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Cardio-cerebrovascular disease (CCVD) is a major comorbidity of Coronavirus disease 2019 (COVID-19). However, the clinical characteristics and outcomes remain unclear. In this study, 102 cases of COVID-19 from January 22, 2020 to March 26, 2020 in Xixi Hospital of Hangzhou were included. Twenty cases had pre-existing CCVD. Results showed that compared with non-CCVD patients, those with CCVD are more likely to develop severe disease (15% versus 1%), and the proportion of pneumonia severity index grade IV was significantly higher (25% versus 3.6%). Computed tomography images demonstrated that the proportion of multiple lobe lesion involvement was significantly higher in the CCVD group than in the non-CCVD group (90% versus 63.4%). Compared with non-CCVD group, the levels of C-reactive protein, fibrinogen, D-dimer, and serum amyloid-A were higher, whereas the total protein and arterial partial PaO2 were lower in the CCVD group. Although no statistical difference was observed in the outcomes between groups, CCVD patients received more intensive comprehensive treatment to improve COVID-19 symptoms compared with non-CCVD patients. Integrated Chinese and Western medicine treatments have certain advantages in controlling the severe conversion rate and mortality of COVID-19. In addition, given that COVID-19 patients are usually related to coagulation disorders and thrombosis risk, the application of Chinese medicine in promoting blood circulation and removing stasis should be strengthened.

With the continued transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout the world, identification of highly suspected COVID-19 patients remains an urgent priority. In this study, we developed and validated COVID-19 risk scores to identify patients with COVID-19. In this study, for patient-wise analysis, three signatures, including the risk score using radiomic features only, the risk score using clinical factors only, and the risk score combining radiomic features and clinical variables, show an excellent performance in differentiating COVID-19 from other viral-induced pneumonias in the validation set. For lesion-wise analysis, the risk score using three radiomic features only also achieved an excellent AUC value. In contrast, the performance of 130 radiologists based on the chest CT images alone without the clinical characteristics included was moderate as compared to the risk scores developed. The risk scores depicting the correlation of CT radiomics and clinical factors with COVID-19 could be used to accurately identify patients with COVID-19, which would have clinically translatable diagnostic and therapeutic implications from a precision medicine perspective.

In this study, novel Ni–Cu–Zn ferrites with the chemical formula [Ni0.6Zn0.4][Cu0.2CoxFe1.8−x]O4 (x = 0, 0.05, 0.10, 0.15, 0.20, 0.25) doped with Co2+ ions were designed and manufactured by standard solid-state reaction method. The magnetic properties, surface characteristics, and ion occupancy of ferrites were studied by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and vibrating sample magnetometer (VSM), and we explained the different mechanisms of the results and the relationship between magnetic properties and microstructures. For the obtained samples, cobalt ions entered the lattice, and all samples were characterized as spinel structures. As the doping amount of Co2+ ions increases, the lattice constant and volume of the sample also increases. With an appropriate doping level, Co2+ ions-doped Ni–Cu–Zn ferrites can maintain higher saturation magnetization, higher magnetic permeability, and lower hysteresis loss. When x ≤ 0.1, the saturation magnetization Ms increases significantly as the doping amount of Co2+ ions increases, but when x > 0.1, the value decreases. The experimental results show that the saturation magnetization value is 118.08 emu/g, the magnetic permeability value is 39.47 H/m, and the hysteresis loss is 1.192 mW/cm3 at an optimum doping amount. Therefore, the sample achieves the best magnetic properties when the doping amount is 0.1.

The cryogenic magnetocaloric effect has attracted great attention due to its application in cryogenic refrigeration technology, which is essential for space science and quantum computing. In this study, the magnetocaloric effect of Gd2GeMoO8 (GGMO) and Dy2GeMoO8 (DGMO), which were prepared by simple solid-state reactions, had been investigated. The XRD refinement analysis suggested that GGMO and DGMO crystallize in a tetragonal structure. A large magnetic entropy change (Δ SM) of −41.2 J kg−1 K−1 was observed at 1.8 K for GGMO under a magnetic field (Δ H) of 7 T. A moderate Δ SM of −14.1 J kg−1 K−1 was obtained at 4.5 K under a Δ H of 7 T in DGMO. The refrigeration capacity and relative cooling power reached 257.4 and 337.8 J kg−1 for GGMO and 133.3 and 143.7 J kg−1 for DGMO, respectively, under a Δ H of 0–7 T. Our results suggest that GGMO is a competitive cryogenic magnetic refrigeration material.

