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In this study, friction stir welding (FSW) technique was applied to the LAZ933 magnesium-lithium (Mg-Li) alloy. Microstructure, mechanical properties and corrosion behaviors of friction stir welded LAZ933 magnesium-lithium alloy were analyzed by optical microscopy (OM), scanning electron microscopy (SEM), X-ray diffractometry (XRD), transmission electron microscopy (TEM), hardness, tensile, and electrochemical test. The experimental results indicated that FSW resulted in significant refinement of β phase, reduction of α phase content as well as dissolution of Mg17Al12 and AlLi (γ) precipitates in the nugget zone (NZ). The generated MgLi2Al (θ) precipitates in the NZ and heat-affected zone (HAZ) which had a coherent structure with the matrix could significantly strengthen the Mg-Li alloy. The ultimate tensile strength of the joint reached 163.5 MPa, and elongation reached 15.21%. In the weakest area of the weld (HAZ), the strengthening caused by the solid solution of α phases and formation of θ precipitates compensated the strength loss induced by the phase coarsening by thermal exposure in FSW, resulting in the joint fractured in the base metal (BM) and showed a ductile pattern. The corrosion current density changed from 4.831 × 10−5 A/cm2 to 2.054 × 10−5 A/cm2, which indicated that the weld had better corrosion resistance than the BM.

Abstract There is still room for improvement in first-line treatment of advanced small cell lung cancer (SCLC). This trial firstly investigated efficacy and safety of antiangiogenic therapy (surufatinib) (200 mg, qd, po) plus anti-PD-1 treatment (toripalimab) (240 mg, d1, ivdrip) combined with etoposide (100 mg/m², d1-d3, iv, drip) and cisplatin (25 mg/m², d1-d3, ivdrip) for advanced SCLC as first-line treatment, which has been registered on ClinicalTrials.gov under the identifier NCT04996771. The four-drug regimen was conducted q3w for 4 cycles with maintenance therapy of surufatinib and toripalimab. The primary endpoint was progression-free survival (PFS). The secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. All of the 38 patients were enrolled for safety analysis, while only 35 patients were enrolled for efficacy analysis since loss of efficacy evaluation in 3 cases after treatment. After a median follow-up of 21.3 months, the ORR was 97.1% (34/35), and the DCR and the tumor shrinkage rate were both 100% (35/35). The median PFS was 6.9 months (95% CI: 4.6 m–9.2 m) and the median OS was 21.1 months (95% CI: 12.1 m–30.1 m). The 12-month, 18-month, and 24-month OS rates were 66.94%, 51.39% and 38.54%. The occurrence rate of grade ≥3 treatment-emergent adverse events (TEAEs) was 63.2% (24/38), including neutrophil count decreased (31.6%, 12/38), white blood cell count decreased (23.7%, 9/38) and platelet count decreased (10.5%, 4/38). No unexpected adverse events occurred. This novel four-drug regimen (surufatinib, toripalimab, etoposide plus cisplatin) revealed impressive therapeutic efficacy and tolerable toxicities.

IntroductionThe approval of chimeric antigen receptor (CAR) T cell therapies for the treatment of B cell malignancies has fueled the development of numerous ex vivo cell therapies. However, these cell therapies are complex and costly, and unlike in hematological malignancies, outcomes with most T cell therapies in solid tumors have been disappointing. Here, we present a novel approach to directly program myeloid cells in vivo by administering novel TROP2 CAR mRNA encapsulated in lipid nanoparticles (LNPs).MethodsThe CAR comprises a TROP2 specific single-chain variable fragment (scFv) fused to a truncated CD89 which requires association with the FcRγ signal adapter to trigger myeloid-specific cell activation. The mRNA encoding the TROP2 CAR was encapsulated in LNPs. Co-immunoprecipitation, flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to measure CAR expression and functional activity in vitro. Anti-tumor efficacy of the TROP2 CAR mRNA/LNP was evaluated after intravenous administration in various murine tumor models.ResultsIn vitro, transient expression of the TROP2 CAR on monocytes triggers antigen-dependent cytotoxicity and cytokine release. In tumor bearing mice and cynomolgus monkeys, the TROP2 CAR mRNA/LNP are primarily expressed by myeloid cells. In a mouse xenograft model, intravenous administration of TROP2 CAR mRNA/LNP results in tumor growth inhibition and in a B16/F10-OVA immunocompetent melanoma mouse model, anti-tumor efficacy of a gp75-specific CAR correlates with increased number of activated T cells, activation of dendritic cells and a humoral response against B16/F10-OVA melanoma tumors.DiscussionsThese findings demonstrate that myeloid cells can be directly engineered in vivo to kill tumor cells and orchestrate an adaptive immune response and guide clinical studies for the treatment of solid tumors.

Abstract Purpose Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials. Methods Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined “EBV response” as 3 consecutive timepoints of load below 50% of baseline, and “EBV progression” as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples. Results We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p

PurposeCurrently, chemoimmunotherapy is effective only in a subset of patients with advanced non-squamous non-small cell lung cancer. Robust biomarkers for predicting the efficacy of chemoimmunotherapy would be useful to identify patients who would benefit from chemoimmunotherapy. The primary objective of our study was to develop an artificial intelligence-based immunoscore and to evaluate the value of patho-immunoscore in predicting clinical outcomes in patients with advanced non-squamous non-small cell lung cancer (NSCLC).MethodsWe have developed an artificial intelligence–powered immunoscore analyzer based on 1,333 whole-slide images from TCGA-LUAD. The predictive efficacy of the model was further validated in the CPTAC-LUAD cohort and the biomarker cohort of the ORIENT-11 study, a randomized, double-blind, phase 3 study. Finally, the clinical significance of the patho-immunoscore was evaluated using the ORIENT-11 study cohort.ResultsOur immunoscore analyzer achieved good accuracy in all the three cohort mentioned above (TCGA-LUAD, mean AUC: 0.783; ORIENT-11 cohort, AUC: 0.741; CPTAC-LUAD cohort, AUC: 0.769). In the 259 patients treated with chemoimmunotherapy, those with high patho-immunoscore (n = 146) showed significantly longer median progression-free survival than those with low patho-immunoscore (n = 113) (13.8 months vs 7.13 months, hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.38 – 0.73; p < 0.001). In contrast, no significant difference was observed in patients who were treated with chemotherapy only (5.07 months vs 5.07 months, HR: 1.04, 95% CI: 0.71 – 1.54; p = 0.83). Similar trends were observed in overall survival.ConclusionOur study indicates that AI-powered immunoscore applied on LUAD digital slides can serve as a biomarker for survival outcomes in patients with advanced non-squamous NSCLC who received chemoimmunotherapy. This methodology could be applied to other cancers and facilitate cancer immunotherapy.

