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PURPOSE The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Ginkgo ketoester tablets (GT) and donepezil are clinically used in combination to treat Alzheimer’s disease (AD). This study aimed to investigate the anti-dementia effects of two drugs alone and in combination by monitoring the distribution patterns of their active components in different biological matrices. A practical analytical method was developed for simultaneously quantifying 38 active compounds in different matrices at trace levels using ultra-performance liquid chromatography coupled with triple-quadrupole linear ion-trap tandem mass spectrometry (UHPLC-MS2). Under optimized conditions, good chromatographic separation of the 38 target compounds was achieved within 14 min, with acceptable linearity, limits of detections and quantifications, precision, stability, and extraction recovery and matrix effects. The developed analytical method quantified the 38 active components in the brain, plasma, intestine, and intestinal contents of AD mice treated with GT alone, donepezil alone, and a combination of the two drugs. The result showed that the combination group had enhanced anti-dementia active compounds and reduced levels of toxic compounds entering the targeted tissues. These findings support the combined use of GT and donepezil for increasing anti-dementia treatment efficiency and reducing toxicity. The proposed UHPLC-MS2 strategy could be used to monitor the levels of active compounds from different biological matrices in future studies.

PURPOSE Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non–small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768 ). METHODS Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.

We propose a universal spin superconducting diode effect (SDE) induced by spin-orbit coupling (SOC), where the critical spin supercurrents in opposite directions are unequal. By analysis from both the Ginzburg-Landau theory and energy band analysis, we show that the spin-$\uparrow \uparrow$ and spin-$\downarrow \downarrow$ Cooper pairs possess opposite phase gradients and opposite momenta from the SOC, which leads to the spin SDE. Two superconductors with SOC, a $p$-wave superconductor as a toy model and a practical superconducting nanowire, are numerically studied and they both exhibit spin SDE. In addition, our theory also provides a unified picture for both spin and charge SDEs. Besides, we propose spin-polarized detection and nonlocal spin transport, as mature experimental technologies, to confirm the spin SDE in superconducting nanowires., 6 pages, 4 figures (+ supplementary materials 4 pages, 1 figure)

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.

IntroductionThe efficacy of postoperative radiotherapy (PORT) is still unclear in non-small cell lung cancer (NSCLC) patients with pIIIA-N2 disease. Estrogen receptor (ER) was proven significantly associated with poor clinical outcome of male lung squamous cell cancer (LUSC) after R0 resection in our previous study.MethodsA total of 124 male pIIIA-N2 LUSC patients who completed four cycles of adjuvant chemotherapy and PORT after complete resection were eligible for enrollment in this study from October 2016 to December 2021. ER expression was evaluated using immunohistochemistry assay.ResultsThe median follow-up was 29.7 months. Among 124 patients, 46 (37.1%) were ER positive (stained tumor cells≥1%), and the rest 78 (62.9%) were ER negative. Eleven clinical factors considered in this study were well balanced between ER+ and ER- groups. ER expression significantly predicted a poor prognosis in disease-free survival (DFS, HR=2.507; 95% CI: 1.629-3.857; log-rank p=1.60×10-5). The 3-year DFS rates were 37.8% with ER- vs. 5.7% with ER+, with median DFS 25.9 vs. 12.6 months, respectively. The significant prognostic advantage in ER- patients was also observed in overall survival (OS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The 3-year OS rates were 59.7% with ER- vs. 48.2% with ER+ (HR, 1.859; 95% CI: 1.132-3.053; log-rank p=0.013), the 3-year LRFS rates were 44.1% vs. 15.3% (HR=2.616; 95% CI: 1.685-4.061; log-rank p=8.80×10-6), and the 3-year DMFS rates were 45.3% vs. 31.8% (HR=1.628; 95% CI: 1.019-2.601; log-rank p=0.039). Cox regression analyses indicated that ER status was the only significant factor for DFS (p=2.940×10-5), OS (p=0.014), LRFS (p=1.825×10-5) and DMFS (p=0.041) among other 11 clinical factors.ConclusionsPORT might be more beneficial for ER negative LUSCs in male, and the examination of ER status might be helpful in identifying patients suitable for PORT.

Background: Inflammation is a common and intractable disease for humans. Current anti-inflammatory drugs have a lot of side effects, which cause irreversible damage to the body. Objective: We predict the activity of the N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitor to find more effective compounds. Methods: we established a quantitative structure-activity relationship (QSAR) model by gene expression programming to predict the IC50 values of natural compounds. The NAAA inhibitor, as a cysteine enzyme, plays an important role in the therapy of pain, anti-inflammatory effects and application of other diseases. A total of 36 NAAA inhibitors were optimized by the heuristic method in the CODESSA program to build a linear model. The 27 compounds and 9 compounds were in train and test sets. On this basis, we selected three descriptors and used them to build nonlinear models in gene expression programming. Results: The best model in the gene expression programming method was found, the square of correlation coefficients of R2 and mean square error for the training set were 0.79 and 0.14, testing set was 0.78 and 0.20, respectively. Conclusion: From this method, the activity of molecules could be predicted, and the best method was found. Therefore, this model has a stronger predictive ability to develop NAAA inhibitors.

