Mfsd2a overexpression alleviates vascular dysfunction in diabetic retinopathy.

Diabetic retinopathy (DR) is one of the common complications in diabetic patients. Nowadays, VEGF pathway is subject to extensive research. However, about 27% of the patients have a poor visual outcome, with 50% still having edema after two years' treatment of diabetic macular edema (DME) with ranibizumab. Docosahexaenoic acid (DHA), the primary ω-3 long-chain polyunsaturated fatty acid (LC-PUFA), reduces abnormal neovascularization and alleviates neovascular eye diseases. A study reported that fish oil reduced the incidence of retinopathy of prematurity (ROP) by about 27.5% in preterm infants. Although ω-3 LC-PUFAs protects against pathological retinal neovascularization, the treatment effectiveness is low. It is interesting to investigate why DHA therapy fails in some patients. In human vitreous humor samples, we found that the ratio of DHA and DHA-derived metabolites to total fatty acids was higher in vitreous humor from DR patients than that from macular hole patients; however, the ratio of DHA metabolites to DHA and DHA-derived metabolites was lower in the diabetic vitreous humor. The expression of Mfsd2a, the LPC-DHA transporter, was reduced in the oxygen-induced retinopathy (OIR) model and streptozotocin (STZ) model. In vitro, Mfsd2a overexpression inhibited endothelial cell proliferation, migration and vesicular transcytosis. Moreover, Mfsd2a overexpression in combination with the DHA diet obviously reduced abnormal retinal neovascularization and vascular leakage, which is more effective than Mfsd2a overexpression alone. These results suggest that DHA therapy failure in some DR patients is linked to low expression of Mfsd2a, and the combination of Mfsd2a overexpression and DHA therapy may be an effective treatment.

Apatinib reverses alectinib resistance by targeting vascular endothelial growth factor receptor 2 and attenuating the oncogenic signaling pathway in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene-positive lung cancer cell lines.

Overexpression of insulin growth factor 1 receptor (IGF-1R) and its ligand, insulin growth factor 1 (IGF-1), is related to treatment resistance and worse prognosis in many types of tumors. We reported recently that IGF-1R activation by IGF induces resistance to alectinib and stimulates the production of vascular endothelial growth factor, which indicates that IGF induces alectinib resistance and angiogenesis. This study aimed to determine the effect of bigeminal inhibition of anaplastic lymphoma kinase (ALK) and angiogenesis on human insulin growth factor 1 receptor (hIGF-1)-triggered drug resistance in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer. Human lung adenocarcinoma H3122 and H2228 cells were exposed to a combination of insulin growth factor 1 receptor (IGF-1), alectinib, or apatinib. The effects of the combination therapy were examined using cell the Cell Counting Kit-8 assay, the colony-forming assay, the scratch test, and flow cytometry analysis, and the molecular mechanism was assessed by western blot. At nontoxic concentrations, apatinib restored alectinib sensitivity by increasing drug-induced apoptosis and inhibiting viability, migration, and invasion in IGF-triggered drug resistant cells. Moreover, we found that apatinib restored sensitivity to alectinib mainly through suppression of the ALK downstream signaling pathway and antiangiogenesis signaling. Taken together, our results indicate that simultaneous inhibition of ALK and vascular endothelial growth factor R2 by the combination of alectinib with apatinib may be useful for controlling progression of EML4-ALK fusion gene lung cancer by reversing ALK-TKI resistance and inhibiting angiogenesis.

[The neuroprotection of brain-derived neurotrophic factor in experimental retinal detachment reattached].

OBJECTIVE: To investigate the effect of exogenous brain-derived neurotrophic factor (BDNF) on the retinal repair after experimental retinal detachment (RD) reattached. METHODS: Experimental study. Forty-eight normal rats were randomly divided into four groups:BDNF group, control group, RD reattached group and normal group. In order to detect the effects of BDNF on retinal degeneration caused by RD, the morphology of retina and the ultrastructure of retinal cells were observed by light microscopy and electron microscopy. The effect of BDNF on the apoptosis of retinal cells after RD reattached was detected by Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) technique. Data were analyzed using one-way analysis of variance (ANOVA) and secondary analysis for significance with independent-samples t-test. RESULTS: The average automatically reattached time was (31.3 ± 3.5) days. Compared with control group, there were less damage in out segment and inner segment, more retinal cells in outer nuclear layer (ONL) and inner nuclear layer (INL), thicker ONL of retina and better organizational structure of retina in BDNF group. The average thickness of ONL and INL of retina were (21.166 ± 3.087) µm, (23.508 ± 3.679) µm respectively in BDNF group, and (16.084 ± 2.928) µm, (12.885 ± 3.070) µm respectively in control group. The thickness of ONL and INL of retina showed a significant difference in BDNF group compared with control (P < 0.01). There were less TUNEL-positive cells in ONL of retina in BDNF group compared with control. CONCLUSIONS: This study indicates that the morphology of retina and the ultrastructure of retinal cells have changed, and the apoptosis of retinal cells are present after RD reattached. Exogenous BDNF can reduce retinal cells degeneration and inhibit the apoptosis of retinal cells and have a certain protection effects on the retinal damage caused by RD.

