharmacological inactivation of KDM5A enhanced the cytotoxicity of cisplatin (CDDP) in liver cells. CPI-455 and CDDP cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that knockdown or inactivation of KDM5A resulted in the downregulation of ROCK1, an oncogene regulating the activation of the PTEN/AKT signaling pathway. In particular, overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and CDDP cotreatment. In HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP treatment alone. In conclusion, this study suggested that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to CDDP by modulating the ROCK1/PTEN/AKT signaling pathway.

Gene therapy for cystic fibrosis: Challenges and prospects.

Cystic fibrosis (CF) is a life-threatening autosomal-recessive disease caused by mutations in a single gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). CF effects multiple organs, and lung disease is the primary cause of mortality. The median age at death from CF is in the early forties. CF was one of the first diseases to be considered for gene therapy, and efforts focused on treating CF lung disease began shortly after the CFTR gene was identified in 1989. However, despite the quickly established proof-of-concept for CFTR gene transfer in vitro and in clinical trials in 1990s, to date, 36 CF gene therapy clinical trials involving ∼600 patients with CF have yet to achieve their desired outcomes. The long journey to pursue gene therapy as a cure for CF encountered more difficulties than originally anticipated, but immense progress has been made in the past decade in the developments of next generation airway transduction viral vectors and CF animal models that reproduced human CF disease phenotypes. In this review, we look back at the history for the lessons learned from previous clinical trials and summarize the recent advances in the research for CF gene therapy, including the emerging CRISPR-based gene editing strategies. We also discuss the airway transduction vectors, large animal CF models, the complexity of CF pathogenesis and heterogeneity of CFTR expression in airway epithelium, which are the major challenges to the implementation of a successful CF gene therapy, and highlight the future opportunities and prospects.

An examination of the protective effects and molecular mechanisms of curcumin, a polyphenol curcuminoid in diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and is an enormous burden on both patients and society. There is an urgent need for effective alternative therapeutic strategies for the treatment of DN, as medical treatment is currently limited. The anti-inflammatory, antioxidative, anti-apoptotic, and anti-fibrosis properties of curcumin, a polyphenol curcuminoid, have been demonstrated in research on diabetic nephropathy. The clinical and preclinical trials and mechanisms by which curcumin affects DN have been discussed in this review. A deeper understanding of the pharmacological effects of curcumin on diabetic nephropathy may provide new therapies to improve the development and occurrence of diabetic nephropathy.

Immunotherapy of targeting MDSCs in tumor microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells which are abnormally accumulated during the differentiation of myeloid cells. Immunosuppression is the main functional feature of MDSCs, which inhibit T cell activity in the tumor microenvironment (TME) and promote tumoral immune escape. The main principle for immunotherapy is to modulate, restore, and remodel the plasticity and potential of immune system to have an effective anti-tumor response. In the TME, MDSCs are major obstacles to cancer immunotherapy through reducing the anti-tumor efficacy and making tumor cells more resistant to immunotherapy. Therefore, targeting MDSCs treatment becomes the priority of relevant studies and provides new immunotherapeutic strategy for cancer treatment. In this review, we mainly discuss the functions and mechanisms of MDSCs as well as their functional changes in the TME. Further, we review therapeutic effects of immunotherapy against MDSCs and potential breakthroughs regarding immunotherapy targeting MDSCs and immune checkpoint blockade (ICB) immunotherapy.

Integrated application of transcriptome and metabolomics reveals potential therapeutic targets for the polarization of atherosclerotic macrophages.

