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Background Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies. Methods This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1. Results A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4–8.3), 11.6 months (95% CI 8.3–13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. Conclusions Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC. Trial registration Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.

Background The aims of the study were to evaluate potential differences among first-line treatment for EGFR mutant (m+) non-small cell lung cancer (NSCLC) patients with brain metastasis in China and to identify the factors influencing survival outcomes. Methods In this retrospective study, 172 EGFRm + patients with advanced NSCLC who received a 1st generation EGFR tyrosine kinase inhibitor (TKI) were divided into 4 groups: A, EGFR-TKI (n = 84); B, EGFR-TKI + pemetrexed + cisplatin/carboplatin chemotherapy (CT) (n = 55); C, EGFR-TKI + bevacizumab (n = 15); and D, EGFR-TKI + pemetrexed + cisplatin/carboplatin CT + bevacizumab (n = 18). Intracranial and extracranial progression-free survival (PFS), the overall survival (OS), objective remission rates (ORRs) and adverse events were analyzed. Results Intracranial PFS of groups C + D was longer than for groups A + B (18.9 m vs. 11.0 m, P = 0.027). Extracranial PFS were longer in group B in comparison with group A (13.0 m vs. 11.5 m, P = 0.039) and in groups C + D compared to groups A + B (18.9 m vs. 11.9 m, P = 0.008). Median OS in groups A and B were 27.9 m and 24.4 m, respectively, while groups C and D have not yet achieved median OS. Significant difference was found in intracranial ORR between groups A + B vs. C + D (31.0% vs. 65.2%, P = 0.002). Most patients suffered grade 1–2 treatment-related adverse events, which were relieved soon after symptomatic treatment. Conclusions First-generation EGFR-TKI + bevacizumab treatment outperformed other regimens in EGFRm + NSCLC patients with brain metastasis. The therapy improved the control and delayed progression of intracranial lesions and prolonged survival times.

Toll-like receptors (TLRs) comprise a class of highly conserved molecules that recognize pathogen-associated molecular patterns and play a vital role in host defense against multiple viral infectious diseases. Although TLRs are highly expressed on innate immune cells and play indirect roles in regulating antiviral adaptive immune responses, intrinsic expression of TLRs in adaptive immune cells, including T cells and B cells, cannot be ignored. TLRs expressed in CD4 + and CD8 + T cells play roles in enhancing TCR signal-induced T-cell activation, proliferation, function, and survival, serving as costimulatory molecules. Gene knockout of TLR signaling molecules has been shown to diminish antiviral adaptive immune responses and affect viral clearance in multiple viral infectious animal models. These results have highlighted the critical role of TLRs in the long-term immunological control of viral infection. This review summarizes the expression and function of TLR signaling pathways in T and B cells, focusing on the in vitro and vivo mechanisms and effects of intrinsic TLR signaling in regulating T- and B-cell responses during viral infection. The potential clinical use of TLR-based immune regulatory drugs for viral infectious diseases is also explored.

45S5 Bioglass® has been widely used in bone tissue engineering scaffold due to its high bioactive properties. 3D printing method is a popular way to fabricate scaffolds. The extrusion printing method causes poor shape and dimensional accuracy of the scaffolds. The ordinary light-cured 3D printing method leads to low solid content of the scaffolds, which causes large shape shrinkages and low mechanical properties after sintering. In this study, we employed the stereolithographic ceramic manufacturing (SLCM) method to fabricate 45S5 Bioglass®-based scaffolds. Coating-then-stereolithographic layer by layer is the core process of SLCM method. Based on the optimization of the parameters of SLCM process and sintering process, the solid content of the 45S5 scaffold can be improved to a maximum of 70 %, and the linear shrinkage and compressive strength were effectively improved. The proposed method can be used not only for fabricating bone tissue engineering scaffold, but also for manufacturing other high solid content ceramic products.

