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Abstract Introduction Whether double filtration plasmapheresis (DFPP) is effective in the patients who do not response to the initial immunotherapy is uncertain. This retrospective study aimed to evaluate the efficacy and safety of DFPP in the treatment of patients who had no improvement after initial immunotherapy (steroids and/or immunoglobulin (IVIG)), and moreover, to investigate the factors associated with the efficacy of DFPP. Methods From January 1st, 2014, to December 30th,2018, a total of 26 patients who were diagnosed autoimmune encephalitis (AE) and were received the treatment of DFPP after unsuccessful or incomplete recovery from their early immune therapy (including intravenous high-dose cortisone, IVIG and or immunosuppressant) for at least 21 days were investigated. Their plasmapheresis volume, the course of disease, treatment sessions, and complications were recorded. The efficacy of DFPP within a week were assessed by modified Rankin scale (mRS). These patients were followed until six months after the last session of DFPP treatment. Results The duration between the onset of symptoms and DFPP administration was 54.5 days (range 21—243 days). The median DFPP sessions for each patient were three (range 2–6 sessions), and the mean volume of plasma exchange was 50.5 ± 11.1 ml/kg/session. Total clinically relevant improvement was observed in 57.7% of the patients. The median mRS was decreased from 5 to 4 within one week after DFPP treatment (P

Abstract Objective To investigate the specificity of Target of Myb1-Like1 (Tom1L1) expression in colorectal adenocarcinoma tissues and analyze the predictive value of Tom1L1 in the efficacy of neoadjuvant chemotherapy for patients with rectal adenocarcinoma. Methods The cancerous tissues and paracancerous normal tissues of 102 patients diagnosed with colorectal adenocarcinoma without treatment were selected; quantitative polymerase chain reaction (qPCR), Western blot and immunohistochemistry (IHC) were adopted to validate the expression level of Tom1L1 in the two groups. Furthermore, 34 patients with locally progressive mid-low rectal adenocarcinoma, who were treated with neoadjuvant Xelox chemotherapy prior to the operation, IHC was adopted to detect the expression of Tom1L1 protein in patients before and after neoadjuvant chemotherapy and to analyze the relationship between the expression level of Tom1L1 and the sensitivity of neoadjuvant therapy. Results The results of qPCR, Western blot and IHC showed that the expression of Tom1L1 in colorectal adenocarcinoma tissues was significantly higher than that in paracancerous normal tissues, with a statistically significant difference (P

Abstract Background Tumorigenicity represents a critical challenge in stem cell-based therapies requiring rigorous monitoring. Conventional approaches for tumorigenicity evaluation are based on animal models and have numerous limitations. Brain organoids, which recapitulate the structural and functional complexity of the human brain, have been widely used in neuroscience research. However, the capacity of brain organoids for tumorigenicity evaluation needs to be further elucidated. Methods A cerebral organoid model produced from human pluripotent stem cells (hPSCs) was employed. Meanwhile, to enhance the detection sensitivity for potential tumorigenic cells, we created a glioblastoma-like organoid (GBM organoid) model from TP53 −/− /PTEN −/− hPSCs to provide a tumor microenvironment for injected cells. Midbrain dopamine (mDA) cells from human embryonic stem cells were utilized as a cell therapy product. mDA cells, hPSCs, mDA cells spiked with hPSCs, and immature mDA cells were then injected into the brain organoids and NOD SCID mice. The injected cells within the brain organoids were characterized, and compared with those injected in vivo to evaluate the capability of the brain organoids for tumorigenicity evaluation. Single-cell RNA sequencing was performed to identify the differential gene expression between the cerebral organoids and the GBM organoids. Results Both cerebral organoids and GBM organoids supported maturation of the injected mDA cells. The hPSCs and immature mDA cells injected in the GBM organoids showed a significantly higher proliferative capacity than those injected in the cerebral organoids and in NOD SCID mice. Furthermore, the spiked hPSCs were detectable in both the cerebral organoids and the GBM organoids. Notably, the GBM organoids demonstrated a superior capacity to enhance proliferation and pluripotency of spiked hPSCs compared to the cerebral organoids and the mouse model. Kyoto Encyclopedia of Genes and Genomes analysis revealed upregulation of tumor-related metabolic pathways and cytokines in the GBM organoids, suggesting that these factors underlie the high detection sensitivity for tumorigenicity evaluation. Conclusions Our findings suggest that brain organoids could represent a novel and effective platform for evaluating the tumorigenic risk in stem cell-based therapies. Notably, the GBM organoids offer a superior platform that could complement or potentially replace traditional animal-based models for tumorigenicity evaluation.

Background Immune checkpoint inhibitors (ICIs) in combination with antiangiogenic drugs have shown promising outcomes in the third-line and subsequent treatments of patients with microsatellite stable metastatic colorectal cancer (MSS-mCRC). Radiotherapy (RT) may enhance the antitumor effect of immunotherapy. However, the effect of RT exposure on patients receiving ICIs and targeted therapy remains unclear. This study aimed to investigate the association between RT exposure and clinical responses to fruquintinib (a highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor) plus sintilimab (an anti-programmed death 1 antibody; F&S) in previously treated patients with MSS-mCRC and to explore predictive biomarkers.Methods In this prospective observational study, patients with mCRC receiving F&S as third-line or subsequent treatment were enrolled. Eligible patients were divided into the RT cohort (RTC) and the non-RT cohort (NRTC) according to their RT history. The primary endpoint was the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Pretreatment fecal and serum samples were collected for microbiome analysis, metabolome analysis, and immune signatures to identify biomarkers for treatment.Results A total of 55 patients were included, of which 25 were in the RTC and 30 in the NRTC. Better ORR (28.0% vs 6.7%, p=0.048), DCR (80.0% vs 36.7%, p=0.002), median PFS (6.2 vs 2.7 months, p

Abstract Immunotherapies employing PD‐1/PD‐L1 immune checkpoint inhibitors (ICIs) are vital for primary liver cancer (PLC), but response rates remain unsatisfying. Accurate differentiation of responders from non‐responders to immunotherapy is imperative. Here, single‐cell‐scaled mass cytometry analysis on sequential peripheral blood mononuclear cells (PBMCs) from ICI‐treated PLC patients is conducted, and tissue residence of immune subpopulations is assessed via multiplex immunohistochemistry. In the discovery cohort (n = 24), responders have lower baseline B cell and HLA‐DR+CD8+T cell, and higher CD14+CD16− classical monocyte (CM) proportions. CMs decrease more in responders PBMCs, while HLA‐DR+CD8+T cells conformably amplify after ICI‐exposure. Responsive individuals display upregulated exhaustion and activation markers in peripheral immune lineages. In the expanded cohort of 77 patients, the augment of the B cells in non‐responders is re‐confirmed. Responders demonstrate much higher enrichment of B cells or tertiary lymphoid structures in tumor compared to non‐responders. A prospective model that excelled in early discrimination of responders is developed using generalized linear model and achieves a satisfactory AUC over 0.9 in all three independent cohorts. Integratedly, the study unveils dynamic immune landscapes in PLC patients undergoing ICI‐based therapy, aiding in PLC patient stratification for ICI‐based treatment and fostering new response monitoring strategies.

Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD), but there is no consensus on its definition. In 2015, Flythe proposed a definition of IDH (Definition 1 in this study): nadir systolic blood pressure (SBP)

Background The burgeoning recognition of the nexus between renal functionality and the prevalence of dementia has precipitated a surge in research endeavors. This study aims to substantiate the causal relationship between kidney functionality and dementia.Methods We utilized clinical renal function metrics from the Chronic Kidney Disease Genetics (CKDGen) Consortium and diverse dementia types (Alzheimer’s disease [AD] and vascular dementia) from the FinnGen Biobank by using Mendelian randomization analysis. At the stratum of genetic susceptibility, we tested the causal relationship between variations index in renal function and the occurrence of dementia. Inverse-variance weighted (IVW) method was the main analysis, and several supplementary analyses and sensitivity analyses were performed to test the causal estimates.Results The findings indicate a significant correlation between each unit increase in cystatin C-based estimated glomerular filtration rate (eGFR-cys) levels was significantly associated with a reduction in the incidence of late-onset Alzheimer’s disease (LOAD) (IVW: OR = 0.35, 95% CI: 0.13–0.91, p = 0.031). After adjusting for creatinine-based eGFR (eGFR-cre) and urinary albumin-to-creatinine ratio (UACR), a causal relationship was still identified between elevated levels of eGFR-cys and decreased risk of LOAD (IVW: OR: 0.08; 95% CI: 0.01–0.97, p = 0.047). Sensitivity tests demonstrated the reliability of causal estimates.Conclusions The association between renal function based on cystatin C and the augmented risk of developing AD lends support to the perspective that regular monitoring of cystatin C may be a valuable investigative biomarker.

Background: Post-stroke epilepsy (PSE) is a critical complication that worsens both prognosis and quality of life in patients with ischemic stroke. An interpretable machine learning model was developed to predict PSE using medical records from four hospitals in Chongqing. Methods: Medical records, imaging reports, and laboratory test results from 21,459 ischemic stroke patients were collected and analyzed. Univariable and multivariable statistical analyses identified key predictive factors. The dataset was split into a 70% training set and a 30% testing set. To address the class imbalance, the Synthetic Minority Oversampling Technique combined with Edited Nearest Neighbors was employed. Nine widely used machine learning algorithms were evaluated using relevant prediction metrics, with SHAP (SHapley Additive exPlanations) used to interpret the model and assess the contributions of different features. Results: Regression analyses revealed that complications such as hydrocephalus, cerebral hernia, and deep vein thrombosis, as well as specific brain regions (frontal, parietal, and temporal lobes), significantly contributed to PSE. Factors such as age, gender, NIH Stroke Scale (NIHSS) scores, and laboratory results like WBC count and D-dimer levels were associated with increased PSE risk. Tree-based methods like Random Forest, XGBoost, and LightGBM showed strong predictive performance, achieving an AUC of 0.99. Conclusions: The model accurately predicts PSE risk, with tree-based models demonstrating superior performance. NIHSS score, WBC count, and D-dimer were identified as the most crucial predictors. Funding: The research is funded by Central University basic research young teachers and students research ability promotion sub-projec t(2023CDJYGRH-ZD06), and by Emergency Medicine Chongqing Key Laboratory Talent Innovation and development joint fund project (2024RCCX10).

Abstract Acute myocardial infarction (AMI) has been treated via injectable hydrogels and biomaterial patches invented using tissue engineering advancements over the past decade. Yet the curative potential of injectable hydrogels and stem cells is limited. Here, we propose the development of an injectable and conductive hydrogel composed of oxidised macromolecular hyaluronic acid and chitosan-grafted aniline tetramer polymeric components. In an attempt to enhance the therapeutic potential of AMI therapy, mesenchymal stem cells derived from human umbilical cord blood (HUCB-MSC) have been integrated into the formulation of a conductive hydrogel. For reliable connection to the beating hearts, the hydrogel exhibited suitable adhesive properties. Hydrogel’s potent biocompatibility was determined by in vitro investigations of cell viability and proliferation of NRCMs and H9C2 cardiomyocytes. After myocardial injection, longer HUCB-MSCs survival length, cardiac functioning, and histology in SD rat myocardium were demonstrated, greatly associated by up-regulation and downregulation of cardiac-related relative gene expressions of angiogenic factors and inflammatory factors, respectively. The injectable hydrogel that contained HUCB-MSCs substantially enhanced the therapeutic benefits, indicating a potentially beneficial therapeutic approach to AMI therapy.

The harvest moisture content (MC) of maize (Zea mays L.) is an important factor affecting industrial processing and harvest quality. However, higher MC levels may escalate drying expenses during production. While augmented plant density has shown potential to enhance maize yield, limited information exists regarding its impact on plant density and MC interaction. This study amassed four year of field trial data from four primary maize ecological areas in China (Longitude: 89°E to 125°E, Latitude: 35°N to 44°N) to examine the relationship between plant density and MC of maize. Our analysis revealed that increasing plant density exerted an effect on the MC of maize. This effect stemmed from a combination of uncertain grain development and premature plant senescence due to overcrowding. We categorized the relationship between plant density and MC into six types: NC-Type (No-changing), I-Type (ever-increasing), L-Type (ever-lessening), V-Type (like the valley), P-Type (like the peak), and W-Type (like a wave). On average, a variation approximately 0.053 % in MC was observed when the plant population changed by 1000 plants/ha. Moreover, different maize varieties contributed to a more substantial variation in MC. Despite the negligible impact of MC variation caused by plant density on grain quality, subsequent harvest management, and industrial production of maize, there was a significant enhancement in maize yield with increased plant density. Thus, increasing plant density presents an opportunity to boost maize output without compromising quality or grain moisture levels.

Abstract Systemic therapy is typically the primary treatment choice for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. Some patients may achieve partial response (PR) or complete response (CR) with systemic treatment, leading to the possibility of their primary tumor becoming resectable. This study aimed to investigate whether these patients could achieve longer survival through surgical resection of their primary tumor. We retrospectively collected data from 150 HCC patients with extrahepatic metastases treated at 15 different centers from January 1st, 2015, to November 30th, 2022. We evaluated their overall survival (OS) and progress-free survival (PFS) and analyzed risk factors impacting both OS and PFS were analyzed. Patients who received surgical treatment had longer OS compared to those who did not (median OS 16.5 months vs. 11.3 months). However, there was no significant difference in progression-free survival between the two groups. Portal vein invasion (P = 0.025) was identified as a risk factor for poor prognosis in patients, while effective first-line treatment (P = 0.039) and surgical treatment (P = 0.005) were protective factors. No factors showed statistical significance in the analysis of PFS. Effective first-line treatment (P = 0.027) and surgical treatment (P = 0.006) were both independent protective factors for prolonging patient prognosis, while portal vein invasion was an independent risk factor (P = 0.044). HCC patients with extrahepatic metastases who achieve PR/CR with conversion therapy may experience longer OS through surgical treatment. This study is the first to analyze the clinical outcomes of patients receiving surgical treatment for HCC with extrahepatic metastases.

Abstract Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

Background: Severe endometrial injury constitutes a significant risk to female fertility, often leading to the development of intrauterine adhesions. Pyroptosis, a form of programmed cell death associated with inflammation, is initiated by the cleavage of gasdermin family proteins by caspase, which has been implicated in endometrial injury. In recent years, hydrogen sulfide (H2S), a gaseous signaling molecule, exerts significant regulatory effects on pyroptosis in diverse pathological processes. The aim of this study is to elucidate the role of H2S in facilitating functional recovery of the endometrium following injury in a murine model. Methods: A prospective laboratory based randomized control trial was performed to evaluate the protective role of H2S in endometrial injury. Ethanol-induced endometrial injury mouse models were established and H2S donor sodium hydrosulfide (NaHS) was randomly administered to the injured mice. Western blot analysis was conducted to assess changes in the expression of endogenous H2S metabolism and pyroptosis-related markers and histological analysis (Hematoxylin & Eosin and Masson staining) was employed to examine alterations in endometrial morphology. Finally, a fertility test was performed to evaluate the restoration of the uterine function. Results: Following endometrial injury, the expression of key endogenous H2S enzymes-cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST)-is significantly reduced, while the levels of pyroptosis-related proteins are elevated (p < 0.05). However, treatment with H2S resulted in an increase in the expression of endogenous H2S enzymes and a decrease in pyroptosis-associated proteins compared to the Model group (p < 0.05). Moreover, endometrial morphology and embryo count showed the most pronounced improvement in the H2S treatment group (p < 0.05). Conclusions: This study confirms the therapeutic efficacy of H2S in facilitating the recovery of injured endometrium and revealed its potential therapeutic mechanism, offering a promising therapeutic avenue for patients with severe endometrial injury.

