Highly accurate carbohydrate-binding site prediction with DeepGlycanSite.

As the most abundant organic substances in nature, carbohydrates are essential for life. Understanding how carbohydrates regulate proteins in the physiological and pathological processes presents opportunities to address crucial biological problems and develop new therapeutics. However, the diversity and complexity of carbohydrates pose a challenge in experimentally identifying the sites where carbohydrates bind to and act on proteins. Here, we introduce a deep learning model, DeepGlycanSite, capable of accurately predicting carbohydrate-binding sites on a given protein structure. Incorporating geometric and evolutionary features of proteins into a deep equivariant graph neural network with the transformer architecture, DeepGlycanSite remarkably outperforms previous state-of-the-art methods and effectively predicts binding sites for diverse carbohydrates. Integrating with a mutagenesis study, DeepGlycanSite reveals the guanosine-5'-diphosphate-sugar-recognition site of an important G-protein coupled receptor. These findings demonstrate DeepGlycanSite is invaluable for carbohydrate-binding site prediction and could provide insights into molecular mechanisms underlying carbohydrate-regulation of therapeutically important proteins.

HER2-targeting CAR-T cells show highly efficient anti-tumor activity against glioblastoma both in vitro and in vivo.

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options for GBM include surgical resection, radiation, and chemotherapy, which predominantly slow cancer growth and reduce symptoms, resulting in a 5-year survival rate of no more than 10%. Chimeric antigen receptor (CAR) T-cell therapy is a new class of cellular immunotherapy that has made great progress in treating malignant tumors. Human epidermal growth factor receptor 2 (HER2) is overexpressed in GBM and may provide a potential therapeutic target for GBM treatment. In this study, we constructed third-generation CAR-T cells targeting the HER2 antigen in GBM. HER2-CAR-T cells showed effective anti-tumor activity both in vitro and in vivo. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting abilities against GBM cells in vitro. Anti-HER2 CAR-T cells also exhibited increased cytotoxicity with increasing effector-to-target ratios. Anti-HER2 CAR-T cells delivered via peritumoral injection successfully stunted tumor progression in vivo. Moreover, peritumoral intravenous administration of anti-HER2 CAR-T cells resulted in therapeutic improvement against GBM cells compared with intravenous administration. In conclusion, our study shows that HER2 CAR-T cells represent an emerging immunotherapy for treating GBM.

Identification of a carbohydrate recognition motif of purinergic receptors.

As a major class of biomolecules, carbohydrates play indispensable roles in various biological processes. However, it remains largely unknown how carbohydrates directly modulate important drug targets, such as G-protein coupled receptors (GPCRs). Here, we employed P2Y purinoceptor 14 (P2Y14), a drug target for inflammation and immune responses, to uncover the sugar nucleotide activation of GPCRs. Integrating molecular dynamics simulation with functional study, we identified the uridine diphosphate (UDP)-sugar-binding site on P2Y14, and revealed that a UDP-glucose might activate the receptor by bridging the transmembrane (TM) helices 2 and 7. Between TM2 and TM7 of P2Y14, a conserved salt bridging chain (K2.60-D2.64-K7.35-E7.36 [KDKE]) was identified to distinguish different UDP-sugars, including UDP-glucose, UDP-galactose, UDP-glucuronic acid, and UDP-N-acetylglucosamine. We identified the KDKE chain as a conserved functional motif of sugar binding for both P2Y14 and P2Y purinoceptor 12 (P2Y12), and then designed three sugar nucleotides as agonists of P2Y12. These results not only expand our understanding for activation of purinergic receptors but also provide insights for the carbohydrate drug development for GPCRs.

Sugars and other types of carbohydrates are biomolecules which play a range of key roles in the body. In particular, they are important messengers that help to coordinate immune responses. For example, a carbohydrate known as UDP-Glucose (a kind of UDP-sugar) can activate P2Y14, a receptor studded through the surface of many cells; this event then triggers a cascade of molecular events associated with asthma, kidney injury and lung inflammation. Yet it remains unclear how exactly UDP-Glucose recognizes P2Y14 ­ and, more broadly, how carbohydrates interact with purinergic receptors, the class of proteins that P2Y14 belongs to. To examine this question, Zhao et al. combined functional experiments in the laboratory with molecular dynamics simulations, a computational approach. This work revealed that UDP-Glucose may activate P2Y14 by bridging its segments anchored within the cell membrane. A component of P2Y14, known as the KDKE chain, was found to have an important role in distinguishing between highly similar types of UDP-sugars. This allowed Zhao et al. to design three sugar molecules which could activate another purinergic receptor that also contained a KDKE chain. Purinergic receptors are promising therapeutic targets. A finer understanding of how they recognise the molecules that activate them is therefore important to be able to identify and design new drug compounds.

Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis.

The decision for definitive therapy for the treatment of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) is difficult. Patients with CTD-ILD received 0.5 g twice a day of mycophenolate mofetil for 2 years (MMF cohort, n = 105) or cyclophosphamide 50 mg once every other day, and the cumulative dose of cyclophosphamide should not exceed 10 g (CYC cohort, n = 140). After complete of treatment (EL), % forced vital capacity (FVC) and % diffusing capacity of the lungs for carbon monoxide were increased in both the MMF and CYC cohorts as compared to before treatment (p < 0.001 for all). There were higher changes in % FVC values and a greater number of patients with significant change in % FVC (>10% change) in the CYC cohort than in the MMF cohort (p < 0.0001 for both) at EL. Patients in the CYC cohort had higher rates of leukopenia, thrombocytopenia, serious adverse effects related to treatment(s), and death than those in the MMF cohort (p < 0.05 for all). Cyclophosphamide plus prednisolone superiorly improved % FVC compared to mycophenolate mofetil plus prednisolone. Mycophenolate mofetil and cyclophosphamide improved pulmonary function. Mycophenolate mofetil is less toxic and increased patient survival.

Improvement of the mechanical and shape memory properties in polylactide/polyethylene glycol blends by reactive graphene oxide.

The widespread application of biodegradable polylactide (PLA) is hindered by its brittleness. Polyethylene glycol (PEG) is commonly utilized as a plasticizer because of its favorable compatibility with PLA. However, the incorporation of PEG considerably diminishes the tensile strength of PLA. To address this issue, reactive isocyanate-modified graphene oxide (mGO) was synthesized and used as an enhancer in PLA/PEG blends. By virtue of the reaction between the isocyanate group in mGO and the terminal hydroxyl groups of PLA and PEG, graphene-based polyurethane (PU) in-situ formed and enhanced the interface between GO and the matrix. Consequently, the PLA/PEG/mGO composites exhibit simultaneously improved tensile and impact strengths, achieving an increase of 20.6% and 29.4%, respectively, compared to PLA/PEG blends. Moreover, the in situ formed PU reduces the relaxation time of the molecule motion and improved the entanglement density, thereby improving the shape-memory recovery rate and final recovery degree of the composites. This work provides a facile method to simultaneously improve the dispersion of GO and enhance its interface with polymer, thereby supplying well comprehensive properties of PLA and extending the applications of biodegradable polymers.

Serum CXCL8 and CXCR2 as diagnostic biomarkers for noninvasive screening of cervical cancer.

BACKGROUND: Cervical cancer (CC) is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related death in women. Identifying new biomarkers for the early detection of CC is an essential requirement in this field. CXCL8 was originally discovered because of its role in inflammation by binding to CXCR1 and CXCR2; however, it is now known to play an important role in cancer. In this study, we aimed to evaluate the expression levels of potential biomarkers (CXCL8, CXCR1, and CXCR2) and to explore their diagnostic potential in CC. METHODS: The expression levels of serum CXCL8, CXCR1, and CXCR2 were investigated by kit method on Immulite-1000 in 30 healthy volunteers, 30 precancerous patients and 70 CC patients. RESULTS: The results indicated that the expression of CXCL8 and CXCR2 was significantly higher in the serum of CC patients than in healthy volunteers, similar to the well-established tumor marker (squamous-cell cancerantigen [SCC]). Receiver operating characteristic analyses showed that the combination of CXCL8, CXCR2, and SCC had the highest diagnostic sensitivity and area under the curve value. Meanwhile, the positive predictive value and negative predictive value were not very low. Moreover, high concentrations of CXCL8 and CXCR2 are associated with an increased risk of CC. CONCLUSIONS: In conclusion, our data demonstrated that combined serum CXCL8, CXCR2, and SCC measurements are helpful for CC diagnosis and can be used as potential biomarkers for the early detection of CC. Cytokines, such as CXCL8 and CXCR2, can be easily measured in most university hospital laboratories and in some private laboratories with a routine test.

Core fucosylation and its roles in gastrointestinal glycoimmunology.