Prognostic Significance of Pretreatment Plasma D-dimer Levels in EGFR-Positive Advanced Non-Small Cell Lung Cancer Patients Receiving Osimertinib: A Multicentre Retrospective Study.

Purpose: This study examined the association between plasma D-dimer levels and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients treated with osimertinib. Methods: In this multicenter study, 88 patients with advanced non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations and receiving osimertinib were enrolled. The target independent and dependent variables were the D-dimer levels before osimertinib treatment and OS time, respectively. The t-test or chi-square test was utilized to analyze the variances among various groups. The predictive significance of D-dimer for overall survival (OS) was assessed using Kaplan-Meier survival analysis and the Cox proportional hazard regression model. Results: The selected patients had an average age of 58.01±10.72 years, with females comprising 54.55%. Based on their D-dimer levels, the patients were categorized into three groups: low-level (< 0.6 mg/L), middle-level (0.6 ~ 2 mg/L), and high-level (≥ 2 mg/L). After accounting for possible confounding variables, the Cox proportional hazard model showed that increased D-dimer levels were linked to a greater likelihood of death (HR 2.28, 95% CI = 1.09 ~ 4.76, p = 0.029). Importantly, there was a significant trend indicating that as D-dimer levels rose, the risk of mortality also increased (p for trend, HR 1.15, 95% CI = 1.03 ~ 1.28, p = 0.012). Consistently comparable outcomes were noted in the majority of subcategories. Patients with low-middle and high D dimer levels had a median OS of 28.6 and 17 months, respectively (p =0.014). Conclusion: In conclusion, elevated levels of D-dimer in the bloodstream were found to have a significant negative correlation with the overall survival (OS) of patients with EGFR-positive non-small cell lung cancer (NSCLC) who underwent treatment with osimertinib.

Relative activity of 15 bacterial strains against the larvae of Helicoverpa armigera, Spodoptera exigua, and Spodoptera litura (Lepidoptera: Noctuidae).

Crystal toxins produced by different strains of entomopathogenic Bacillus thuringiensis (Bt) have been characterized and widely applied as commercial biological pesticides owing to their excellent insecticidal properties. This study aimed to identify novel bacterial strains effective in controlling Spodoptera exigua Hübner, Helicoverpa armigera Hübner, and Spodoptera litura Fabricius. Fifteen culturable bacterial strains were isolated from 60 dead larvae (H. armigera and S. exigua) collected in the field. The biochemical characteristics and 16S rRNA sequences of these strains indicated that one strain (B7) was Lysinibacillus sp., 12 strains (B1, B3, B4, B5, B6, B8, P2, P3, P4, P5, P6, and DW) were Bt kurstaki, and P2-2 and B2 were Bacillus velezensis subsp. Laboratory bioassays indicated that strains B3, P6, B6, and P4 showed high toxicity to second-instar larvae of S. exigua, with LC50 values of 5.11, 6.74, 205.82, and 595.93 µg/ml, respectively; while the strains P5, B5, B6, and P6, were the most efficient against second-instar larvae of H. armigera with LC50 values of 725.82, 11,022.72, 1,282.90, 2,005.28, respectively, and strains DW, P3, P2, and B4 had high insecticidal activity against second-instar larvae of S. litura with LC50 values of 576.69, 1,660.96, 6,309.42, and 5,486.10 µg/ml, respectively. In conclusion, several Bt kurstaki strains with good toxicity potential were isolated and identified in this study. These strains are expected to be useful for biointensive integrated pest management programs to reduce the use of synthetic insecticides.

Development of Quality Indicators for the Ultrasound Department through a Modified Delphi Method.