The application of three-dimensional printed polymer scaffolds in repairing bone defects is a promising strategy. Among them, polycaprolactone (PCL) scaffolds are widely studied due to their good processability and controlled degradation rate. However, as an alternative graft for repairing bone defects, PCL materials have poor hydrophilicity, which is not conducive to cell adhesion and growth. In addition, the poor mechanical properties of PCL materials cannot meet the strength required to repair bone defects. In this paper, nano-zirconium dioxide (ZrO2) powder is embedded in PCL material through a melt-mixing process, and a regular grid scaffold is constructed by 3D printing. The embedding of nanometer zirconium dioxide powder improves the hydrophilicity and water absorption of the composite scaffold, which is conducive to cell adhesion, proliferation and growth and is beneficial to the exchange of nutrients. Therefore, the PCL/ZrO2 composite scaffold showed better biological activity in vitro. At the same time, the PCL/ZrO2 composite material system significantly improves the mechanical properties of the scaffold. Among them, compared with the pure PCL scaffold, the Young’s modulus is increased by about 0.4 times, and the compressive strength is increased by about 0.5 times. In addition, the osteogenic differentiation results also showed that the PCL/ZrO2 composite scaffold group showed better ALP activity and more effective bone mineralization than the pure PCL group. We believe that the 3D printed PCL/ZrO2 composite scaffold has certain application prospects in repairing bone defects.

Retrospective analysis of data from 14,528 lung cancer patients with multiple primary malignant neoplasm (MPMN) revealed that 2.5% (364/14,528) were MPMN cases and 96.2% (350/364) were diagnosed with two primary malignancies, 3.6% (13/364) with three primary malignancies, and 0.3% (1/364) with four primary malignancies. Among 350 lung cancer patients diagnosed with two primary malignancies, 26.6% (93/350) had lung cancer diagnosed first (LCF) and 73.4% (257/350) had other cancers diagnosed initially (OCF), whereas synchronous MPMN (SMPMN) accounted for 21.1% (74/350) and metachronous MPMN (MMPMN) accounted for 78.9% (276/350) of the cases. Detection of first primary neoplasms were at an early stage for LCF patients and the age of the first lung cancer diagnosis was 59.3 years vs. 55.4 years in the OCF group (P = 0.008), whereas the onset age of second primary neoplasm diagnosis was similar in both groups (62.5 and 61.6 years, P = 0.544). Median survival times of MMPMN and SMPMN patients in the LCF group were 6.83 and 2.42 years and in the OCF group 8.67 years and 2.25 years, respectively. Multivariate analysis showed that SMPMN, LCF and the age of the primary cancer diagnosed first ( ≥ 60 years) and NSCL staging > II were significant independent factors for inferior prognosis of patients.

Purpose To evaluate the efficacy of maintenance apatinib after chemotherapy for extensive-stage (ED) small-cell lung cancer (SCLC). Patients and methods This was a retrospective analysis of 23 cases of extensive-stage SCLC admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2015 to December 2017. The patients without progression after induction chemotherapy received apatinib 250 mg per day until disease progression or unacceptable toxicity occurred. We analyzed the median progression-free survival (PFS), median overall survival (OS) and safety. Results Of 23 enrolled patients, 1 was lost to follow-up. The median PFS from the time of maintenance therapy was 4.1 months (95% CI 3.63–4.57 months). The median PFS from the time of induction chemotherapy was 8.3 months (95% CI 7.20–9.40 months). The median OS from the time of maintenance therapy was 12.5 months (95% CI 5.51–19.49 months). The median OS from the time of induction chemotherapy was 17.0 months (95% CI 9.86–24.14 months). The most frequent treatment-related adverse events were hand–foot syndrome (43.5%, 10/23) and secondary hypertension (30.4%, 7/23), followed by fatigue, proteinuria, nausea, and oral mucositis (17.4%, 13.0%, 13.0%, and 8.7%, respectively). Hematologic toxicity included thrombocytopenia (30.4%), leucopenia (26.1%), and anemia (17.4%). The main grade 3 or 4 toxicities were hand–foot syndrome (8.7%, 2/23) and hypertension (4.3%, 1/23). Conclusion Maintenance apatinib was safe and achieved encouraging PFS and OS in extensive-stage SCLC.

The outcome of hepatitis B viral (HBV) infection is determined by the complex interactions between replicating HBV and the immune system. While the role of the adaptive immune system in the resolution of HBV infection has been studied extensively, the contribution of innate immune mechanisms remains to be defined. Here we examined the role of the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) signaling pathway in adaptive immune responses and viral clearance by exploring the HBV mouse model. Hydrodynamic injection with a replication-competent HBV genome was performed in wild-type mice (WT) and a panel of mouse strains lacking specific innate immunity component expression. We found higher levels of HBV protein production and replication in Tlr2-/-, Tlr23479-/-, 3d/Tlr24-/-, Myd88/Trif-/- and Irak4-/- mice, which was associated with reduced HBV-specific CD8+ T-cell responses in these mice. Importantly, HBV clearance was delayed for more than 2 weeks in 3d/Tlr24-/-, Myd88/Trif-/- and Irak4-/- mice compared to WT mice. HBV-specific CD8+ T-cell responses were functionally impaired for producing the cytokines IFN-γ, TNF-α and IL-2 in TLR signaling-deficient mice compared to WT mice. In conclusion, the IL-1R/TLR signaling pathway might contribute to controlling HBV infection by augmenting HBV-specific CD8+ T-cell responses.