Glycosylation is a common post-translational modification in eukaryotic cells. It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function. Core fucosylation plays a vital role in the immune response. Most immune system molecules are core fucosylated glycoproteins such as complements, cluster differentiation antigens, immunoglobulins, cytokines, major histocompatibility complex molecules, adhesion molecules, and immune molecule synthesis-related transcription factors. These core fucosylated glycoproteins play important roles in antigen recognition and clearance, cell adhesion, lymphocyte activation, apoptosis, signal transduction, and endocytosis. Core fucosylation is dominated by fucosyltransferase 8 (Fut8), which catalyzes the addition of α-1,6-fucose to the innermost GlcNAc residue of N-glycans. Fut8 is involved in humoral, cellular, and mucosal immunity. Tumor immunology is associated with aberrant core fucosylation. Here, we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.

Hinge region mediates signal transmission of luteinizing hormone and chorionic gonadotropin receptor.

Luteinizing hormone-choriogonadotropin receptor (LHCGR), a class A G protein-coupled receptor (GPCR), plays a pivotal role in the maturation of reproductive organs and embryonic development. Compared with other GPCRs, the subfamily of LHCGR has a large extracellular domain (ECD) to interact with glycoprotein hormones. A unique hinge region connects the ECD and transmembrane domain (TMD) to transfer the activation signal. However, the signal transmission mechanism remains largely unknown. Here, both molecular dynamics simulation and evolutional analysis were applied to explore the effect of the hinge region on signal transmission. The glycoprotein hormone determined specific hinge region conformations, including the position of a long hinge loop and the ECD-TMD interface. With the hormone, the hinge region showed a characteristic rotation and displayed an active-like conformational landscape of the ECD-TMD interface with an extended TMD. The active-like hinge region conformation transduces the hormone binding signal downwards from ECD to TMD. The relationship between the hinge region and the intracelluar G protein-binding pocket was also inferred. The hinge region-mediated signal transmission mechanism offers a deeper understanding of LHCGR and provides insights into the elucidation of GPCR activation.

Gefitinib-induced hemorrhagic cystitis and inflammatory contracted bladder in a patient with advanced lung adenocarcinoma harboring compound epidermal growth factor receptor G719S and S768I missense mutations: a case report.

Background: Numerous clinical studies have established the efficacy and safety of gefitinib for treating patients with epidermal growth factor receptor (EGFR)-mutant lung cancer. Gefitinib-induced urinary system-related adverse reactions are rare but may lead to discontinuation of gefitinib. Case Description: In our report, we describe a patient with advanced lung adenocarcinoma harboring compound EGFR G719S and S768I who developed hemorrhagic cystitis and inflammatory contracted bladder during first-line gefitinib therapy. A 56-year-old male smoker, presented with chronic cough, sputum expectoration, and shortness of breath for 6 months that had worsened over the last 2 weeks, was diagnosed with T2N2M1A stage IV adenocarcinoma of the right lower lung with bilateral lung metastases. Upon detecting a compound EGFR G719S and S768I using a next-generation sequencing-based assay, the patient was administered with gefitinib (250 mg/day) as a first-line regimen. Despite achieving partial response (PR) within 6 weeks of gefitinib therapy, the patient developed several drug-related adverse reactions, including diarrhea, elevated liver enzymes, and inflammatory contracted bladder with hemorrhagic cystitis. Routine urinalysis indicated full high-power field (HPF) view of red blood cell (RBC) and 40-50 white blood cell (WBC) counts/HPF at 1.5 months of gefitinib therapy as compared with no RBC and WBC per HPF before gefitinib therapy (normal range: 0-1 RBC/HPF and 0-3 WBC/HPF). The urinary symptoms and hematuria were alleviated after discontinuation of gefitinib. Icotinib was administered without benefit and subsequently switched to afatinib as the third-line therapy. A PR was achieved; however, it only lasted for 3 months. Then the patient was lost to follow-up. Conclusions: Our case shows that gefitinib can induce hemorrhagic cystitis and contracted bladder. Clinicians must be aware that these uncommon adverse reactions affecting the urinary system could occur in patients with EGFR-mutant lung adenocarcinoma. Monitor for urinary symptoms and hematuria in this cohort of patients is essential.

Enteromorpha cellulose micro-nanofibrils/poly(vinyl alcohol) based composite films with excellent hydrophilic, mechanical properties and improved thermal stability.