This study aims to establish precise quality indicators for evaluating and enhancing ultrasound performance, employing a methodology based on a comprehensive review of the literature, expert insights, and practical application experiences. We conducted a thorough review of both the domestic and international literature on ultrasound quality control to identify potential indicators. A dedicated team was formed to oversee the complete indicator development process. Utilizing a three-round modified Delphi method, we sought expert opinions through personalized email correspondence. Subsequently, data from diverse hospital indicators were collected to validate and assess feasibility. A novel set of seven indicators was compiled initially, followed by the convening of a 36-member nationally representative expert panel. After three rounds of meticulous revisions, consensus was reached on 13 indicators across three domains. These finalized indicators underwent application in various hospital settings, demonstrating their initial validity and feasibility. The development of thirteen ultrasound quality indicators represents a significant milestone in evaluating ultrasound performance. These indicators empower hospitals to monitor changes in quality effectively, fostering efficient quality management practices.

Feeding Spodoptera exigua larvae with gut-derived Escherichia sp. increases larval juvenile hormone levels inhibiting cannibalism.

Feed quality influences insect cannibalistic behavior and gut microbial communities. In the present study, Spodoptera exigua larvae were fed six different artificial diets, and one of these diets (Diet 3) delayed larval cannibalistic behavior and reduced the cannibalism ratio after ingestion. Diet 3-fed larvae had the highest gut bacterial load (1.396 ± 0.556 × 1014 bacteria/mg gut), whereas Diet 2-fed larvae had the lowest gut bacterial load (3.076 ± 1.368 × 1012 bacteria/mg gut). The gut bacterial composition and diversity of different diet-fed S. exigua larvae varied according to the 16S rRNA gene sequence analysis. Enterobacteriaceae was specific to the Diet 3-fed larval gut. Fifteen culturable bacterial isolates were obtained from the midgut of Diet 3-fed larvae. Of these, ten belonged to Escherichia sp. After administration with Diet 1- or 2-fed S. exigua larvae, two bacterial isolates (SePC-12 and -37) delayed cannibalistic behavior in both tested larval groups. Diet 2-fed larvae had the lowest Juvenile hormone (JH) concentration and were more aggressive against intraspecific predation. However, SePC-12 loading increased the JH hormone levels in Diet 2-fed larvae and inhibited their cannibalism. Bacteria in the larval midgut are involved in the stabilization of JH levels, thereby regulating host larval cannibalistic behavior.

Efficacy and Safety of Denosumab Biosimilar QL1206 Versus Denosumab in Patients with Bone Metastases from Solid Tumors: A Randomized Phase III Trial.

BACKGROUND: Denosumab has been approved for the treatment of bone metastases from solid tumors. QL1206 is the first denosumab biosimilar and needs to be compared with denosumab in a phase III trial. OBJECTIVE: This phase III trial aims to compare the efficacy, safety, and pharmacokinetics between QL1206 and denosumab in patients with bone metastases from solid tumors. METHODS: This randomized, double-blind, phase III trial was conducted in 51 centers in China. Patients aged 18-80 years, with solid tumors and bone metastases, and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. This study was divided into a 13-week double-blind period, a 40-week open-label period, and a 20-week safety follow-up period. In the double-blind period, patients were randomly assigned (1:1) to receive three doses of QL1206 or denosumab (120 mg subcutaneously every 4 weeks, each). Randomization was stratified by tumor types, previous skeletal-related events, and current systemic anti-tumor therapy. In the open-label period, up to ten doses of QL1206 could be given in both groups. The primary endpoint was percentage change in urinary N-telopeptide/creatinine ratio (uNTX/uCr) from baseline to Week 13. Equivalence margins were ± 0.135. Secondary endpoints included percentage change in uNTX/uCr at Week 25 and 53, percentage change in serum bone-specific alkaline phosphatase at Week 13, 25, and 53, and time to on-study skeletal-related events. The safety profile was evaluated based on adverse events and immunogenicity. RESULTS: From September 2019 to January 2021, in the full analysis set, 717 patients were randomly assigned to receive QL1206 (n = 357) or denosumab (n = 360). Median percentage changes in uNTX/uCr at Week 13 in two groups were - 75.2% and - 75.8%, respectively. Least-squares mean difference in the natural log-transformed ratio of uNTX/uCr at Week 13 to baseline between the two groups was 0.012 (90% confidence interval - 0.078 to 0.103), within the equivalence margins. There were no differences in the secondary endpoints between the two groups (all p > 0.05). Adverse events, immunogenicity, and pharmacokinetics were similar in the two groups. CONCLUSIONS: Denosumab biosimilar QL1206 had promising efficacy, tolerable safety, and pharmacokinetics equivalent to denosumab and could benefit patients with bone metastases from solid tumors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04550949, retrospectively registered on 16 September, 2020.

Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study.

Background: KL-A167 is a fully humanized monoclonal antibody targeting programmed cell death-ligand 1. This phase 2 study aimed to evaluate the efficacy and safety of KL-A167 in Chinese patients with previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Methods: This was a multicentre, single-arm, phase 2 study of KL-A167 in R/M NPC (KL167-2-05-CTP) (NCT03848286), conducted at 42 hospitals across the People's Republic of China. Eligible patients had histologically confirmed non-keratinising R/M NPC, and had failed at least two lines of chemotherapy. Patients received KL-A167 900mg intravenously once every 2 weeks until confirmed disease progression, intolerable toxicity, or withdrawal of informed consent. The primary endpoint was objective response rate (ORR) assessed by the independent review committee (IRC) according to RECIST v1.1. Findings: Between Feb 26th, 2019 and Jan 13th, 2021, 153 patients were treated. Totally, 132 patients entered full analysis set (FAS) and were evaluated for the efficacy. As of data cutoff date on Jul 13th, 2021, the median follow-up time was 21.7 months (95%CI 19.8-22.5). For FAS population, the IRC-assessed ORR was 26.5% (95%CI 19.2-34.9%), and disease control rate (DCR) was 56.8% (95%CI 47.9-65.4%). Median progression-free survival (PFS) was 2.8 months (95%CI 1.5-4.1) . Median duration of response was 12.4 months (95%CI 6.8-16.5), and median overall survival (OS) was 16.2 months (95%CI 13.4-21.3). When using the cutoff of 1000 copies/ml, 5000 copies/ml and 10,000 copies/ml for plasma EBV DNA titer, baseline low plasma EBV DNA was consistently related with better DCR, PFS and OS. Dynamic change of plasma EBV DNA was significantly associated with ORR and PFS. Among 153 patients, treatment related-adverse events (TRAEs) occurred in 73.2% of patients, and grade ≥3 TRAEs were in 15.0% of patients. No TRAE leading to death was reported. Conclusion: In this study, KL-A167 showed promising efficacy and an acceptable safety profile in patients with previously treated R/M NPC. Baseline plasma EBV DNA copy number might be a potentially useful prognostic biomarker for KL-A167 treatment, and post-treatment EBV DNA decrease might be correlated with better response to KL-A167. Funding: Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd., China National Major Project for New Drug Innovation (2017ZX09304015).

[The effects of individualized therapeutic programs on chronic hepatitis C and the influential factors of virological response].

OBJECTIVE: To investigate the effect of individualized therapeutic programs with combination of interferon and ribavirin (RBV) in chronic hepatitis C (CHC) and study the influential factors of virological response rates. METHODS: A total of 139 patients with CHC were enrolled and given the intensive treatment doses of interferon and RBV according to their basic clinical condition. At the treatment of 0, 4, 12, 24 weeks, the end of treatment and 24 weeks after treatment stop, the serum HCV RNA was determined. Timely adjustment to dosage and time periods was made according to the virological response to treatment, and the predictive value of rapid virological response (RVR) and complete early virological response (cEVR) for sustained virological response (SVR) were analyzed. RESULTS: At the 4th week of treatment, the level of serum HCV RNA was monitored in 120 patients, and 84.2% (101/120) of patients obtained RVR; among them, 90.7% (88/97) obtained SVR. The virus load of patients obtained RVR at pretherapy was lower than that of patients didn't obtained RVR [(5.883 ± 1.246) lg copies/ml vs(6.502 ± 0.693) lg copies/ml, P = 0.034]. The RVR rate of initial treatment patients with PEG-IFNα-2a [87.8% (79/90)] was significantly higher than that of retreatment patients with PEG-IFNα-2a [65.0% (13/20)] (P = 0.031). At the 12th week of treatment, the level of serum HCV RNA was monitored in 132 patients, and 92.4% (122/132) of patients obtained cEVR; among them, 90.8% (108/119) obtained SVR. The SVR rate of patients obtained cEVR was significantly higher than that of patients didn't obtained cEVR (5/9) (P = 0.007). There was no significant difference between the cEVR rate of initial treatment patients [94.7% (90/95)] and retreatment patients [85% (17/20)] with PEG-IFNα-2a (P = 0.158). CONCLUSIONS: cEVR was predictor of SVR. Individualized therapy can increase the obtaining probability of RVR, cEVR and SVR. Adjusting drug dose timely and extending treatment period of HCV RNA-negative based on virological response to treatment are important in CHC individualized therapy.