Material extrusion-based additive manufacturing (AM) is an effective tool in producing prototypes and final parts without geometrical complexity limitations. Despite having widespread applications and enormous advantages over conventional manufacturing techniques, the proliferation of extrusion-based AM has been limited by the low deposition quality and the poor surface finish of printed parts. To address these issues, an optimized path planning technique is proposed in this paper. The sharp corners and the non-uniform spacing between adjacent path elements in the final planned path are two major causes of unevenness of the deposited surface. The proposed method tries to decrease the number of sharp corners by using an implicit algorithm derived from the level sets of the input contours. The curvature information is used to smooth the generated contour paths. Subsequently, to achieve uniform spacing, local optimization is applied on the smoothed path by adaptively adjusting the locations of points on the path. These optimizations lead to a smoother part surface, when compared to those of typical fill path techniques. The proposed method is validated using several examples of parts, many of which are then constructed using a 3D printer.

In a world widely using wind turbines, the frequency converter is connected with the generator to obtain power grid-connected frequency, which makes their electric power quality weaker than that of conventional synchronous generators. Some researches apply a driveline at the high speed end of the gearbox in wind turbines with a continuously variable transmission (CVT), which can provide the constant rotation speed output for the generator under variable rotor speed of the wind power without the frequency converter. However, shafts in the CVT are subject to the pulsating torque from subsynchronous resonance (SSR), which can affect the speed control seriously. This note proposes the speed control for the permanent magnet synchronous motor as the speed regulator in the CVT at wind turbines under SSR. A linear quadratic controller with load torque observer is developed for the speed control. The simulation results verify the developed speed controller for the CVT in a 1.5 MW variable-speed wind turbine based on the simulation of SSR on Simulink and different wind speed conditions on the FAST software developed by the National Renewable Energy Laboratory.

Under rain-wind conditions, rain-wind induced aerodynamic instability phenomenon often occurs on high-voltage transmission lines. Like the effects of any other oscillations, this kind of vibration intensifies the fatigue of high-voltage conductors, especially on line supports or clamps. The presence of raindrops and wind associated with electric field maybe the main cause of this phenomenon. On rainy days, raindrops hit the transmission line and suspends to the high-voltage conductor. The suspended raindrops form upper rivulet and lower rivulet and take an elliptical arch shape along the surface of the high-voltage conductor by action of the wind, if rainfall is sufficient. Moreover, the rivulets are enlarged as a cone shape with the electric field of high-voltage conductor. The upper rivulet’s effect on the original cross-section formation of the high-voltage conductor and its movement are likely to be the cause of aerodynamic instability. The objective of this paper is to validate a two-dimensional model to investigate the effects of different parameters (electric field strength, wind velocity, frequency and damping ratio of the dynamic system) on aerodynamic stability of the conductor. The Lyapunov stability theory is applied to the model to derive the criterion for the instable angle of the rivulet. Moreover, an experimental conductor model with a moveable artificial upper rivulet is set-up and tested in a wind tunnel. The theoretical results are in good agreement with the experimental data. The model enable better comprehension of the rain-wind induced aerodynamic instability on the conductor.

Whether bisphosphonates could enhance the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation and bone metastases (BM) remains unknown. EGFR mutation status were collected from 1560 patients with NSCLC and BM. 356 NSCLC patients with EGFR mutation and BM were identified. Among them, 91 patients received EGFR-TKIs alone and 105 patients received EGFR-TKIs plus bisphosphonates as first-line therapy. Comparing to TKIs alone, EGFR-TKIs plus bisphosphonates had a statistically significant longer progression-free survival (PFS: 11.6 vs. 9.3 months; HR = 0.68, P = 0.009), while a similar overall survival (OS: 20.5 vs. 19.5 months; HR = 0.95, P = 0.743) in patients with EGFR-mutant NSCLC and BM. The incidence of skeletal-related events in combined group was numerically lower than that in EGFR-TKIs alone group (29.7% vs. 39.4%, P = 0.147). In multivariate analysis, EGFR mutation was found to be a significant independent prognostic factor for OS in NSCLC patients with BM (HR = 0.710, P = 0.021). In conclusion, EGFR mutation was the significant independent prognostic factor for OS and the addition of bisphosphonates to EGFR-TKIs could enhance the antitumor effect of EGFR-TKIs in patients with EGFR-mutant NSCLC and BM.