Purpose:The induced death signals following oncogene inhibition underlie clinical efficacy of molecular targeted therapies against human cancer, and defects of intact cell apoptosis machinery often lead to therapeutic failure. Despite potential importance, other forms of regulated cell death triggered by pharmacologic intervention have not been systematically characterized.Experimental Design:Pyroptotic cell death was assessed by immunoblot analysis, phase-contrast imaging, scanning electron microscopy, and flow cytometry. Tumor tissues of patients with lung cancer were analyzed using IHC. Functional impact of pyroptosis on drug response was investigated in cell lines and xenograft models.Results:We showed that diverse small-molecule inhibitors specifically targeting KRAS-, EGFR-, or ALK-driven lung cancer uniformly elicited robust pyroptotic cell death, in addition to simultaneously invoking cellular apoptosis. Upon drug treatment, the mitochondrial intrinsic apoptotic pathway was engaged and the mobilized caspase-3 protease cleaved and activated gasdermin E (GSDME, encoded by DFNA5), which permeabilized cytoplasmic membrane and executed cell-lytic pyroptosis. GSDME displayed ubiquitous expression in various lung cancer cell lines and clinical specimens, including KRAS-mutant, EGFR-altered, and ALK-rearranged adenocarcinomas. As a result, cooccurrence and interplay of apoptosis and pyroptosis were widespread in lung cancer cells, succumbing to genotype-matched regimens. We further demonstrated that pyroptotic cell death partially contributed to the drug response in a subset of cancer models.Conclusions:These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anticancer therapeutics.

A. TCGA pan-cancer genomic analysis of all the gasdermin family members. B. DFNA5 gene expression in TCGA lung adenocarcinomas classified by indicated genetic alterations. C. Western blot analysis of indicated proteins in nucleus, cytosol, mitochondria-enriched membrane, and cytoskeleton fractions prepared from A549, PC9 and NCI-H3122 cells. D. Immunofluorescent staining of GSDME (green), F-actin (red) and nuclear 4',6-diamidino-2-phenylindole (DAPI; blue) in A549, PC9 and NCI-H3122 cells.

Cell lines with diverse oncogenic alterations were treated with indicated inhibitors.

A. A549, PC9 and NCI-H3122 cells were treated with indicated inhibitors for 72 hours. Drug-treated adherent and supernatant cells were separately collected and subjected to TUNEL analysis. The right panel showed quantification of TUNEL positive apoptotic cells. B. A549 cells were treated with trametinib either alone or in combination with indicated inhibitors (500 nM). Cell images were recorded and cells were stained with crystal violet. C. Immunofluorescent staining of cleaved PARP (green) and nuclear 4',6-diamidino-2-phenylindole (DAPI; blue) in inhibitor-treated A549, PC9 and NCI-H3122 cells with or without DFNA5 deletion.

Tables S1-S4 shows details of patient information and Table S5 shows the sgRNA information.

A. Cell morphology of inhibitor-treated A549, PC9 and NCI-H3122 cells with or without DFNA5 or CASP3 deletion. Red arrows indicated pyroptotic cells. B. LDH release in A549, PC9 and NCI-H3122 cells treated with indicated inhibitors (zVAD, zDEVD: 100 μM). C. GSDME cleavage and cell morphology of A549, PC9 and NCI-H3122 cells treated with indicated inhibitors. Red arrows indicated pyroptotic cells.

A. Cell morphology of inhibitor-treated NCI-H2009, HCC4006 and HCC827 cells with or without DFNA5 overexpression. Red arrows indicated pyroptotic cells. B. LDH release in trametinib-treated A549 cells with genetic depletion of indicated apoptotic genes.

Immunohistochemical staining of GSDME in a lung cancer tissue microarray and a patient cohort with KRAS-mutant, EGFR-altered or ALK-rearranged lung adenocarcinoma.

A. A549, PC9 and NCI-H3122 cells were treated with trametinib, erlotinib and ceritinib, respectively, either alone or in combination with indicated inhibitors. B. HCC827, NCI-H358, HCC44 and NCI-1648 were treated with erlotinib, trametinib or crizotinib as indicated.

Objective: The influence of continuous renal replacement therapy (CRRT) on the steady-state plasma concentration of high-dose tigecycline was investigated in septic shock patients to provide references for drug dosing.Methods: In this prospective observational study, 17 septic shock patients presenting with severe infections needing a broad-spectrum antibiotic therapy with high-dose tigecycline (100 mg per 12 h) in the intensive care unit were included and divided into CRRT group (n = 6) or non-CRRT group (n = 11). The blood samples were collected and plasma drug concentration was determined by SHIMADZU LC-20A and SHIMADZU LCMS 8040. The steady-state plasma concentration was compared between groups using unpaired t-test. Furthermore, between-groups comparisons adjusted for baseline value was also done using multivariate linear regression model.Results: Peak concentration (Cmax) of tigecycline was increased in CRRT group compared to non-CRRT group, but there were no statistical differences (505.11 ± 143.84 vs. 406.29 ± 108.00 ng/mL, p-value: 0.129). Trough concentration (Cmin) of tigecycline was significantly higher in CRRT group than in non-CRRT group, with statistical differences (287.92 ± 41.91 vs. 174.79 ± 33.15 ng/mL, p-value: 0.000, adjusted p-value: 0.000). In safety, Cmin was reported to be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL. In our studies, Cmin of all patients in CRRT group was lower than 474.8 ng/mL.Conclusion: The plasma concentration of tigecycline was increased in septic shock patients with CRRT treatment and only Cmin shown statistical differences. No dose adjustment seems needed in the view of hepatotoxicity.Clinical Trial Registration:https://www.chictr.org.cn/, identifier ChiCTR2000037475.

Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation.Patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review.A total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6-74.6). The disease control rate was 93.4% (95% CI: 89.6-96.2). The median duration of response was 15.1 months (95% CI: 12.5-16.6). The median progression-free survival was 12.4 months (95% CI: 9.7-15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5-80.3) and 91.3% (95% CI: 72.0-98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6-not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study.Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People's Republic of China for patients positive for EGFR T790M NSCLC.

BACKGROUND Rheumatoid arthritis (RA) is a prevalent clinical autoimmune disease that is commonly treated with diclofenac and methotrexate. In recent years, the application of traditional Chinese medicine in RA has received widespread attention; it promotes blood circulation, strengthens the immune system, and eliminates evil. The sinomenine preparation of Zhingqeng Fengtongning is studied as a possible treatment for patients with RA. AIM To explore the value of sinomenine injection into the articular cavity for the treatment of RA. METHODS A total of 94 patients with RA treated from January 2019 to January 2021 were selected and divided into the study and control groups with 47 patients each using a simple random number table method. Both groups received conventional treatment with diclofenac sodium and methotrexate tablets. The control group received diproxone and lidocaine by intra-articular administration while the study group received an intra-articular administration of the sinomenine preparation of Zhengqing Fengning and lidocaine. χ2 test was used to evaluate the therapeutic effect and synovial thickness, degree of pain through the visual analog scale (VAS), blood flow grade, arthroinflammatory indexes [rheumatoid factor (RF), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR)] before and after treatment in the two groups. RESULTS The total effective rate of the study group (93.62%) was higher than that of the control group (78.72%) (P < 0.05). Before treatment, there were no significant differences between the two groups in terms of synovial thickness, VAS score, blood flow grading, levels of RF, and ESR (P > 0.05). After treatment, the synovial thickness and VAS score were significantly lower (P < 0.05) in the study group than in the control group (2.05 ± 0.59 mm vs 2.87 ± 0.64 mm and 2.11 ± 0.62 vs 2.90 ± 0.79 scores, respectively). The rate of blood flow at grade 0 in the study group (76.60%) was higher than that in the control group (57.45%), and the rate of blood flow at grade I (10.64%) was lower than that in the control group (31.91%) (P < 0.05). Furthermore, the levels of RF (55.61 ± 6.13 U/mL), CRP (11.43 ± 3.59 mg/L), and ESR (29.60 ± 5.56 mm/h) in the study group were lower than those in the control group (73.04 ± 9.23 U/mL, 15.07 ± 4.06 mg/L, 36.64 ± 6.10 mm/h, respectively) (P < 0.05). CONCLUSION Sinomenine administration of Zhengqing Fengtongning in the articular cavity with conventional treatment of RA can improve ultrasonographic blood flow and synovial thickness, reduce pain, regulate inflammation, and enhance therapeutic effect.

Physical Unclonable Functions (PUFs) are promising security primitives for resource-constrained IoT devices. And the XOR Arbiter PUF (XOR-PUF) is one of the most studied PUFs, out of an effort to improve the resistance against machine learning attacks of probably the most lightweight delay-based PUFs - the Arbiter PUFs. However, recent attack studies reveal that even XOR-PUFs with large XOR sizes are still not safe against machine learning attacks. Increasing PUF stages or components and using different challenges for different components are two ways to improve the security of APUF-based PUFs, but more stages or components lead to more hardware cost and higher operation power, and different challenges for different components require the transmission of more bits during operations, which also leads to higher power consumption. In this paper, we present a strategy that combines the choice of XOR Arbiter PUF (XOR-PUF) architecture parameters with the way XOR-PUFs are used to achieve lightweights in hardware cost and energy consumption as well as security against machine learning attacks. Experimental evaluations show that with the proposed strategy, highly lightweight component-differentially challenged XOR-PUFs can withstand the most powerful machine learning attacks developed so far and maintain excellent intra-device and inter-device performance, rendering this strategy a potential blueprint for the fabrication and use of XOR-PUFs for resource-constrained IoT applications., arXiv admin note: text overlap with arXiv:2206.01314

