[Correlations between serum BDNF, IL-18 and hs-CRP levels in patients with acute cerebral infarction and vascular cognitive impairment].

OBJECTIVE: To explore the correlations between serum levels of brain-derived neurotrophic factor (BDNF), interleukin-18 (IL-18) and hypersensitivity C-reactive protein (hs-CRP) in patients with acute cerebral infarction and vascular cognitive impairment (VCI), and to provide some clinical bases for early prevention of VCI. METHODS: A total of 160 patients with acute cerebral infarction admitted in Department of Neurology of Jincheng People' s Hospital from May 2019 to April 2020 were enrolled in this study and were devided into three groups according to whether or not combined with cognitive impairment, including no cognitive impairment group (NCI, 57 cases), vascular cognitive impairment no dementia group (VCIND, 56 cases) and vascular dementia group (VaD, 47 cases). The cognitive function of all the patients were evaluated by Montreal cognitive assessment (MoCA). The National Institute of Health stroke scale (NIHSS) was used to assess the degree of neurological deficit (mild-, moderate-, severe-neurologic deficit group). The infarct size was calculated by Pullicino' s method (small-, middle-, large-infarct group). The levels of serum BDNF and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA), and serum levels of hs-CRP were measured by immunoturbidimetry during the acute phase (0-7 d), recovery period (15-30 d) and 6 months after cerebral infarction. The effects of varying degrees of neurological deficits and different size of infarction on BDNF, IL-18 and hs-CRP were observed. The levels of serum BDNF, IL-18 and hs-CRP in the patients of the three groups with acute, convalescent and six-month cerebral infarction were compared, and their correlations with VCI were analyzed. RESULTS: Serum BDNF level and MoCA scores in mild-neurologic deficit group and small-infarct group were significantly higher than those in moderate- and severe-deficit group, middle- and large-infarct group, respectively (P < 0.05). Their levels of IL-18 and hs-CRP were significantly lower than those in moderate- and severe-deficit group, middle- and large-infarct group, respectively (P < 0.05). The levels of serum BDNF in NCI group, VCIND group and VaD group during the acute phase, convalescence and 6 months after cerebral infarction were in a significant decline, and the differences during the acute phase and recovery period were statistically significant (P < 0.05). The levels of IL-18 and hs-CRP during the acute phase, recovery period and 6 months after cerebral infarction showed a significant increasing trend with significance (P < 0.05). Correlation analysis revealed that the levels of BDNF was positively correlated with MoCA scores but negatively correlated with the severity of cognitive impairment while the expression levels of IL-18 and hs-CRP were negatively correlated with MoCA scores but positively correlated with the severity of cognitive impairment. CONCLUSION: Serum BDNF, IL-18 and hs-CRP are involved in the pathological process of occurrence and development of VCI in the patients with acute cerebral infarction. BDNF has a protective effect on VCI while IL-18 and hs-CRP cause severe cognitive impairment. The levels of serum BDNF、IL-18 and hs-CRP in the patients with acute ischemic cerebral infarction are closely related to the severity of cognitive impairment and can be used as biomarkers of early diagnosis of VCI.

Construction and validation of an immune infiltration-related risk model for predicting prognosis and immunotherapy response in low grade glioma.