SAMHD1 is a type I interferon (IFN) inducible host innate immunity restriction factor that inhibits an early step of the viral life cycle. The underlying mechanisms of SAMHD1 transcriptional regulation remains elusive. Here, we report that inducing SAMHD1 upregulation is part of an early intrinsic immune response via TLR3 and RIG-I/MDA5 agonists that ultimately induce the nuclear translocation of the interferon regulation factor 3 (IRF3) protein. Further studies show that IRF3 plays a major role in upregulating endogenous SAMHD1 expression in a mechanism that is independent of the classical IFN-induced JAK-STAT pathway. Both overexpression and activation of IRF3 enhanced the SAMHD1 promoter luciferase activity, and activated IRF3 was necessary for upregulating SAMHD1 expression in a type I IFN cascade. We also show that the SAMHD1 promoter is a direct target of IRF3 and an IRF3 binding site is sufficient to render this promoter responsive to stimulation. Collectively, these findings indicate that upregulation of endogenous SAMHD1 expression is attributed to the phosphorylation and nuclear translocation of IRF3 and we suggest that type I IFN induction and induced SAMHD1 expression are coordinated.

In this paper, we establish a decay result of global solutions and the existence of the global attractor for higher-dimensional linear thermoviscoelastic equations by introducing a velocity feedback on a part of the boundary and using multiplier techniques. We extend the results in Messaoudi and Mustafa (Nonlinear Anal. TMA 10:3132---3140, 2009) for a viscoelastic system to those for a thermoviscoelastic system.

The outbreak of a novel influenza A (H1N1) virus across the globe poses a threat to human health. It is of paramount importance to develop a rapid, reliable and inexpensive diagnostic procedure. Based on the bioinformatic information from public database, primers specific for influenza A virus surface protein haemagglutinin (HA) of several subtypes (including H1, H2, H3, H5, H7 and H9) were designed. Primer-specific PCR products were subjected to sequencing for accurately distinguishing H1 and H3 subtypes from others. This sequencing-based detection method will not only be applied to rapid detection and simultaneous subtype identification of new influenza A virus H1N1, but also provide the strategies to monitor other new types of influenza virus with explosive potential.

We consider a one-dimensional continuous model of nutron star, which is described by a compressible thermoviscoelastic system with a non-monotone equation of state, due to the effective Skyrme nuclear interaction between particles. We will prove that, despite a possible destabilizing influence of the pressure, which is non-monotone and not always positive, the presence of viscosity and a sufficient thermal dissipation can yield the global existence of solutions in H4 with a mixed free boundary problem for our model.

Background p53 is a tumor suppressor that contributes to the host immune response against viral infections in addition to its well-established protective role against cancer development. In response to influenza A virus (IAV) infection, p53 is activated and plays an essential role in inhibiting IAV replication. As a transcription factor, p53 regulates the expression of a range of downstream responsive genes either directly or indirectly in response to viral infection. We compared the expression profiles of immune-related genes between IAV-infected wild-type p53 (p53WT) and p53-deficient (p53KO) mice to gain an insight into the basis of p53-mediated antiviral response. Methods p53KO and p53WT mice were infected with influenza A/Puerto Rico/8/1934 (PR8) strain. Clinical symptoms and body weight changes were monitored daily. Lung specimens of IAV-infected mice were collected for analysis of virus titers and gene expression profiles. The difference in immune-related gene expression levels between IAV-infected p53KO and p53WT mice was comparatively determined using microarray analysis and confirmed by quantitative real-time reverse transcription polymerase chain reaction. Results p53KO mice showed an increased susceptibility to IAV infection compared to p53WT mice. Microarray analysis of gene expression profiles in the lungs of IAV-infected mice indicated that the increased susceptibility was associated with significantly changed expression levels in a range of immune-related genes in IAV-infected p53KO mice. A significantly attenuated expression of Ifng (encoding interferon (IFN)-gamma), Irf7 (encoding IFN regulator factor 7), and antiviral genes, such as Mx2 and Eif2ak2 (encoding PKR), were observed in IAV-infected p53KO mice, suggesting an impaired IFN-mediated immune response against IAV infection in the absence of p53. In addition, dysregulated expression levels of proinflammatory cytokines and chemokines, such as Ccl2 (encoding MCP-1), Cxcl9, Cxcl10 (encoding IP-10), and Tnf, were detected in IAV-infected p53KO mice during early IAV infection, reflecting an aberrant inflammatory response. Conclusion Lack of p53 resulted in the impaired expression of genes involved in IFN signaling and the dysregulated expression of cytokine and chemokine genes in IAV-infected mice, suggesting an essential role of p53 in the regulation of antiviral and inflammatory responses during IAV infection. Electronic supplementary material The online version of this article (doi:10.1186/s12920-015-0127-8) contains supplementary material, which is available to authorized users.