[Detection of antibodies to cyclic citrullinated peptides and its clinical significance in patients with chronic hepatitis B virus infection].

OBJECTIVE: To detect the presence of antibodies to cyclic citrullinated peptides (anti-CCP) in patients with chronic hepatitis B virus (HBV) infection and evaluate its potential clinical significance. METHODS: Serum samples of 280 patients with chronic HBV infection and 40 healthy controls were collected from May 2011 to October 2011 and tested for anti-CCP and IgM-rheumatoid factor (RF). Anti-CCP was detected by ELISA and RF by immunonephelometry. All of 280 patients with chronic HBV infection were divided into 3 groups according to joint symptoms: asymptomatic group, HBV-associated arthropathy group and HBV concomitant RA group. Meanwhile, according to liver disease, they were divided into 3 groups: carrier group, chronic hepatitis group and cirrhosis group. RESULTS: The positive rates of anti-CCP and RF were 5.7% and 13.9% in patients with chronic HBV infection respectively. Anti-CCP was detected in 3 of 265 non-RA (1.1%) and 13 of 15 RA patients (86.7%). And RF were detected in 27 of 265 non-RA (10.2%) and 12 of 15 RA patients (80.0%). Twelve of 15 RA patients were positive for both anti-CCP and RF. The specificity of anti-CCP for RA was 98.9% in chronic HBV infection while the specificity of RF 89.8% (P < 0.01). Compared with the positive detection rates of anti-CCP and RF among liver disease subgroups, no significant difference existed between the subgroups. The levels of anti-CCP and RF in HBV concomitant RA group were statistically higher than those in asymptomatic group, HBV-associated arthropathy group and healthy controls (all P < 0.01). The level of RF in patients with HBV-associated arthropathy group was higher than that in asymptomatic group (U = 6017, P < 0.05). CONCLUSION: It is better to detect anti-CCP than RF to discriminate non-RA from concomitant RA in patients with chronic HBV infection.

Pharmacological Properties and Function of the PxOctß3 Octopamine Receptor in Plutella xylostella (L.).

The diamondback moth (Plutella xylostella) is one of the most destructive lepidopteran pests of cruciferous vegetables, and insights into regulation of its physiological processes contribute towards the development of new pesticides against it. Thus, we investigated the regulatory functions of its ß-adrenergic-like octopamine receptor (PxOctß3). The open reading frame (ORF) of PxOctß3 was phylogenetically analyzed, and the levels of expression of the receptor mRNA were determined. This ORF was also cloned and expressed in HEK-293 cells. A series of octopamine receptor agonists and antagonists were tested against PxOctß3. We showed that the receptor is a member of the Octß3 protein family, and an analysis using quantitative PCR showed that it was expressed at all developmental stages of P. xylostella. Octopamine activated PxOctß3, resulting in increased levels of intracellular cAMP. Furthermore, the agonists naphazoline, clonidine, 2-phenethylamine, and amitraz activated the PxOctß3 receptor, and naphazoline was the most effective. Only metoclopramide and mianserin had significant antagonistic effects on PxOctß3, whereas yohimbine, phentolamine, and chlorpromazine lacked obvious antagonistic effects. The injection of double-stranded RNA in an RNA interference assay indicated that PxOctß3 regulates development in P. xylostella. This study demonstrated the pharmacological properties and functions of PxOctß3 in P. xylostella, thus, providing a theoretical basis for the design of pesticides that target octopamine receptors.

C/EBPα Regulates PxTreh1 and PxTreh2 Trehalase-Related Bt Resistance in Plutella xylostella (L.).