This study presents the preparation of cellulose micro-nanofibrils (CMNFs) from Enteromorpha (EP) and the application in PVA/acetylated distarch phosphate (ADSP)/CMNFs composite films. The Micro-nano scale, hydrophilicity, and strong hydrogen bond characteristics of CMNFs prepared form EP by acid hydrolysis were confirmed through the granular statistics, XRD analysis and chemical structure analysis. With the addition of CMNFs, the ultimate tensile strength and elongation at break of composite films are increased by 42.4 % and 90.3 %. An original Weibull statistical analysis shows the impact of CMNFs' added amount on strength distribution and ultimate stress. SEM and polarizing microscope images show the CMNFs' dispersion state in that films is optimal, when their addition was to be 2 %-3 % of total dry weight of PVA/ADSP matrix， which is consistent with the results of Weibull modulus analysis. The main thermal weight-loss process of the composite film is divided into four stages, CMNFs can significantly increase the thermostability at 280 °C to 400 °C. The experiment of water contact angle and water vapor transmission rate of the composite films confirmed that CMNFs can improve films' hydrophilicity. This study provides basis for the preparation of hydrophilic CMNFs and mechanism of modification study PVA-based composites.

Anti-corrosion and self-healing coatings with polyaniline/epoxy copolymer-urea-formaldehyde microcapsules for rusty steel sheets.

Polyaniline (PANI)/Epoxy copolymer as a core material was synthesized via a chemical oxidation method. Various analytical techniques, including scanning electron microscope, Fourier transform infrared spectroscopy, energy dispersive spectroscopy, thermogravimetry, and electrochemical impedance spectroscopy, were used to characterize the morphology, compositions, and self-healing and anticorrosion properties of the prepared microcapsules and coatings. The prepared PANI/Epoxy copolymer showed the best electrochemical corrosion resistance when the ratio of PANI to epoxy was 0.05: 1 (wt.:wt.). For the mass fraction of the core (PANI/Epoxy copolymer) of 60.84 ± 0.06 wt%, the mean particle diameter of the prepared microcapsules was 4.20 ± 0.92 µm. The coatings with 15 wt% microcapsules possessed excellent self-healing performance and corrosion resistance. The low-frequency impedance modulus at 0.01 Hz of scratched coatings immersed in the NaCl solution for 24 h was 5.27 × 106 Ω·cm2. Scratched self-repairing coating samples were able to resist corrosion for 384 h; thus, the microcapsules can be used to significantly extend the service life of the coatings. Microcapsule-containing PANI/Epoxy copolymers are expected to find use in anticorrosion coating systems, where the coatings could be applied directly on rusty steel surfaces.

SPINK2 is a prognostic biomarker related to immune infiltration in acute myeloid leukemia.

BACKGROUND: Serine peptidase inhibitor Kazal type 2 (SPINK2) has been reported to be involved in certain cancers. We conducted an in-depth investigation on the role and mechanism of SPINK2 in acute myeloid leukemia (AML). METHODS: The relationship between SPINK2 expression and AML clinicopathologic characteristics was determined using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Concomitantly, we used Kaplan-Meier survival analysis, as well as univariate and multivariate regression analyses to evaluate SPINK2 as a prognostic marker of AML. Additionally, we annotated the enrichment and function of SPINK2 using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Sets Enrichment Analysis (GSEA). The CIBERSORT algorithm was used to analyze the relationship between SPINK2 expression and immune infiltration. RESULTS: SPINK2 expression was significantly higher in AML patients compared to healthy individuals (P<0.001). The area under receiver operating characteristic curve in the GSE9476 dataset was 0.660, whereas that in the Genotype-Tissue Expression (GTEx) and TCGA datasets was 0.935. In addition, GSEA also showed that several pathways were enriched in the group with high SPINK2 expression, such as PI3K-AKT signaling, PD-L1 expression, and checkpoint pathways. Analysis of immune infiltration showed that SPINK2 expression was correlated with certain immune infiltrating cells. Cox multivariate analysis revealed that the level of SPINK2 was an independent risk factor for the progression of AML (P<0.001). Moreover, age, M1, M5, M6, and CytoRisk-Poor also affected the progression of AML (P<0.05). The C-index of the nomogram in our internal validation was 0.702. CONCLUSION: The high expression of SPINK2 in AML suggests that SPINK2 may play an important role in the immune microenvironment and thus could be a biomarker for diagnosis and prognosis of AML.

Perceived Discrimination at School and Developmental Outcomes among Bai Adolescents: The Mediating Roles of Self-Esteem and Ethnic Identity.