Abstract On 2022‐02‐15, solar eruptions caused one of the most intensive Solar Particle Events (SPEs) in Solar Cycle 25 observed at various heliospheric locations. This study focuses on the enhancements of energetic proton flux observed by multiple detectors located at the orbit and on the surface of Mars. We carry out the first analysis by the Mars Energetic Particle Analyzer (MEPA) instrument on board the Chinese Tianwen‐1 spacecraft (TW‐1) at Mars orbit which also serves to validate the instrument's capability to measure protons of up to 100 MeV. We reconstruct the event spectrum up to 1 GeV and further model the event doses at Mars's orbit and surface which are then validated against the corresponding dosimetry data. Our study utilizes all available radiation detectors at Mars, advances our understanding of Mars's radiation environment induced by large SPEs, and emphasizes the necessity of continuous and synergistic radiation monitoring at Mars.

Integration of aluminum (Al) and titanium (Ti) alloys offers an effective approach to sustainable and high-quality development of the automotive and aviation industries. However, challenges arise when welding Al alloys to Ti alloys due to the formation of detrimental intermetallic compounds at the interface. With the implementation of ultrasonic vibrations, the temperature and strain rate were both increased during Al/Ti friction stir welding (FSW), leading to the formation of an amorphous interlayer, instead of intermetallic compound (IMC), at the interface. The interfacial microcracks were eliminated in the ultrasonic vibrations assisted friction stir welding (UVFSW). There were Ti particles separated from the Ti substrate and dispersed in the Al alloy, thereby resulting in a more gradual and moderate evolution of the interfacial microstructure. Due to the improved interfacial microstructure with ultrasonic vibrations, the lap shear strength was almost twice that of the conventional FSW welds within same welding conditions. Meanwhile, ultrasonic vibrations also improved the fabrication efficiency with a higher optimal traversing speed. The failure mode shifted from interface separation of FSW welds to a shear dimple fracture of the UVFSW welds, demonstrating the better plasticity and reliability of the UVFSW Al/Ti dissimilar joints.

Abstract Sequential immunotherapy has shown certain advantages in malignancy. Here, we aim to evaluate the efficacy of sequential anti-CTLA-4 and anti-PD-1 treatment for recurrent or metastatic nasopharyngeal carcinoma patients (R/M NPC). We retrospectively analysis 2 phase I trial of ipilimumab and camrelizumab in Chinese R/M NPC patients. These patients were initially treated with ipilimumab, a CTLA4 blockade, followed by anti-PD-1 treatment. We observed a durable tumor remission in these patients (mPFS: 12.3 months; mDoR: 20.9 months). Multimodal investigations of biopsy samples disclosed remodeling of tumor-immune microenvironment triggered by ipilimumab. In responders, we found increased tumoral PD-L1/PD-L2 expression and T-cell infiltration after ipilimumab treatment, accompanied by reduced stroma and malignant cell components. In contrast, non-responders exhibited increased B-cell infiltration and increased peripheral CD19 + B cells, suggesting a defective transition from memory B cells to plasma cells. This study proposes that sequential therapy can potentially enhance treatment efficacy in chemotherapy-resistant NPC patients and provides insights into how preexisting anti-CTLA4 blockade can influence subsequent anti-PD-1 efficacy by remodeling the TME. Additionally, our results highlight the need for therapeutic strategies targeting naïve/memory B cells.

Abstract End-stage nasopharyngeal carcinoma (NPC) has unsatisfactory survival. The limited benefit of chemotherapy and the scarcity of targeted drugs are major challenges in NPC. New approaches to treat late-stage NPC are urgently required. In this study, we explored whether the dual PI3K/mTOR inhibitor, PQR309, exerted a favorable antineoplastic effect and sensitized the response to gemcitabine in NPC. We observed that PI3K expression was positive and elevated in 14 NPC cell lines compared with that in normal nasopharygeal cell lines. Patients with NPC with higher PI3K levels displayed poorer prognosis. We subsequently showed that PQR309 alone effectively decreased the viability, invasiveness, and migratory capability of NPC cells and neoplasm development in mice xenograft models, and dose-dependently induced apoptosis. More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3β and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition. Thus, targeting PI3K/mTOR using PQR309 might represent a treatment option to promote the response to gemcitabine in NPC, and provides a theoretical foundation for the study of targeted drugs combined with chemotherapy for NPC.

Background The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal carcinoma (NPC), and the specific biomarker determining the response to immunotherapy in NPC remains uncertain.Methods We assessed the associations between pre-immunotherapy and post-immunotherapy serum lipoproteins and survival in a training cohort (N=160) and corroborated these findings in a validation cohort (N=100). Animal studies were performed to explore the underlying mechanisms. Additionally, the relationship between high-density lipoprotein-cholesterol (HDL-C) levels and M1/M2-like macrophages, as well as activated CD8+T cells in tumor tissues from patients with NPC who received immunotherapy, was investigated.Results The lipoproteins cholesterol, HDL-C, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein A-1 (ApoA1), and apolipoprotein B, were significantly altered after immunotherapy. Patients with higher baseline HDL-C or ApoA1, or those with increased HDL-C or ApoA1 after immunotherapy had longer progression-free survival, a finding verified in the validation cohort (p

Abstract TP53 comutation is related to poor prognosis of non‐small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third‐generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third‐generation EGFR‐TKIs in two independent cohorts. A total of 117 patients from the Sun Yat‐sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress‐free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha‐helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p = 0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha‐helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01–4.18), p = 0.048] and OS [HR 3.62(1.60–8.17), p = 0.002] in the SYSUCC cohort. TP53 mutation in alpha‐helix region was related to inferior clinical outcomes in patients treated with third‐generation EGFR‐TKIs.

