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Background: Chemotherapy plus immunotherapy has become the standard first-line treatment of advanced or metastatic esophageal squamous cell carcinoma (ESCC), but median duration of response is only 7.0–8.3 months and progression-free survival (PFS, ∼6 months) is still far from satisfactory. We aim to evaluate whether early involvement of radiotherapy might improve the treatment outcome if objective response to first-line chemo-immunotherapy was observed in locally advanced or metastatic ESCC. Methods: Patients were retrospectively collected from 3 institutions in China. Patients with histopathologically confirmed diagnoses of locally advanced or metastatic ESCC were identified, who objectively responded to first-line chemo-immunotherapy (complete or partial response, or stable disease) and also received radiotherapy of primary lesions with radiation dose of over 40 Gy, with or without radiotherapy of metastatic lesions before the first disease progression. Results: A total of 72 eligible patients were identified. With median follow-up duration of 14.6 (range, 7.1–34.8) months, median progression-free survival (PFS) and overall survival (OS) were 13.5 (95 % CI,10.4-NA) months and 31.8 (95 % CI, 23.0-NA) months, respectively. Median duration from initiation of chemo-immunotherapy to radiotherapy was 2.9 (range, 0–15.1) months. Besides lower tumor burden as a significant factor of better treatment outcome, radiation dose ≥ 50 Gy was associated with superior PFS, while OS might be mainly related to tumor response to the induction chemo-immunotherapy. A low incidence of Grade 3 or above treatment-related adverse events were observed (19 %), and no treatment-related death occurred. Conclusion: Our multi-center retrospective study showed survival benefit brought by early involvement of radiotherapy after first-line chemo-immunotherapy for patients with locally advanced or metastatic ESCC. However, further investigation is warranted in future prospective, controlled trials to assess the value of radio-immunotherapy in advanced or metastatic ESCC.

Background: We aimed to assess the value of stereotactic body radiotherapy (SBRT) delivered under the situation of controlled or progressed disease during ICI therapy in advanced or recurrent NSCLC. Methods: We retrospectively collected patients with advanced or recurrent NSCLC who received SBRT concurrently with ICI in our institution between January 2017 and December 2021. Patients were divided into two groups, including those for whom SBRT was delivered initially or to the residual tumors during the first- or later-line ICI treatment (Group 1), and those for whom SBRT was given to the progressed tumors irrespective of first- or later-line ICI treatment (Group 2). Results: A total of 144 patients were included. With median follow-up duration of 25.6 (range: 3.6 to 56.2) months, median progression-free survival (PFS) was 13.7 (95 % CI: 10.4 to 17.1) months and median overall survival (OS) was 52.8 [95 % CI: 30.6 to not available (NA)] months. In Group 1 (n = 78), median PFS was 17.9 (95 % CI: 14.5 to 29.8) months while median OS was not reached and 5-year OS rate was 61.2 %. In Group 2 (n = 66), median PFS was 8.0 (95 % CI: 6.0 to 13.1) months and median OS was 30.6 (95 % CI: 21.5 to NA) months. Conclusions: SBRT combined with ICI demonstrated favorable survival for advanced or recurrent NSCLC, delivered in a controlled-disease situation as well as to progressed diseases with salvage-intent. Future prospective studies are warranted to investigate the optimal SBRT dose regimen and appropriate combination strategy to synergize ICI.

ObjectiveTo estimate the cost-effectiveness of adding serplulimab to chemotherapy for metastatic squamous non-small cell lung cancer (NSCLC) patients in a first-line setting from a Chinese perspective.MethodsA three-health state partitioned survival model was constructed to simulate disease development. The clinical data used in the model were derived from the ASTRUM-004 clinical trial. Only direct medical costs were included, and the utilities were derived from published literature. The quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were employed to evaluate health outcomes. Additionally, a sensitivity analysis was performed to verify the robustness of the results.ResultsCompared with chemotherapy alone, the addition of serplulimab resulted in an increase of 0.63 QALYs with an incremental cost of $5,372.73, leading to an ICER of $8,528.14 per QALY. This ICER was significantly lower than 3 times China’s per capita GDP. The one-way sensitivity analysis suggested that the utility of PFS was the most sensitive factor on ICERs, followed by the price of serplulimab.ConclusionThe combination of serplulimab and chemotherapy has been shown to be a cost-effective initial treatment option for patients with metastatic squamous NSCLC with the commonly accepted willingness-to-pay threshold of 3 times the GDP per capita per QALY in China.