Trehalase regulates energy metabolism in insects by converting trehalose into two glucose molecules. High amounts of trehalase are critical for insect flight and larval stress resistance. However, whether trehalase participates in the development of pesticide resistance remains unclear. In this study, we explored this phenomenon and the mechanism that underlies the regulation of Trehalase transcription. We found that overexpression of PxTreh1 and PxTreh2 induced Bacillus thuringiensis (Bt) resistance in Plutella xylostella. The promoter sequences of PxTreh1 and PxTreh2 were also cloned and identified. The dual-luciferase reporter system and RNA interference technology revealed that the expression of PxTreh1 and PxTreh2 genes is possibly regulated by the CCAAT enhancer-binding protein (C/EBPα). A yeast one-hybrid experiment confirmed the interaction between C/EBPα and the PxTreh2 promoter. The findings of this study suggest that C/EBPα mediates the adaptability of P. xylostella to adverse environmental stressors by regulating the expression of trehalase.

PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer: A real-world retrospective cohort study.

Background: The aim of this study was to assessment the efficacy and safety of Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer. Methods: In this study, pre-treatment clinical and laboratory indicators from 73 patients with advanced non-small cell lung cancer were retrieved for retrospective analysis. According to the therapy regimes they received, the patients were separated into groups, PD-1/PD-L1 inhibitors plus chemotherapy group (PC group), PD-1/PD-L1 inhibitors plus anti-angiogenic agents' group (PA group), PD-1/PD-L1 inhibitors plus anti-angiogenic agents plus chemotherapy group (PAC group). Cox's proportional hazards regression model and Kaplan-Meier (KM) curves were used to assess the connection between treatment regimens and progression free survival (PFS) and overall survival (OS). In addition, the association of treatment regimens with the risk of disease progression and death was evaluated by subgroup analysis. Results: The average age of the enrolled patients was 58.2 ± 10.2 years and 75.3% were male. Multivariate analyses showed that patients in PA group (Disease progression: HR 0.4, P=0.005. Death: HR 0.4, P=0.024) and PAC group (Disease progression: HR 0.3, P=0.012. Death: HR 0.3, P=0.045) had a statistically significant lower hazard ratio (HR) for disease progression and death compared to patients in PC group. Kaplan-Meier analysis showed that patients in PA group (mPFS:7.5 vs.3.5, P=0.00052. mOS:33.1 vs.21.8, P=0.093) and PAC group (mPFS:5.1 vs.3.5, P=0.075. mOS:37.3 vs.21.8, P=0.14) had a longer PFS and OS compared to patients in PC group. In all the pre-defined subgroups, patients in PA and PAC groups showed a decreasing trend in the risk of disease progression and death in most subgroups. The patients in PA group (DCR:96.3% vs.58.3%, P=0.001) and PAC group (DCR:100% vs.58.3%, P=0.019) had a better disease control rate (DCR) than patients in PC group. Conclusion: PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy were superior to PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment in patients with advanced non-small cell lung cancer.

Efficacy and Safety of SH-1028 in Patients With EGFR T790M-Positive NSCLC: A Multicenter, Single-Arm, Open-Label, Phase 2 Trial.

INTRODUCTION: As a novel third-generation EGFR tyrosine kinase inhibitor (TKI), SH-1028 (formerly oritinib) is developed to inhibit both sensitizing EGFR mutations and EGFR T790M mutation. METHODS: This was a multicenter, single-arm, open-label, phase 2 trial (NCT03823807). Eligible patients were those with advanced NSCLC with centrally confirmed EGFR T790M mutation who progressed after first- or second-generation EGFR TKIs or with primary EGFR T790M mutations. Each patient received SH-1028 tablets orally at 200 mg/d until disease progression or intolerable toxicity. Tumor response was evaluated every 6 weeks per the Response Evaluation Criteria in Solid Tumors, version 1.1. The primary end point was objective response rate by an independent review committee. The secondary end points were progression-free survival, overall survival (OS), disease control rate, safety, and so on. RESULTS: A total of 286 patients with EGFR T790M-positive advanced NSCLC were enrolled in this study, including 59 patients in part A (dose-verification study) and 227 patients in part B (second-line registration study). By data cutoff on September 17, 2021, the independent review committee-assessed objective response rate was 55.9% (95% confidence interval [CI]: 42.4-68.8) in part A and 60.4% (95% CI: 53.7-66.8) in part B. The median progression-free survival was 12.4 months (95% CI: 8.3-20.8) in part A and 12.6 months (95% CI: 9.7-15.3) in part B. The median OS was 26.0 months (95% CI: 23.3-not reached) in part A, and OS was immature in part B. Among the 286 patients, 44 of them experienced at least one grade 3 or higher treatment-related adverse event, with the most common ones as increased serum creatinine phosphokinase level (13 [4.5%]), diarrhea (six [2.1%]), and prolonged QT interval (three [1.0%]). Treatment-related skin rash was reported in 26 patients (9.1%), all grade 1 or 2. There was no interstitial lung disease reported in this study. CONCLUSIONS: SH-1028 is efficacious and tolerable in second-line treatment of patients with advanced NSCLC with positive EGFR T790M.