BACKGROUND: Low grade glioma (LGG) is considered a heterogeneous tumor with highly variable survival and limited efficacy of immunotherapy. To identify high-risk subsets and apply immunotherapy effectively in LGG, the status and function of immune infiltration in the glioma microenvironment must be explored. METHODS: Four independent glioma cohorts comprising 1,853 patients were enrolled for bioinformatics analysis. We used ConsensusClusterPlus to cluster patients into four different immune subtypes based on immune infiltration. The immune-infiltration signature (IIS) was constructed by LASSO regression analysis. Somatic mutation and copy number variation (CNV) analyses were performed to explore genomic and transcriptomic traits in the high- and low- risk groups. The correlation between response to programmed cell death 1 (PD-1) blockade and the IIS risk score was confirmed in an in vivo glioma model. RESULTS: Patients were clustered into four different immune subtypes based on immune infiltration, and the high immune infiltration subtype was associated with worse survival in LGG. The high immune infiltration subtype had stronger inflammatory response, immune response and immune cell chemotaxis. The IIS, consisting of EMP3, IQGAP2, METTL7B, SLC1A6 and TNFRSF11B, could predict LGG malignant progression, which was validated with internal clinical samples. M2 macrophage infiltration positively correlated with the IIS risk score. The high-risk group had significantly more somatic mutations and CNVs. The IIS risk score was related to immunomodulatory molecules and could predict immunotherapy clinical benefit. In vivo, immunotherapy-sensitive glioma model exhibited higher IIS risk score and more infiltration of immune cells, especially M2 macrophages. The IIS risk score was decreased in an immunotherapy-sensitive glioma model after anti-PD1 immunotherapy. CONCLUSION: Different immune subtypes of LGG had unique immune cell infiltration characteristics, and the high immune infiltration subtype was associated with immunosuppressive signaling pathways. A novel IIS prognostic model based on immune infiltration status was constructed for immunophenotypic classification, risk stratification, prognostication and immunotherapy response prediction in LGG.

Effect of prophylactic antiviral intervention on T cell immunity in hepatitis B virus-infected pregnant women.

BACKGROUND: Antiviral intervention in hepatitis B virus (HBV)-infected pregnant women can effectively reduce mother-to-child transmission. However, the immunological characteristics of pregnant women with chronic HBV infection and the effects of antiviral intervention during pregnancy on maternal immune response remain unknown. We aimed to investigate these effects by comparing mothers who received antiviral intervention during pregnancy with those who did not. METHODS: Pregnant women positive for hepatitis B surface antigen and hepatitis B e-antigen (HBsAg+ HBeAg+) were enrolled at delivery, including 34 received prophylactic antiviral intervention during pregnancy (AVI mothers) and 15 did not (NAVI mothers). T lymphocyte phenotypes and functions were analysed using flow cytometry. RESULTS: At delivery, maternal regulatory T cell (Treg) frequency in AVI mothers was significantly higher than that in NAVI mothers (P < 0.002), and CD4+ T cells in AVI mothers displayed a decreased ability to secrete IFN-γ (P = 0.005) and IL-21 (P = 0.043), but an increased ability to secrete IL-10 and IL-4 (P = 0.040 and P = 0.036), which represented a higher Treg frequency, enhanced Th2 response and suppressed Th1 response. Treg frequency among AVI mothers was correlated negatively with serum HBsAg and HBeAg levels. After delivery, the ability of CD4+ T cells or CD8+ T cells to secrete IFN-γ or IL-10 was similar and no significant difference in Treg frequency was found between the two groups. CONCLUSIONS: Prophylactic antiviral intervention during pregnancy has an effect on T cell immunity in pregnant women, which was characterised by increased maternal Treg frequency, enhanced Th2 response and suppressed Th1 response at delivery.

Polymorphonuclear neutrophils promote endothelial apoptosis by enhancing adhesion upon stimulation by intermittent hypoxia.

PURPOSE: This study explored the interactive effects between polymorphonuclear neutrophils (PMNs) and vascular endothelial cells under intermittent hypoxia (IH) and investigated the mechanisms underlying these effects. METHODS: Endothelial cells were co-cultured with PMNs isolated from rats exposed to normoxia or IH. The PMN apoptotic rate was determined using flow cytometry. Expression of apoptosis-related proteins in the endothelial cells were evaluated using Western blotting, and the levels of intercellular adhesion molecules in the co-culture supernatants were measured using enzyme-linked immunosorbent assay. RESULTS: The PMN apoptotic rate in the IH-exposed rat group was significantly lower than that of the normoxia control group. There was a positive relationship between the PMN apoptotic rate and IH exposure time. In endothelial cells co-cultured with PMNs isolated from IH-exposed rats, a significant increase in the protein expression levels of Bax, Bcl-2, and caspase-3 and a significant decrease in the Bcl-2/Bax ratio were observed. Furthermore, the intercellular cell adhesion molecule-1(ICAM-1) and E-select element (E-S) levels were elevated significantly in the co-cultured supernatants of endothelial cells and PMNs from IH-exposed rats compared to that from controls. The above IH-induced alterations were partially restored by tempol pretreatment. CONCLUSIONS: The apoptotic rate was low in PMNs from IH-exposed rats, which consequently increased the apoptotic signals in endothelial cells in vitro. This may be associated with the increased levels of intercellular adhesion molecules. Further, tempol partially attenuates the PMN-mediated pro-apoptotic effects on endothelial cells under IH.