Although discrimination is widely acknowledged to impair developmental outcomes among ethnic minority adolescents, literature differentiating discrimination based on personal characteristics and group membership is lacking, especially in Chinese contexts, and the mechanisms of those relationships remain unclear. In response, the study presented here examined whether self-esteem mediates the relationship between perceived academic discrimination and developmental outcomes among such ethnic minority adolescents, and whether ethnic identity mediates the relationship between perceived ethnic discrimination and developmental outcomes. Multistage cluster random sampling performed in Dali and Kunming, China, yielded a sample of 813 Bai adolescents whose data was analysed in structural equation modelling. The results indicate that perceived academic discrimination had a direct negative effect on adolescents' mental health, while perceived ethnic discrimination had direct negative effects on their behavioural adjustment and social competence. Perceived academic discrimination also indirectly affected adolescents' behavioural adjustment, mental health, and social competence via self-esteem, whereas perceived ethnic discrimination indirectly affected their behavioural adjustment and social competence via ethnic identity. These findings deepen current understandings of how perceived discrimination, self-esteem, and ethnic identity affect the developmental outcomes of ethnic minority adolescents and provide practical recommendations for policymakers and social workers to promote those outcomes in China.

Computational characterization of transducer recognition of ß2 adrenergic receptor.

As an important drug target, ß2 adrenergic receptor (B2AR) regulates many physiological processes, including cardiac function, airway tone and metabolic functions. The selective coupling between B2AR and specific transducers is critical for the physiological action of the receptor. However, the molecular mechanism by which B2AR recognizes different transducers remains elusive. Here, molecular dynamics simulations of B2AR binding to three functionally important transducers (Gs, Gi and ß-arrestin 1) unveiled distinct binding modes of the receptor. Involving transmembrane helices TMs 2-7 and intracellular loops ICLs 2-3, different binding interfaces for Gs and ß-arrestin 1 were identified in the simulation models and further validated by various assays. The distinct recognition mode of B2AR for Gi was computationally characterized. Insights into receptor-transducer communication not only enhance our understanding of signaling bias, but also offer hints for rational drug design targeting specific signaling pathways of G-protein coupled receptors (GPCRs).

Validating the evaluation capacity scale among practitioners in non-governmental organizations.

The growing emphasis on demonstrating the effectiveness of social services through evaluation has heightened demand for nongovernmental organization (NGO) practitioners to enhance evaluation capacity. However, a lack of validated instruments in the NGO context has hampered efforts to assess NGO practitioners' current evaluation capacity and understand how capacity-building activities could be tailored to meet NGO practitioners' actual needs and enhance their evaluation capacity. Hence, this study aims to develop the Evaluation Capacity Scale (ECS), a self-reporting instrument of NGO practitioners' capacity to conduct an effective evaluation of their service programs. Validation data was derived from 439 NGO practitioners who attended the Jockey Club MEL Institute Project in Hong Kong, China. Exploratory factor analysis of the ECS revealed three factors-evaluation mindset, evaluation implementation, and evaluation communication-and confirmatory factor analysis further validated this three-factor structure. Moreover, MANCOVA analysis demonstrated the ECS's predictive validity. Overall, the ECS demonstrated satisfactory convergent validity, high internal consistency reliability, and predictive validity, and its factor structure was supported in subgroups based on gender, age, and level of education. Theoretical and practical implications of the findings are discussed.

Mir-204 Regulates LPS-Induced A549 Cell Damage by Targeting FOXK2.

Objective: To assess whether miR-204 and HA affect A549 cell injury induced by lipopolysaccharide. Material and Methods. A549 cells were treated with hirsutanol A, and cell damage was induced by LPS followed by analysis of cell proliferation by CCK-8, cell apoptosis by flow cytometry, apoptosis-related protein expression by western blot, downstream target of miR-20 by dual-luciferase reporter gene, and inflammatory factors by ELISA and PCR. Results: LPS can significantly inhibit the viability of A549 cells, induce cell apoptosis, and promote the release of IL-6, IL-1ß, and TNF-α, while HA pretreatment can target FOXK2 by upregulating miR-204 levels, thereby alleviating apoptosis and promoting cell viability and at the same time inhibiting the release of inflammatory factors by inhibiting the activation of NF-κB. Conclusions: miR-204 participates in the protection of HA acute lung injury by targeting FOXK2.

TRIM37 negatively regulates inflammatory responses induced by virus infection via controlling TRAF6 ubiquitination.