RNA modification has become an exciting underexplored field in recent years. In lung adenocarcinoma (LUAD), m6A was the best characterized and most studied RNA modification, while knowledge about other kinds of RNA modifications in LUAD is limited. In our study, we included a total of 100 RNA modification regulators of eight types of cancer-related RNA modifications (m6A, m1A, m5C, Nm, m7G, Ψ, A-to-I, and mcm5s2U) to systematically profile their specific roles in LUAD. By gene mutation and expression analysis, we identified extensive dysregulations and complicated interactions of 100 RNA modification regulators in LUAD. Based on unsupervised clustering analysis, gene set variation analysis (GSVA), and single-sample gene-set enrichment analysis (ssGSEA), two RNA modification patterns in LUAD were defined to show distinct biological characteristics. The favorable prognostic pattern was enriched with infiltrated immune cells, including activated B cells, CD8 T cells, eosinophil cells, dendritic cells, and natural killer cells, while the unfavorable prognostic pattern was enriched with cancer hallmarks, including hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, PI3K-AKT-mTOR pathway, MYC pathway, and glycolysis pathway. We also constructed an RNA modification score (RMScore) based on five critical genes (CYP17A1, NTSR1, PITX3, KRT6A, and ANLN) to evaluate the RNA modification status of individual LUAD patients. RMScore was revealed to be related to the infiltrated immune cells and cancer hallmarks and was an independent prognostic factor in the TCGA-LUAD cohort and two external GEO-LUAD cohorts. Our study was the first to comprehensively investigate the dysregulations, crosstalk, and potential prognostic value of eight types of RNA modifications in LUAD. Our results highlighted the significance of eight types of RNA modifications in tumor microenvironments and cancer hallmarks and provided novel prognostic biomarkers and potential therapeutic targets in the management of LUAD patients in the future.

Here, we sought to develop a PET radioligand based on trastuzumab labeled with 124I, 124I-trastuzumab, to evaluate its distribution, internal dosimetry, and initial PET images of HER2-positive lesions in gastric cancer (GC) patients. In animal studies, micro-PET imaging and bio-distribution were performed to examine the specificity of 124I-trastuzumab in HER2-positive and HER2-negative mouse models. Subsequently, 124I-trastuzumab was applied in human clinic trial. Six gastric cancer patients with metastases underwent 124I-trastuzumab PET imaging, with 18F-FDG PET/CT in each to compare. In animal studies, PET imaging of 124I-trastuzumab showed significant higher tumor uptake than that of 124I-IgG1 in HER2-positive PDX mouse models at 24 h. The low tumor uptake of 124I-trastuzumab in HER2-negative PDX models further confirmed the specificity. In human clinical studies, 18 HER2-positive lesions and 11 HER2-negative lesions were evaluated in PET imaging analysis. The detection sensitivity of 124I-trastuzumab was 100% (18/18) at 24 h. The PET images showed significant difference in tumor uptake between HER2-positive and HER2-negative lesions at 24 h (SUVmax 7.83 ± 0.55 vs. 1.75 ± 0.29, p

The spin glass (SG) behavior of Ni substituted spinel ferrites having chemical formula Zn0.8-xNixCu0.2Fe2O4 (0 ≤ x ≤ 0.28) has been systematically investigated. By means of zero-field-cooling and field-cooling magnetizations, the strong irreversibility is distinct demonstrated. The measurement results demonstrate a typical SG behavior for 0 ≤ x ≤ 0.28. Antiferromagnetic (AFM) interaction is dominant in the competition between ferromagnetic (FM) and AFM interaction for x = 0. In addition, the freezing temperature of the SG state exhibits a decrease with increasing pressure since the SG state is inhibited. As the substitution of Ni for Zn increase, the interaction of FM gradually is equivalent to the AFM interaction and dominant, while the MS and TC increase which is due to the enhancement of the super-exchange interaction JAB.