Comparative Ubiquitination Proteomics Revealed the Salt Tolerance Mechanism in Sugar Beet Monomeric Additional Line M14.

Post-translational modifications (PTMs) are important molecular processes that regulate organismal responses to different stresses. Ubiquitination modification is not only involved in human health but also plays crucial roles in plant growth, development, and responses to environmental stresses. In this study, we investigated the ubiquitination proteome changes in the salt-tolerant sugar beet monomeric additional line M14 under salt stress treatments. Based on the expression of the key genes of the ubiquitination system and the ubiquitination-modified proteins before and after salt stress, 30 min of 200 mM NaCl treatment and 6 h of 400 mM NaCl treatment were selected as time points. Through label-free proteomics, 4711 and 3607 proteins were identified in plants treated with 200 mM NaCl and 400 mM NaCl, respectively. Among them, 611 and 380 proteins were ubiquitinated, with 1085 and 625 ubiquitination sites, in the two salt stress conditions, respectively. A quantitative analysis revealed that 70 ubiquitinated proteins increased and 47 ubiquitinated proteins decreased. At the total protein level, 42 were induced and 20 were repressed with 200 mM NaCl, while 28 were induced and 27 were repressed with 400 mM NaCl. Gene ontology, KEGG pathway, protein interaction, and PTM crosstalk analyses were performed using the differentially ubiquitinated proteins. The differentially ubiquitinated proteins were mainly involved in cellular transcription and translation processes, signal transduction, metabolic pathways, and the ubiquitin/26S proteasome pathway. The uncovered ubiquitinated proteins constitute an important resource of the plant stress ubiquitinome, and they provide a theoretical basis for the marker-based molecular breeding of crops for enhanced stress tolerance.

Post-COVID-19 Epidemic: Allostatic Load among Medical and Nonmedical Workers in China.

BACKGROUND: As the fight against the COVID-19 epidemic continues, medical workers may have allostatic load. OBJECTIVE: During the reopening of society, medical and nonmedical workers were compared in terms of allostatic load. METHODS: An online study was performed; 3,590 Chinese subjects were analyzed. Socio-demographic variables, allostatic load, stress, abnormal illness behavior, global well-being, mental status, and social support were assessed. RESULTS: There was no difference in allostatic load in medical workers compared to nonmedical workers (15.8 vs. 17.8%; p = 0.22). Multivariate conditional logistic regression revealed that anxiety (OR = 1.24; 95% CI 1.18-1.31; p < 0.01), depression (OR = 1.23; 95% CI 1.17-1.29; p < 0.01), somatization (OR = 1.20; 95% CI 1.14-1.25; p < 0.01), hostility (OR = 1.24; 95% CI 1.18-1.30; p < 0.01), and abnormal illness behavior (OR = 1.49; 95% CI 1.34-1.66; p < 0.01) were positively associated with allostatic load, while objective support (OR = 0.84; 95% CI 0.78-0.89; p < 0.01), subjective support (OR = 0.84; 95% CI 0.80-0.88; p < 0.01), utilization of support (OR = 0.80; 95% CI 0.72-0.88; p < 0.01), social support (OR = 0.90; 95% CI 0.87-0.93; p < 0.01), and global well-being (OR = 0.30; 95% CI 0.22-0.41; p < 0.01) were negatively associated. CONCLUSIONS: In the post-COVID-19 epidemic time, medical and nonmedical workers had similar allostatic load. Psychological distress and abnormal illness behavior were risk factors for it, while social support could relieve it.