Abstract Objectives The purpose of this study was to assess the impact of polypharmacy, potentially inappropriate medications, and drug-drug interactions on in-hospital mortality in older COVID-19 inpatients. Methods A cross-sectional study was conducted using electronic medical data from a tertiary hospital in Chengdu from December 2022 to January 2023. The 2019 AGS/Beers criteria was used to evaluate the potentially inappropriate mediation (PIM) status of older COVID-19 inpatients (age ≥ 65 years), the drug-drug interactions were evaluated on Medscape, and multivariate logistic regression was used to identify the risk factors associated with in-hospital mortality. Results A total of 206 older COVID-19 inpatients were included in the study. The mean number of drugs per day was 13.04. The prevalence of PIM use based on the 2019 AGS Beers Criteria was 66.99%. The prevalence of drug-drug interactions was 61.65%. Logistic regression demonstrated that age ≥ 80 (OR: 10.321, 95% CI: 1.649, 64.579, P = 0.013), renal insufficiency (OR: 4.740, 95% CI: 1.366, 16.447, P = 0.014), long-term hospitalization (OR: 6.637, 95% CI: 1.030, 42.779, P = 0.046), severe pneumonia (OR: 50.230, 95% CI: 5.180, 487.041, P = 0.001) were influencing factors associated with in-hospital mortality in older COVID-19 inpatients. Conclusions The polypharmacy, potentially inappropriate medications, and drug-drug interactions were seen in many older COVID-19 inpatients.

This study sought to explore potential roles of endothelial ferroptosis in radiation-associated atherosclerosis (RAA) and molecular mechanisms behind this phenomenon. Here, an in vivo RAA mouse model was used and treated with ferroptosis inhibitors. We found that the RAA group had a higher plaque burden and a reduction in endothelial cells with increased lipid peroxidation compared to the control group, while ameliorated by liproxstatin-1. In vitro experiments further confirmed that radiation induced the occurrence of ferroptosis in human artery endothelial cells (HAECs). Then, proteomics analysis of HAECs identified domain-containing protein 2 (DDHD2) as a co-differentially expressed protein, which was enriched in the lipid metabolism pathway. In addition, the level of lipid peroxidation was elevated in DDHD2-knockdown HAECs. Mechanistically, a significant decrease in the protein and mRNA expression of glutathione peroxidase 4 (GPX4) was observed in HAECs following DDHD2 knockdown. Co-immunoprecipitation assays indicated a potential interaction between DDHD2 and nuclear factor erythroid 2-related factor 2 (Nrf2). The downregulation of Nrf2 protein was also detected in DDHD2-knockdown HAECs. In conclusion, our findings suggest that radiation-induced endothelial ferroptosis accelerates atherosclerosis, and DDHD2 is a potential regulatory protein in radiation-induced endothelial ferroptosis through the Nrf2/GPX4 pathway.

Cancer is a leading cause of death worldwide, and the development of new diagnostic and treatment methods is crucial. Manganese-based nanomaterials (MnNMs) have emerged as a focal point in the field of cancer diagnosis and treatment due to their multifunctional properties. These nanomaterials have been extensively explored as contrast agents for various imaging technologies such as magnetic resonance imaging (MRI), photoacoustic imaging (PAI), and near-infrared fluorescence imaging (NIR-FL). The use of these nanomaterials has significantly enhanced the contrast for precise tumor detection and localization. Moreover, MnNMs have shown responsiveness to the tumor microenvironment (TME), enabling innovative approaches to cancer treatment. This review provides an overview of the latest developments of MnNMs and their potential applications in tumor diagnosis and therapy. Finally, potential challenges and prospects of MnNMs in clinical applications are discussed. We believe that this review would serve as a valuable resource for guiding further research on the application of manganese nanomaterials in cancer diagnosis and treatment, addressing the current limitations, and proposing future research directions.

The current quality control method for Turkish gall (TG) is limited to assessing total tannin or gallic acid (GA), which offers a basic level of quality control but does not fully capture the true quality of TG. Therefore, it is essential to establish a comprehensive method that utilizes multiple indicators to assess the intrinsic quality of TG. This research utilized UPLC-Q-TOF-MS/MS technology to qualitatively analyze the chemical composition of TG. Subsequently, the potential main active ingredients, targets, and pathways of TG in treating recurrent aphthous ulcers (RAU) were explored and analyzed using network pharmacology technology. Quantitative analysis of multicomponents by single marker (QAMS) was then employed to quantify the primary pharmacodynamic components in TG. Finally, chemometrics analysis was utilized to interpret the measured results and identify the markers of scavenging quality. The study identified 36 chemical components in TG, highlighting ellagic acid (EA), GA, and so on as key components in treating RAU. A method for simultaneously determining GA, EA, 1,2,3,6-tetra-O-galloyl-β-D-glucose (TEGG) and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PEGG) in TG was established. Statistical analysis revealed significant differences in the content of these 4 components across 14 batches of TG, with GA and PEGG identified as the primary contributors to the variations. This study determined a quality index for TG, providing a reference for quality evaluation and introducing a cost-effective and efficient quality control method. Furthermore, it addressed the challenge of developing new Chinese medicine by overcoming the lack of reference substances.