We have found that the Curie temperature (Tc) of Co-based amorphous alloy Co90Nb10Ta3 (Tc = 360 K) is much lower than many amorphous alloy systems. Through further research, we have found Co90Nb10Ta3 exists second-order ferromagnetic (FM) to paramagnetic (PM) phase transition near the Tc. Co90Nb10Ta3 amorphous alloy near the Tc has a larger magnetocaloric effect (MCE), under the ΔH = 60 kOe, - Δ S M max =2.43 J kg−1K−1, relative cooling power (RCP) can reach 203.55 J/kg. Compared with Fe-B-Cr, Fe-Cr-Cu-Nb-Si-B, FeCoSiAlGaPCB and FeCrMoCuGaPCB amorphous alloy, the Co-Nb-Ta amorphous alloy has better properties. Co-Nb-Ta amorphous alloy has better mechanical and chemical properties than other amorphous alloys, it is a potential MCE material.

To investigate the solubility of carbon dioxide (CO2) in geological fluids at different temperatures and pressures, we developed a method for measuring solubility using an optically transparent fus...

In this paper, we successfully prepared FeSiAl powders passivated by aqueous phosphoric acid solution and studied the passivation process and magnetic properties. The SEM, XRD and XPS were used to tested the morphology and structure. From our study, we had confirmed that passivation and corrosion processes occur simultaneously and undergo competitive mechanism between them. In the later stage of the passivation, Al3+ and PO3− dominated the reaction process. After forming toroid-shaped magnetic core by cold compaction, soft magnetic properties like saturation magnetization, initial permeability, core loss and DC-bias had been tested and analyzed by VSM, B-H alternating current magnetic characteristic analyzer and Agilent 4284 ALCR meter. We found that ultrasound could improve the soft magnetic properties of core but reduce its permeability. Optimized magnetic properties (Ms = 117.91emu/g, μi = 33.02, Pcv = 614.1 mW/cm3, Δμ = 60.29% and Ms = 116.53emu/g, μi = 33.79, Pcv = 629 mW/cm3, Δμ = 58.11%) had been achieved for the FeSiAl SMCs with and without ultrasound for 10 min.

Background Pyrotinib was well tolerated but its efficacy was unsatisfactory in patients with HER2-positive gastric cancer (GC) (NCT02378389). This study was to optimize the efficacy of pyrotinib. Methods Human GC cell lines and AVATAR mice were used to explore the refractory mechanisms of pyrotinib. A pyrotinib-combined strategy was proposed, which was validated in preclinical AVATAR mouse and in clinical patients enrolled in a phase I clinical trial (NCT03480256). Results Dysregulation of CCND1-CDK4/6-Rb axis might be the key to pyrotinib refractory. The strategy of pyrotinib combined with a CDK4/6 inhibitor SHR6390 was proposed and validated in preclinical AVATAR mouse, which was successfully verified in clinical patients. For five patients treated with pyrotinib plus SHR6390 who had available response evaluation, the best response was partial response in three patients, stable disease in one patient, and progressive disease in one patient. The progression-free survival times were 120, 200, 532, 109, and 57 days, respectively. Conclusions This translational study suggests that pyrotinib combined with SHR6390 may serve as a promising strategy for patients with HER2-positive GC. Trial registration The ClinicalTrials.gov identifiers are NCT02378389 (https://clinicaltrials.gov/ct2/show/study/NCT02378389, registered in 11 February 2015) and NCT03480256 (https://clinicaltrials.gov/ct2/show/study/NCT03480256, registered in 8 March 2018).