Effects of intrauterine exposure to maternal-derived HBeAg on T cell immunity in cord blood.

Immature immune system and immune tolerance induced by exposure to HBeAg in utero and/or shortly after infection in newborns were reportedly the causes of chronic HBV infection. To investigate the effect of maternal-derived HBeAg on neonatal T cell immunity, we analysed and compared T cell phenotypes and functions among neonates born to HBsAg+ /HBeAg+ mothers (HBeAg+ neonates), HBsAg+ /HBeAg- mothers (HBeAg- neonates) and healthy control mothers (HC neonates), using flow cytometry. The results showed that neonatal T cell phenotypes were similar regardless of HBeAg exposure. Upon anti-CD3 and anti-CD28 stimulation in HBeAg+ neonates, CD4+ T cell production of IFN-γ (P < .05) was significantly enhanced, while CD8+ T cells secreted significantly more IL-2 compared with those in HBeAg- and HC groups (P < .05). Moreover, similar levels of IFN-γ and IL-10 were observed in the culture supernatant after stimulation with rHBsAg, rHBcAg or rHBeAg among HBeAg+ , HBeAg- and HC neonates, whereas HBeAg+ neonates produced more TNF-α than HBeAg- neonates upon stimulation with rHBcAg. In conclusion, the results indicated that the HBsAg+ /HBeAg+ maternal environment did not influence the phenotypes of cord blood T cells but boosted neonatal non-specific Th1-type cytokine production.

Risk of Pneumonia with Different Inhaled Corticosteroids in COPD Patients: A Meta-Analysis.

ICS are anti-inflammatory agents which have been suggested to benefit people with worsening symptoms of COPD, by improving lung function, reducing exacerbation of disease, and enhancing overall quality of life. This systematic review and meta-analysis explored the association of the risk of pneumonia in COPD patients that were undergoing treatment using ICS alone or together with LABAs or LAMAs. PubMed, Cochrane Library and EMBASE were systematically searched through August 1, 2019; only double-blinded randomized controlled trials were eligible for this study. Eighteen randomized controlled trials were included. ICS treatment was linked to increased pneumonia incidence (RR, 1.47; 95% CI, 1.26-1.71; p < 0.001; I2 = 39.6%). Patients treated with salmeterol/fluticasone were more likely to have experience pneumonia-related adverse events than those treated using budesonide/formoterol or beclomethasone/formoterol. In subgroup analyses, pneumonia risk was found to be higher in the subgroups: >65 years old, lowest baseline forced expiratory volume in the first second of expiration (FEV1) < 50% of the predicted value, highest ICS dose, and long duration of ICS use. Furthermore, we compared fluticasone propionate with fluticasone furoate and determined that pneumonia incidence was higher in the former group and pneumonia incidence rose as doses rose in these two groups. However, no difference was observed between the budesonide and beclomethasone groups. ICS treatment was linked to an elevated pneumonia risk, different kinds of ICS lead to different rates of pneumonia.

Bone morphogenetic protein 2 mediates epithelial-mesenchymal transition via AKT and ERK signaling pathways in gastric cancer.

Although deregulation of bone morphogenetic protein 2 (BMP2) signaling has been linked to various types of cancers, the relationships between abnormal activation of these signaling pathways and tumorigenesis are not clear in gastric cancer. We hypothesized that BMP2 might be involved in epithelial-mesenchymal transition (EMT) process of gastric cancer. Here, BMPR-II activation and inhibition in gastric cancer cell line AGS were induced with exogenous BMP2 and with BMPR-II small interfering RNA (siRNA), respectively. BMPR-II downstream signal molecules AKT, ERK phosphorylation, and EMT biomarkers (vimentin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. In the present study, our results showed that BMP2 can induce AKT and ERK phosphorylation in a dose-dependent method, and endogenous BMPR-II can be inhibited completely by BMPR-II siRNA in AGS. Notably BMP2 alone treatment can induce the up-regulation of vimentin, snail, and N-cadherin in AGS cells, besides, the down-regulation of E-cadherin also occurred. On the contrary, BMPR-II siRNA significantly prohibited BMP2-induced AKT and ERK phosphorylation, at the same time, EMT biomarkers changes were not observed. On the other hand, BMPR-II knockdown could significantly affect AGS wound closure and the migration ability (p < 0.001) compared to control siRNA and BMP2 alone. In conclusion, this study suggested that EMT process can be triggered by the BMP2/BMPR axis in gastric cancer and then involved in the tumor cell migration, invasion, and metastasis via the activation of PI3K/AKT and MEK/ERK pathways. Our study lays a new foundation for the treatment of gastric cancer through antagonizing BMP2 system.