The development and progression of diseases in multicellular organisms unfold within the intricate three-dimensional body environment. Thus, to comprehensively understand the molecular mechanisms governing individual development and disease progression, precise acquisition of biological data, including genome, transcriptome, proteome, metabolome, and epigenome, with single-cell resolution and spatial information within the body’s three-dimensional context, is essential. This foundational information serves as the basis for deciphering cellular and molecular mechanisms. Although single-cell multi-omics technology can provide biological information such as genome, transcriptome, proteome, metabolome, and epigenome with single-cell resolution, the sample preparation process leads to the loss of spatial information. Spatial multi-omics technology, however, facilitates the characterization of biological data, such as genome, transcriptome, proteome, metabolome, and epigenome in tissue samples, while retaining their spatial context. Consequently, these techniques significantly enhance our understanding of individual development and disease pathology. Currently, spatial multi-omics technology has played a vital role in elucidating various processes in tumor biology, including tumor occurrence, development, and metastasis, particularly in the realms of tumor immunity and the heterogeneity of the tumor microenvironment. Therefore, this article provides a comprehensive overview of spatial transcriptomics, spatial proteomics, and spatial metabolomics-related technologies and their application in research concerning esophageal cancer, gastric cancer, and colorectal cancer. The objective is to foster the research and implementation of spatial multi-omics technology in digestive tumor diseases. This review will provide new technical insights for molecular biology researchers.

Background: The neurogenic bladder symptom score (NBSS) has been widely used to specifically measure symptoms and consequences of neurogenic bladder (NB). The cognitive interviewing (CI) is effective in assessing item clarity and identifying key issues related to the comprehension of the instrument. We aim to translate the NBSS into Chinese and use the CI approach to explore the thought processes of patients with NB in responding the Chinese Version of the NBSS, identify and modify the factors hinder the thought processes to enhance the face validity of the NBSS. Methods: The translation of the NBSS into Chinese was conducted with the guidance of the recommended frameworks. Patients with NB were recruited by purpose sampling. CI with the combination of thinking aloud and verbal probing techniques were used to explore thought processes. The interviews were transcribed and analyzed based on Tourangeau four-stage response model. Results: Two rounds of CI were carried out. The problems of comprehension, judgement and response mapping were identified in 8 items. Four items were revised based on the results of the interview. The revised items were verified and eventually integrated into the final version. Conclusion: The Chinese Version of the NBSS was easy to comprehend and use. The use of CI methodologies can increase the comprehensibility and cultural applicability of the NBSS, providing the evidence for the development of a clearer and more appropriate questionnaire.

Ophiorrhiza reflexa, a new species from Guangxi, China, is described and illustrated in this study. It is morphologically similar to O. alatiflora due to the branched inflorescence, distylous flowers and the tubular-funnelform corolla with five longitudinal wings. The new species can be distinguished from O. alatiflora by its erect inflorescence, its smaller and equal-sized calyx lobes 0.5–0.7 mm long, its corolla tubes winged to the middle and the wings straight and its strongly reflexed corolla lobes at anthesis. Ophiorrhiza reflexa is assessed as least concern (LC) according to IUCN Categories and Criteria.

Pearlitic steel rods are subjected to cold-drawing processes to produce pearlitic steel wires with true strains ranging from 0.81 to 2.18. Tensile tests are utilized to attain mechanical properties of cold-drawn pearlitic steel wires. TEM and XRD investigations were performed on the microstructure of the cold-drawn steel wires. With an increasing cold-drawn strain, both the interlamellar spacing and cementite lamellae thickness decrease, while the dislocation density significantly increases. The drawn wire has a tensile strength of 2170 MPa when the true stain reaches 2.18. Deformation-induced cementite dissolution occurs during cold-drawing progress, which releases many C atoms. The findings indicate that the supersaturation of C is heterogeneously distributed in the ferrite matrix. The ordered distribution of the released C in ferrite phases creates short-range order (SRO). SRO clusters and disordered Cottrell atmospheres contribute to solution strengthening, which, together with dislocation strengthening and interlamellar boundary strengthening, form an effective strengthening mechanism in cold-drawn pearlitic steel wires. Our work provides new insights into carbon redistribution and the mechanism of solution strengthening within ferrous phases.

The 7A04 Al alloy is a commonly used lightweight metal material; however, its low wear resistance limits its application. In this study, the wear resistance of this alloy was improved by preparing micro-arc oxidation (MAO) coatings, MAO/MoS2 composite coatings, and hard-anodized (HA) coatings on its surface. The friction and wear behaviors of these three coatings with diamond-like coated (DLC) rings under oil lubrication conditions were investigated using a ring–block friction tester. The wear rates of the coatings on the block surfaces were determined using laser confocal microscopy, and the wear trajectories of the coatings were examined using scanning electron microscopy. The results indicated that, among the three coatings, the MAO/MoS2 coating had the lowest coefficient of friction of 0.059, whereas the HA coating had the lowest wear rate of 1.47 × 10−6 mm/Nm. The MAO/MoS2 coatings exhibited excellent antifriction properties compared to the other coatings, whereas the HA coatings exhibited excellent anti-wear properties. The porous structure of the MAO coatings stored lubricant and replenished the lubrication film under oil lubrication. Meanwhile, the introduced MoS2 enhanced the densification of the coating and functioned as a solid lubricant. The HA coating exhibited good wear resistance owing to the dense structure of the amorphous-phase aluminum oxide. The mechanisms of abrasive and adhesive wear of the coatings under oil lubrication conditions and the optimization of the tribological properties by the solid–liquid synergistic lubrication effect were investigated. This study provides an effective method for the surface modification of Al alloys with potential applications in the aerospace and automotive industries.

Abstract Introduction The SARS-CoV-2 Omicron variant has decreased virulence and pathogenicity, yet the number of Omicron infections worldwide is unprecedentedly high, with rather high mortality and severe disease rate. Chronic kidney disease (CKD) patients are particularly vulnerable to the SARS-CoV-2 Omicron variant and have unique clinical outcomes. Methods We retrospectively collected data from 2140 hospitalized patients with SARS-CoV-2 Omicron variant infection from March 29, 2022, to May 17, 2022. Demographic characteristics, ancillary examination results, and clinical treatments were described. Occurrence of critical COVID-19 or death and time of positive-to-negative conversion was defined as primary outcomes. The presence of COVID-19 pneumonia and the usage of respiratory or circulatory support was defined as secondary outcomes. Univariate or multivariate logistic regression analyses were performed to identify risk factors for primary outcomes. Results 15.74% of CKD patients infected with the SARS-CoV-2 Omicron variant ended up with critical COVID-19 or death. Pre-existing CKD was a risk factor for critical COVID-19 or death and prolonged time of positive-to-negative conversion of SARS-CoV-2. Nirmatrelvir-ritonavir facilitated viral clearance among COVID-19 patients with non-severe CKD. Conclusion We found patients with CKD and COVID-19 due to Omicron experienced worse clinical outcomes and prolonged time of positive-to-negative conversion of SARS-CoV-2 compared to patients without CKD, which helps rationalize limited medical resources and offers guidance for appropriate clinical treatments.