The present study investigated the inhomogeneity of microstructure and properties of hybrid laser-MIG welded 10-mm-thick 316L/AH36 joints. The study focused on the inhomogeneity of the laser zone, hybrid zone, and transition zone. The temperature field was simulated using ABAQUS and showed a higher cooling rate in the laser zone. As a result, the microstructure in the laser zone was dominated by martensite while that in the hybrid zone was composed of 84 % austenite and 16 % ferrite. The laser zone showed poorer impact toughness and corrosion resistance than the hybrid zone. However, the corrosion resistance of the whole weld was the worst. Because the inhomogeneous microstructure formed a galvanic couple that accelerated the corrosion process. This work indicated that the energy ratio (the ratio of laser to arc energy) should be considered in the welding of dissimilar thick steel to reduce the inhomogeneity in the two zones and obtain a desirable property balance among hardness, toughness, and corrosion resistance.

Abstract First-line chemoimmunotherapy (with or without bevacizumab) has improved outcomes in advanced non-small cell lung cancer (NSCLC). Here, this open-label, multi-cohort phase II study (NCT05329025) was done to investigate the safety and efficacy of QL1706 (a single bifunctional MabPair product against PD-1 and CTLA-4) and chemotherapy with or without bevacizumab in this population. Patients were enrolled into five different cohorts based on genotype (cohorts 1-4, epidermal growth factor receptor [EGFR] wild-type; cohort 5, EGFR-mutant and progressed on EGFR-tyrosine kinase inhibitors [TKIs]). Between June 11, 2021 and December 29, 2021, 91 patients were enrolled. Most frequent treatment-related adverse events (TRAEs) included decreased appetite (60 [65.9%]), anemia (60 [65.9%]), infusion-related reactions (48 [52.7%]), and pruritus (44 [48.4%]). Grade ≥ 3 TRAEs occurred in 30 (33.0%) patients. Twenty-seven (45%) patients with wild-type EGFR achieved partial response (PR) (objective response rate [ORR] = 45%) and had a median progression-free survival (mPFS) of 6.8 months (95% CI: 5.2-9.7). For 31 patients harboring mutated EGFR, 17 (54.8%) achieved PR (ORR = 54.8%), with an mPFS of 8.5 months (95% CI: 5.72-not evaluable). Overall, QL1706 plus chemotherapy, regardless of having bevacizumab, was generally tolerable and had promising antitumor activity for EGFR wild-type advanced NSCLC in first-line setting. Moreover, QL1706 plus chemotherapy and bevacizumab showed favorable antitumor activity for patients who had EGFR mutated NSCLC but failed in TKI therapy, demonstrating a potential for treating this population.

Laser powder-bed fusion (LPBF) possesses unique advantages in manufacturing complex structures. The mechanical properties of thin-wall structures are crucial for the application. This study investigates the influence of wall thickness on defects and mechanical properties of LPBF Hastelloy X (HX) superalloy. As the wall thickness decreases from 1.5 mm to 0.25 mm, the diameter of sub-grains inside the molten pool increases, exhibiting a progressively enhanced //transverse direction (TD) texture in thin wall structure. Meanwhile, decreasing wall thickness leads to increased porosity and cracks due to unstable molten pool and higher residual stress. The crack initiates at columnar to equiaxed transition (CET) position and propagates along the building direction (BD). The tensile strength of the LPBF HX specimens in the horizontal and vertical directions is 773.5 MPa and 642.1 MPa with thickness of 1.5 mm, respectively, while the elongation of both specimens is close to 35%. When the wall thickness decreases to 0.25 mm, the elongation significantly decreases due to the evolution of microstructure anisotropy and the cracks along the BD, reaching 10.1% and 24.3% for horizontal and vertical specimens. This work illustrates the defects, microstructural evolution and the mechanical properties anisotropy in thin-wall structures of LPBF HX, providing a foundation for adjusting and optimizing the performance of subsequent thin-wall printing processes.

Abstract There remains an unmet need for targeted therapies against advanced non‐small‐cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti‐HER2 agent, this prospective, single‐arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti‐HER2 antibody inetetamab and pan‐HER TKI pyrotinib in HER2‐posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose‐escalation part, 240 mg, 320 mg; dose‐expansion part, 320 mg). Primary endpoints were dose‐limiting toxicity (DLT) dosage and safety. Secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 48 patients were enrolled. During the dose‐escalation period, no DLT occurred. Diarrhea was the most commonly reported treatment‐related adverse event (TRAE). Grade 3 TRAEs occurred in seven patients. The median PFS (mPFS) was 5.5 months [95% confidence interval (CI): 4.4–8.6 months]. The confirmed ORR and DCR reached 25% (11/44) and 84.1% (37/44), respectively. Responses were shown in patients with distinct HER2 aberrations. In summary, inetetamab in combination with pyrotinib demonstrated acceptable safety and antitumor activity among patients with advanced HER2‐mutant NSCLC.

Abstract The Multi-purpose Time Projection Chamber (TPC) for nuclear AsTrophysical and Exotic beam experiments (MATE) is being upgraded for the decay and active target experiments at the Heavy Ion Research Facility in Lanzhou (HIRFL). We have developed a gating grid driver to control the transitions between the closed and open states of the gating grid of the MATE-TPC to detect interesting rare decay events from a large amount of implanted ions. The gating grid driver is mainly composed of a digital control unit and a high-voltage switch unit. The digital control unit responds to the external trigger and generates control signals for the operation of the high-voltage control part based on the presetting instruction. The high-voltage switch unit is connected to two negative high voltages with different values and changes the voltages of neighboring wires of the gating grid based on the request for closing or opening the gate. A 500 ns switching time of the gating grid driver has been achieved from the closed to open state. The duration of the open state can be adjusted from 1 µs to 99 ms based on the experimental requirements. This gating grid driver can be used in a particle detector with a high voltage bias of up to ± 3000 V.