Lymphocytes from intermittent hypoxia-exposed rats increase the apoptotic signals in endothelial cells via oxidative and inflammatory injury in vitro.

OBJECTIVE: Obstructive sleep apnea (OSA) has been implicated as a risk factor for atherosclerosis. Intermittent hypoxia (IH) induces oxidative and immuno-inflammatory alterations that could contribute to atherosclerosis. The aim of this study was to examine the effect of lymphocytes from intermittent hypoxia-exposed rats on the apoptotic signals in endothelial cells and the interventional role of tempol. METHOD: Male Wistar rats were randomly distributed into three groups (n = 8 each): control group, IH group, and tempol group (exposed to IH and treated with tempol). Lymphocytes isolated from the rats were coincubated subsequently with endothelial cells under normoxia or IH condition. We analyzed endothelial apoptosis-related proteins (Bcl-2, Bax, and caspase-3) by Western blotting and measured the marks of oxidative stress (MDA, SOD, and CAT) and inflammation (TNF-α, IL-8, CRP, and ICAM-1) in cocultural supernatants by ELISA. We also determined endothelial p22(phox), c-fos, and HIF-1α messenger RNA (mRNA) expressions using real time PCR. RESULTS: A significant decrease in the Bcl-2 level and the Bcl-2/Bax ratio and a significant increase in Bax and caspase-3 levels in endothelial cells were observed when coincubated normoxically with lymphocytes from IH-exposed rats compared to control (P < 0.01). Moreover, the oxidative stress, inflammation, and mRNA expressions of endothelial p22(phox), c-fos, and HIF-1α were elevated significantly (P < 0.01). The alterations induced by lymphocytes were partially restored by tempol pretreatment while exacerbated by intermittent hypoxic coincubation. CONCLUSIONS: Lymphocytes from intermittent hypoxia-exposed rats increased the apoptotic signals in endothelial cells via oxidative and inflammatory injury in vitro, which could be attenuated by tempol.

Permanent interstitial 125I seed implantation as a salvage therapy for pediatric recurrent or metastatic soft tissue sarcoma after multidisciplinary treatment.

BACKGROUND: The management of pediatric recurrent or metastatic soft tissue sarcoma after multimodal treatment remains challenging. We investigated the feasibility, efficacy, and morbidity of permanent interstitial (125)I seed implantation under image guidance as a salvage treatment for pediatric patients with recurrent or metastatic soft tissue sarcoma. METHODS: This was a retrospective study of 10 patients who underwent percutaneous ultrasound or computed tomography (CT) guided permanent (125)I seed implantation. Postoperative dosimetry was performed for all patients. Actuarial D90 was 121-187.1 Gy (median, 170.3 Gy). The number of (125)I seeds implanted was 6-158 (median, 34.5), with a median specific activity of 0.7 mCi per seed (range, 0.62-0.8 mCi); total activity was 4.2-113.76 mCi. Follow-up time was 6-107 months (median, 27.5 months); no patients were lost to follow-up. RESULTS: The overall response rate (complete response + partial response) was 8/10 (80 %), including two patients with complete response (CR) (20 %) and five patients with partial response (PR) (60 %). Local control rates after 1 and 2 years were 70.1 and 62.3 %, respectively, with a mean local control time of 70.6 months (95 % confidence interval (CI) 45.1-96.0). Survival rates after 1 and 2 years were 68.6 and 57.1 %, respectively, with a mean survival time of 65.3 months (95 % CI 34.1-96.5). Three patients died from distant metastasis; one died from local recurrence 12 months after seed implantation. Three patients suffered a grade I skin reaction and one developed ulceration. No severe adverse neurologic sequelae or blood vessel damage occurred. CONCLUSIONS: Image guided permanent interstitial (125)I seed implantation as a salvage treatment appears to have a satisfactory outcome in children with recurrent or metastatic soft tissue sarcoma.