Abnormal amplification of centrosomes, commonly found in human cancer, is the major cause of mitotic defects and chromosome instability in cancer cells. Like DNA, centrosomes duplicate once in each cell cycle, hence the defect in the mechanism that ensures centrosome duplication to occur once and only once in each cell cycle results in abnormal amplification of centrosomes and mitotic defects. Centrosomes are non-membranous organelles, and undergo dynamic changes in its constituents during the centrosome duplication cycle. Through a comparative mass spectrometric analysis of unduplicated and duplicated centrosomes, we identified mortalin, a member of heat shock protein family, as a protein that associates preferentially with duplicated centrosomes. Further analysis revealed that mortalin localized to centrosomes in late G1 before centrosome duplication, remained at centrosomes during S and G2, and dissociated from centrosomes during mitosis. Overexpression of mortalin overrides the p53-dependent suppression of centrosome duplication, and mortalin-driven centrosome duplication requires physical interaction between mortalin and p53. Moreover, mortalin promotes dissociation of p53 from centrosomes through physical interaction. The p53 mutant that lacks the ability to bind to mortalin remains at centrosomes, and suppresses centrosome duplication in a transactivation function-independent manner. Thus, our present findings not only identify mortalin as an upstream molecule of p53 but also provide evidence for the involvement of centrosomally localized p53 in the regulation of centrosome duplication.

A mutation network for the hemagglutinin gene (HA) of the novel type A (H1N1) influenza virus was constructed. Sequence homology analysis indicated that one HA sequence type from the viruses mainly isolated from Mexico was likely the original type in this epidemic. Based on the 658A and 1408T mutations in HA, the viruses evolving into this epidemic were divided into three categories, the Mexico, the transitional and the New York type. The three groups of viruses presented distinctive clustering features in their geographic distributions.

Background The purpose of this study was to evaluate the role of osteoprotegerin gene (OPG) polymorphisms as genetic modifiers in the etiology of prostate cancer (PCa) and disease progression. Methods Three hundred and sixty one patients with PCa and 195 normal controls were enrolled in the study, and two genetic polymorphisms, 149 T/C and 950 T/C in the putative promoter region of OPG, were genotyped. Results There was no significant difference in the genotype frequencies between PCa patients and controls (P = 0.939 and 0.294 for 149 T/C and 950 T/C polymorphisms, respectively). However, those patients with TC and TT genotypes in the 950 T/C polymorphism had a significantly increased risk of extraprostatic (age-adjusted odds ratio; aOR = 1.74 and 2.03 for TC and TT genotypes compared with the CC genotype, P = 0.028) and metastatic disease (aOR = 1.72 and 2.76 for TC and TT genotypes compared with the CC genotype, P = 0.009) compared with those with the CC genotype. In addition, analysis of the metastatic PCa patients (Stage D) showed that the presence of the T allele of the OPG 950 T/C polymorphism was an independent risk factor predicting survival by Cox proportional hazard regression analyses (P = 0.031). Conclusion Progression of PCa may be influenced by an intrinsic genetic factor of the host's bone metabolism. The variant C allele of 950 T/C in the OPG promoter may play a major role as a genetic safe guard against progression in patients with PCa.

Inserting a titanium layer between cobalt and silicon can control the phase formation sequence for cobalt silicide. In this study we show that sputtered Ti combines with surface oxide to form a stable permeable membrane 2 to form above and below the interlayer, respectively. Because the interlayer is very thin, the type of substrate doping dominates the reaction sequence at higher temperatures. Given sufficient cobalt supply, at 500-600°C the initial phases transform to CoSi for an n-type Si substrate. For a p-type substrate the Co2Si phase converts to CoSi while the bottom CoSi2 phase remains stable. Above 650°C, the deposited cobalt fully converts to the final CoSi2 phase.