Laser powder-bed fusion (LPBF) technique has broad prospects in lightweight structure designing and rapid manufacturing. In this study, solution treatment (ST), hot isostatic pressing (HIP), and HIP+ST were performed on crack-free LPBF Hastelloy X. The corresponding microstructure, precipitates, and mechanical properties after different heat treatments were compared to identify the critical factor affecting the fracture mechanisms at room and elevated temperature. The specimens exhibited a high recrystallization degree under all heat treatment conditions, which had little contribution to the performance differences. However, different holding time and cooling rate led to variations in carbide distribution. Granular M6C carbides were formed in ST specimens, while linear M23C6 carbides were formed in HIP specimens. In contrast, barely no carbides were observed in the HIP+ST specimen. At room temperature, all specimens showed similar tensile strength, while the ranking of elongation was HIP+ST=ST>HIP. The decreased elongation of the HIP specimen was attributed to the linear carbides at grain boundaries. However, the ranking of elongation was presented as HIP>HIP+ST>ST at high temperature. Carbides at grain boundaries coarsened and affected the crack propagation behaviors. The HIP specimen had appropriate carbide size, which restricted the crack propagation within a single grain boundary, forming wedge-shaped cracks. When the carbide was too small or oversized, crack propagated along the grain boundaries and reduced the plasticity. This work demonstrated that the carbide size was a critical factor for the performance control. In addition, the room temperature performance was insufficient for evaluating suitable heat treatment conditions for LPBF Hastelloy X.

Background We aimed to investigate the determinant factors of anti-PD-1 therapy outcome in nasopharyngeal carcinoma (NPC). Methods In this retrospective study, we included 64 patients with recurrent/metastatic NPC. The association of patients’ characteristics, C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and lactate dehydrogenase (LDH) with survival benefit of anti-PD-1 therapy were analyzed using Cox regression models and Kaplan-Meier analyses. Patients were divided based on the median value of CRP, NLR or LDH into different subgroups. Results At a median follow-up time of 11.4 months (range: 1-28 months), median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% CI, .18-3.6) and 15 months (95% CI, 10.9-19.1) months, respectively. Pretreatment metastases numbers was significant predictor of PFS (HR = 1.99; 95% CI 1.10-3.63; P = .024) and OS (HR = 2.77; 95% CI 1.36-5.61; P = .005). Baseline LDH level was independent predictor of OS (HR = 7.01; 95% CI 3.09-15.88; P < .001). Patients with LDH level >435 U/L at the baseline had significantly shorter PFS and OS compared to patients with LDH level ≤435 U/L (median PFS: 1.7 vs 3.5 months, P = .040; median OS: 3.7 vs 18.5 months, P < .001). Patients with non-durable clinical benefit (NDB) had significantly higher LDH level at the baseline compared to patients who achieved durable clinical benefit (DCB) ( P = .025). Post-treatment levels of CRP, LDH, and NLR were decreased compared to baseline in patients with DCB ( P = .030, P = .088, and P = .066, respectively), whereas, there was a significant increase in post-treatment level of LDH compared with baseline in patients with NDB ( P = .024). Conclusions LDH level at the baseline was an independent predictor of OS and pretreatment metastases numbers was a significant predictor of PFS and OS.

AbstractBackground Immune checkpoint inhibitors (ICIs) have achieved substantial advancements in clinical care. However, there is no strong evidence for identified biomarkers of ICIs in NPC.Methods In this retrospective study, 284 patients were enrolled into a training or validation cohort. Inflammatory indexes based on peripheral blood parameters were evaluated, including the systemic immune-inflammation index (SII), the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), the lymphocyte-to-C-reactive protein ratio (LCR), and the lymphocyte-monocyte ratio (LMR). The optimum cut-off value for patient stratification was identified using X-tile. The Kaplan-Meier method and Cox’s proportional regression analyses were used to identify prognostic factors.Results Immunotherapy significantly changed the levels of SII, NLR, PLR, LCR and LMR in NPC patients. Patients with lower SII, NLR, and PLR, as well as those with higher LCR and LMR, before immunotherapy had superior PFS (all p

Abstract Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Background: For Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1), measuring up to two target lesions per organ is an arbitrary criterion. Objectives: We sought to compare response assessment using RECIST1.1 and modified RECIST1.1 (mRECIST1.1, measuring the single largest lesion per organ) in advanced non-small cell lung cancer (aNSCLC) patients undergoing anti-PD-1/PD-L1 monotherapy. Methods: Concordance of radiologic response categorization between RECIST1.1 and mRECIST1.1 was compared using the Kappa statistics. C-index was calculated to evaluate prognostic accuracy of radiologic response by the two criteria. The Kaplan–Meier method and Cox regression analysis were conducted for progression-free survival (PFS) and overall survival (OS). Results: Eighty-seven patients who had at least two target lesions in any organ per the RECIST1.1 were eligible for comparison analysis. Tumor response showed excellent concordance when measured using the RECIST1.1 and mRECIST1.1 (Kappa = 0.961). C-index by these two criteria was similar for PFS (0.784 versus 0.785) and OS (0.649 versus 0.652). Responders had significantly longer PFS and OS versus non-responders ( p < 0.05), whichever criterion adopted. Radiologic response remained a significant predictor of PFS and OS in multivariate analysis ( p < 0.05). Conclusion: The mRECIST1.1 was comparable to RECIST1.1 in response assessment among aNSCLC patients who received single-agent PD-1/PD-L1 inhibitor. The mRECIST1.1, with reduced number of lesions to be measured, may be sufficient and more convenient to assess antitumor activity in clinical practice.

Hepatotoxicity is a common side effect for patients treated with gefitinib, but the related pathogenesis is unclear and lacks effective predictor and management strategies. A multi-omics approach integrating pharmacometabolomics, pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution. Here, we found that patients with rs4946935 AA, located in Forkhead Box O3 (FOXO3) which is a well-known autophagic regulator, had a higher risk of hepatotoxicity than those with the GA or GG variant (OR = 18.020, 95%CI = 2.473 to 459.1784, P = 0.018) in a gefitinib-concentration dependent pattern. Furthermore, functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity, increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury. In contrast, erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3. This study reveals that FOXO3 mutation, leading to autophagic imbalance, plays important role in gefitinib-induced hepatotoxicity, especially for patients with high concentration of gefitinib. In conclusion, FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.

Summary: The immune and stromal contexture within the tumor microenvironment (TME) interact with cancer cells and jointly determine disease process and therapeutic response. We aimed at developing a risk scoring model based on TME-related genes of squamous cell lung cancer to predict patient prognosis and immunotherapeutic response. TME-related genes were identified through exploring genes that correlated with immune scores and stromal scores. LASSO-Cox regression model was used to establish the TME-related risk scoring (TMErisk) model. A TMErisk model containing six genes was established. High TMErisk correlated with unfavorable OS in LUSC patients and this association was validated in multiple NSCLC datasets. Genes involved in pathways associated with immunosuppressive microenvironment were enriched in the high TMErisk group. Tumors with high TMErisk showed elevated infiltration of immunosuppressive cells. High TMErisk predicted worse immunotherapeutic response and prognosis across multiple carcinomas. TMErisk model could serve as a robust biomarker for predicting OS and immunotherapeutic response.