PurposeTo investigate whether there exists a statistically significant distinction between the effectiveness and tolerance of perampanel (PER) and the number of antiseizure medications (ASMs) that were tried prior to administering PER.MethodA prospective, observational study was performed at West China Hospital of Sichuan University. The study included patients diagnosed with epilepsy who were prescribed PER and were monitored for a minimum of 6 months. The efficacy of PER was evaluated at 1, 3, 6, and 12-month intervals by examining the retention rate and the 50% response rate. All statistical analyses were conducted using IBM SPSS Statistics version 25 (IBM Corporation, Armonk, New York).ResultsA total of 1,025 patients were identified, of which 836 were included in the analysis. Seven hundred and eighty-nine patients (94.4%) were followed up for a year. The median age of the patients was 29.32 ± 14.06 years, with 45.81% of the patients being male and 17.0% being adolescents. The average duration of epilepsy was 11.22 ± 8.93 years. Overall, PER was discontinued in 49.5% of patients, with the most common reasons being inadequate therapeutic effect and treatment-emergent adverse events (TEAEs). At the 6-month follow-up, the retention rate was 54.2% (454/836), and 39.6% of patients had a 50% response. At the 12-month follow-up, the retention rate was 49.4% (340/789), and 44.5% of patients had a 50% response. Patients who received PER as monotherapy had the highest retention rates (P = 0.034) and 50% response rates (P < 0.001) at any follow-up point. TEAEs were reported in 32.0% of patients, and these led to discontinuation in 15.4% of patients. The most common TEAEs were dizziness and somnolence. There was no significant difference between subgroups (P = 0.57), but there was a significant difference between the dosage of PER and TEAEs (P < 0.001).Main findingsThe study concludes that PER is effective in treating both focal and generalized tonic-clonic seizures. Patients who had fewer previous exposures to ASMs exhibited higher response rates to PER. TEAEs related to PER dosage were more prevalent during the first 3 months of treatment and tended to improve with continued use, ultimately demonstrating favorable long-term tolerability.

Abstract Background microRNAs (miRNAs) and N6‐methyladenosine (m6A) play important roles in ovarian cancer (OvCa). However, the mechanisms by which miRNAs regulate m6A in OvCa have not been elucidated so far. Methods To screen m6A‐related miRNAs, Pearson's correlation analysis of miRNAs and m6A regulators was implemented using The Cancer Genome Atlas database (TCGA). To determine the level of m6A, RNA m6A quantitative assays were used. Then, colony formation assays, EdU assays, wound healing assays, and Transwell assays were performed. The dual‐luciferase reporter assay was used to confirm the miRNA target genes. Protein–protein interaction (PPI) analysis of the target genes was performed, and hub genes were discovered using the cytoHubba/Cytoscape software. The underlying molecular mechanisms were explored by bioinformatics and RNA stability assays. Results A total of 126 miRNAs were identified as m6A‐related miRNAs by Pearson's correlation analysis. Among them, the high level of miR‐30c‐5p was associated with good prognosis in OvCa patients. In vitro, the miR‐30c‐5p agomir lowered the m6A level and inhibited OvCa cell proliferation, migration, and invasion. The hub target genes of miR‐30c‐5p were identified as (i) XPO1, (ii) AGO1, (iii) HNRNPA2B1, of which m6A reader HNRNPA2B1 was highly expressed in OvCa tissues and related with poor prognosis. In vitro, knockdown of HNRNPA2B1 significantly reduced m6A level and hampered the proliferation and migration of OvCa cells. The inhibition of m6A reader HNRNPA2B1 attenuated the suppression of proliferation and migration and the low m6A level induced by the miR‐30c‐5p downregulation. Mechanistically, m6A reader HNRNPA2B1 might regulate CDK19 mRNA stability to alter m6A level. Conclusions miR‐30c‐5p inhibits OvCa progression and reduces the m6A level by inhibiting m6A reader HNRNPA2B1, thus providing new insights into the m6A regulatory mechanism in OvCa.