Colorectal cancer exhibits a notable prevalence and propensity for metastasis, but the current therapeutic interventions for metastatic colorectal cancer have yielded suboptimal results. ICIs can decrease tumor development by preventing the tumor’s immune evasion, presenting cancer patients with a new treatment alternative. The increased use of immune checkpoint inhibitors (ICIs) in CRC has brought several issues. In particular, ICIs have demonstrated significant clinical effectiveness in patients with MSI-H CRC, whereas their efficacy is limited in MSS. Acquired resistance can still occur in patients with a positive response to ICIs. This paper describes the efficacy of ICIs currently in the clinical treatment of CRC, discusses the mechanisms by which acquired resistance occurs, primarily related to loss and impaired presentation of tumor antigens, reduced response of IFN-λ and cytokine or metabolic dysregulation, and summarizes the incidence of adverse effects. We posit that the future of ICIs hinges upon the advancement of precise prediction biomarkers and the implementation of combination therapies. This study aims to elucidate the constraints associated with ICIs in CRC and foster targeted problem-solving approaches, thereby enhancing the potential benefits for more patients.

Introduction Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China. The combination of immune checkpoint inhibitors (ICIs) and antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors, has been recommended as first-line treatment for advanced HCC. However, two-thirds of patients did not benefit from this form of immunotherapy. Currently, data on the subsequent regimen for patients previously treated with ICIs are lacking. Studies have shown that the combination of radiotherapy (RT) and ICIs is a potentially effective second-line therapy for HCC. This study aims to assess the efficacy and safety of combined therapy with stereotactic body RT (SBRT), sintilimab and IBI305 (a biosimilar of bevacizumab) in patients with HCC following the progression of first-line ICI therapy.Methods and analysis This study is an open-label, single-arm, single-centre, phase 2 trial of 21 patients with advanced HCC in whom previous ICI therapy has failed. Participants will receive approximately 30–40 Gy/5–8F SBRT, followed by 200 mg sintilimab and 15 mg/kg IBI305 intravenously every 3 weeks. Treatment will continue until the development of unacceptable toxicity or disease progression. We will use Simon’s two-stage design, with the objective response rate (ORR) as the primary endpoint. Secondary endpoints include ORR of lesions without RT, disease control rate, progression-free survival, overall survival and safety.Ethics and dissemination The study was authorised by the Medical Ethics Committee. Dissemination of results will occur via a peer-reviewed publication and other relevant media.Trial registration number ChiCTR2200056068.

BackgroundFor decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors.MethodsThis is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study’s main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL.ResultsThe study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy.ConclusionIn this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

Abstract Background Intradialytic hypotension (IDH) is frequently accompanied by symptoms of nausea, dizziness, fatigue, muscle spasm, and arrhythmia, which can adversely impact the daily lives of patients who undergo hemodialysis and may lead to decreased quality of life (QoL). This study employed the KDQOL™-36 scale to evaluate the impact of frequent IDH, based on the definition determined by predialysis blood pressure (BP) and nadir systolic blood pressure (SBP) thresholds, on the QoL of patients. Methods This is a single center retrospective cohort study involving 160 hemodialysis patients. We enrolled adult patients with uremia who received routine hemodialysis (4 h/time, 3 times/week) from October 1, 2019, to September 30, 2021. Frequent IDH was defined as an absolute nadir SBP

Abstract KDM4C, which is a histone lysine demethylase, has been proposed to participate in the malignant transformation and progression of several types of cancer. However, its roles in hepatocellular carcinoma (HCC) remain poorly understood. Here, we find that KDM4C protein expression is increased in HCC and promotes HCC cell growth, proliferation and migration. Furthermore, we provide evidence that depletion of KDM4C leads to a defective G2/M checkpoint, increases radiation-induced DNA damage, impairs DNA repair and enhances radiosensitivity in HCC cells. Using RNA sequencing, we identify that the chemokine CXCL2 is a downstream effector of KDM4C. KDM4C knockdown increases the binding of H3K36me3 to the promoter of CXCL2, thus upregulating CXCL2 expression and promoting CXCL2 secretion in HCC cells. Importantly, the observed effects of KDM4C depletion in HCC cells can be partially rescued by CXCL2 silencing. Thus, our findings reveal that KDM4C is involved in cell migration and radiosensitivity by modulating CXCL2 transcription, indicating that KDM4C may be a potential therapeutic target in HCC.

Improving crop yield and resource utilization efficiency is essential for agricultural productivity. In the Huang-Huai-Hai maize region of China, optimizing planting density, nitrogen (N) application, and fertilization methods are key strategies for enhancing maize yield and N use efficiency. However, traditional approaches have often hindered these improvements. To address this issue, we conducted a study in Baoding, Hebei, from 2022 to 2023, focusing on planting density, the N application rate, and the fertilization method on grain yield, N use efficiency, water use efficiency (WUE), and economic benefits. The trial involved two planting densities: 6.0 × 104 plants ha−1 (D1, typical local density) and 9.0 × 104 plants ha−1 (D2). Five N application rates were tested: 0 (N0), 120 kg ha−1 (N1), 180 kg ha−1 (N2), 240 kg ha−1 (N3), and 300 kg ha−1 (N4). The control treatment (D1N4) utilized the local planting density and traditional fertilization methods. Our findings revealed a positive correlation between the maize yield and N application rate, with the maximum yields (13.78–13.88 t ha−1), high WUE (24.42–29.85 kg m−3), agronomic efficiency of N (AEN) (18.11–19.00 kg kg−1), and economic benefits (2.44 × 104–2.47 × 104 CNY ha−1) observed with D2N3 and surface drip fertilization. This was significantly higher than the yield and resource efficiency of traditional fertilization methods and saved fertilizer and production costs. Therefore, adopting surface drip fertilization, adjusting planting density, and optimizing N application rates proved effective in enhancing maize yield and resource utilization efficiency in the Huang-Huai-Hai maize region.

IntroductionTumor-infiltrating T lymphocytes in the tumor microenvironment are critical factors influencing the prognosis and chemotherapy outcomes. As a Chinese herbal medicine, Marsdenia tenacissima extract (MTE) has been widely used to treat cancer in China. Its immunoregulatory effects on tumor-associated macrophages is well known, but whether it regulates tumor-infiltrating T-cell functions remains unclear.MethodWe collected 17 tumor samples from MTE-administered colorectal cancer patients, 13 of which showed upregulation of CD3+/CD8+ tumor-infiltrating T cells. Further in vitro and in vivo experiments were performed to investigate the regulatory effects of MTE on tumor-infiltrating T cells and immune escape of tumors.ResultsUnder single and co-culture conditions, MTE inhibited TGF-β1 and PD-L1 expression in the colorectal cancer (CRC) cell lines HCT116 and LoVo. In Jurkat cells, MTE inhibited FOXP3 and IL-10 expression, increased IL-2 expression, but had no effect on PD-1 expression. These findings were confirmed in vitro using subcutaneous and colitis-associated CRC mouse models. MTE also increased the density of CD3+/CD8+ tumor-infiltrating T cells and exhibited considerable tumor-suppressive effects in these two tumor mouse models.ConclusionsOur findings suggested that MTE inhibits the immune escape of cancer cells, a precipitating factor increasing the immune response of T lymphocytes.