Background KN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors.Methods Patients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5 mg/kg every 2 weeks (Q2W), 5 mg/kg every 3 weeks (Q3W), and 300 mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform.Results Totally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade ≥3 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5 mg/kg Q2W according to the pharmacokinetic–pharmacodynamic model, the preliminary exposure–response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression.Conclusions KN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response.Trial registration numbers NCT03733951 .

Abstract Background Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)‐rearranged non–small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)‐based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies. Methods A total of 75 eligible patients were enrolled from Sun Yat‐sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis‐free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log‐rank test was performed to describe the difference of BMFS risk. Results Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C‐index], 0.762; 95% confidence interval [CI], 0.663–0.861) and validation cohort (C‐index, 0.724; 95% CI, 0.601–0.847). Conclusion We have developed a CT‐based radiomics model to predict subsequent BM in patients with non‐brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM.

ObjectiveFew data are available on the optimal treatment options after disease progression from first-line treatment of immune checkpoint inhibitors (ICIs) plus chemotherapy. This study aimed to describe the safety and efficacy of continuing ICIs beyond first progress disease (PD) in non-small cell lung cancer (NSCLC).MethodsPatients with NSCLC previously treated with first-line anti-PD-1 antibody plus platinum-doublet chemotherapy and hence had PD as per Response Evaluation Criteria in Solid Tumors v1.1 were enrolled. For the subsequent line, patients received physician’s choice (PsC) with or without an anti-PD-1 antibody. The primary outcome was progression-free survival after second-line treatment (PFS2). Secondary outcomes included overall survival (OS) from the initiation of first-line treatment, post-second-progression survival (P2PS), overall response rate (ORR), disease control rate (DCR), and safety during second-line treatment.ResultsBetween July 2018 and January 2021, 59 patients were included. A total of 33 patients received a physician-decided second-line regimen plus ICIs (PsC plus ICIs group), and 26 patients did not continue ICIs (PsC group). There was no significant difference in PFS2 between the PsC plus ICIs group and the PsC group (median, 6.5 vs. 5.7 months, p = 0.46). median OS (28.8 vs. 29.2 months), P2PS (13.4 vs. 18.7 months), ORR (18.2% vs. 19.2%), and DCR (78.8% vs, 84.6%) were also similar between the two groups. No new safety signals were observed.ConclusionIn this real-world setting, patients treated with continued ICIs beyond their first disease progression did not experience clinical benefit but without compromising safety.

The accuracy and enrichment rate of targeted drugs largely determine the clinical diagnosis and treatment effect. Therefore, the accuracy and enrichment rate of targeted drugs should be improved. We designed a visual diagnosis and treatment system based on hierarchical targeting. It consists of multifunctional magnetic nanoparticles and a bio magnetic material. Bio-magnet mediated primary targeting can effectively improve the drug enrichment rate in the target tissue. SNF peptide/epithelial cell adhesion molecule antibody mediated targeting liver cancer stem cells (LCSCs) (secondary target) can improve the accuracy of the treatment and its outcomes. Low intensity focused ultrasound irradiation can explode nanoparticles around LCSCs, which can cause physical damage to cells. The combination of released interferon gamma and its receptor (tertiary target) can be used to initiate chemotherapy and immunotherapy. Using the optical properties of Fe3O4 and the phase transformation ability of perfluoropentane, the system can enhance photoacoustic and ultrasonic molecular imaging enabling diagnosis and treatment visualization. Targeting LCSCs can accurately provide physical, chemical, and immune treatment of Hepatocellular carcinoma, making the therapeutic effect more effective and thorough. This system may provide a new method for a more accurate visual diagnosis and treatment of tumors.

The present study investigated the influence of energy ratio on microstructure and mechanical properties in the transition zone of hybrid laser-MIG welded 316L/AH36 joints. The region between the laser zone and hybrid zone was defined as the transition zone. The ratio of laser to arc energy was defined as energy ratio. Similar microstructure types including ferrite, austenite, and martensite were observed in the transition zone under each energy ratio. However, obvious difference in microstructure distribution and crystallographic characteristic in transition zone was found in varying energy ratio. With the energy ratio decreasing from 2:1 to 1:2, the fraction of martensite was decreased from 83.1% to 65.6%, the fraction of high angle grain boundaries was increased from 44.8% to 61.3% and the average grain size was increased from 3.62 to 17.20 μm. The phenomenon was attributed to the improvement of cooling rate and reduction of filler metal. Therefore, the highest average microhardness value of 445 HV in the fusion zone was obtained under the highest energy ratio compared to that of 223 HV under the lowest energy ratio. Besides, the low-temperature impact absorption energy was increased from 41 to 90 J and the tensile fracture mode was changed from cleavage fracture mode to ductile fracture mode as the energy ratio decreased from 2:1 to 1:2.

A real-time digital time-stamp sorting algorithm used in the In-Beam positron emission tomography (In-Beam PET) is presented. The algorithm is operated in the field programmable gate array (FPGA) and a small amount of registers, MUX and memory cells are used. It is developed for sorting the data of annihilation event from front-end circuits, so as to identify the coincidence events efficiently in a large amount of data. In the In-Beam PET, each annihilation event is detected by the detector array and digitized by the analog to digital converter (ADC) in Data Acquisition Unit (DAQU), with a resolution of 14 bits and sampling rate of 50 MS/s. Test and preliminary operation have been implemented, it can perform a sorting operation under the event count rate up to 1 MHz per channel, and support four channels in total, count rate up to 4 MHz. The performance of this algorithm has been verified by pulse generator and 22Na radiation source, which can sort the events with chaotic order into chronological order completely. The application of this algorithm provides not only an efficient solution for selection of coincidence events, but also a design of electronic circuit with a small-scale structure.