Abstract Background Emerging evidence has highlighted the biological significance of pyroptosis in tumor tumorigenesis and progression. Nonetheless, the potential roles of pyroptosis in tumor immune microenvironment and target therapy of ovarian cancer (OC) remain unknown. Methods In this study, with a series of bioinformatic and machine learning approaches, we comprehensively evaluated genetic alterations and transcriptome profiles of pyroptosis-associated genes (PYAGs) with TCGA-OV datasets. Consensus molecular clustering was performed to determine pyroptosis-associated clusters (PACs) and gene clusters in OC. Subsequently, component analysis algorithm (PCA) was employed to construct Pyrsig score and a highly accurate nomogram was established to evaluate its efficacy. Meanwhile, we systematically performed association analysis for these groups with prognosis, clinical features, TME cell-infiltrating characteristics, drug response and immunotherapeutic efficacy. Immunohistochemistry was conducted to verify molecular expression with clinical samples. Results The somatic mutations and copy number variation (CNV) of 51 PYRGs in OC samples were clarified. Two distinct PACs (PAC1/2) and three gene clusters (A/B/C) were identified based on 1332 OC samples, PAC1 and gene cluster A were significantly associated with favorable overall survival (OS), clinicopathological features and TME cell-infiltrating characteristics. Subsequently, Pyrsig score was successfully established to demonstrate the prognostic value and immune characteristics of pyroptosis in OC, low Pyrsig score, characterized by activated immune cell infiltration, indicated prolonged OS, increased sensitivity of some chemotherapeutic drugs and enhanced efficacy of anti-PD-L1 immunotherapy, Consequently, a nomogram was successfully established to improve the clinical applicability and stability of Pyrsig score. With clinical OC samples, GSDMD and GZMB proteins were validated highly expressed in OC and associated with immune infiltration and Pyrsig score, GZMB and CD8 proteins were regarded as independent prognostic factors of OC. Conclusion This work revealed pyroptosis played a non-negligible role in prognosis value, clinicopathological characteristics and tumor immune infiltration microenvironment in OC, which provided novel insights into identifying and characterizing landscape of tumor immune microenvironment, thereby guiding more effective prognostic evaluation and tailored immunotherapy strategies of OC.

Objectives Liver fibrosis is a key stage in the progression of various chronic liver diseases to cirrhosis and liver cancer, but at present, there is no effective treatment. This study investigated the therapeutic effect of the new antifibrotic drug fluorofenidone (AKF-PD) on liver fibrosis and its related mechanism, providing implications for liver cancer. Materials and Methods The effects of AKF-PD on hepatic stellate cell (HSC) autophagy and extracellular matrix (ECM) expression were assessed in a carbon tetrachloride (CCl4)-induced rat liver fibrosis model. In vitro, HSC-T6 cells were transfected with Smad2 and Smad3 overexpression plasmids and treated with AKF-PD. The viability and number of autophagosomes in HSC-T6 cells were examined. The protein expression levels of Beclin-1, LC3 and P62 were examined by Western blotting. The Cancer Genome Atlas (TCGA) database was used for comprehensively analyzing the prognostic values of SMAD2 and SMAD3 in liver cancer. The correlation between SMAD2, SMAD3, and autophagy-related scores in liver cancer was explored. The drug prediction of autophagy-related scores in liver cancer was explored. Results AKF-PD attenuated liver injury and ECM deposition in the CCl4-induced liver fibrosis model. In vitro, the viability and number of autophagosomes in HSCs were reduced significantly by AKF-PD treatment. Meanwhile, the protein expression of FN, α-SMA, collagen III, Beclin-1 and LC3 was increased, and P62 was reduced by the overexpression of Smad2 and Smad3; however, AKF-PD reversed these effects. SMAD2 and SMAD3 were hazardous factors in liver cancer. SMAD2 and SMAD3 correlated with autophagy-related scores in liver cancer. Autophagy-related scores could predict drug response in liver cancer. Conclusions AKF-PD alleviates liver fibrosis by inhibiting HSC autophagy via the transforming growth factor (TGF)-β1/Smadpathway. Our study provided some implications about how liver fibrosis was connected with liver cancer by SMAD2/SMAD3 and autophagy.

Gynogenesis, as a special method of distant hybridization, can be used to accelerate the formation of breeding lines such as fish varieties and populations, and cultivate lines or varieties with higher dominant traits. While, there are few reports on the study of gynogenesis between trans order species in freshwater fish. Even the meat quality comparison between the gynogenetic offspring obtained above and their parents is rarely studied. In order to understand whether the meat quality of naturally gynogenetic blunt snout bream (GBSB) is better than that of its parents (blunt snout bream♀ and Chinese perch♂), we analyzed the texture, composition, antioxidant capacity and nutrients of natural gynogenesis blunt snout bream and its parent muscle. In the muscle of texture characteristics of hardness, springiness, gumminess and chewiness, natural GBSB were better than those of the normal BSB. Muscle fiber size of GBSB is between the maternal and the paternal fish. Compared with the maternal parent, the natural GBSB had higher antioxidant enzyme activities (CAT, SOD and GSH) and higher mineral element (Na, Mg, Ca, P and Zn) contents. In muscle nutrients, the gynogenetic offspring also had more delicious amino acids (Asp, Glu, Gly, Ala, Tyr and Phe) and fatty acids than the maternal parents. Collectively, through distant hybridization between common BSB and Chinese perch (CP), a high-quality gynogenetic fish with more nutrition and stronger muscle performance than maternal fish was obtained. The above results not only provide evidence for the hybridization origin of gynogenetic fish, but also provide new ideas for the innovation of new species.