Abstract Introduction Over half of the patients with hepatitis B virus associated membranous nephropathy (HBV-MN) were found to be phospholipase A2 receptor (PLA2R) positive. Whether MN is really secondary to hepatitis B or just coincidence of hepatitis and PLA2R positive idiopathic MN (IMN) remains controversial. Methods We retrospectively studied seven PLA2R positive HBV-MN patients with complete data in Huashan Hospital from 2009 to 2016 and compared them with PLA2R positive idiopathic MN patients. Results Proteinuria and renal function of these 7 HBV-MN patients were similar to that of IMN patients. However, 5 of them were female and half showed hypocomplementemia, while in IMN group only 32.4% were female and 20% had hypocomplementemia, and the level of hematuria was 94.5/μL in HBV-MN patients and 64.9 /μL in IMN patients, though there was no statistically significant difference. Renal biopsies revealed significantly increased mesangial eletron-deposits in HBV-MN patients. All 7 patients received antiviral therapy, and one patient received immunosuppresants due to severe nephrotic syndrome with acute myocardial infarction and elevated serum creatinine. Compared with IMN group, the prevalence of remission without immunosuppressive therapy of HBV-MN patients was higher (85.7% vs. 43.7%), while the percentage of patients receiving immunosuppresants was lower (14.3% vs. 47.9%) (P=0.048). Conclusion Compared with IMN patients, PLA2R positive HBV-MN patients had a more favorable prognosis after antiviral therapy, indicating a secondary form of MN. For these patients, antiviral treatment is recommended and long observation time should be provided before use of immunosuppressive treatment.

We investigated the effects of variety, planting density, and irrigation amount on grain yield, water-use efficiency (WUE), and evapotranspiration (ETc). The trial was conducted in Tong Liao, Inner Mongolia, from 2021 to 2022, with compact variety Dika159 (DK159) and conventional variety Zhengdan958 (ZD958) as the test materials. The planting density was set to 6.0 × 104 plants/ha (D1, local farmer planting density) and 9.0 × 104 plants/ha (D2), with five irrigation levels: 450 mm (W450, irrigation amount used by local farmers, CK); 360 mm (W360); 270 mm (W270); 180 mm (W180); and 90 mm (W90). The results indicate that the yield and WUE of variety DK159 increased by 7.48% and 5.00%, compared to ZD958, respectively. Increasing planting density enhanced yield by 13.32–15.57% in maize yield and 9.55–11.47% in WUE. Maize yield exhibited a trend of increasing linearly with the irrigation amount before reaching a plateau, reaching a maximum (16.62–17.39 t/ha) and high WUE (2.45–2.49 kg/m3) with DK159-D2-W270. The highest water consumption intensity occurred during the silking stage to the milk stage for different densities and varieties. The results indicate that selecting compact varieties, increasing planting density, and optimizing irrigation amount through integrated drip irrigation and water fertilizer can effectively improve maize yield and WUE.

Whitfordiodendron filipes var. tomentosum is an endemic plant in China. There have been no chemical or pharmacological studies of this plant reported before. In the current research, eight triterpenes and two steroids were obtained. Their structures were established by the analysis of NMR data and comparison with those reported in the literature. These ten structurally diverse compounds comprised five distinct carbon frameworks with different functionalities. The chemotaxonomic significance of these secondary metabolites was discussed, disclosing the common components between the variant W. filipes var. tomentosum and the species W. filipe. Evaluation of α-glucosidase inhibitory activities of these isolates disclosed that compounds 1, 2, 4, and 6 exhibited significant α-glucosidase inhibitory activities (IC50 = 16.6–19.2 μM), which were close in value to the positive control acarbose (IC50 = 11.5 μM). Moreover, the binding modes between the biologically active compounds 1, 2, 4, and 6 and the α-glucosidase protein were preliminarily studied using molecular docking. This study not only showed the chemical and biological profile of the plant W. filipes var. tomentosum but also revealed that these components could be developed as hypoglycemic lead compounds.

Laser-spot-location detection technology based on photodetectors is widely used in the aerospace, medical, military and communication fields. However, most of the current research focuses on continuous laser detection in the visible and near-infrared bands, and the real-time high-precision position detection of a long-wave infrared pulsed laser is lacking. In this paper, a spot-position detection system based on a four-quadrant detector is designed for a 10.6 μm CO2-driven laser in extreme ultraviolet light source, and a second-order extended error compensation algorithm based on a Gaussian-spot model is proposed. Finally, the algorithm is verified and analyzed experimentally by a spot-position detection system under both focusing and defocusing conditions. The experimental results show that the root-mean-square error, maximum absolute error and average absolute error of the second-order error compensation algorithm are significantly reduced compared with the traditional algorithm, and the detection accuracy of the spot-position is better than 9 μm. The above results show that this spot-position detection system has obvious advantages and high accuracy, which can realize the high-precision real-time detection of a laser’s spot position to obtain accurate spot position information, provide feedback adjustments for subsequent beam pointing control, and provide a theoretical basis for the beam pointing stability of the extreme ultraviolet light source system.

A high grain moisture content at harvest has been an important problem in the high latitude region of Northeast China, and it is closely related to the genotypes of varieties, local meteorological factors and planting management. However, delayed harvest at a low temperature could not effectively reduce the grain moisture content. In this study, we continuously observed the grain drying during the late stage of different maturing types of maize varieties in Daqing, Heilongjiang Province, China in 2016 and 2017. A two-segment linear model was used to analyze the different stages of the drying processes: 1) Two-segment linear model fitting can divide the grain drying process of all varieties into two separate linear drying processes with different slopes. 2) During the rapid drying stage, the drying was faster at a higher temperature. The rate of slow drying was influenced by air vapor pressure. 3) The moisture content and meteorological factors when the drying rate turns from one stage into the other were not consistent between varieties and years. After entering the frost period, temperatures below 0°C will significantly reduce the rate of grain drying. 4) Due to the short growth period of early-maturing varieties, the drying time was prolonged, and the grain moisture content was lower than that of the mid-late maturing varieties. Local meteorological conditions do not allow the drying of mid-late maturing varieties to achieve a lower moisture content. When the temperature falls below 0°C, the drying rate of grain decreases markedly. Therefore, one feasible way to solve the problem of high moisture content is to replace the early-maturing varieties and implement the corresponding cultivation techniques.

The rate of corn kernel breakage in the grain combine harvesters is a crucial factor affecting the quality of the grain shelled in the field. The objective of the present study was to determine the susceptibility of corn kernels to breakage based on the kernel moisture content in order to determine the moisture content that corresponds to the lowest rate of breakage. In addition, we evaluated the resistance to breakage of various corn cultivars. A total of 17 different corn cultivars were planted at two different sowing dates at the Beibuchang Experiment Station, Beijing and the Xinxiang Experiment Station (Henan Province) of the Chinese Academy of Agricultural Sciences. The corn kernel moisture content was systematically monitored and recorded over time, and the breakage rate was measured by using the grinding method. The results for all grain samples from the two experimental stations revealed that the breakage rate y is quadratic in moisture content x, y=0.0796x2−3.3929x+78.779; R2=0.2646, n=512. By fitting to the regression equation, a minimum corn kernel breakage rate of 42.62% was obtained, corresponding to a corn kernel moisture content of 21.31%. Furthermore, in the 90% confidence interval, the corn kernel moisture ranging from 19.7 to 22.3% led to the lowest kernel breakage rate, which was consistent with the corn kernel moisture content allowing the lowest breakage rate of corn kernels shelled in the field with combine grain harvesters. Using the lowest breakage rate as the critical point, the correlation between breakage rate and moisture content was significantly negative for low moisture content but positive for high moisture content. The slope and correlation coefficient of the linear regression equation indicated that high moisture content led to greater sensitivity and correlation between grain breakage and moisture content. At the Beibuchang Experiment Station, the corn cultivars resistant to breakage were Zhengdan 958 (ZD958) and Fengken 139 (FK139), and the corn cultivars non-resistant to breakage were Lianchuang 825 (LC825), Jidan 66 (JD66), Lidan 295 (LD295), and Jingnongke 728 (JNK728). At the Xinxiang Experiment Station, the corn cultivars resistant to breakage were HT1, ZD958 and FK139, and the corn cultivars non-resistant to breakage were ZY8911, DK653 and JNK728. Thus, the breakage classifications of the six corn cultivars were consistent between the two experimental stations. In conclusion, the results suggested that the high stability of the grinding method allowed it to be used to determine the corn kernel breakage rates of different corn cultivars as a function of moisture content, thus facilitating the breeding and screening of breakage-resistant corn.

Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.

BackgroundThere is growing evidence that immune cells are strongly associated with the prognosis and treatment of clear cell renal cell carcinoma (ccRCC). Our aim is to construct an immune subtype-related model to predict the prognosis of ccRCC patients and to provide guidance for finding appropriate treatment strategies.MethodsBased on single-cell analysis of the GSE152938 dataset from the GEO database, we defined the immune subtype-related genes in ccRCC. Immediately afterwards, we used Cox regression and Lasso regression to build a prognostic model based on TCGA database. Then, we carried out a series of evaluation analyses around the model. Finally, we proved the role of VMP1 in ccRCC by cellular assays.ResultInitially, based on TCGA ccRCC patient data and GEO ccRCC single-cell data, we successfully constructed a prognostic model consisting of five genes. Survival analysis showed that the higher the risk score, the worse the prognosis. We also found that the model had high predictive accuracy for patient prognosis through ROC analysis. In addition, we found that patients in the high-risk group had stronger immune cell infiltration and higher levels of immune checkpoint gene expression. Finally, cellular experiments demonstrated that when the VMP1 gene was knocked down, 786-O cells showed reduced proliferation, migration, and invasion ability and increased levels of apoptosis.ConclusionOur study can provide a reference for the diagnosis and treatment of patients with ccRCC.

Quantifying the effects of various environmental conditions on maize leaf number is essential to understanding the environmental adaptations and population structure of maize plants and for enhancing maize productivity. In this study, seeds of three temperate-adapted maize cultivars, each belonging to different maturity classes, were sown on eight different dates. Sowing dates ranged from the middle of April to early July, which allowed us to cover a wide range of environmental conditions. Random forest regression and multiple regression models with variance partitioning analyses were used to assess the effects of environmental factors on the number of leaves and their distributions on maize primary stems. We demonstrated that the total leaf number (TLN) increased in the three cultivars in the following order: FK139 < JNK728 < ZD958, and variations in TLN for each cultivar were 1.5, 1.76, and 2.75 leaves, respectively. The variation in TLN was ascribed to changes in LB (leaf number below the primary ear), which were higher than variations in LA (leaf number above the primary ear). Variations in TLN and LB were mainly affected by the photoperiod during growth stages V7 to V11, and differences in TLN and LB in response to different photoperiods ranged from 1.34 to 2.95 leaves h-l. Variations in LA was mainly affected by temperature-related factors. Therefore, the results of this study enhanced our current understanding of key environmental conditions that affect maize leaf numbers, and provides scientific support for the benefits of adjusting sowing dates and selecting suitable cultivars to mitigate the effects of climate change on maize production.

BackgroundIce hockey is a high-intensity dynamic sport for which competitive athletes train for longer than 20 hours each week for several years. The cumulative time of myocardial exposure to hemodynamic stress affects cardiac remodeling. However, the intracardiac pressure distribution of the elite ice hockey athletes' heart during adaptation to long-term training remains to be explored. This study aimed to compare the diastolic intraventricular pressure difference (IVPD) of the left ventricle (LV) between healthy volunteers and ice hockey athletes with different training times.MethodsFifty-three female ice hockey athletes (27 elite and 26 casual) and 24 healthy controls were included. The diastolic IVPD of the LV during diastole was measured by vector flow mapping. The peak amplitude of the IVPD during isovolumic relaxation (P0), diastolic rapid filling (P1), and atrial systole (P4); the difference in the peak amplitude between adjacent phases (DiffP01, DiffP14); the time interval between the peak amplitude of adjacent phases (P0P1, P1P4); and the maximum decrease rate in diastolic IVPD were calculated. Differences between groups, as well as correlations between hemodynamic parameters and training time, were analyzed.ResultsStructural parameters of the LV were significantly higher in elite athletes than in casual players and controls. No significant difference in the peak amplitude of the IVPD during the diastolic phase was found among the three groups. The analysis of covariance with heart rate as a covariate showed that P1P4 in the elite athlete and casual player groups was significantly longer than that in the healthy control group (p < 0.001 for all). An increased P1P4 was significantly associated with an increased training year (β = 4.90, p < 0.001).ConclusionsThe diastolic cardiac hemodynamics of the LV in elite female ice hockey athletes could be characterized by a prolonged diastolic IVPD, and P1P4 prolonged with an increase in the training years, reflecting a time–domain adaptation in diastolic hemodynamics after long-term training.

Timely and accurate pre-harvest estimates of maize yield are vital for agricultural management. Although many remote sensing approaches have been developed to estimate maize yields, few have been tested under lodging conditions. Thus, the feasibility of existing approaches under lodging conditions and the influence of lodging on maize yield estimates both remain unclear. To address this situation, this study develops a lodging index to quantify the degree of lodging. The index is based on RGB and multispectral images obtained from a low-altitude unmanned aerial vehicle and proves to be an important predictor variable in a random forest regression (RFR) model for accurately estimating maize yield after lodging. The results show that (1) the lodging index accurately describes the degree of lodging of each maize plot, (2) the yield-estimation model that incorporates the lodging index provides slightly more accurate yield estimates than without the lodging index at three important growth stages of maize (tasseling, milking, denting), and (3) the RFR model with lodging index applied at the denting (R5) stage yields the best performance of the three growth stages, with R2 = 0.859, a root mean square error (RMSE) of 1086.412 kg/ha, and a relative RMSE of 13.1%. This study thus provides valuable insight into the precise estimation of crop yield and demonstra\tes that incorporating a lodging stress-related variable into the model leads to accurate and robust estimates of crop grain yield.

Nitrogen fertilizer application is an important measure to obtain high and stable corn yield, and the moisture content of corn grains is an important factor affecting the quality of mechanical grain harvesting. In this study, four different nitrogen fertilizer treatments from 0 to 450 kg ha–1 pure nitrogen were set for a planting density of 12.0×104 plants ha–1 in 2017 and 2018, and 18 different nitrogen fertilizer treatments from 0 to 765 kg ha–1 pure nitrogen were set for planting densities of 7.5×104 and 12.0×104 plants ha–1 in 2019, to investigate the effect of nitrogen application rate on the moisture content of corn grains. Under each treatment, the growth of corn, leaf area index (LAI) of green leaves, grain moisture content, and grain dehydration rate were measured. The results showed that, as nitrogen application increased from 0 to 765 kg ha–1, the silking stage was delayed by about 1 day, the maturity stage was delayed by about 1–2 days, and the number of physiologically mature green leaves and LAI increased. At and after physiological maturity, the extreme difference in grain moisture content between different nitrogen application rates was 1.9–4.0%. As the amount of nitrogen application increased, the corn grain dehydration rate after physiological maturity decreased, but it did not reach statistical significance between nitrogen application rate and grain dehydration rate. No significant correlation was observed between LAI at physiological maturity and grain dehydration rate after physiological maturity. In short, nitrogen application affected the grain moisture content of corn at and after physiological maturity, however, the difference in grain moisture content among different nitrogen application rates was small. These results suggest that the effect of nitrogen application on the moisture content of corn grains should not be considered in agricultural production.