Can the multi-walled carbon nanotubes be used to alleviate the phytotoxicity of herbicides in soils?

Herbicides are commonly used globally. However, residual herbicides in soils for ages often result in phytotoxicity and serious yield loss to subsequent crops. In this paper, the multi-walled carbon nanotubes (MWCNTs) were utilized to amend the herbicide polluted soil, and the adsorption performance of herbicides to MWCNTs amended soil was studied. Results indicate efficient alleviation of herbicide-induced phytotoxicity to rice and tobacco due to MWCNTs amendment. When 0.4% MWCNTs were applied, the concentration of sulfentrazone that inhibited the same rice height by 50% (IC50) increased to more than 3 times that of pure soil. When the MWCNTs were used to alleviate the phytotoxicity of quinclorac to tobacco, the MWCNTs not only alleviated the phytotoxicity of quinclorac but also promoted the growth of tobacco. The MWCNTs amended soil significantly increased the adsorption of herbicide to soil than biochar. The soil microbial analysis shows that MWCNTs had no significant effect on soil microbial community diversity, but the long-term exposure to MWCNTs could change the structure of the soil microbial community. Above all, our results highlighted the potential implication of the MWCNTs to ensure crop production by promoting crop growth and reducing the residual bioavailability of herbicides.

Anthocyanin Genes Involved in the Flower Coloration Mechanisms of Cymbidium kanran.

The Orchidaceae, otherwise known as orchids, is one of the largest plant families and is renowned for its spectacular flowers and ecological adaptations. Various polymorphisms of orchid flower colour can attract pollinators and be recognised as valuable horticultural ornamentals. As one of the longest historic cultured orchids, Cymbidium kanran has been domesticated for more than 2,500 years and is an ideal species to study coloration mechanisms because of plentiful variations in floral coloration and abundant traditional varieties. In this study, we used two distinct colour-type flowers of C. kanran as experimental materials to elucidate the mechanism of flower coloration. High-performance liquid chromatography (HPLC) analysis revealed that anthocyanins in purple-red-type flowers include three types of anthocyanidin aglycones, peonidin, malvidin, and cyanidin, whereas anthocyanins are lacking in white-type flowers. Through comparative transcriptome sequencing, 102 candidate genes were identified as putative homologues of colour-related genes. Based on comprehensive correlation analysis between colour-related compounds and gene expression profiles, four candidates from 102 captured genes showed a positive correlation with anthocyanidin biosynthesis. Furthermore, transient expression of CkCHS-1, CkDFR, and CkANS by particle bombardment confirmed that recovery of their expression completed the anthocyanin pathway and produced anthocyanin compounds in white-type flowers. Collectively, this study provided a comprehensive transcriptomic dataset for Cymbidium, which significantly facilitate our understanding of the molecular mechanisms of regulating floral pigment accumulation in orchids.

Efficacy and safety of MIL60 compared with bevacizumab in advanced or recurrent non-squamous non-small cell lung cancer: a phase 3 randomized, double-blind study.

BACKGROUND: We compared the efficacy, safety, and immunogenicity of MIL60 with reference bevacizumab as first-line treatment in patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) in this phase 3, randomized, double-blind study. METHODS: Patients with untreated advanced or recurrent NSCLC were randomized (1:1 ratio) to receive either MIL60 or bevacizumab in combination with paclitaxel/carboplatin. Patients with non-progressive disease continued maintenance single-agent MIL60 until disease progression, or intolerable toxicity. The primary endpoint was the 12-week objective response rates (ORR12) by independent review committee (IRC) using RECIST 1.1. Bioequivalence was established if the ORR ratio located between 0.75 and 1/0.75. The trial was registered with clinicaltrials.gov (NCT03196986). FINDINGS: Between Aug 23, 2017, and May 8, 2019, 517 patients were randomly assigned to MIL60 group (n=257) and bevacizumab group (n=260). In the full analysis set (FAS) population including all randomized and evaluable patients who received at least one dose of MIL60 or bevacizumab, the ORR12 in MIL60 group and bevacizumab group were 48.6% and 43.1%, respectively. The ORR ratio of these two groups were 1.14 (90% CI 0.97-1.33), which fell within the pre-specified equivalence boundaries (0.75-1/0.75). The median DOR was 5.7 months (95% CI 4.5-6.2) for MIL60 and 5.6 months (95% CI 4.3-6.4) for bevacizumab. No significant difference was noted in median PFS (7.2 vs. 8.1 months; HR 1.01, 95% CI 0.78-1.30, p=0.9606) and OS (19.3 vs. 16.3 months; HR 0.81, 95% CI 0.64-1.02, p=0.0755). Safety and tolerability profiles were similar between the two groups. No patient detected positive for Anti-drug antibody (ADA). INTERPRETATION: The efficacy, safety and immunogenicity of MIL60 were similar with bevacizumab, providing an alternative treatment option for advanced or recurrent non-squamous NSCLC. FUNDING: This study was sponsored by Betta Pharmaceutical Co., Ltd.