Abstract Animal experiments play an essential role in advances in the research and treatment of burns. Currently, researchers often rely on personal experience or the literature to complete the construction of animal disease models, which may lead to a lack of scientific rigor and a wide range of animal disease models with reference value. The purposes of this study were to establish a third-degree burn model of rats using the Delphi method to provide a reference. Two rounds of a Delphi expert consultation survey were conducted on experts (n = 13) in this study, and then the boundary value method was used to screen, modify and supplement the indicators. Next, the indicator weight was determined by dividing the boundary value, and finally, the index system of the rat model of third-degree burns was established. The statistical analysis results show that the positive coefficients of the two rounds of expert consultation are 100% and 88.67% respectively. The expert authority coefficient values were 0.73 and 0.67, respectively, and the expert coordination coefficient test was P

Abstract Background Compound Turkish gall ointment (CTGO) has a long history of being widely used as a folk medicine in Xinjiang for the treatment of eczema. CTGO is currently in the pre-investigational new drug application stage, but its pharmacological mechanisms of action have not yet been clarified. Methods First, a sensitive and reliable ultra-high performance liquid chromatography-Q exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS) technique was established. Second, an integrative strategy of network analysis and molecular docking based on identified and retrieved ingredients was implemented to investigate the potential targets and pathways involved in the treatment of eczema with CTGO. Finally, Sprague–Dawley (SD) rats with eczema were prepared to verify the predicted results. The skin conditions of the rats were observed, evaluated, and scored. Skin tissues were observed by hematoxylin–eosin (HE) staining, and the levels of serum interferon-γ (IFN-γ) and interleukin-4 (IL-4) were determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Results A total of 29 compounds were identified. We found 38 active components and 58 targets for the treatment of eczema, which included 118 signaling pathways related to inflammation, immunity, and apoptosis. CTGO significantly improved the skin surface and histopathological characteristics of eczema-affected rats, downregulated the expression of IL-4, TLR4, NF-κB (p65), IL-1β, and TNF-α, and upregulated the expression level of IFN-γ. Conclusion We predicted and validated our prediction that CTGO may be used to treat eczema by affecting the TLR4/NF-κB signaling pathway, which provides guidance for future experimental studies.

Abstract Super-refractory status epilepticus (SRSE) is an important neurological emergency associated with high mortality and morbidity and poses a heavy economic burden on patients. Ketogenic diet parenteral nutrition (KD-PN) is ketogenic diet therapy provided through parenteral administration and may be an adjuvant treatment for these who cannot accept enteral diet. However, the calculation and management of KD-PN presents a challenge for clinicians. This review focuses on the practical aspects of KD-PN therapy for treatment of SRSE, including the dietary composition, potential drug-diet interactions, and monitoring during KD-PN treatment. As with all SRSE treatments, KD-PN has many adverse effects, like hyperlipemia, hepatotoxicity, metabolic acidosis, insufficient ketosis or hyper-ketosis, and propofol infusion syndrome. We summarize monitoring and treatment methods in our review. This review provides some practical aspects for treatment of SRSE.

Objectives: To explore the rationale and value of consolidative cranial local therapy (CLT) in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). Methods: EGFR-mutant NSCLC patients with baseline BMs who received first-line EGFR-tyrosine kinase inhibitors (TKIs) at two academic centers from May 2015 to June 2020 were retrospectively enrolled. Patterns of tumor response and treatment failure were extensively analyzed in order to explore the rationale of CLT. Cranial lesions with number ⩽3 and largest tumor size ⩽3 cm at baseline and best response to EGFR-TKIs were defined as oligo-BMs and oligo-residual cranial disease (ORCD), respectively. To provide preliminary data supporting CLT, survival outcomes were compared in patients with ORCD, stratified by CLT status. Results: Of the 216 patients enrolled, 57.1% had oligo-BMs and 24.5% received first-line osimertinib. At best response to the first-line EGFR-TKIs, intracranial complete response, partial response, and stable disease occurred in 18.5, 31.9, and 44.4% of the whole population, respectively. For patients without CLT ( n = 193), ORCD was observed in 78.1% of the 105 patients with baseline oligo-BMs and 10.2% of the 88 patients with baseline multiple-BMs. With a median follow-up of 22.8 months, 107 patients had cranial first progressive disease (PD); more than 60% developed their first PD solely from the residual tumor sites at best response to EGFR-TKIs. Moreover, among patients with ORCD ( n = 108), patients who received CLT ( n = 17) achieved significantly longer progression-free survival (13.4 versus 8.5 months, p = 0.001) and overall survival (58.9 versus 28.8 months, p = 0.021) than those without CLT. Meanwhile, CLT remained as an independent prognostic factor associated with improved survival after Cox regression analyses. Conclusions: Cranial progressive disease developed mostly at the residual cranial lesions in EGFR-mutant NSCLC patients with baseline BMs who received first-line EGFR-TKIs. Consolidative cranial local therapy targeting the oligo-residual cranial tumor lesions may provide survival benefit, which warrants future validation.