Abstract Background With the identification of new targetable drivers and the recent emergence of novel targeted drugs, using comprehensive genomic profiling in lieu of the routine testing for classic drivers in the clinical care for advanced NSCLC has been increasingly advocated. However, the key assumption justifying this practice, that comprehensive genomic profiling could lead to effective anticancer therapies and improve patient outcomes, remains unproved. Methods Comprehensive genomic profiling was prospectively applied in 1564 advanced NSCLC patients to identify potentially actionable genomic alterations. Patients were assigned to genotype-matched targeted therapies or nonmatched therapies based on the profiling results. Its utility in directing treatments was determined by the proportion of patients receiving genotype-matched targeted therapies and the proportion of patients being enrolled into genotype-matched clinical trials. Its impacts on patient outcomes were assessed by comparing progression-free survival (PFS) and overall survival (OS) between patients who received a genotype-matched and nonmatched therapy. Results From October 2016 to October 2019, tumor genomic profiles were established in 1166 patients, leading to a matched targeted therapy in 37.7% (n = 440) and a genotype-matched trial enrollment in 20.9% of patients (n = 244). Potentially actionable alterations were detected in 781 patients (67.0%). For these patients, a genomic profiling-directed matched therapy significantly improved PFS (9.0 months vs 4.9 months, P

Abstract Background Immunotherapy has shown promising efficacy in patients with nasopharyngeal carcinoma (NPC). Lymphocyte activating 3 gene (LAG-3) represents a significant immune target, however, its relationship with NPC remains unclear. This study aimed to evaluate LAG-3 expression in NPC and its association with CD3+ tumor-infiltrating lymphocytes (TILs), Granzyme B (GZMB), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) expression. Methods A total of 182 patients with NPC from Sun Yat-sen University Cancer Center, China, were included in this retrospective study. LAG-3 expression in 15 NPC cell lines and LAG-3, CD3+ TILs, GZMB, PD-L1 and PD-1 in clinical samples were estimated using immunohistochemistry. The Chi-square test was used to estimate the association between LAG-3, other biomarkers, and clinical characteristics. Survival analysis was performed using the Kaplan–Meier method and the Cox regression model. Results LAG-3 was negatively expressed in all of the 15 NPC cell lines, whereas, 147 patients with NPC (80.8%) exhibited high LAG-3 expression on TILs from tumor tissues. Male patients and those who were EBV-positive presented higher LAG-3 expression. Correlation analyses showed that LAG-3 expression was related to PD-1 expression on TILs, as well as, PD-L1 expression on tumor cells (TCs) and TILs. Both the univariate and multivariate Cox models indicated that pathological type III (P = 0.036), higher LAG-3 on TILs (P

Abstract Background The bispecific antibody (bsAbs) research around the world has undergone great changes. We analyzed the global trend of bsAbs research and compared the differences in clinical research of bsAbs between China and worldwide. Methods BsAbs research clinical trials information was retrieved through the online open-resource clinical trial registration platform. Research information including organizations, identity numbers, locations, phases, participating centers, conditions, status, enrollment, targets, spectrums of mechanism of action (MOA), and start date was collected. Clinical trials were divided into two categories based on the attributes of pharmaceutical companies (international or China-initiated or involved). Results From 1997 to 2020, 272 clinical trials regarding bsAbs research were retrieved. Twenty-nine percent of the studies were contributed by companies from Chinese institutions, which followed the USA and ranked second. The clinical trials of bsAbs are mainly concentrated on phase I (n = 161), phase I/II (n = 54), and phase II (n = 51), and the number of phase III trials is still rare (n = 4). Tumor species distribution analysis shows that there are significantly higher focuses on gastric cancer (n = 18), esophageal/gastroesophageal junction cancer (n = 16), bladder cancer (n = 10), biliary malignant tumor (n = 8), nasopharyngeal cancer (n = 6), and thymic cancer (n = 2) in China. BsAbs target and spectrums of MOA analysis showed that international companies mainly focus on bsAbs with CD3-based (n = 63) target with MOA of T-cell redirection, while researches in China pay more attention to PD-1 (n = 9)/PD-L1 (n = 7) axises with MOA of double immune checkpoint blocking. Conclusion Global bsAbs research increased rapidly during the 1997 to 2020 period. The developed countries in America and Europe are leading the trend of bsAbs research. Anticancer bsAbs clinical research in China is booming and chasing after the world trend.

A thermomechanical coupling model for the solid-state flashing process of high nitrogen steel was established, based on finite element simulations and experiments. The effect of flash current on the microstructure and mechanical properties of the welded joint was investigated, and the temperature field of the flash-butt welding (FBW) process was simulated. The phase composition of the joint was determined according to the phase diagram and cooling curve. In addition, the joint with optimal parameters was subjected to full immersion corrosion tests. The results demonstrated that the interface structure was composed of austenite and δ-ferrite with a thyristor angle (flash current) of 45°. The microstructure of the overheated zone (OZ) was composed of austenite, ferrite and a small amount of the M2 phase, in which the heat-affected zone exhibited a single-phase austenite microstructure. The joint hardness displayed a “V” shaped distribution with the lowest interface hardness. As the flash current increased, the hardness and tensile strength of the interface area of the joint first increased and then decreased, with a maximum tensile strength of 902 MPa at 45°. During the full immersion corrosion tests, the joint exhibited the most serious corrosion in the interface center and gradually reduced corrosion on both sides.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts’ discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.

Seed germination is precisely controlled by a variety of signals, among which light signals and the phytohormones abscisic acid (ABA) and gibberellin (GA) play crucial roles. New findings have greatly increased our understanding of the mechanisms by which these three signals regulate seed germination and the close connections between them. Although much work has been devoted to ABA, GA, and light signal interactions, there is still no systematic description of their combination, especially in seed germination. In this review, we integrate ABA, GA, and light signaling in seed germination through the direct and indirect regulation of ABSCISIC ACID INSENSITIVE5 (ABI5), the core transcription factor that represses seed germination in ABA signaling, into our current understanding of the regulatory mechanism of seed germination.