Shukui Qin,1 Rui-Hua Xu,2 Lin Shen,3 Jianming Xu,4 Yuxian Bai,5 Lei Yang,6 Yanhong Deng,7 Zhen-dong Chen,8 Haijun Zhong,9 Hongming Pan,10 Weijian Guo,11 Yongqian Shu,12 Ying Yuan,13 Jianfeng Zhou,14 Nong Xu,15 Tianshu Liu,16 Dong Ma,17 Changping Wu,18 Ying Cheng,19 Donghui Chen,20 Wei Li,21 Sanyuan Sun,22 Zhuang Yu,23 Peiguo Cao,24 Haihui Chen,25 Jiejun Wang,26 Shubin Wang,27 Hongbing Wang,28 Ning Wang,29 Bin Zhang,29 Qiang Zhang,29 Weiguo Su,30 Xiaojun Guo,30 Jin Li31 1Cancer Center, Jinling Hospital, Nanjing, People’s Republic of China; 2Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China; 3Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 4Department of Medical Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 6Department of Medical Oncology, Nantong Cancer Hospital, Nantong, People’s Republic of China; 7Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 8Department of Medical Oncology, The Second Hospital of Anhui Medical University, Hefei, People’s Republic of China; 9Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China; 10Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 11Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 12Department of Medical Oncology, Jiangsu Provincial Hospital, Nanjing, People’s Republic of China; 13Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 14Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 15Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, People’s Republic of China; 16Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, People’s Republic of China; 17Department of Medical Oncology, Guangdong Provincial People’s Hospital, Guangzhou, People’s Republic of China; 18Department of Medical Oncology, The First People’s Hospital of Changzhou, Changzhou, People’s Republic of China; 19Department of Medical Oncology, Jilin Province Cancer Hospital, Changchun, People’s Republic of China; 20Department of Medical Oncology, Shanghai Jiaotong University Affiliated First People’s Hospital, Shanghai, People’s Republic of China; 21Department of Medical Oncology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 22Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou, People’s Republic of China; 23Department of Medical Oncology, The Affiliated Hospital of Medical College Qingdao University, Qingdao, People’s Republic of China; 24Department of Medical Oncology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 25Department of Medical Oncology, Liuzhou Worker’s Hospital, Liuzhou, People’s Republic of China; 26Department of Medical Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, People’s Republic of China; 27Department of Medical Oncology, Peking University Shenzhen Hospital, Beijing University, Shenzhen, People’s Republic of China; 28Department of Medical Oncology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou Medical College, Xuzhou, People’s Republic of China; 29Eli Lilly and Company, Shanghai, People’s Republic of China; 30Hutchison MediPharma Limited, Shanghai, People’s Republic of China; 31Department of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Jin LiDepartment of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, People’s Republic of ChinaTel +8613761222111Email lijin@csco.org.cnObjective: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups.Results: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45– 0.77, P< 0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17– 0.30; P< 0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group.Conclusion: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.ClinicalTrials.gov Identifier: NCT02314819.Keywords: colorectal cancer, FRESCO trial, fruquintinib, liver metastasis

Summary Background Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumour activity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitors have been done in populations with a high prevalence of hepatitis B virus infection. The aim of this study was to evaluate the efficacy and safety of apatinib in patients with pretreated advanced hepatocellular carcinoma. Methods AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31 hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinoma who had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receive apatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocation was done with a central randomisation system, with a block size of six, and was stratified by Eastern Cooperative Oncology Group performance status, previous sorafenib treatment, and presence of vascular invasion or extrahepatic metastasis. The primary endpoint was overall survival, which was defined as time from randomisation to death from any cause, and was analysed in patients who were randomly assigned and received at least one dose of the study drug. Safety analyses were done in patients who received at least one dose of the study treatment and had post-dose safety assessments. This trial is registered with ClinicalTrials.gov , NCT02329860 . Findings Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinib group and one in the placebo group) did not receive study treatment and were excluded from efficacy analyses. Overall survival was significantly improved in the apatinib group compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients (257 in the apatinib group and 130 in the placebo group) had a safety assessment after study treatment and were included in safety analyses. The most common treatment-related adverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinib group vs three [2%] in the placebo group), hand–foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo group died due to adverse events, but none of these deaths were deemed to be related to treatment by investigators. Interpretation Apatinib significantly improved overall survival in patients with pretreated advanced hepatocellular carcinoma compared with placebo, with a manageable safety profile. Funding Jiangsu Hengrui Medicine.

Sustainable processes for semi-hydrogenation of alkynes/alkadienes impurities in alkenes feedstocks are in great demand in industry as the utilization of excessive hydrogen, high temperature and unsatisfactory alkenes selectivity of the current thermo-catalytic route, however, their development is still challenging. Herein, we innovate a light-assisted semi-hydrogenation process in gas-feed fixed bed reactor, with water as hydrogen atom source by in situ photocatalysis. Using Pd/TiO2 as model catalyst, this process shows an excellent catalytic performance for the semi-hydrogenation of 1,3-butadiene, with 100 % of butenes selectivity at ≈99 % of conversion over 180 h of reaction at ambient temperature driven by 66 mW cm−2 of irradiation intensity. This light-driven, H2-free, ambient temperature semi-hydrogenation process, with superior performance to that of thermocatalytic route, shows attractive to bring an evolution in industrial hydrogenation technology to an economical and safe way.

Intestinal microecology was closely related to immune regulation, but the related mechanism was still unclear. This study aimed to reveal how microorganisms improved immune response via casepase-3 and Bak of FAS/CD95 pathway. Bifidobacterium animalis F1-7 inhibited the melanoma B16-F10 cells in vitro effectively; had a potent anticancer effect of lung cancer mice; effectively improved the spleen immune index and CD3