ObjectiveTo compare the complications and long-term survival of esophageal cancer patients with chronic obstructive pulmonary disease (COPD) after minimally invasive esophagectomy (MIE) versus open esophagectomy (OE) using propensity score matching (PSM).MethodsEsophageal cancer patients who underwent esophagectomy at the Thoracic Surgery Department of the First Affiliated Hospital of Hebei North University from January 2010 to December 2018 were retrospectively enrolled. The incidence of postoperative complications and prognosis of the MIE (n = 132) and OE (n = 138) groups were compared. To reduce bias, 1:1 PSM was adopted for the analysis.ResultsThe median disease-free survival (DFS) of the MIE and OE groups were 24 months and 26 months, respectively, and neither group reached median survival. There was no significant difference between the two groups in terms of 3-year DFS and overall survival (OS). The stratification of the patients on the basis of the percentage of estimated forced expiratory volume in the first second (%FEV1) did not result in significant differences in the survival rates. A total of 42 patients (50%) in the MIE group and 55 patients (65.48%) in the OE group experienced complications, and the difference was statistically significant (OR=0.527, 95% CI: 0.283–0.981, P=0.042). The incidence of acute COPD exacerbation (OR=0.213, 95% OR, CI: 0.068–0.666, P=0.004) and pulmonary atelectasis requiring bronchoscopic aspiration (OR=0.232, 95% OR, CI: 0.082–0.659, P=0.004) were significantly higher in the OE versus the MIE group. In addition, the distribution of the various grades of complications also differed significantly between the two groups (P=0.016). While the incidence of minor complications (≤Grade II) was similar in both groups (P=0.503), that of severe complications (≥Grade III) was markedly higher in the OE group (P=0.002) and the Grade-IIIa complications were predominant (P=0.001). The severity of complications was correlated with the postoperative duration of hospital stay in both groups (r=0.187, P=0.015). No significant difference was observed in the incidence of minor complications (≤Grade II) between the two groups following stratification on the basis of %FEV1, whereas severe complications were more frequent in the OE group among patients with %FEV1 between 60% and 70% (P=0.001

The harvest method of shelling corn (Zea mays L.) kernels in the field decreases labor costs associated with transporting, drying and threshing the crop. However, it was previously found that the kernel moisture content increased after field harvest, which decreased the value of corn kernels. To identify the reasons underlying the increase, we conducted a multiyear and -area trial in the Huang-Huai-Hai Plain, China and performed a staged-harvest test at several phases of kernel dry-down. The test investigated a range of parameters such as the kernel moisture content pre- and post-harvest, the kernel breakage rate, the amount of impurities, and the moisture content of various other plant tissues. An analysis of 411 pairs of pre- and post-harvest samples found that kernel moisture content after harvest was 2.2% higher than that before harvest. In the staged-harvest test, however, a significant increase was only observed when the kernel moisture content before harvest was higher than 23.9%. The increase in post-harvest kernel moisture content was positively associated with the pre-harvest kernel moisture content, breakage rate and impurity rate. Typically, at harvest time in this region, there is a significant fraction of immature crops with a high moisture content, resulting in kernels that are prone to breakage or impurities that ultimately lead to increases in water content after harvest. Therefore, we suggest using hybrids that quickly wither late in the growing stage. Additionally, farmers should delay harvest in order to minimize the pre-harvest kernel moisture content and thus reduce breakages and impurities, thereby improving the quality of kernels after harvest and the efficiency of corn kernel farming in China.

Understanding the water status of specific organs can be helpful in evaluating the life activities and growth conditions of maize. To accurately judge organ growth conditions and thus design appropriate interventions, it is necessary to clarify the true water dynamics of each maize organ. Using multiple maize cultivars with different growth periods, spatio-temporal water dynamics were analyzed here in the leaves, stalks, and ear components. Leaf water content was found to gradually decrease from both the bottom and top of the plant to the middle, whereas stalk water content decreased sequentially from the top to the bottom. Each successively higher node from the bottom of the plant was associated with decreases of 0.99% and 1.27% water content in the leaves and stalks, respectively. The water dynamics in leaves and internodes showed three clear stages: the slow loss, rapid loss, and balance stage. A water content of 60% appeared to be an irreversible turning point for initiation of senescence. Using normalized growth period as a measure, each of the tested cultivars could be assigned into one of two types based on their water dynamics: stay-water or general type. General-type cultivars had a shorter duration with a high water content and a water loss rate approximately twice as high as that of the stay-water type. This may have been related to the leaf senescence characteristics. However, the stay-water trait did not interfere with water dynamics of the ear components. Therefore, it may not be robust to evaluate the kernel dehydration of maize according to leaf senescence conditions due to the weak correlation between kernel water content and leaf senescence characteristics.

Abstract This study aimed to explore the effect of calcitonin gene-related peptide (CGRP) on bladder smooth muscle cells (BSMCs) under high glucose (HG) treatment in vitro. BSMCs from Sprague–Dawley rat bladders were cultured and passaged in vitro. The third-generation cells were cultured and divided into control group, HG group, HG + CGRP group, HG + CGRP + asiatic acid (AA, p-p38 activator) group, CGRP group, AA group, HG + CGRP + CGRP-8-37 (CGRP receptor antagonist) group and HG + LY2228820 (p38 MAPK inhibitor) group. The cell viability, apoptosis, malondialdehyde (MDA) and superoxide dismutase (SOD) levels of BSMCs were observed by the relevant detection kits. The expressions of α-SM-actin, p38 and p-p38 were detected by qRT-PCR or Western blot analysis. Compared with the control group, the cell viability, SOD and α-SM-actin levels of BSMCs were decreased and apoptotic cells, MDA and p-p38 levels were increased after HG treatment, while these changes could be partly reversed when BSMCs were treated with HG and CGRP or LY2228820 together. Moreover, AA or CGRP-8-37 could suppress the effect of CGRP on BSMCs under HG condition. Our data indicate that CGRP protects BSMCs from oxidative stress induced by HG in vitro, and inhibit the α-SM-actin expression decrease through inhibiting the intracellular p38 MAPK signaling pathway.

Animal models play a key role in life science research, especially in the study of human disease pathogenesis and drug screening. Because of the closer proximity to humans in terms of genetic evolution, physiology, immunology, biochemistry, and pathology, nonhuman primates (NHPs) have outstanding advantages in model construction for disease mechanism study and drug development. In terms of animal model construction, gene editing technology has been widely applied to this area in recent years. This review summarizes the current progress in the establishment of NHPs using gene editing technology, which mainly focuses on rhesus and cynomolgus monkeys. In addition, we discuss the limiting factors in the applications of genetically modified NHP models as well as the possible solutions and improvements. Furthermore, we highlight the prospects and challenges of the gene-edited NHP models.