Met tyrosine kinase inhibitors (Met-TKIs) subjected to ongoing clinical trials are a promising option for Met-amplified gastric cancer (GC), but how to optimize their antitumor activity especially with combination schemes remains unclear. Since autophagy is known to be initiated by Met-TKIs, we investigated its underlying mechanisms and therapeutic potentials of Met-TKIs combined with autophagy inhibitors against Met-amplified GC. As expected, four Met-TKIs induced autophagy in Met-amplified GC cells marked by p62 degradation, LC3-II accumulation and increased LC3-positive puncta. Autophagy flux activation by Met-TKIs was further validated with combined lysosomal inhibitors, bafilomycin A1 (Baf A1) and hydroxychloroquine (HCQ). Molecular investigations reveal that autophagy induction along with mTOR and ULK1 de-phosphorylation upon Met-TKI treatment could be relieved by hepatocyte growth factor (HGF) and mTOR agonist MHY1485 (MHY), suggesting that autophagy was initiated by Met-TKIs via Met/mTOR/ULK1 cascade. Intriguingly, Met-TKIs further suppressed cell survival and tumor growth in the presence of autophagy blockade in Met-amplified GC preclinical models. Thus, these findings indicate Met/mTOR/ULK1 cascade responsible for Met-TKI-mediated autophagy and Met-TKIs combined with autophagy inhibitors as a promising choice to treat Met-amplified GC.

Purpose We aimed to compare chest HRCT lung signs identified in scans of differently aged patients with COVID-19 infections. Methods Case data of patients diagnosed with COVID-19 infection in Hangzhou City, Zhejiang Province in China were collected, and chest HRCT signs of infected patients in four age groups ( Results Small patchy, ground-glass opacity (GGO), and consolidations were the main HRCT signs in 98 patients with confirmed COVID-19 infections. Patients aged 45–59 years and aged ≥60 years had more bilateral lung, lung lobe, and lung field involvement, and greater lesion numbers than patients Conclusions Chest HRCT manifestations in patients with COVID-19 are related to patient’s age, and HRCT signs may be milder in younger patients.

Background Since December 2019, when Coronavirus Disease 2019 (COVID-19) emerged in Wuhan, China, it is currently causing outbreaks in many countries worldwide. No specific therapeutics have yet been proven effective for the treatment of COVID-19. Methods A retrospective, single-center case series study was conducted in a designated hospital for special treatment of COVID-19 in Hangzhou, China. Clinical characteristics of COVID-19 patients were described and compared between the common and severe groups. Multiple linear regression and sensitivity analysis was conducted to evaluate the antiviral effects of the 3-drug combination therapy (lopinavir/ritonavir, interferon, and arbidol). Results One hundred and ten confirmed COVID-19 patients were enrolled, including 99 common cases and 11 severe cases. The mean age was 43.1 years and 54.5% were female. Severe patients might be older (P P P = 0.016), blood sodium (P = 0.039) and chloride (P P P P = 0.014, in Model 2). Conclusions Severe patients might be older and have more comorbidities. The combination of lopinavir/ritonavir, interferon, and arbidol may be a well choice for antiviral therapy, especially in adult common cases.

The purpose of this study was to establish the quality control and quantify the novel 64Cu-NOTA-Trastuzumab in gastric cancer patient-derived xenografts (PDX) mice models and patients by applying the molecular imaging technique. Trastuzumab was labeled with 64Cu using NCS-Bz-NOTA as bifunctional chelator, and hIgG1 was labeled with the same procedures as a negative control agent. HER2-positive (case 176, n = 12) and HER2-negative (case 168, n = 3) PDX models were established and validated by Western blot, DNA amplification, and immunohistochemistry (IHC). Both models were conducted for micro-PET imaging by tail injection of 18.5 MBq of 64Cu-NOTA-Trastuzumab or 64Cu-NOTA-hIgG1. Radioprobe uptake in tumor and main organs was quantified by region of interested (ROI) analysis of the micro-PET images and autoradiography. Finally, gastric cancer patients were enrolled in preliminary 64Cu-NOTA-Trastuzumab PET/CT scans. NOTA-Trastuzumab was efficiently radiolabeled with 64Cu over a 99% radiochemical purity and 17.5 GBq/μmol specific activity. The immune activity was preserved as the nonmodified antibody, and the radiopharmaceutical proved to be stable for up to 5 half-decay lives of 64Cu both in vitro and in vivo. Two serials of PDX gastric cancer models were successfully established: case 176 for HER2 positive and case 168 for HER2 negative. In micro-PET imaging studies, 64Cu-NOTA-Trastuzumab exhibits a significant higher tumor uptake (11.45 ± 0.42 ID%/g) compared with 64Cu-NOTA-IgG1 (3.25 ± 0.28 ID%/g, n = 5, p = 0.0004) at 36 h after intravenous injection. Lower level uptake of 64Cu-NOTA-Trastuzumab (6.35 ± 0.48 ID%/g) in HER2-negative PDX tumor models further confirmed specific binding of the radioprobe. Interestingly, the coinjection of 2.0 mg of Trastuzumab (15.52 ± 1.97 ID%/g) or 2.0 mg of hIgG1 (15.64 ± 3.54 ID%/g) increased the 64Cu-NOTA-Trastuzumab tumor uptake in PDX tumor (HER2+) models compared with 64Cu-NOTA-Trastuzumab alone ( p < 0.05) at 36 h postinjection. There were good correlations between micro-PET images and IHC ( n = 4) and autoradiography in PDX (HER2+) tumor tissues. Therefore, 64Cu-NOTA-Trastuzumab successfully translated to clinical PET imaging, and 64Cu-NOTA-Trastuzumab PET/CT scan in gastric cancer patients showed good detection ability. In conclusion, we reported quality control and application of novel 64Cu-NOTA-Trastuzumab for HER2 expression in PDX gastric cancer mice models and gastric cancer patients. Moreover, 64Cu-NOTA-Trastuzumab holds great potential for noninvasive PET detection, staging, and follow-up of HER2 expression in gastric cancer.