Hexavalent chromium [Cr(VI)] is a dangerous heavy metal which can impair the gastrointestinal system in various species; however, the processes behind Cr(VI)-induced intestinal barrier damage are unknown. Forty-eight healthy 1-day-old ducks were stochastically assigned to four groups and fed a basal ration containing various Cr(VI) dosages for 49 days. Results of the study suggested that Cr(VI) exposure could significantly increase the content of Cr(VI) in the jejunum, increase the level of diamine oxidase (DAO) in serum, affect the production performance, cause histological abnormalities (shortening of the intestinal villi, deepening of the crypt depth, reduction and fragmentation of microvilli) and significantly reduced the mRNA levels of intestinal barrier-related genes (ZO-1, occludin, claudin-1, and MUC2) and protein levels of ZO-1, occludin, cand laudin-1, resulting in intestinal barrier damage. Furthermore, Cr(VI) intake could increase the contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) but decrease the activities of total superoxide dismutase (T-SOD), catalase (CAT), and glutathione reductase (GR), as well as up-regulate the mRNA levels of TLR4, MyD88, NF-κB, TNFα, IL-6, NLRP3, caspase-1, ASC, IL-1β, and IL-18 and protein levels of TLR4, MyD88, NF-κB, NLRP3, caspase-1, ASC, IL-1β, and IL-18 in the jejunum. In conclusion, Cr(VI) could cause intestinal oxidative damage and inflammation in duck jejunum by activating the NF-κB signaling pathway and the NLRP3 inflammasome.

C10H16N12O6S2, triclinic, P 1 ‾ $P\overline{1}$ (no. 2), a = 7.6977(2) Å, b = 11.5353(3) Å, c = 11.7533(3) Å, α = 67.973(2)°, β = 87.916(2)°, γ = 88.347(2)°, V = 966.69(5) Å3, Z = 2, R gt (F) = 0.0290, wR ref (F 2) = 0.0818, T = 170K.

Background and objective Studies have shown that elevated serum lactate dehydrogenase (LDH) concentration can lead to poor prognosis in patients with small cell lung cancer and lung adenocarcinoma, but its relationship with the prognosis of patients with lung large-cell neuroendocrine carcinoma (L-LCNEC) is not clear. This study aims to explore the influence of L-LCNEC preoperative serum LDH concentration and postoperative LDH concentration change trend on the disease-free survival (DFS) of patients after surgery, so as to judge the clinical prognosis of L-LCNEC provides new ideas. Methods Collected the clinical data. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value, while the Kaplan-Meier and Cox proportional hazard model were used to analyze data. Results DFS was shortened in patients with high serum LDH concentration before operation and increased LDH concentration after operation (P

To explore a better treatment strategy for patients with advanced non‐small cell lung cancer harboring sensitive epidermal growth factor receptor mutations, a total of 271 patients were retrospectively analyzed. The patients were divided into two groups: the combination group (58 cases), which received concurrent icotinib, pemetrexed, and platinum treatment, and the sequential group (213 cases), which received the sequential pemetrexed and platinum therapy, followed by icotinib treatment. The primary end points were progression‐free survival (PFS) and PFS on the subsequent line of therapy (PFS2). PFS in the combination group was significantly higher compared with that in the sequential group (16.89 months vs. 9.90 months; p

By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC.In a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel.A total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation.Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.

Background: FRESCO study demonstrated efficacy and safety of fruquintinib in metastatic colorectal cancer patients. Impact of prior targeted therapy (PTT) on efficacy and safety of fruquintinib was evaluated. Materials & methods: In this subgroup analysis of FRESCO trial, patients were divided into PTT and non-PTT subgroups, and efficacy and safety of fruquintinib were assessed, respectively. Results: In non-PTT subgroup, fruquintinib significantly prolonged overall survival (OS) and progression-free survival (PFS) of patients compared with placebo. In PTT subgroup, the median OS and PFS of patients in fruquintinib arm was significantly higher than those in placebo. Treatment-emergent adverse events (TEAEs) rates were similar in both subgroups. Conclusion: Fruquintinib demonstrated clinically meaningful improvement in OS, PFS, objective response rate, and disease control rate with manageable TEAEs in both subgroups. Clinical trial registration: NCT02314819 ( ClinicalTrials.gov )

Can-Can Zhou,1,&ast; Fang Huang,1,&ast; Jing-Ming Zhang,1 Yu-Gang Zhuang2 1Department of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China; 2Department of Emergency Medicine, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu-Gang Zhuang, Email zhuangyg07@sina.comAbstract: Although tigecycline is widely used in clinical practice, its efficiency and optimal dosage regimens remain controversial. The purpose of this article was to help guide tigecycline dosing in different patient subpopulations through comparing the published population pharmacokinetic models of tigecycline, as well as summarizing and determining the potential covariates that markedly influence tigecycline pharmacokinetics. In this review, literature was systematically searched from the PubMed database from inception to March 2022. The articles focusing on population pharmacokinetics for tigecycline in healthy volunteers or patients were included; finally, a total of eight studies were included in this review. NONMEM methods were used in five studies to generate the population pharmacokinetic models. Tigecycline pharmacokinetics were mostly described by a two-compartment model in these included studies. Estimated clearance and volumes of distribution of tigecycline at steady state (Vss) varied widely in different target patient populations, with a range of 7.5– 23.1 L/h and 212.7– 1087.7 L, respectively. Body-weight and creatinine clearance were the most important predictors of clearance in these studies, while other predictors include age, gender, bilirubin and aspartate aminotransferase. In conclusion, this review showed the large variability of tigecycline population pharmacokinetics, which can provide guide dosing in different target populations. For clinicians, the individual dosing adjustment should be based not only on the indication and pathogen susceptibility but also on the potential important predictors. However, more studies were needed to confirm the necessity of modified dosage regimens in different patient subpopulations.Keywords: tigecycline, population pharmacokinetics, modelling, NONMEM