The work aimed to investigate the effects of alternating magnetic field on the microstructure, mechanical properties and plasma characteristics during laser-MIG hybrid welding of HG785D steel. The weld appearance was improved and the weld depth was significantly enhanced by an alternating magnetic field. The same microstructure type of lath martensite (LM) was obtained in the arc zone and laser zone of all hybrid welded joints. However, grains in the arc zone were significantly refined and the ratio of high-misorientation angles was increased under alternating magnetic field. The average grain size in the arc zone reduced from 4.60 to 3.67 μm with a magnetic flux density of 30 mT. The average microhardness of the arc part and the laser part increased from 356 and 378 to 388 and 393 HV, respectively. The grain refinement and increased ratio of high-misorientation angles led to an improvement in low-temperature impact toughness. The low-temperature impact toughness was 184 J with a magnetic flux density of 30 mT, which was 95.7% higher than that without the alternating magnetic field. Additionally, the shielding effect of the hybrid plasma was suppressed with the magnetic flux density of 10–30 mT, leading to an increase in the penetration ability of hybrid heat sources and weld depth. However, the penetration ability of the hybrid heat source was no longer enhanced with a further increase in magnetic flux density.

Oscillating laser welding of 2-mm-thick 6061-T6 aluminum alloy and AISI304 steel in overlap configuration was performed under various oscillation amplitudes of 0, 3, and 5 mm. The experimental results indicated that the welding window of Al/steel dissimilar joints was improved with increasing oscillation amplitudes. The beam oscillation broadened weld width and interfacial bonding width while reducing weld depth. In the joint produced under 0-mm oscillation, a multi intermetallic compound (IMC) layer formed with a thickness of about 90 μm. In the joint produced under 3-mm oscillation, the IMC layer with the compositions of η-Fe2Al5+block-shaped θ-Fe4Al13) was obtained and its corresponding thickness reduced to 20 μm. When the oscillation amplitude further increased to 5 mm, only a η-Fe2Al5+little θ-Fe4Al13 layer with a thickness of 5 μm generated. Simulation results for the temperature history indicated that an oscillating laser beam would disperse laser energy, restraining the steel penetrating. Besides, dispersed heat energy depressed the melting of lower aluminum sheets and interfacial element diffusion. Thus, the formation of IMCs was suppressed. The limited IMCs and increased bonding width led to an improvement in the tensile–shear properties. The maximum fracture load of the joint under 5-mm oscillation was 185 N/mm, which was twice higher than that of joints welded without beam oscillation. Less Al atoms dissolved into the fusion zone under beam oscillation, resulting in lower microhardness and better toughness. Fracture locations changed from the fusion zone to the interface due to weakened steel penetration and improved toughness.

Fiber laser welding of QP980 steel and press-hardened 22MnB5 steel in butt configuration was performed in this study. The effect of heat input on microstructure evolution and mechanical properties of dissimilar joint was investigated. Laser power employed was varied from 1.6 to 2.4 kW while welding speed was kept constant at 2 m/min. The microstructure of fusion zone (FZ) was changed with the increasing laser power. Martensite and few bainite were observed when laser power ranged from 1.8 to 2.2 kW. Out of this range, the microstructure in FZ consisted of mixed structure of martensite and ferrite. Transformation from liquid phase to ferrite was promoted by Al-Si coating on the surface of press-hardened 22MnB5 steel. Heat affected zones (HAZs) of dissimilar joint were composed of martensite and bainite. Softened zone (SZ) appeared at the HAZ of 22MnB5 steel due to tempering behavior. The hardness of SZ and QP980 steel base metal declined with microstructure evolution. The fracture occurred at QP980 base metal when dissimilar joints were produced at laser power of 1.8 and 2.0 kW. When laser power reached 2.2 kW, the tensile samples failed at SZ owing to the increased softening degree. With further increasing laser power, the weakest region was FZ since ferrite declined the whole joint strength. A better Erichsen value was obtained at 2.0 kW (4.04 mm), which was balanced by more crash energy absorption and better deformation resistance.

In this study, laser-arc hybrid welding of 5A06 aluminum alloys was performed firstly. To improve the surface quality of welded joints, ultrasonic peening (UP) process was employed. The influence of different peening needle velocities on surface microstructure and properties was investigated. The results indicated that UP produced protrusions and grooves on treated surface of welded joints. EBSD analysis showed that grains in UP-treated surface layers was refined from 100 to 50 μm. Improved dislocation structure was observed via TEM analysis. Increasement in full width at half maximum (FMHW) and Bragg angle of diffraction peaks in XRD analysis further demonstrated the formation of fine grains. The surface microhardness increased by 38.9% from 92.6 to 132 HV due to the work hardening effects. In addition, UP-treated welded joints possessed better wear resistance. After UP process, a 50% decrease in wear rate was obtained. The wear mechanism changed from adhesive to abrasive wear for the UP-treated joints. Besides, the possibility of corrosion initiation and the corrosion rate of UP-treated joints were lower than those of non-treated joints implying better corrosion resistance.

Advanced ovarian cancer usually spreads to the omentum. Here, the authors show that circulating intelectin-1 (ITLN1) has prognostic significance in patients with advanced ovarian cancer, and that mesothelial cell-derived ITLN1 in the omental tumor microenvironment suppresses ovarian cancer progression.

The first Mars exploration mission of China (Tianwen-1) is scheduled to be launched in 2020; a charged particle telescope, the Mars Energetic Particle Analyzer (MEPA), is carried as one of the payloads on the orbiter. The MEPA is designed to measure solar energetic particles (SEPs) and galactic cosmic rays (GCRs) in the near-Mars space and in the transfer orbit from Earth to Mars. Before the launch, the MEPA was calibrated in ground experiments with radioactive sources, electronic pulses, and accelerator beams. The calibration parameters, such as energy conversion constants, threshold values for the triggers, and particle identification criteria, were determined and have been stored for onboard use. The validity of the calibration parameters has been verified with radioactive sources and beams. The calibration results indicate that the MEPA can measure charged particles reliably, as designed, and that it can satisfy the requirements of the Tianwen-1 mission.