In this paper, we compounded the FeSiAl powder with a novel amorphous inorganic insulation agent (AIIA). Silicone resin (3 wt.%) was used as organic insulating agent, and the inorganic insulating agent was Fe83.5Si7.5B5Cr4 amorphous powder (0, 1, 2, 3, and 4 wt.%). Amorphous powder was prepared by passivation pretreatment before compounding. The results showed that the addition of amorphous inorganic insulating agent will significantly affect the soft magnetic properties of FeSiAl powders. Compared with the pure FeSiAl powder having only silicone resin the saturation magnetization of composite powders slightly increased (by 0.1–4.9%). When AIIA content was 2 wt.%, the sample had the highest initial permeability, which increased by 14.6%. At the same time, the core loss was also reduced by 15.7% (Bm = 5 mT, f = 1000 kHz) when AIIA content was also 2 wt.%.

In this paper, the effect of adding Permalloy (

Alternative mRNA splicing (AS) contributes greatly to expanding the diversity and function of the proteome. Increasing evidence has suggested that dysregulation of mRNA splicing may be associated with various types of cancer. In the present study, RNA sequencing data were used to investigate alterations to the global mRNA splicing landscape of cellular genes from 452 stomach adenocarcinoma (STAD) tissues available in The Cancer Genome Atlas. Seven types of AS events, including the profiles of exon skipping events, were analyzed using SpliceSeq software. A total of 60,754 AS events in 10,611 genes were detected, more than half of which were exon skipping events. The AS events were compared between 415 STAD tissues and 37 normal tissues, and 3,895 differentially spliced cancer-specific events were identified. In addition, the association of the AS events with the overall survival of 373 STAD patients was analyzed. Multivariate Cox regression analysis revealed that prognosis prediction models based on the AS events with clinical parameters had an excellent performance in predicting the survival of STAD patients. This study provides a comprehensive portrait of global changes in mRNA splicing signatures that occur in gastric cancer. These results allowed the identification of a core set of AS in gastric cancer and indicated that AS events may serve as prognostic indicators.

We first developed NdFeB/PrCo5 nanocomposite magnetic material by high-energy ball milling, and the influence of the different contents of PrCo5 on the magnetic properties of NdFeB was studied by means of XRD, DSC, and VSM. The results showed that compared with single-phase NdFeB permanent-magnet material, NdFeB/PrCo5 nanocomposite magnetic material has superior magnetic properties. When the content of PrCo5 is 10% and the time of ball milling is 10 h, the magnetic properties for NdFeB/PrCo5 nanocomposite magnetic material is best: coercivity is 13.2 kOe, which increased by 14.8% over pure NdFeB phase. Remanent magnetization is 96.31 emu/g and the saturation magnetization is 132.29 emu/g. The remanence ratio is 0.728.