Abstract Objective The last decade has seen an increase in the use of anti‐seizure medications (ASMs); however, the burden of treating drug‐resistant epilepsy has not fallen. We performed this meta‐analysis to evaluate the optimal dose of Perampanel (PER) as a new adjunctive treatment for drug‐resistant seizures. Methods We searched for studies published from inception to February 1, 2021 from PubMed, Central Register of Controlled Trials (CENTRAL), and ScienceDirect. Research characteristics, patients' characteristics, and treatment regimen, concomitant ASMs, clinical outcomes were extracted. The practical outcome included a reduction in seizures frequency ≥50%, ≥75%, and ≥100% from baseline convulsive seizure frequency, and the safety outcome included the proportion of drug withdrawal and adverse reactions. Odds ratios (OR) for 95% confidence intervals (95% CI) were estimated by the inverse variance method. Results Four trials which enrolled 2187 participants (1569 in the PER group and 618 in the placebo group) were included. Results showed that 8 or 12 mg per day had the best effect on all three outcomes, with no significant difference between 8 and 12 mg per day (≥50% reduction, 35.5% vs 36.1%, P = .84; ≥75% reduction, 17.8% vs 19.1%, P = .64; seizure‐free, 3.5% vs 3.7%, P = .85). In addition, 12‐mg PER compared to 8 mg had a higher proportion of trial withdrawal (8.7% vs 17.0%; P

Abstract Background The clinical features, survival outcomes and patterns of treatment failure of advanced non-small cell lung cancer (NSCLC) patients harboring distinct subtypes of EGFR mutations and receiving first-line EGFR tyrosine kinases inhibitor (TKIs) are not fully understood. Methods Consecutive metastatic EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs from October 2010 to March 2020 were enrolled and classified into two main groups based on the EGFR mutation subtypes: common mutation (L858R or exon 19 deletion), uncommon mutation (other EGFR mutations). Results Of the 1081 patients included, 74 (6.8%) harbored uncommon mutations. The baseline characteristics were generally balanced between the two groups, except that bone metastasis developed less frequently in patients with uncommon mutations (p = 0.02). No significant difference of survival outcomes was found between the two groups, except that among patients with baseline brain metastasis, the intracranial time to progression was significantly shorter in patients with uncommon mutations. Nine of the 17 patients with de novo T790M mutation received Osimertinib, whose overall survival tended to be longer than the remaining 8 patients without Osimertinib treatment (p = 0.08). The patterns of treatment failure were generally consistent between the two groups, except which patients with uncommon mutations had a higher risk developing progressive disease in the brain. Conclusion First-line EGFR-TKIs seemed to be less effective in controlling and preventing brain metastasis in patients with uncommon EGFR mutations and Osimertinib was associated with promising efficacy in patients with de novo T790M mutation, which warranted further validation.

Abstract Background Pelvic lymph node metastasis (LNM) is a crucial independent prognostic factor in cervical cancer (CCa) and serves as an indicator for radiation therapy as the primary or an adjuvant treatment option. However, preoperative diagnosis of LNM remains challenging. Thus, we aimed to identify biomarkers of LNM in patients with presumed early-stage CCa. Methods The differentially expressed genes (DEGs) between tumours with different lymph node statuses were identified by using The Cancer Genome Atlas database. Then, univariate Cox regression analysis and Kaplan–Meier analyses were utilized to screen overall survival (OS)-associated genes. Multivariate Cox analysis and logistical analysis were utilized to evaluate independent risk factors for OS and LNM, respectively. Subsequently, the protein level of fatty acid binding protein 4 (FABP4) was detected in normal cervical and CCa tissues by immunohistochemistry assays. EdU assays were performed to determine whether FABP4 altered the proliferation of cervical cancer cells. Wound healing and Transwell assays were conducted to explore the effects of FABP4 depletion on migratory and invasive abilities of cervical cancer cells. F-actin fluorescence staining were performed to investigate morphological change and Western blotting analyses were performed to determine epithelial mesenchymal transition-related marker expression and downstream signalling pathways. Results A total of 243 DEGs, including 55 upregulated and 188 downregulated DEGs, were found in CCa patients with LNM versus those without LNM. Among these, FABP4 was found to be closely associated with poor OS. Multivariate analysis uncovered that FABP4 was an independent risk factor for OS and LNM in patients with CCa. The immunohistochemical results verified dramatically increased FABP4 expression in CCa tissues compared to normal cervical epithelia and its association with poor OS and LNM. In vitro, The proliferation, migration and invasion of cervical cancer cells were significantly inhibited after knocking down of FABP4, which was accompanied by elevated expression of E-cadherin and downregulated expression of N-cadherin, Vimentin and p-AKT. Conclusions FABP4 might be a promising biomarker of LNM and survival in patients with early-stage CCa and therefore could significantly contribute to the development of personalized prognosis prediction and therapy optimization.