Prognostic Value of Pretreatment Albumin-to-Alkaline Phosphatase Ratio in Extensive-Disease Small-Cell Lung Cancer: A Retrospective Cohort Study.

PURPOSE: Evidence regarding the relationship between albumin-to-alkaline phosphatase ratio (AAPR) and overall survival (OS) in extensive-disease small-cell lung cancer (ED-SCLC) patients is limited. This study aimed to investigate whether AAPR was independently related to OS in ED-SCLC patients after adjusting for potential covariates. PATIENTS AND METHODS: This was a retrospective cohort study of 224 patients with ED-SCLC. The target independent and dependent variables were pretreatment AAPR and OS, respectively. Covariates included age; sex; Eastern Cooperative Oncology performance status score; smoking history; existence of metastasis to organs such as the bone, lung, liver, brain, malignant plural effusion and others; sum of organ metastasis (≤3, >3), evaluation of first-line treatment; and sum of treatment lines (<2, ≥2). Student's t test or chi-squared test was used to analyze the associations between AAPR and clinical characteristics. Kaplan-Meier survival analysis and Cox's proportional hazards regression model were used to assess the prognostic value of AAPR for OS. RESULTS: The average patient age was 60.51±8.73 years, and 87.95% were men. A non-linear relationship between AAPR and OS was detected, with an inflection point of 0.35. The hazard ratios (HRs) of the left (AAPR <0.35) and right sides (AAPR ≥0.35) of inflection point were 0.04 (95% CI=0.00-0.70, p=0.0268) and 0.52 (95% CI=0.16-1.64, p=0.2659), respectively. Kaplan-Meier analysis showed a median OS of 9.73 months (95% CI=8.6-12.33) for AAPR <0.35 and 13.7 months (95% CI=11.43-16.37) for AAPR ≥0.35 (log-rank p<0.0001). The Cox proportional hazards model showed that AAPR <0.35 increased the risk of death after adjusting for potential confounders (HR=1.65, 95% CI=1.11-2.46). In subgroup analysis, the trends of HRs were increased across all subgroups with AAPR <0.35 after stratification. CONCLUSION: Pretreatment AAPR might be served as an independent prognostic indicator in ED-SCLC patients. Our findings should be further validated in large-scale and prospective clinical trials.

Pretreatment plasma d-dimer levels as an independent prognostic factor for overall survival among patients with advanced non-small-cell lung cancer.

OBJECTIVE: To evaluate the prognostic accuracy of d-dimer levels for advanced non-small-cell lung cancer (NSCLC). METHODS: This retrospective cohort study included 651 patients initially diagnosed with advanced NSCLC. Patients with d-dimer levels ≥0.5 mg/L were included in the high d-dimer group, whereas patients with lower levels were included in the normal group. Cumulative survival was estimated using Kaplan-Meier curves and compared using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards model. RESULTS: The median plasma d-dimer level in the study cohort was 0.61 ± 0.49 mg/L. d-dimer levels were elevated in 60.98% of patients, and 80.1% of such patients had adenocarcinoma. Univariate and multivariate analyses identified d-dimer content as an independent factor for the prognosis of NSCLC (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.19-1.98). Kaplan-Meier analysis revealed that high plasma d-dimer levels were associated with shorter overall survival (HR = 1.48, 95% CI = 1.19-1.84). In addition, the receipt of <2 lines of treatment was associated with a higher risk of death than the receipt of >2 lines. CONCLUSION: The present results imply that pretreatment plasma d-dimer levels could represent a prognostic factor for advanced NSCLC.