The polarization of macrophages often leads to severe calcification and necrosis in aged atherosclerotic plaques, which eventually leads to poor prognosis of ischaemic cardiovascular and cerebrovascular diseases. More reliable diagnostic methods are urgently needed to discover therapeutic targets of macrophage polarization in aged atherosclerotic plaques. Metabolomics of aged plaques (n = 20) and macrophage polarization transcriptomes (n = 30) were integrated to identify metabolic therapeutic targets of macrophage polarization associated with aged plaque. Finally, metabolic inhibitors were used to verify the reliability of the target genes. Integrated multiomics analysis revealed that 6 metabolic pathways (including 21 genes) regulate macrophage polarization in aged atherosclerosis. Targeted treatment of macrophage polarization with metabolic inhibitors can effectively reduce the adverse risk of aged atherosclerosis. The combination of transcriptomics and metabolomics approaches can identify effective therapeutic targets for macrophage polarization in arteriosclerosis.

Lox as the Potential Key Gene of Clear Cell Renal Carcinoma.

Clear cell renal carcinoma (CCRC) is the most common type of renal carcinoma. We hope to find out the potential key genes playing important roles in CCRC genesis and progression by analysing the recent expression profiling by array from 2014 to 2016. In order to find out the differentially expressed genes (DEGs) between CCRC and normal renal tissue. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, and Genomes (KEGG) pathway enrichment were carried out by the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8. Protein-Protein Interaction (PPI) Networks Functional Enrichment Analysis of these DEGs was analyzed using the Search Tool for Recurring Instances of Neighbouring Genes (STRING). The results were then visualized by the software Cytoscape. The authors also used the online tool of Kaplan-Meier plotter survival analysis to assess the significance of the top ten genes in the prognosis of CCRC. A total of 192 DEGs were identified and the top ten key genes were picked out by the software Cytoscape. FN1, CXCR4, LOX, and PLG were then further screened out based on the overall survival analysis; SLC12A1 and LOX were screened out after the recurrence-free survival analysis. LOX was finally believed to be the most reliable prognostic factor since it has prognostic value for both overall survival and recurrence-free survival analysis. Our analysis suggests that LOX is the most reliable prognostic factor for CCRC patients. Key Words: Renal clear cell carcinoma, Microarray datasets, Bioinformatics approach, Prognostic factor, LOX.

MicroRNAs/LncRNAs Modulate MDSCs in Tumor Microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature cells derived from bone marrow that play critical immunosuppressive functions in the tumor microenvironment (TME), promoting cancer progression. According to base length, Non-coding RNAs (ncRNAs) are mainly divided into: microRNAs (miRNAs), lncRNAs, snRNAs and CircRNAs. Both miRNA and lncRNA are transcribed by RNA polymerase II, and they play an important role in gene expression under both physiological and pathological conditions. The increasing data have shown that MiRNAs/LncRNAs regulate MDSCs within TME, becoming one of potential breakthrough points at the investigation and treatment of cancer. Therefore, we summarize how miRNAs/lncRNAs mediate the differentiation, expansion and immunosuppressive function of tumor MDSCs in TME. We will then focus on the regulatory mechanisms of exosomal MicroRNAs/LncRNAs on tumor MDSCs. Finally, we will discuss how the interaction of miRNAs/lncRNAs modulates tumor MDSCs.

RAGE Inhibitors as Alternatives to Dexamethasone for Managing Cerebral Edema Following Brain Tumor Surgery.

Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood-brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema.

Sempervirine Inhibits Proliferation and Promotes Apoptosis by Regulating Wnt/ß-Catenin Pathway in Human Hepatocellular Carcinoma.

Gelsemium elegans (G. elegans) Benth., recognized as a toxic plant, has been used as traditional Chinese medicine for the treatment of neuropathic pain and cancer for many years. In the present study, we aim to obtain the anti-tumor effects of alkaloids of G. elegans and their active components in hepatocellular carcinoma (HCC) and the potential mechanism was also further investigated. We demonstrated that sempervirine induced HCC cells apoptosis and the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and down-regulation of cyclin D1, cyclin B1 and CDK2. Furthermore, sempervirine inhibited HCC tumor growth and enhances the anti-tumor effect of sorafenib in vivo. In addition, inactivation of Wnt/ß-catenin pathway was found to be involved in sempervirine-induced HCC proliferation. The present study demonstrated that alkaloids of G. elegans were a valuable source of active compounds with anti-tumor activity. Our findings justified that the active compound sempervirine inhibited proliferation and induced apoptosis in HCC by regulating Wnt/ß-catenin pathway.