Recent evidence suggests that endoplasmic reticulum (ER) stress plays a vital role in inflammatory bowel disease (IBD). Therefore, the aim of this study was to investigate the mechanism by which ER stress promotes inflammatory response in IBD. The expression of Gro-α, IL-8 and ER stress indicator Grp78 in colon tissues from patients with Crohn’s disease (CD) and colonic carcinoma was analyzed by immunohistochemistry staining. Colitis mouse model was established by the induction of trinitrobenzene sulphonic acid (TNBS), and the mice were treated with ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Then the body weight, colon length and colon inflammation were evaluated, and Grp78 and Gro-α in colon tissues were detected by immunohistochemistry. Epithelial cells of colon cancer HCT116 cells were treated with tunicamycin to induce ER stress. Grp78 was detected by Western blot, and chemokines were measured by PCR and ELISA. The expression levels of Grp78, Gro-α and IL-8 were significantly upregulated in intestinal tissues of CD patients. Mice with TNBS induced colitis had increased expression of Grp78 and Gro-α in colonic epithelia. TUDCA reduced the severity of TNBS-induced colitis. In HCT116 cells, tunicamycin increased the expression of Grp78, Gro-α and IL-8 in a concentration-dependent manner. Furthermore, p38 MAPK inhibitor significantly inhibited the upregulation of Gro-α and IL-8 induced by tunicamycin. In conclusion, ER stress promotes inflammatory response in IBD, and the effects may be mediated by the activation of p38 MAPK signaling pathway.

Abstract Background There was no study investigating real-world utilization and outcome of LCT in Osimertinib-treated NSCLC with oligo-residual disease. This study was to analyze the clinical value of local consolidative therapy (LCT) in Osimertinib-treated non-small cell lung cancer (NSCLC) patients with oligo-residual disease. Methods Patients receiving standard Osimertinib treatment and developing oligo-residual disease (five or fewer residual metastatic lesions) were retrospectively reviewed. Local therapies performed to the oligo-residual tumor lesions or primary lung site before Osimertinib treatment failure were considered as LCT. Results Of 108 patients recruited, first-line and second-line Osimertinib were administered in 25 and 83 patients, respectively, while LCT was performed in 14 patients. With a median follow-up of 43.6 months, 69 patients developed progressive disease. LCT significantly improved progression-free survival (PFS) (NR vs 12.8 months, p = 0.01) and was independently associated with prolonged PFS (HR = 0.29, 95%CI 0.12 to 0.68, p = 0.004). Patients receiving LCT had a numerically longer overall survival (OS) (85.8 vs 77.1 months, p = 0.58) and after adjusting for potentially confounding factors, LCT was associated with a non-significantly prolonged OS (HR = 0.37, 95%CI 0.12–1.16, p = 0.089). Pattern of failure analyses indicated that progressive disease developed at the originally existed oligo-residual lesions in 76.2% of the 63 patients who didn’t receive LCT and had Osimertinib treatment failure. Of note, 7 (70%) of the 10 patients who had oligo-residual cranial disease but didn’t receive LCT, developed more than five progressive lesions in the brain, which were no longer suitable for stereotactic radiosurgery. Conclusion Among Osimertinib-treated NSCLC patients having oligo-residual lesions, LCT could improve local control and significantly increase PFS, which need to be verified by further investigations.

Abstract Background Hyssopus cuspidatus Boriss has been used as an important ethnomedicinal plant for long to eliminate phlegm, relieve cough and as well as having antibacterial, antioxygenation, and antitumor activities. In this study, the polyphenol contents, flavonoid contents, free radical scavenging assay and animal antioxygenation property assay of ethanol extract of H. cuspidatus were measured. Methods This study determined the total polyphenol and flavonoid contents in H. cuspidatus by UV-VIS. Caffeic, ferulic, and rosmarinic acids were measured using HPLC-DAD. Free radical scavenging assay of H. cuspidatus was studied by colorimetric method. Animal antioxygenation property assay of H. cuspidatus was studied with mice by biochemical assay kits. Results The total polyphenol and flavonoid contents of H. cuspidatus in 2017, 2018, 2019 were determined and the contents of H. cuspidatus in 2019 was the highest. In addition, rosmarinic acid was the phenolic acid with the highest content in H. cuspidatus. Compared with those of DPPH free radical, hydroxyl free radical, and superoxide anion free radical, the scavenging ability of H. cuspidatus of ABTS free radical was stronger, the average IC50 value was 0.0245 mg/mL. In animal antioxygenation property experiment, the model group was successfully established with decreased activities of SOD, CAT, and GSH-px and increased content of MDA. The ethanol extract of H. cuspidatus increased the activities of SOD, CAT, and GSH-px and reduced the content of MDA. Each group of samples and the ascorbic acid positive control group showed significant differences in the results of free radical scavenging and animal antioxygenation property experiments (P