Virus-induced cytokine storm has been a devastating actuality in clinic. The abnormal production of type I interferon (IFN-1) and upregulation of multiple cytokines induced strong inflammation and thus lead to shock and organ failure. As an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37) regulates the ubiquitination of multiple proteins including TRAFs. RNA sequencing was performed to investigated the alteration of transcriptional profile of H1N1-infected patients. qRT-PCR assay was performed to investigate the RNA levels of certain genes. The group of immune cells was examined by the Flow cytometry analysis. H&E staining was applied to evaluate lung inflammation of WT and TRIM37-KO mice. ELISA assay was performed to demonstrate the alteration of multiple cytokines. The protein levels in NF-kB signaling was estimated by western blotting and immunoprecipitation assays were applied to demonstrate the direct interaction between TRIM37 and TRAF-6. The RNA level of TRIM37 decreased in CD11b+ cells of Flu-infected patients. Knockout of TRIM37 inhibited the immune responses of H1N1-infected mice. TRIM37 deficiency reduced the levels of virous proinflammatory cytokines in bone marrow derived macrophages (BMDMs). Mechanically, TRIM37 promoted the K63-linked ubiquitination of TRAF6. TRIM37 negatively regulated inflammatory responses induced by virus infection via promoting TRAF6 ubiquitination at K63.

Selective N-glycan editing on living cell surfaces to probe glycoconjugate function.

Cell surfaces are glycosylated in various ways with high heterogeneity, which usually leads to ambiguous conclusions about glycan-involved biological functions. Here, we describe a two-step chemoenzymatic approach for N-glycan-subtype-selective editing on the surface of living cells that consists of a first 'delete' step to remove heterogeneous N-glycoforms of a certain subclass and a second 'insert' step to assemble a well-defined N-glycan back onto the pretreated glyco-sites. Such glyco-edited cells, carrying more homogeneous oligosaccharide structures, could enable precise understanding of carbohydrate-mediated functions. In particular, N-glycan-subtype-selective remodeling and imaging with different monosaccharide motifs at the non-reducing end were successfully achieved. Using a combination of the expression system of the Lec4 CHO cell line and this two-step glycan-editing approach, opioid receptor delta 1 (OPRD1) was investigated to correlate its glycostructures with the biological functions of receptor dimerization, agonist-induced signaling and internalization.

Retraction Note: Functional screen analysis reveals miR-3142 as central regulator in chemoresistance and proliferation through activation of the PTEN-AKT pathway in CML.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical Outcomes and Safety of Apatinib Mesylate in the Treatment of Advanced Non-Squamous Non-Small Cell Lung Cancer in Patients Who Progressed After Standard Therapy and Analysis of the KDR Gene Polymorphism.

PURPOSE: This study investigated the clinical outcomes and safety of apatinib mesylate in the treatment of advanced non-squamous non-small cell lung cancer (NSCLC) in patients who progressed after standard therapy, and analyzed the kinase insert domain receptor (KDR) gene polymorphism. METHODS: A total of 135 patients with advanced non-squamous NSCLC who received apatinib mesylate were included. Objective response rates were evaluated. Subsequently, progression-free survival (PFS) and overall survival (OS) were assessed and safety data were recorded. Additionally, peripheral blood and biopsy cancer tissue specimens were collected from the patients with NSCLC for the genotyping of the genetic polymorphism and mRNA expression of the KDR gene, respectively. Analysis on the association between genotypes and prognosis was conducted. RESULTS: The objective response rate of the 135 patients with NSCLC was 18.52%, disease control rate was 65.19%, median PFS was 3.95 months, and median OS was 10.05 months. Regarding the KDR gene polymorphism analysis, the distribution of the 4397T>C polymorphism genotypes was in accordance with the Hardy-Weinberg Equilibrium (P=0.868). Moreover, the prognosis analysis indicated that the median PFS of patients with the CC/TC and TT genotypes was 2.80 and 4.80 months, respectively (P=0.002). Furthermore, the median OS of patients with the two genotypes was 9.10 and 10.56 months, respectively (P=0.041). The multivariate Cox regression analysis showed that the TC/CC genotypes were an independent factor for PFS (odds ratio: 1.72, P=0.009). There was no correlation between the polymorphism and adverse reactions. Additionally, the mRNA expression analysis suggested that the mRNA levels of KDR in cancer tissues were significantly different between the TT and TC/CC genotypes (P<0.001). CONCLUSION: The clinical outcomes of treatment with apatinib mesylate for advanced non-squamous NSCLC in patients who progressed after standard therapy may be influenced by the KDR 4397T>C polymorphism through mediation of the mRNA expression of KDR.