Enhanced oral bioavailability of koumine by complexation with hydroxypropyl-ß-cyclodextrin: preparation, optimization, ex vivo and in vivo characterization.

Koumine (KME) is an active alkaloid extracted from Gelsemium elegans, and its diverse bioactivities have been studied for decades. However, KME exhibits poor solubility and low oral bioavailability, which hampers its potential therapeutic exploitation. This work aimed to develop optimized inclusion complexes to improve the bioavailability of KME. The KME/hydroxypropyl-ß-cyclodextrin (KME/HP-ß-CD) inclusion complexes were prepared by the solvent evaporation method and later optimized using the Box-Behnken design. The optimal KME/HP-ß-CD was characterized by scanning electron microscopy, Fourier transforms infrared spectroscopy, differential scanning calorimetry, and nuclear magnetic resonance spectroscopy. The physicochemical characterization results revealed that the crystalline state of KME was transformed into an amorphous form, forming KME/HP-ß-CD inclusion complexes. Compared with KME, the solubility and in vitro release rate of KME/HP-ß-CD was significantly enhanced by 52.34- and 1.3-fold, respectively. Further research was performed to investigate the intestinal absorption characteristics and in vivo bioavailability in rats. The optimal KME/HP-ß-CD showed enhanced absorptive permeability and relative bioavailability increased more than two-fold compared to that of raw KME. These results indicate that the optimal KME/HP-ß-CD can be used as an effective drug carrier to improve the solubility, intestinal absorption, and bioavailability of KME.

Development and validation of a predictive score for venous thromboembolism in newly diagnosed non-small cell lung cancer.

INTRODUCTION: The risk of venous thromboembolism (VTE) varies among tumour types, and different cancer type-specific risks for VTE prediction remain undefined. We aimed to establish a prediction model for non-small lung cancer (NSCLC)-associated VTE. MATERIALS AND METHODS: We analysed data from a prospective cohort of patients with newly diagnosed NSCLC. We then developed a VTE risk prediction model using data of patients who were recruited from 2013 to 2017 (n = 602, development cohort) and validated this model using date of patients recruited from 2018 to 2019 (n = 412, validation cohort). The cumulative 6 months VTE incidence observed in both cohorts was calculated. RESULTS: The parameters in this new model included Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (1 point), EGFR mutation (-1 point), neutrophil count ≥7.5 × 109/L (2 points), hemoglobin <115 g/L (1 point), CEA ≥5.0 ng/mL (2 points), and D-dimer level ≥1400 ng/mL (4 points). The cross-validated concordance indices of the model in the development and validation cohorts were 0.779 and 0.853, respectively. Furthermore, the areas under the curve in the two cohorts were 0.7563 (95% confidence interval [CI]: 0.6856-0.8129, P < 0.001) and 0.8211 (95% CI: 0.7451-0.8765, P < 0.001) for development and validation cohorts, respectively. CONCLUSIONS: The new VTE risk prediction model incorporated patient characteristics, laboratory values, and oncogenic status, and was able to stratify patients at high risk of VTE in newly diagnosed NSCLC within 6 months of diagnosis.

Association of Venous Thromboembolism and Early Mortality in Patients with Newly Diagnosed Metastatic Non-Small Cell Lung Cancer.