An analytical apparatus with improved recirculating and sampling mechanisms was presented to investigate phase behavior of binary and multicomponent systems, which effectively avoided undesirable pressure gradients across the cell and serious disturbance of equilibrium during sampling procedure. Two one-channel magnetic recirculation pumps were designed and built to provide better mass transfer between the coexisting phases. Two six-port switching valves were used for sampling, quantitative fluid injection, and online compositional analysis by gas chromatography. The apparatus was validated by means of isothermal vapor–liquid equilibrium data for CO2 + hexane, and the results were found to be in good agreement with the literature data. High pressure phase equilibria data of CO2 + n-alkanes and CO2 + crude oil + n-alkanes were measured from 353.15 to 373.15 K. Three thermodynamic models of RR, PRSV, and YQE, based on Peng–Robinson and a modified quartic equation of state coupled with various mixing rules, ...

To investigate the volume expansion of a carbon dioxide (CO2) + n-hexane mixture at different temperatures and pressures, we developed a measurement setup using an optically transparent fused silica capillary cell (FSCC) combined with Raman spectra. The results showed that the method is feasible, the water seal is effective in its ability to avoid vaporization of n-hexane, and Raman spectra can help ensure the system equilibrium. The volume expansion factor of the CO2 + n-hexane mixture increased with increasing pressure from 1 to 10 MPa and decreased with increasing temperature from 30 to 80 °C. It was found that the trend of the expansion factor of the CO2 + n-hexane mixture was steeper at a higher temperature. When the temperature was 30 °C, the volume expansion factor increased from 2.15 to 13.61 as the pressure increased from 5.0 to 6.5 MPa. Meanwhile, the volume expansion factor increased from 2.36 to 19.40 as the pressure increased from 8.0 to 9.2 MPa at 60 °C. In addition, we obtained a significan...

Here, we sought to develop a PET radioligand based on trastuzumab labeled withIn animal studies, micro-PET imaging and bio-distribution were performed to examine the specificity ofIn animal studies, PET imaging ofThe findings described here demonstrated that

The purpose is to investigate the crystal structure and magnetic properties of MgFe2O4 ferrites with divalent Co2+ cations substitute in CoxMg1-xFe2O4 (x = 0.0, 0.2, 0.5, 0.8, and 1.0) successfully synthesized using standard ceramic technology. The crystal structure, valence state distribution, functional groups, ion occupancy rate and magnetic properties were systematically investigated, revealing that the changes in magnetic properties are closely related to the microstructure. All samples were characterized by XRD as a pure spinel structure with space group Fd-3m. The intrinsic coercivity (Hc), saturation magnetization (Ms) and core loss (Pcv) performance of Co2+ ions doped MgFe2O4 ferrites were significantly optimized under the appropriate doping level. Hc and Ms continuously strengthen in the range of 0 ≤ x ≤ 1 at 300 K, where the maximum saturation magnetization (Ms) reaches 102.0 emu/g and the maximum intrinsic coercive force reaches 253.9 Oe. Besides, compared with x = 1, the sample obtained the lowest core loss and comparatively high magnetic susceptibility at x = 0.8. Simultaneously, the saturation magnetization and coercivity at 300 K are 76.5 emu/g and 184.7 Oe, respectively. Comprehensive experimental results show that the sample possesses a wider range of application when the doping amount x = 0.8.

Gastric cancer is characterized by chromosomal instability. In this study, we investigated chromosomal instability quantified by copy number instability (CNI) score of circulating tumor DNA (ctDNA) during the drug treatment in advanced gastric cancer (AGC). A total of 55 pretherapeutic plasmas from 55 AGC patients and 75 plasmas during drug treatment of 26 AGC patients were collected. Plasma ctDNA was extracted and assessed by whole-genome sequencing (WGS) for somatic copy number alteration (SCNA), and according to which we calculated the CNI scores. We next assessed the correlations between chromosomal instability and therapeutic response. The cutoff value of chromosomal instability was defined as the mean + SD of the CNI scores (56.60) in cfDNA of plasmas from 100 healthy people. For 55 enrolled cases, chromosomal instability was observed in 27 (49%) prior to drug treatment, whose response rate (59%, 16/27) was higher than in 28 patients with stable chromosomes (32%, 9/28, P = 0.043). We also observed that CNI scores fluctuated during treatment in 26 patients. Specifically, the CNI scores in 93% (14/15) of patients sensitive to drug treatment reduced to the level of chromosomal stability and the CNI scores in 52% (13/25) of patients resistant to treatment elevated again. For ctDNA with developed resistance, the SCNA patterns were identical to those before treatment, whereas the CNI scores were lower than the pretherapeutic scores. We found that chromosomal instability based on ctDNA could predict and monitor therapeutic response in gastric cancer, although validation in a larger cohort will be necessary.