Abstract Background Platinum‐based chemotherapy is the standard of care as first‐line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM‐NPC); however, the prognosis of patients with RM‐NPC remains poor. The aim of this study was to evaluate the role of anti‐epidermal growth factor receptor (anti‐EGFR) antibody plus chemotherapy for RM‐NPC. Methods RM‐NPC patients who received first‐line chemotherapy plus an anti‐EGFR antibody were recruited from Sun Yat‐Sen University Cancer Center between July 2007 and November 2017. Survival analyses were performed using the Kaplan‐Meier method with a log‐rank test. A Cox proportional hazards model was used for the multivariate analyses. Results A total of 203 patients were enrolled in the present study. The median follow‐up time was 34.3 months (interquartile range: 19.7‐66.5 months). The median progression‐free survival (PFS) was 8.9 months (95% CI: 7.7‐10.0 months) and the median overall survival (OS) was 29.1 months (95% CI: 23.5‐34.6 months). The 1‐, 3‐, and 5‐year PFS and OS rates were 35.5% and 79.6%, 15.2% and 42.5%, and 11.6% and 23.6%, respectively. The objective response rate (ORR) was 67.5% and the disease control rate (DCR) was 91.1%. The multivariate analysis identified the following prognostic factors for PFS: anti‐EGFR agent (P = .010), recurrence/metastasis sequence (P = .016), KPS (P = .017), and combined chemotherapy regimen (P = .015). Independent risk factors for OS included age >43 years (P = .002), Karnofsky performance score ≤80 (P

Automated severity assessment of coronavirus disease 2019 (COVID-19) patients can help rationally allocate medical resources and improve patients' survival rates. The existing methods conduct severity assessment tasks mainly on a unitary modal and single view, which is appropriate to exclude potential interactive information. To tackle the problem, in this paper, we propose a multi-view multi-modal model to automatically assess the severity of COVID-19 patients based on deep learning. The proposed model receives multi-view ultrasound images and biomedical indices of patients and generates comprehensive features for assessment tasks. Also, we propose a reciprocal attention module to acquire the underlying interactions between multi-view ultrasound data. Moreover, we propose biomedical transform module to integrate biomedical data with ultrasound data to produce multi-modal features. The proposed model is trained and tested on compound datasets, and it yields 92.75% for accuracy and 80.95% for recall, which is the best performance compared to other state-of-the-art methods. Further ablation experiments and discussions conformably indicate the feasibility and advancement of the proposed model.

BackgroundProgrammed death 1 (PD-1) and the ligand of PD-1 (PD-L1) are central targets for immune-checkpoint therapy (ICT) blocking immune evasion-related pathways elicited by tumor cells. A number of PD-1 inhibitors have been developed, but the efficacy of these inhibitors varies considerably and is typically below 50%. The efficacy of ICT has been shown to be dependent on the gut microbiota, and experiments using mouse models have even demonstrated that modulation of the gut microbiota may improve efficacy of ICT.MethodsWe followed a Han Chinese cohort of 85 advanced non-small cell lung cancer (NSCLC) patients, who received anti-PD-1 antibodies. Tumor biopsies were collected before treatment initiation for whole exon sequencing and variant detection. Fecal samples collected biweekly during the period of anti-PD-1 antibody administration were used for metagenomic sequencing. We established gut microbiome abundance profiles for identification of significant associations between specific microbial taxa, potential functionality, and treatment responses. A prediction model based on random forest was trained using selected markers discriminating between the different response groups.ResultsNSCLC patients treated with antibiotics exhibited the shortest survival time. Low level of tumor-mutation burden and high expression level of HLA-E significantly reduced progression-free survival. We identified metagenomic species and functional pathways that differed in abundance in relation to responses to ICT. Data on differential enrichment of taxa and predicted microbial functions in NSCLC patients responding or non-responding to ICT allowed the establishment of random forest algorithm-adopted models robustly predicting the probability of whether or not a given patient would benefit from ICT.ConclusionsOverall, our results identified links between gut microbial composition and immunotherapy efficacy in Chinese NSCLC patients indicating the potential for such analyses to predict outcome prior to ICT.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, most NSCLC patients are at advanced stage at the time of diagnosis. For patients without sensitive driven-oncogene mutations, chemotherapy is still the main treatment at present, the overall prognosis is poor. Improving outcomes and obtaining long-term survival are the most urgent needs of patients with advanced NSCLC. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs), especially targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), have made a breakthrough in the treatment of NSCLC, beneficial to patients’ survival and changed the treatment pattern for NSCLC. It shows more and more important role in the treatment of NSCLC. Led by NSCLC expert committee of Chinese society of clinical oncology (CSCO), relevant experts in this field were organized. On the basis of referring to domestic and foreign literature, systematically evaluating the results of Chinese and foreign clinical trials, and combining the experiences of the experts, the experts group reached an agreement to develop this consensus. It will guide domestic counterparts for better application of ICIs to treat NSCLC.

Abstract Background Despite the impressive anti-tumor activity of osimertinib in epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) patients, 30–40% of patients still show limited response. There is therefore a need to identify biomarkers that accurately predict the response to osimertinib therapy. In this study, 54 patients with targeted next-generation sequencing of circulating tumor DNA before osimertinib treatment and known T790M positivity were included. We investigated the predictive value of baseline circulating tumor DNA-derived biomarkers on osimertinib therapy. Results Baseline maximum somatic allele frequency (MSAF) level was not associated with objective response rate (ORR) (P = 0.886) and progression-free survival (PFS) (P = 0.370) of osimertinib treatment. T790M relative mutation purity (RMP, defined here as the ratio of T790M AF to MSAF) quartiles were found to be significantly associated with ORR (P for trend = 0.002) and PFS (P for trend = 0.006), and a cut off value of 0.24 identified two distinct prognostic groups [Hazard ratio (HR) = 0.36 for low T790M RMP, 95% confidence interval (CI) 0.18–0.72, P = 0.004). Additionally, although T790M relative mutation abundance (RMA, defined as T790M AF/EGFR driver AF) quartiles were not significantly associated with ORR (P for trend = 0.063), a cut off value of 0.30 also identified two distinct prognostic groups (HR = 0.43 for low T790M RMA, 95% CI 0.22–0.85, P = 0.015). However, in multivariate analysis, grouping of T790M RMP showed a better predictive value (HR = 0.46, 95% CI 0.20–1.05, P = 0.066) than T790M RMA (HR = 0.71, 95% CI 0.31–1.61, P = 0.409). Moreover, T790M RMP as continuous covariate was independently predictive of PFS (HR = 0.15, 95% CI 0.03–0.79, P =0.025), while T790M RMA was not (HR = 1.14, 95% CI 0.49–2.66, P =0.766). An external validation cohort further confirmed the T790M RMP was significantly associated with PFS of osimertinib therapy. Conclusions This study established the independent predictive role of T790M RMP in NSCLC patients receiving osimertinib treatment.