PURPOSE: To explore the relationship between venous thromboembolism (VTE) and early mortality (within six months) in Chinese patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) after entering the era of precision treatment. METHODS: A cohort of 706 consecutive subjects with newly diagnosed metastatic NSCLC were prospectively observed. Clinical and survival data were recorded over a six-month follow-up period. The predictive factors for the occurrence of VTE and the relationship with early mortality were evaluated through univariate and multivariate analyses. RESULTS: During the six-month follow-up period, VTE events occurred in 12.2% (86/706) of the enrolled patients. In the multivariate analyses for VTE, an age older than 70 years (vs < 70: sub-distribution hazard radio [SHR], 1.678; 95% confidence interval (CI), 1.073-2.600; P=0.022), an Eastern Cooperative Oncology Group performance status ≥2 (vs 0/1: SHR, 1.946; 95% CI, 1.277-2.970; P=0.002), and having an ALK rearrangement (vs non-rearrangement: SHR, 2.377; 95% CI, 1.186-4.760; P=0.015) were significantly associated with the occurrence of VTE. Within six months, 116 subjects (16.4%) died, and the occurrence of VTE (vs no VTE: adjusted HR: 1.863; 95% CI: 1.178-2.947, P=0.008) was remarkably associated with early mortality. Further analysis showed 98 patients (13.9%) with early mortality had EGFR/ALK wild-type genes, with a risk of early mortality 5.935-fold higher than that of patients with an EGFR mutation/ALK rearrangement. Finally, subgroup analyses showed that VTE occurrence was a significant factor for predicting early mortality in patients with EGFR/ALK wild-type genes (adjusted HR: 1.682; 95% CI: 1.023-2.768, P=0.041). CONCLUSION: Patients with an EGFR mutation/ALK rearrangement had a significantly decreased risk of early mortality in the era of targeted therapy; however, VTE occurrence remained an important predictor for early mortality in metastatic NSCLC patients, especially in patients with EGFR/ALK wild-type genes.

Research advances in molecular mechanisms underlying the pathogenesis of cystic fibrosis: From technical improvement to clinical applications (Review).

Cystic fibrosis (CF) is a chronic disease causing severe impairment to the respiratory system and digestive tracts. Currently, CF is incurable. As an autosomal recessive disorder, the morbidity of CF is significantly higher among Caucasians of European descent, whereas it is less pervasive among African and Asian populations. The disease is caused by identical mutations (homozygosity) or different mutations (heterozygosity) of an autosomal recessive mutation at position 7q31.2­q31.1 of chromosome 7. Diagnostic criteria and guidelines work concurrently with laboratory detection to facilitate precise CF detection. With technological advances, the understanding of CF pathogenesis has reached an unprecedented level, allowing for increasingly precise carrier screening, more effective early stage CF intervention and improved prognostic outcomes. These advances significantly increase the life quality and expectancy of patients with CF. Given the numerous improvements in the field of CF, the current review summarized the technical advances in the study of the molecular mechanisms underlying CF, as well as how these improvements facilitate the clinical outcomes of CF. Furthermore, challenges and obstacles to overcome are discussed.

Immunotherapy Targeting Myeloid-Derived Suppressor Cells (MDSCs) in Tumor Microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in tumor-bearing hosts to reduce T cells activity and promote tumor immune escape in the tumor microenvironment (TME). The immune system in the TME can be stimulated to elicit an anti-tumor immune response through immunotherapy. The main theory of immunotherapy resides on the plasticity of the immune system and its capacity to be re-educated into a potent anti-tumor response. Thus, MDSCs within the TME became one of the major targets to improve the efficacy of tumor immunotherapy, and therapeutic strategies for tumor MDSCs were developed in the last few years. In the article, we analyzed the function of tumor MDSCs and the regulatory mechanisms of agents targeting MDSCs in tumor immunotherapy, and reviewed their therapeutic effects in MDSCs within the TME. Those data focused on discussing how to promote the differentiation and maturation of MDSCs, reduce the accumulation and expansion of MDSCs, and inhibit the function, migration and recruitment of MDSCs, further preventing the growth, invasion and metastasis of tumor. Those investigations may provide new directions for cancer therapy.