Abstract Background The brown planthopper (BPH) has become the most destructive and a serious threat to the rice production in Asia. Breeding the resistant varieties with improved host resistance is the most effective and ecosystem-friendly strategy of BPH biological management. As host resistance was always broken down by the presence of the upgrading BPH biotype, the more resistant varieties with novel resistance genes or pyramiding known identified BPH resistance genes would be needed urgently for higher resistant level and more durability of resistance. Results Here, we developed near isogenic lines of Bph9 (NIL-Bph9) by backcrossing elite cultivar 93–11 with Pokkali (harboring Bph9) using marker-assisted selection (MAS). Subsequently, we pyramided Bph6 and Bph9 in 93–11 genetic background through MAS. The resulting Bph6 and Bph9 pyramided line LuoYang69 had stronger antixenotic and antibiosis effects on BPH and exhibited significantly enhanced resistance to BPH than near isogenic lines NIL-Bph6 and NIL-Bph9. LuoYang69 derived hybrids, harboring heterozygous Bph6 and Bph9 genes, also conferred high level of resistance to BPH. Furthermore, LuoYang69 did not affect the elite agronomic traits and rice grain quality of 93–11. The current study also developed functional markers for Bph9. Using functional dominant marker, we screened and evaluated worldwide accessions of rice germplasm. Of the 673 varieties tested, 8 cultivars were identified to harbor functional Bph9 gene. Conclusion The development of Bph6 and Bph9 pyramided line LuoYang69 provides valuable resource to develop hybrid rice with highly and durable BPH resistance. The development of functional markers will promote MAS of Bph9. The identified Bph9 containing cultivars can be used as new sources for BPH resistance breeding programs.

Abstract The brown planthopper (BPH) is the most devastating insect pest of rice. The rice gene BPH15 confers resistance to BPH. MicroRNAs (miRNAs) regulate a spectrum of development and defense response processes in plants. In this study, we analyzed six miRNA profiles of a BPH15 introgression line (P15) and a susceptible recipient line (PC) at three time points (0 h, 6 h and 48 h) after BPH attack, and identified 464 known miRNAs and 183 potential novel miRNAs. Before the BPH feeding, we identified 23 miRNAs differentially expressed in P15 and PC. We speculated that the resistant plant is in a priming state by the regulation of miRNAs. After the BPH feeding, 104 miRNAs were found to be expressed differentially in P15 (68 in P15-6/P15-0, 36 in P15-48/P15-0), and 80 miRNAs were found expressed differentially in PC (32 in PC-6/PC-0, 48 in PC-48/PC-0), which illustrated that miRNA expression is activated upon attack. These miRNAs regulate different pathways that contribute to the basal defense and specific resistance of rice to the BPH. Our study provides additional data for scientists to further explore the mechanism of plant defense against insect attack and to find a way for efficient insect control.

Advanced glycation end products (AGEs), which are present in heat-processed foods, have been associated with several chronic diseases. Sodium chloride (NaCl) modulates the formation of furfurals and acrylamide in the Maillard reaction; however, the effects of NaCl on AGE formation are inconsistent. In this study, we investigated the effects of NaCl on pyrraline formation using glucose-lysine model systems. NaCl, especially at 0.50%, promoted Maillard browning and pyrraline formation, with a simultaneous increase in the 3-deoxyglucosone concentration. To reduce the rate of pyrraline formation, NaCl coated with different gums and starches were used. The results showed that NaCl encapsulation is an effective approach to mitigate pyrraline and 3-deoxyglucosone formation. The content of NaCl in the microparticles were 284 ± 12, 269 ± 6, 258 ± 8, 247 ± 10, 273 ± 16, and 288 ± 15 mg/g (coated with waxy maize starch, normal maize starch, HYLON VII high amylose maize starch, gelatinized resistant starch, xanthan gum, and gum arabic, respectively). The heat resistance of the coating material was negatively correlated with the pyrraline and 3-deoxyglucosone formation, whereas the solubility of the coating material had the opposite results. Coating the material with gum had little effects on the reduction of pyrraline and 3-deoxyglucosone.

It has been reported that the receptor-like cytoplasmic kinases (RLCKs) regulate many biological processes in plants, but only a few members have been functionally characterized. Here, we isolated a rice gene encoding AtRRK1 homology protein kinase, OsRRK1, which belongs to the RLCK VI subfamily. OsRRK1 transcript accumulated in many tissues at low to moderate levels and at high levels in leaves. Overexpression of OsRRK1 (OE-OsRRK1) caused adaxial rolling and erect morphology of rice leaves. In the rolled leaves of OE-OsRRK1 plants, both the number and the size of the bulliform cells are decreased compared to the wild-type (WT) plants. Moreover, the height, tiller number, and seed setting rate were reduced in OE-OsRRK1 plants. In addition, the brown planthopper (BPH), a devastating pest of rice, preferred to settle on WT plants than on the OE-OsRRK1 plants in a two-host choice test, indicating that OE-OsRRK1 conferred an antixenosis resistance to BPH. The analysis of transcriptome sequencing demonstrated that several receptor kinases and transcription factors were differentially expressed in OE-OsRRK1 plants and WT plants. These results indicated that OsRRK1 may play multiple roles in the development and defense of rice, which may facilitate the breeding of novel rice varieties.