Objective: Inonotus obliquus (Fr.) Pilat extract (IOPE) is a major active carbohydrate, an important herb used in traditional medicine, the aim of this study was to investigate the immunomodulatory effects and possible underlying mechanisms of IOPE in B16-F10 cells induced low immunity mice. Material and Methods: IOPE was extracted and prepared, the inhibitory effect on B16-F10 cells was determined in vitro, different concentrations of the IOPE (0.1, 0.2, 0.4, 0.8 mg/mL) were added to cells for 2, 12, 24, 48 h. BALB/c mice model was established by B16-F10 cells, and the IOPE (500, 250, 125 mg/kg/bw) were oral administration into mice. Results: The IOPE could not only owned inhibitory effect on B16-F10 cells (0.8 mg/mL), but also had a potent immune response improvement (250 mg/kg/bw), and effectively improved spleen immune index, CD3+ and CD8+ cell expression (79.8%,20.1%), strengthened phagocytosis of macrophages, significantly inhibited the over expression of inflammatory factors IL-6(308.02±6.48 pg/mL), IL-8(381.84±8.93 pg/mL), TNF-α(1877.50±11.11 pg/mL), promoted the expression of anti-inflammatory factor IL-10 (419.90±5.55 pg/mL), finally activated the LKB1-Bax-Casepase-3-PARP pathway. Conclusions: IOPE might be potentially used as an effective regulator for the immunity improvement in future.

Since the concept, DNA damage repair has been stated as a natural biological event, and research has increasingly revealed its strong association to tumors, aging, immunity, biochemical detection, and other factors. The discovery of abnormal DNA repair in cancers has been heralded as a paradigm shift in the treatment of malignancies. A poly (ADP-ribose) polymerase (PARP) activates poly (ADP-ribosylation) to repair single-strand DNA breaks after DNA damage. In some cancers, such as breast cancer and gastric cancer, a PARP inhibitor can target the DNA damage response pathway, prevent DNA repair, and induce homologous recombination deficiency (HRD) tumors to create the phenomena of synthetic lethality. Increasingly, clinical trials are being submitted to research the uses of PARP inhibitors in various types of cancers. Small cell lung cancer (SCLC) is a quickly growing malignancy with numerous therapeutic limitations and a dismal prognosis. Sequencing of mutant genes revealed multiple gene connections that may contribute to its carcinogenesis, indicating a viable study direction. Furthermore, the therapy of SCLC with PARP inhibitors has been further explored. The mechanism of PARP action, as well as the advancement of its preclinical and clinical applications in SCLC, will be discussed in this review.

Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy.This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156.A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively.Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastaticPatients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment.A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60;Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for

In order to solve the problem of serious attenuation of the performance of heat pump air conditioning system for pure electric bus at high temperature in summer and at low temperature in winter, a heat pump air conditioning system for medium-pressure air-supply pure electric bus with economizer is developed. The performance of the system working at from +50? to ?20? ambient temperature and at different compressor speed is studied. The results show that the exhaust temperature of the compressor can be reduced greatly.

Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.

When the exhaust temperature of heat pump air conditioning system of pure electric bus is too high, the performance of the system is attenuated. In order to solve the problem, an alternative system with low pressure air supply is developed. The experimental platform is set up to reveal the main factors affecting the refrigeration and heating performance of the system. The results show that the low pressure air-supply technology can significantly reduce the exhaust temperature of the compressor.

798 Background: Claudin18.2 (CLDN18.2) is specifically expressed in the tight junction of gastric epithelial cells, and has been identified as a promising target in gastric and pancreatic cancer as well as several other malignancies. MIL93 is a humanized afucosylated IgG1 monoclonal antibody targeting CLDN18.2 with enhanced ADCC function, which demonstrated superior activity compared with zolbetuximab in vitro and in vivo, respectively. We conducted a multicenter, dose escalation and expansion phase 1 study of MIL93 for advanced solid tumors. Methods: We enrolled pts aged 18 years or older with advanced solid tumors whose disease had progressed after standard systemic treatments in the monotherapy part of this study. Pts were required to have measurable lesion as per RECIST v1.1; ECOG PS score of 0-1 and adequate organ functions. In the dose escalation phase, 6 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg and 30mg/kg, Q3W) of MIL93 were conducted for assessment. Accelerated titration was adopted for the first 2 dose levels, and the 3+3 design was used afterwards. In the dose expansion phase, pts with CLDN18.2-positive cancers received the selected RP2D. The primary objectives were the safety and tolerability, dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MIL93. Secondary objectives included pharmacokinetics, immunogenicity and preliminary efficacy. Results: At the data cut-off date (August 9, 2022), 30 pts were enrolled from 6 centers in China. MIL93 was well-tolerated for the dosages tested (0.3mg/kg through 30mg/kg Q3W). DLT was observed in one pt during the 3-week window at 30mg/kg. However, none of the three additional patients at 30mg/kg had DLT, and MTD has not been reached. In further expansion study 9 additional pts were enrolled into the expansion phase at the 20 mg/kg Q3W dose and 3 pts were enrolled into the dose escalation at the 10mg/kg Q2W. The most common TEAE occurring in ≥20% of pts were nausea (60%), hypoalbuminemia (46.7%), vomiting (43.3%), anemia (36.7%), hyponatremia (33.3%), hypocalcemia (23.3%), decreased appetite (23.3%), asthenia (23.3%), aspartate aminotransferase increased (20.0%). Serious adverse events (SAEs) were observed in 9 (30%) pts, and MIL93-related SAEs occurred in 6 (20%) pts including hypoalbuminemia/hypoproteinemia, malnutrition, anorexia and vomiting. No treatment related Grade 4 or 5 event was reported. Among the 25 pts who had at least one post-treatment radiological evaluation, 2 gastric cancer pts who progressed on multiple lines of therapies achieved partial response (PR). The disease control rate (DCR) reached 44%. Conclusions: MIL93 had a manageable and tolerable safety profile in patients with advanced solid tumors and preliminary anti-tumor activity in 2 heavily pretreated gastric cancer pts. Combination of MIL93 and standard treatment in selected tumor types is currently underway. Clinical trial information: NCT04671875 .