Patients with colon adenocarcinoma (COAD) are at a higher probability of infection with COVID-19 than healthy individuals. However, there is no globally accepted treatment protocol for patients with COAD/COVID-19. Quercetin has been found to have significant antitumor, antiviral and anti-inflammatory effects in several studies. Therefore, this study sought to evaluate the potential of quercetin as the agent for COAD/COVID-19 and to explore its mechanisms. We used bioinformatics algorithms to obtain COAD/COVID-19-related genes (CCRG) from COAD-related transcriptome data and COVID-related transcriptome sequencing data, and used these genes to construct a COAD prognostic model. We intersected the CCRG with the therapeutic target genes of quercetin and obtained a total of 105 genes (potential target genes of quercetin for the treatment of COAD/COVID-19). By constructing a protein-protein interaction (PPI) network, we ascertained FOS, NFKB1, NFKB1A, JUNB, and JUN as possible core target genes of quercetin for the treatment of COAD/COVID-19. Bioinformatic analysis of these 105 genes revealed that the mechanisms for quercetin the treatment of COAD/COVID-19 may be associated with oxidative stress, apoptosis, anti-inflammatory, immune, anti-viral and multiple pathways containing IL-17, TNF, HIF-1. In this study, we constructed a prognostic model of COAD/COVID19 patients by using CCRG and elucidated for the first time the potential target genes and molecular mechanisms of quercetin for the treatment of COAD/COVID-19, which may benefit the clinical treatment of COAD/COVID-19 patients. However, no clinical trials have yet been conducted to further validate the findings, but this will be the future direction of our research.

Unhealthy diet especially high-fat diet (HFD) is the major cause of hyperlipidemia leading to deterioration of chronic kidney diseases (CKD) in patients. Trimethylamine N-oxide (TMAO) is a gut-derived uremic toxin. Our previous clinical study demonstrated that the elevation of TMAO was positively correlated with CKD progression. Finasteride, a competitive and specific inhibitor of type II 5a-reductase, has been reported recently to be able to downregulate plasma TMAO level thus preventing the onset of atherosclerosis by our research group. In this study, we established a protein-overload nephropathy CKD mouse model by bovine serum albumin (BSA) injection to investigate whether hyperlipidemia could accelerate CKD progression and the underlying mechanisms. Finasteride was administrated to explore its potential therapeutic effects. The results of biochemical analyses and pathological examination showed that HFD-induced hyperlipidemia led to aggravated protein-overload nephropathy in mice along with an elevated level of circulating TMAO, which can be alleviated by finasteride treatment possibly through inhibition of Fmo3 in liver. The 16 S rRNA sequencing results indicated that HFD feeding altered the composition and distribution of gut microbiota in CKD mice contributing to the enhanced level of TMAO precursor TMA, while finasteride could exert beneficial effects via promoting the abundance of Alistipes_senegalensis and Akkermansia_muciniphila. Immunofluorescence staining (IF) and qRT-PCR results demonstrated the disruption of intestinal barrier by decreased expression of tight junction proteins including Claudin-1 and Zo-1 in HFD-fed CKD mice, which can be rescued by finasteride treatment. Cytokine arrays and redox status analyses revealed an upregulated inflammatory level and oxidative stress after HFD feeding in CKO mice, and finasteride-treatment could alleviate these lesions. To summarize, our study suggested that finasteride could alleviate HFD-associated deterioration of protein-overload nephropathy in mice by inhibition of TMAO synthesis and regulation of gut microbiota.

Objective: This study aims to explore the clinical significance of haptoglobin (HP) and protein disulfide-isomerase A3 (PDIA3) in human serum in the screening, diagnosis and staging of colorectal cancer (CRC), and to provide novel screening approaches featuring high specificity, sensitivity, and accuracy for early screening and diagnosis of clinical colorectal cancer.Methods: 88, 77, and 36 blood specimens were respectively harvested from colorectal cancer patients, colorectal polyp patients, and normal subjects (the health examination) who requested medical assistance from our hospital between Oct2019 and February 2022. The serum contents of HP and PDIA3 in each sample were determined through an enzyme linked immunosorbent assay (ELISA). This step was taken to analyze the differences among different specimen groups in terms of the serum contents of HP and PDIA3, to analyze the relationships between the expression levels of HP and PDIA3 and the pathological characteristics of colorectal cancer, and to explore the critical role of HP and PDIA3 in the screening, diagnosis, and staging of colorectal cancer.Results: Serum contents of HP and PDIA3 were higher in colorectal cancer patients, with statistical differences (p < 0.05), than those in the colonic polyp patients and healthy subjects. Receiver operating characteristic (ROC) curve demonstrated that the cut-offs of HP and PDIA3 serum contents indicating colorectal cancer were 149 ug/ml and 66 ng/ml respectively. The individually and jointly tested AUCs of HP (0.802) and PDIA3 (0.727) were higher than those of serum CEA and CA199, the sensitivity and specificity of HP were 64.8 and 91.2%, the sensitivity and specificity of PDIA3 were 65.9 and 71.7%. Moreover, the contents of HP and PDIA3 increased alongside disease progression, with differences (p < 0.05).Conclusion: Our research indicated that joint testing of HP and PDIA3 was of reference value for progressive stage and reliable biological indicators of colorectal cancer screening.

Background This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. Methods In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. Results In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14–1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p

The most significant problem of maize grain mechanical harvesting quality in China at present is the high grain breakage rate (BR). BR is often the key characteristic that is measured to select hybrids desirable for mechanical grain harvesting. However, conventional BR evaluation and measurement methods have challenges and limitations. Microstructural crack parameters evaluation of maize kernel is of great importance to BR. In this connection, X-ray computed microtomography (μ-CT) has proven to be a quite useful method for the assessment of microstructure, as it provides important microstructural parameters, such as object volume, surface, surface/volume ratio, number of closed pores, and others. X-ray computed microtomography is a non-destructive technique that enables the reuse of samples already measured and also yields bidimensional (2D) cross-sectional images of the sample as well as volume rendering. In this paper, six different maize hybrid genotypes are used as materials, and the BR of the maize kernels of each variety is tested in the field mechanical grain harvesting, and the BR is used as an index for evaluating the breakage resistance of the variety. The crack characteristic parameters of kernel were detected by X-ray micro-computed tomography, and the relationship between the BR and the kernel crack characteristics was analyzed by stepwise regression analysis. Establishing a relationship between crack characteristic parameters and BR of maize is vital for judging breakage resistance. The results of stepwise multiple linear regression (MLR) showed that the crack characteristics of the object surface, number of closed pores, surface of closed pores, and closed porosity percent were significantly correlated to the BR of field mechanical grain harvesting, with the standard partial regression coefficients of −0.998, −0.988, −0.999, and −0.998, respectively. The R2 of this model was 0.999. Results validation showed that the Stepwise MLR Model could well predict the BR of maize based on these four variables.

Abstract Background The accurate evaluation of the stalk-lodging resistance during the late stage of maize growth can provide a basis for the selection of cultivars, the evaluation of cultivation techniques, and timely mechanical grain harvesting. In this study, the critical wind speed of stalk breaking, plant morphology, stalk mechanical strength, and lodging rate were investigated in 10 maize cultivars to identify the parameters evaluate lodging resistance during the later growth stage of maize. Clarify the relationship with the stalk mechanical strength, critical wind speed of stalk breaking, and natural lodging rate in the field. Results The results showed that, in the late growth stage, with increasing number of days after physiological maturity, (1) the stalk lodging rate gradually increased, (2) the stalk breaking force and rind penetration strength (RPS) of the third internode above the soil gradually decreased, and (3) the critical wind speed of stalk breaking increased first and then decreased, and was highest at about 16–24 days after physiological maturity. The position of stalk lodging mostly occurred between second and fifth internodes. The torque at the base of maize plant increased as wind speed increased, and the different of torque was excited among different maize cultivars under same wind speed. Furthermore, the stalk lodging rate was significantly negatively correlated with the critical wind speed of stalk breaking. Additionally, the critical wind speed of stalk breaking was significantly positively correlated with the stalk breaking force and the RPS. Conclusion This indicates that the critical wind speed of stalk breaking is a superior way to determine the stalk lodging resistance. These results suggest that, in the late growth stage, the decrease in the stalk mechanical strength is an important reason for the decrease in the critical wind speed of stalk breaking and the increase in the lodging rate.