Biological effects of (125)i seeds radiation on A549 lung cancer cells: G2/M arrest and enhanced cell death.

External beam radiation (EBRT) and (125)I seeds continuous low dose rate radiation (CLDR) were used to treat patients with lung cancer. We herein investigated the biological effects of EBRT and CLDR on lung cancer cells. A549 human lung cancer cell line was thus exposed to different doses of EBRT and CLDR. CLDR was more efficient to inhibit cell growth than EBRT. CLDR induced increased DNA damage as evidenced by long-lasting p-H2AX activity. The enhanced inhibitory effects of CLDR on lung cancer cell growth may be, at least in part, due to the increased Bax/Bcl2 ratio and cyclin B1-mediated G2/M arrest.

Prediction of early neurologic deterioration in patients with perforating artery territory infarction using machine learning: a retrospective study.

Background: Early neurological deterioration (END) is a frequent complication in patients with perforating artery territory infarction (PAI), leading to poorer outcomes. Therefore, we aimed to apply machine learning (ML) algorithms to predict the occurrence of END in PAI and investigate related risk factors. Methods: This retrospective study analyzed a cohort of PAI patients, excluding those with severe stenosis of the parent artery. We included demographic characteristics, clinical features, laboratory data, and imaging variables. Recursive feature elimination with cross-validation (RFECV) was performed to identify critical features. Seven ML algorithms, namely logistic regression, random forest, adaptive boosting, gradient boosting decision tree, histogram-based gradient boosting, extreme gradient boosting, and category boosting, were developed to predict END in PAI patients using these critical features. We compared the accuracy of these models in predicting outcomes. Additionally, SHapley Additive exPlanations (SHAP) values were introduced to interpret the optimal model and assess the significance of input features. Results: The study enrolled 1,020 PAI patients with a mean age of 60.46 (range 49.11-71.81) years. Of these, 30.39% were women, and 129 (12.65%) experienced END. RFECV selected 13 critical features, including blood urea nitrogen (BUN), total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), atrial fibrillation, loading dual antiplatelet therapy (DAPT), single antiplatelet therapy (SAPT), argatroban, the basal ganglia, the thalamus, the posterior choroidal arteries, maximal axial infarct diameter (measured at < 15 mm), and stroke subtype. The gradient-boosting decision tree had the highest area under the curve (0.914) among the seven ML algorithms. The SHAP analysis identified apoB as the most significant variable for END. Conclusion: Our results suggest that ML algorithms, especially the gradient-boosting decision tree, are effective in predicting the occurrence of END in PAI patients.

Reinforcement learning based proportional-integral-derivative controllers design for consensus of multi-agent systems.

This paper develops a novel Proportional-Integral-Derivative (PID) tuning method for multi-agent systems with a reinforced self-learning capability for achieving the optimal consensus of all agents. Unlike the traditional model-based and data-driven PID tuning methods, the developed PID self-learning method updates the controller parameters by actively interacting with unknown environment, with the outcomes of guaranteed consensus and performance optimization of agents. Firstly, the PID control-based consensus problem of multi-agent systems is formulated. Then, finding the PID gains is converted into solving a nonzero-sum game problem, thus an off-policy Q-learning algorithm with the critic-only structure is proposed to update the PID gains using only data, without the knowledge of dynamics of agents. Finally, simulations are given to verify the effectiveness of the proposed method.

Learning-based near-optimal tracking control for industrial processes with slow and fast modes.