To realize online measurement of power, frequency, and phase for a modularized relativistic triaxial klystron amplifier in a narrow space, a compact directional coupler with high directivity, high power handling capacity, and large bandwidth has been investigated numerically and experimentally. The method with coupling holes distributed in both the longitudinal and lateral directions is proposed, and the simulation results indicate that when two holes are employed, directivity larger than 20 dB is achieved over a 300 MHz bandwidth in the X-band and the maximal electric field strength is controlled to be 198.5 kV/cm with 1 GW power injection, while the whole coupler longitude is optimized to be as short as 50 mm. High power experiments have been performed with a 10 GHz relativistic triaxial klystron amplifier, and the results show that the measured power, frequency, and phase shift of the directional coupler have good agreement with the results obtained in the far-field.

Background and objective Lung cancer is the leading cause of cancer-related death, and small cell lung cancer (SCLC) has a poor prognosis in all types of lung cancer. This study evaluated the relationship between pretreatment serum apolipoprotein levels and prognosis in patients with SCLC, seeks a new index can guide diagnosis and treatment of SCLC. Methods This study retrospectively analyzed the clinical data of 122 patients with SCLC. The clinical results of patients with serum apolipoprotein levels within 2 weeks before treatment were collected, including apolipoprotein AI (ApoA-I), apolipoprotein B (ApoB), and the ratio of apolipoprotein B to apolipoprotein AI (ApoB/ApoA-I). Patients' progression-free survival (PFS) and overall survival (OS) are the main outcome indicators. The best critical to determine the index's value by X-tile tool. For survival analysis, Kaplan-Meier method was used for analysis, and Cox regression analysis method was used for single factor analysis and multifactor analysis. Results Compared with patients with low ApoA-I levels, patients with high ApoA-I levels (ApoA-I>1.12 g/L) had better OS (21.5 mon vs 12.3 mon, P=0.007) and PFS (7.3 mon vs 5.5 mon, P=0.017). In contrast, patients with higher ApoB/ApoA-I levels had worse median OS than patients with lower ApoB/ApoA-I levels (13.4 mon vs 20.7 mon, P=0.012). Multivariate Cox regression analysis showed that ApoA-I was an independent prognostic factor affecting PFS in SCLC patients (HR=0.67, 95%CI: 0.45-0.99, P=0.043). ApoB/ApoA-I is an independent risk factor for OS in patients with SCLC (HR=1.98, 95%CI: 1.21-3.23, P=0.007). Conclusion Serum ApoA-I level and ApoB/ApoA-I level before treatment can be important prognostic factors for SCLC, which is helpful to judge the prognosis of patients.

Investment and construction of energy and transport-related infrastructure are closely linked to the achievement of sustainable development goals. China’s infrastructure-led foreign investment, technical integration, and tourism with Belt and Road Initiative (BRI) countries have maintained exponential growth. This growth certainly has an impact on economic development mode and environmental sustainability. Therefore, this study examines the impact of infrastructure-led Chinese outward foreign direct investment, tourism development, and technology innovation on carbon emissions across the selected BRI node countries and respective regions. This study employs cross-sectional autoregressive distributive lag model to deal with parameters and cross-sectional heterogeneity. The results exhibit that foreign direct investment and technology innovation reduces carbon emissions in the long run, while tourism development and its interaction with foreign direct investment led to higher emissions in the overall BRI sample. In contrast, the regional estimates show significant variations in the magnitude and direction of the relationship, where foreign direct investment produces an emissions-increasing effect in South Asian and MENA countries. Moreover, the results support the validity of the Environmental Kuznets Curve hypothesis in overall and regional samples. These results are also endorsed by common correlated effects means group estimator and imply relevant policies.