Afatinib is a pan-HER inhibitor approved for specific types of lung cancer. We explored antitumor activity, predictive biomarkers and the potential mechanisms underlying antitumor effect and acquired resistance of afatinib in gastric cancer (GC) in vitro and in vivo. Five human GC cell lines and eight patient-derived xenograft (PDX) models with clear molecular profiling were used to evaluate the antitumor activity and mechanisms of afatinib. The ErbB family and downstream PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) pathways were evaluated before and after afatinib treatment. An afatinib-resistant PDX model was established to explore both the potential mechanisms of drug resistance and reversal strategies. We found that afatinib exerted a strong tumor suppression in EGFR/HER2 highly amplified (copy number >6) or overexpressed (IHC 3+) PDX models and a moderate tumor suppression in EGFR/HER2 moderately expressed (IHC 2+) PDX models. Afatinib selectively inhibited the proliferation of HER2 highly amplified GC cells in a dose-dependent manner in vitro. Afatinib also exerted its antitumor effect by inducing cell apoptosis and cell arrest at G1 phase. Diminished activation of the ErbB family and downstream PI3K/AKT/mTOR and MAPK pathways was also observed. Erythropoietin-producing hepatocellular receptor A2 (EPHA2) upregulation and phosphorylation might be involved in afatinib-acquired resistance, and EPHA2 blockade could restore afatinib sensitivity. GC patients with amplification (copy number >6) or overexpression (IHC 3+) of EGFR/HER2 were most likely to benefit from afatinib treatment and EPHA2 blockade reversed acquired resistance to afatinib treatment, which could provide solid evidences for future clinical trials.

Background: Gastric cancer is characterized by frequent somatic copy number alterations (SCNV) and a high level of genomic instability. In this study, we investigated the genomic instability changes of circulating tumor DNA (ctDNA). Methods: A total of 101 plasmas and paired blood cells from 26 patients with AGC before (n = 26) and after (n = 75) drug treatment were collected. Plasma ctDNA was separated and assessed for SCNV by whole-genome sequencing (WGS), and the whole genome abnormality score (WGAS) was calculated. We next assessed the correlations between WGAS and therapeutic response. Findings: Genomic instability was observed in 20 of 26 patients (77%) prior to drug treatment. For patients with genomic instability prior to treatment, the response rate (55%, 11/20) was higher than that (17%, 1/6) of patients with stable genomes. Notably, genomic instability fluctuated during therapy, with 93% (14/15) of post-therapeutic ctDNAs showing low-genomic instability when sensitive to drug therapy and 52% (13/25) of ctDNAs with developed resistance to therapy showing high genomic instability. For ctDNAs with developed resistance, the genomic instability patterns were identical to those before treatment, but the instability level was lower than the pretherapeutic level. Interpretation: We found that genomic instability based on ctDNA could be used to predict and monitor therapeutic response in gastric cancer, although validation in a larger cohort will be necessary. Funding Statement: This work was supported by the National Key Research and Development Program of China (No. 2017YFC1308900, 2017YFC0908400) and the Beijing Municipal Science & Technology Commission Program (No. Z161100002616036). Declaration of Interests: The authors declare no conflict of competing interest. Ethics Approval Statement: This study was approved by the Medical Ethics Committee of Peking University Cancer Hospital, and written informed consent was obtained from all of the patients for their samples to be used in the future.