This paper devotes to solving the optimal tracking control (OTC) problem of singular perturbation systems in industrial processes under the framework of reinforcement learning (RL) technology. The encountered challenges include the different time scales in system operations and an unknown slow process. The immeasurability of slow process states especially increases the difficulty of finding the optimal tracking controller. To overcome these challenges, a novel off-policy ridge RL method is developed after decomposing the singular perturbed systems using the singular perturbation (SP) theory and replacing unmeasured states using important mathematical manipulations. Theoretical analysis of approximate equivalence of the sum of solutions of subproblems to the solution of the OTC problem is presented. Finally, a mixed separation thickening process (MSTP) and a numerical example are used to verify the effectiveness.

A novel inflammation-related signature for predicting prognosis and characterizing the tumor microenvironment in colorectal cancer.

Inflammation is a critical component of tumor progression, and it modifies the tumor microenvironment by various mechanisms. Here, we explore the effect of the inflammatory response on the tumor microenvironment in colorectal cancer (CRC). A prognostic signature consisting of inflammation-related genes (IRGs) was constructed and verified based on the inflammatory response by bioinformatics analysis. IRG risk model was identified as an independent prognostic factor in CRC, and was related to biological processes of extracellular matrix, cell adhesion and angiogenesis. The IRG risk score predicted the clinical benefit of ipilimumab. Weighted correlation network analysis identified TIMP1 as the hub gene of the inflammatory response in the IRG risk model. Coculture experiments with macrophages and CRC cells revealed that TIMP1 promoted macrophage migration, inhibited the expression of M1 markers (CD11C and CD80), and promoted the expression of M2 markers (ARG1 and CD163). TIMP1 promoted the expression of ICAM1 and CCL2 by activating the ERK1/2 signaling pathway to promote macrophage migration and M2-like polarization. These IRGs in the risk model regulated stromal and immune components in the tumor microenvironment and could serve as potential therapeutic targets in CRC. TIMP1 promoted macrophage migration and meditated macrophage M2 polarization by activating ERK1/2/CLAM1 and CCL2.

Data-Driven H∞ Optimal Output Feedback Control for Linear Discrete-Time Systems Based on Off-Policy Q-Learning.

This article develops two novel output feedback (OPFB) Q -learning algorithms, on-policy Q -learning and off-policy Q -learning, to solve H∞ static OPFB control problem of linear discrete-time (DT) systems. The primary contribution of the proposed algorithms lies in a newly developed OPFB control algorithm form for completely unknown systems. Under the premise of satisfying disturbance attenuation conditions, the conditions for the existence of the optimal OPFB solution are given. The convergence of the proposed Q -learning methods, and the difference and equivalence of two algorithms are rigorously proven. Moreover, considering the effects brought by probing noise for the persistence of excitation (PE), the proposed off-policy Q -learning method has the advantage of being immune to probing noise and avoiding biasedness of solution. Simulation results are presented to verify the effectiveness of the proposed approaches.

A Retrospective Study of Trifluridine/Tipiracil with Fruquintinib in Patients with Chemorefractory Metastatic Colorectal Cancer.

INTRODUCTION: Trifluridine/tipiracil (TAS-102) and fruquintinib are novel antitumor agents for patients with refractory metastatic colorectal cancer (mCRC). We conducted a retrospective study to explore the clinical efficacy and drug toxicities of combination therapy with TAS-102 and fruquintinib in real-life clinical practice. METHODS: Between March 2021 and February 2023, patients at two different centers with mCRC who failed two or more lines of prior therapy and received TAS-102 in combination with fruquintinib were recruited. RESULTS: In total, 32 mCRC patients were included in the analysis. The objective response rate (ORR) and the disease control rate (DCR) were 9.4% and 75%. The median progression-free survival (PFS) and overall survival (OS) were 6.3 (95% CI: 5.3-7.3) and 13.5 (95% CI: 9.5-17.5) months, respectively. Patients without liver metastasis or peritoneal metastasis obtained better median PFS (7.1 m vs. 5.6 m, p = 0.03 and 6.3 m vs. 3.4 m, p = 0.04), and OS (15.2 m vs. 10.4 m, p = 0.01 and 13.6 m vs. 7.1 m, p = 0.03), respectively. Other clinicopathological features, including age, tumor site, KRAS status, dosage of fruquintinib, and treatment line, did not affect the clinical efficacy of TAS-102 combined with fruquintinib. The most common grade three-four toxicities were neutropenia (46.9%), anemia (21.9%), diarrhea (15.6%), nausea (12.5%), and hand-foot syndrome rash (12.5%). CONCLUSIONS: Our results suggest that TAS-102 combined with fruquintinib has promising clinical efficacy and manageable safety for refractory mCRC patients in a real-world clinical setting. Further prospective trials are warranted to confirm our results.