In relativistic physics, both atomic collapse in heavy nucleus and Hawking radiation in black hole are predicted to occur through Klein tunneling process that couples particles and antiparticles. Recently, atomic collapse states (ACSs) were explicitly realized in graphene because of its relativistic Dirac excitation with large fine structure constant. However, essential role of the Klein tunneling on the ACSs remains elusive in experiment. Here we systematically study the quasibound states in elliptical graphene quantum dots (GQDs). Bonding and antibonding molecular collapse states formed by two coupled ACSs are observed in the elliptical GQDs. Our experiments, supported by theoretical calculations, indicate that the antibonding state of the ACSs will change into a Klein-tunneling-induced quasibound state, revealing deep connection between the ACSs and the Klein tunneling., Comment: 3 figures in main text

In FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese patients with metastatic colorectal cancer (mCRC). However, its safety profile, including adverse events of special interest (AESIs) and treatment-emergent adverse events (TEAEs) by age, sex, and body mass index (BMI), is not well known. The present analysis evaluated the safety profile and AESIs for fruquintinib in the FRESCO trial. In FRESCO, eligible Chinese patients were randomized (2:1) to receive fruquintinib (5 mg once daily for 3 weeks, followed by 1 week off in 28-day cycles) or placebo plus best supportive care. Treatment-related AESIs and time to first occurrence of AESIs were summarized. Treatment-related TEAEs by age, sex, and BMI were also summarized. A total of 266 patients (95.7%) in the fruquintinib group and 97 (70.8%) in the placebo group had at least one treatment-related TEAE; the mean relative dose intensity was 92% and 98%, respectively. In the fruquintinib group, the most common (in > 40% of patients) treatment-related AESIs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome [known as hand-foot skin reaction (HFSR)] (49.3%), and proteinuria (42.1%). The most common treatment-related grade ≥ 3 AESIs (≥ 3% of patients) were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively. Subgroup analysis by age, sex, and BMI revealed that the frequencies of treatment-related TEAEs were similar across all subgroups, and were consistent with the overall safety profile of fruquintinib. The most common treatment-related grade ≥ 3 AEs were hypertension, HFSR, and proteinuria. The treatment-related TEAE profile of fruquintinib in Chinese patents with mCRC was comparable among different subgroups and consistent with that reported in the overall population. Trial Registration: Clinical Trials identifier NCT02314819.

The relentless debate on postoperative adjuvant radiotherapy in gastric adenocarcinoma (GA) has been lasting for decades. In this study, a new biomarker, named promoter methylation burden of DNA repair genes (RPMB), was established to identify the subgroup of patients who might benefit from adjuvant radiotherapy. Methylation profiles of 397 GA tumor samples were downloaded from The Cancer Genome Atlas (TCGA). RPMB for a patient was defined as the ratio of methylated DNA repair genes to the number of all DNA repair genes. Subgroup analyses in term of overall survival (OS) and disease-free survival (DFS) indicated that most of the subgroups favored the high-RMPB group. Kaplan-Meier analysis showed that overall the patients with high RPMB after R0 resection had a significantly better clinical outcome regarding DFS (hazard ratio [HR] = 0.013, p = 0.042). Additionally, high-RPMB patients, who underwent adjuvant radiotherapy with both ≥T2 tumor and positive lymph nodes, showed superior DFS in comparison with the low-RPMB group (HR = 5.35 × 10−10, n = 26, p = 0.010). RPMB might be considered as a promising biomarker for decision-making with regard to postoperative adjuvant radiotherapy for GA patients., Graphical Abstract, To identify the subgroup of gastric adenocarcinoma (GA) patients who can benefit from postoperative adjuvant radiotherapy, An et al. proposed a new biomarker, named promotor methylation burden of DNA repair genes (RPMB), closely associated with patient prognosis, hopefully to provide guidance for treating GA patients after radical resection.

Triglycerides (TG) not only provide energy for infants but have important physiological functions. Understanding the composition and structure of TG in human milk is conducive to the development of infant formulas. In this study, TG species in human milk from 3 provincial capitals (Zhengzhou, Wuhan, and Harbin) in different regions of China were determined through C18 HPLC electrospray ionization tandem mass spectrometry (MS). The results showed that in human milk from these 3 regions, oleoyl-palmitoyl-linoleoylglycerol (OPL; 16.55, 19.20, and 18.67%, respectively) was more abundant than oleoyl-palmitoyl-oleoylglycerol (OPO; 10.08, 10.22, and 12.03%, respectively). Subsequently, regioisomeric and enantiomeric analysis of main TG in the human milk were performed on silver ion and chiral HPLC atmospheric pressure chemical ionization mass spectrometry (APCI)-MS, respectively. The results showed that rac-OPL (above 85%), rac-OPO (above 85%), rac-palmitoyl-oleoyl-oleoylglycerol (PPO; above 90%), and rac-OLaO (above 70%) were the main regioisomers of OPL, OPO, PPO, and lauroyl-oleoyl-oleoylglycerol (LaOO), respectively. The relative ratios of enantiomer pairs of rac-OPL (rac-OPL1 and rac-OPL2) were about 37 and 63%, respectively.

In recent years, lung cancer has become the leading cause of cancer-related deaths. There is increasing evidence that many lipids and lipid analogs are key regulators of tumorigenesis, and factors that affect blood lipid levels such as smoking, diet, and obesity may be associated with cancer risk. With the deepening of research on the relationship between lipids and tumorigenesis, exploring the correlation between blood lipids and lung cancer risk and prognosis has become a research hotspot. This article reviews the research progress of the relationship between blood lipid levels and the risk of lung cancer, blood lipid levels and the prognosis of lung cancer patients, and the adjustment of blood lipid drugs and the prevention and treatment of lung cancer.