The purpose of this study was to establish the quality control and quantify the novel

Esophageal squamous cell carcinoma (ESCC) is a frequently diagnosed and deadly malignancy with few standard therapeutic options. Camptothecins are considered one of the most promising antitumor drugs. A modified lipophilic analog, gimatecan, was synthesized as a novel oral camptothecin and showed impressive effects in various tumors, but its therapeutic efficacy and mechanisms in ESCC remain unclear. This study investigated the antitumor efficacy and mechanisms of gimatecan in ECSS both in vitro and in vivo. Using ESCC cell lines, cell line-derived xenografts and patient-derived xenografts models, we evaluated gimatecan’s inhibition of tumor growth, and compared its antitumor efficacy with that of irinotecan. Topoisomerase I function and expression were assessed using the DNA relaxation assay and Western blotting, respectively. DNA damage was evaluated by Western blotting. Cell cycle progression and cell apoptosis were assessed using flow cytometry and Western blotting. Gimatecan could significantly suppress tumor growth in vivo and inhibit tumor cell proliferation in vitro, which was superior to irinotecan. Gimatecan suppressed the function and expression of topoisomerase I. It also caused DNA damage and activated the phosphorylation of multiple checkpoint gatekeepers, such as ATM, ATR, BRCA1, H2AX, CHK1, CHK2, and p53. It induced S phase arrest, enhanced the expression of p21WAF1/CIP, and suppressed the expression of CDK2 and cyclin A. Induction of apoptosis was accompanied by increases in Bax, cleaved-caspase 3 activation, cleaved-caspase 9 induction, and a decrease in Bcl-2. The molecular and phenotypic changes induced by gimatecan were stronger than that of irinotecan. In ESCC, gimatecan suppressed the expression and function of topoisomerase I, induced DNA damage and intra-S phase cell cycle arrest, and resulted in apoptosis. And the results suggest that gimatecan has higher potency in inhibiting ESCC tumor growth than irinotecan, providing a rational novel therapeutic strategy for future clinical evaluation.

Background The aim of the present study was to explore the mechanism underlying the poor efficacy of pyrotinib, propose and validate a strategy for pyrotinib-combined therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Methods Human GC cell lines and patient-derived xenograft (PDX) models were used to evaluate the antitumor activity and mechanisms of pyrotinib. One pyrotinib-refractory PDX model was established to explore the potential mechanisms underlying drug resistance, propose an optimal therapeutic strategy, and further validate in a phase I clinical trial (NCT03480256). Results Pyrotinib exerted strong antitumor activity in HER2-positive GC cells and PDX models via suppressing the activation of the AKT/S6 signaling pathway. In addition, dysregulation of the cell cycle, represented by aberrant activation of the CCND1-CDK4/6-Rb axis, was found in the pyrotinib-refractory PDX model compared with the parental model. Then, combination therapy of pyrotinib with a CDK4/6 inhibitor (SHR6390) was proposed and its strong tumor growth inhibition was observed in the pyrotinib refractory-PDX model. Three HER2-positive GC patients after multiline therapies were subsequently enrolled in our clinical trial treatment with pyrotinib (400 mg/d for 28 days per cycle) combined with SHR6390 (100 mg/d for 21 days per cycle). After two cycles of therapy, two patients achieved a partial response (PR) and one patient achieved decreased stable disease (SD) with a progression-free survival of 120, 199, and 110 d, respectively. The common adverse events included leucopenia (grade 2 to 3), neutropenia (grade 2 to 4), anemia (grade 1 to 3), and thrombocytopenia (grade 1). Conclusions This representative translational study suggests that a combination treatment of pyrotinib with SHR6390 may serve as a promising strategy for patients with HER2-positive GC after systematic treatment failure. The optimal drug doses and tolerability of this combination treatment will be explored in future studies. Legal entity responsible for the study Zuhua Chen. Funding The National Key Research and Development Program of China (No. 2017YFC1308900, 2017YFC0908400). Disclosure All authors have declared no conflicts of interest.

Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G2/M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.

Table S6. The expression of PD-L1 in EBV-positive and EBV-negative xenografts. (DOCX 12Â kb)

Table S5. Summary of SNVs, InDels, CNVs, and fusions of the 50 xenografts by targeted sequencing. (DOCX 14Â kb)

Figure S1. The work flow of gene variation calling. (DOCX 195Â kb)