Genome-wide analysis of WD40 protein family and functional characterization of BvWD40-82 in sugar beet.

Sugar beet is one of the most important sugar crops in the world. It contributes greatly to the global sugar production, but salt stress negatively affects the crop yield. WD40 proteins play important roles in plant growth and response to abiotic stresses through their involvement in a variety of biological processes, such as signal transduction, histone modification, ubiquitination, and RNA processing. The WD40 protein family has been well-studied in Arabidopsis thaliana, rice and other plants, but the systematic analysis of the sugar beet WD40 proteins has not been reported. In this study, a total of 177 BvWD40 proteins were identified from the sugar beet genome, and their evolutionary characteristics, protein structure, gene structure, protein interaction network and gene ontology were systematically analyzed to understand their evolution and function. Meanwhile, the expression patterns of BvWD40s under salt stress were characterized, and a BvWD40-82 gene was hypothesized as a salt-tolerant candidate gene. Its function was further characterized using molecular and genetic methods. The result showed that BvWD40-82 enhanced salt stress tolerance in transgenic Arabidopsis seedlings by increasing the contents of osmolytes and antioxidant enzyme activities, maintaining intracellular ion homeostasis and increasing the expression of genes related to SOS and ABA pathways. The result has laid a foundation for further mechanistic study of the BvWD40 genes in sugar beet tolerance to salt stress, and it may inform biotechnological applications in improving crop stress resilience.

Association between morphologic features of intracranial distal arteries and brain atrophy indexes in cerebral small vessel disease: a voxel-based morphometry study.

Background: Brain atrophy represents a final common pathway for pathological processes in patients with cerebral small vessel disease (CSVD) and is now recognized as a strong independent predictor of clinical status and progression. The mechanism underlying brain atrophy in patients with CSVD is not yet fully comprehended. This study aims to investigate the association of morphologic features of intracranial distal arteries (A2, M2, P2 and more distal) with different brain structures [gray matter volume (GMV), white matter volume (WMV), and cerebrospinal fluid volume (CSFV)]. Furthermore, we also examined whether a correlation existed between these cerebrovascular characteristics and GMV in different brain regions. Method: A total of 39 participants were eventually enrolled. The morphologic features of intracranial distal arteries based on TOF-MRA were extracted and quantified using the intracranial artery feature extraction technique (iCafe). The brain 3D-T1 images were segmented into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) using the "Segment" tool in CAT12 for the voxel-based morphometry (VBM) analysis. Univariable and multivariable linear regression models were used to investigate the relationship between these cerebrovascular features and different brain structures. Partial correlation analysis with a one-tailed method was used to evaluate the relationship between these cerebrovascular features and GMV in different brain regions. Results: Our findings indicate that both distal artery length and density were positively correlated with GM fraction in CSVD patients, regardless of whether univariable or multivariable linear regression analyses were performed. In addition, distal artery length (ß = -0.428, p = 0.007) and density (ß = -0.337, p = 0.036) were also found to be negative associated with CSF fraction, although this relationship disappeared after adjusting for potential confounders. Additional adjustment for the effect of WMHs volume did not change these results. In subgroup anasysis, we found that participants in the highest distal artery length tertile had significantly higher GM fraction and lower CSF fraction level than participants in the lowest distal artery length tertile. In partial correlation analysis, we also found that these cerebrovascular characteristics associated with regional GMV, especially subcortical nuclear. Conclusion: The morphologic features of intracranial distal arteries, including artery length, density and average tortuosity, measured from 3D-TOF MRA, are associated with generalized or focal atrophy indexes of CSVD.