The neurotransmitter calcitonin gene-related peptide shapes an immunosuppressive microenvironment in medullary thyroid cancer.

Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP's function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.

Early Use of PCSK9 Inhibitors in the Prognosis of Patients with Acute Coronary Syndrome by Protecting Vascular Endothelial Function.

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has a protective effect on acute coronary syndrome (ACS). However, most studies have shown that this protective effect is based on a decrease in low-density lipoprotein cholesterol, while other mechanisms remain limited. This study aimed to determine whether PCSK9i can improve the prognosis of ACS patients by protecting endothelial function. METHODS: A total of 113 ACS patients were enrolled and randomly assigned to PCSK9i group (PCSK9i combined with statins) and control group (statins only). Blood lipids and endothelial function indicators were measured and analyzed 6 weeks before and after treatment. The effect of PCSK9i on the expression and secretion of endothelial function indicators in vascular endothelial cells were studied by cell experiments. RESULTS: After 6 weeks of treatment, endothelial function indicators such as nitric oxide (NO), thrombomodulin, intercellular cell adhesion molecule-1, endothelin-1, and flow-mediated vasodilation were significantly improved in PCSK9i group compared with control group. Only the changes of NO and von Willebrand factor were associated with blood lipid levels, whereas the changes of other endothelial function indicators were not significantly associated with blood lipid levels. PCSK9i reduced the incidence of major adverse cardiovascular events in patients with ACS compared to those in the control group. In cell experiments, PCSK9i treatment significantly ameliorated LPS induced endothelial injury in HUVECs. CONCLUSION: PCSK9i can protect vascular endothelial function partly independently of its lipid-lowering effect and ameliorate the prognosis of patients with ACS within 6 weeks. This mechanism may involve heat shock transcription factor 1/heat shock proteins -related signaling pathways. Early use of PCSK9i in patients with ACS should be strongly considered in clinical practice.

Performance of various pneumonia severity models for predicting adverse outcomes in elderly inpatients with community-acquired pneumonia.

OBJECTIVE: We aimed to assess the performance of common pneumonia severity scores, such as pneumonia severity index (PSI), CURB-65, CRB-65, A-DROP, and SMART-COP, in predicting adverse outcomes in elderly community-acquired pneumonia cohort and to determine the optimal scoring system for specific outcomes of interest. METHODS: A total of 822 elderly inpatients were included in the retrospective cohort study. Clinical and laboratory results on admission were used to calculate the above scores. The primary outcome was 30-day mortality. Secondary outcomes were in-hospital mortality, need for mechanical ventilation (MV) and ICU admission. Model discrimination was evaluated by the area under receiver operating characteristic curves (AUCs). RESULTS: The 30-day and in-hospital mortality rates were 6.8% (56/822) and 8.6% (71/822), respectively. One hundred and ninety-eight (24.0%) received MV and 111 (13.5%) were admitted to the ICU. All five scoring systems showed the same trend of increasing rates of each adverse outcome with increasing risk groups (all p < 0.001). PSI had the highest AUC, sensitivity, and negative predictive value (NPV) in predicting 30-day mortality and in-hospital mortality. SMART-COP had the highest AUC for predicting the need for MV and ICU admission, but PSI had the highest sensitivity and NPV for these two outcomes. DISCUSSION: PSI performed well in identifying elderly patients at risk for 30-day mortality and its high NPV is helpful in excluding patients who are not at risk. Considering their effectiveness and simplicity, SMART-COP and CURB-65 are easier to perform in clinical practice than PSI.

Selenium enhancement strategy under precise fertilization in foxtail millet rhizosphere.

Enhancing selenium content in millet is a crucial strategy to address malnutrition due to selenium deficiency. Jingu 21 was used as the experimental material in this study. The effects of selenium fertilizer application amount, vertical position of fertilization, and horizontal position of fertilization on the selenium content in various millet organs were assessed using a three-factor, five-level quadratic rotation combination design. The results indicate that selenium fertilizer application amount, vertical fertilization position, and horizontal fertilization position significantly affected the selenium content in various millet organs. Analysis of the selenium accumulation for different millet organs show that the recommended optimal agronomic strategy for producing selenium-enriched millet comprises a selenium fertilizer application amount ranging from 100.65 to 120.15 kg/hm2, a vertical fertilization position of 10.28-11.76 cm, and a horizontal fertilization position of 6.74-7.29 cm. This study elucidates the patterns of selenium content accumulation under precise fertilization measures of millet and provides valuable insights for implementing selenium enhancement techniques in the production of selenium-enriched millet.

PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from Mendelian randomization, a retrospective study and basic experiments.

Background: Current evidences suggest that Proprotein Convertase Subtilisin/kexin Type 9 inhibitors (PCSK9i) exhibit a protective influence on acute coronary syndrome (ACS). Nevertheless, further investigation is required to comprehend the impact and mechanisms of these pharmaceutical agents on inflammatory factors and arterial stiffness (AS) in patients with ACS. Consequently, the objective of this study is to ascertain the influence of PCSK9i on arterial stiffness in ACS patients and elucidate the underlying mechanisms behind their actions. Methods: This study employed Mendelian randomization (MR) analysis to examine the association between genetic prediction of PCSK9 inhibition and arterial stiffness. Data of 71 patients with ACS were retrospectively collected, including PCSK9i group (n = 36, PCSK9 inhibitors combined with statins) and control group (n = 35, statins only). Blood lipid levels, inflammatory markers and pulse wave velocity (PWV) data were collected before treatment and at 1 and 6 months after treatment for analysis. Additionally, cell experiments were conducted to investigate the impact of PCSK9i on osteogenesis of vascular smooth muscle cells (VSMCs), utilizing western blot (WB), enzyme-linked immunosorbent assay (ELISA), and calcification index measurements. Results: The results of the MR analysis suggest that genetic prediction of PCSK9 inhibition has potential to reduce the PWV. Following treatment of statins combined with PCSK9 inhibitors for 1 and 6 months, the PCSK9i group exhibited significantly lower levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen (FIB) and procalcitonin (PCT) compared to the control group (p < 0.05). Additionally, PWV in the PCSK9i group demonstrated significant reduction after 6 months of treatment and was found to be associated with the circulating CRP level. In cell experiments, PCSK9i pretreatment ameliorated osteogenesis of VSMCs through reducing the deposition of calcium ions, alkaline phosphatase (ALP) activity, and expression of runt-related transcription factor 2 (RUNX2). Conclusion: PCSK9i have potential to enhance arterial stiffness in ACS patients. Specifically, at the clinical level, this impact may be attributed to alterations in circulating CRP levels. At the cellular level, it is associated with the signaling pathway linked to RUNX2.

Tongqiao Huoxue Decoction inhibits ferroptosis by facilitating ACSL4 ubiquitination degradation for neuroprotection against cerebral ischemia-reperfusion injury.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) refers to brain tissue injury caused by the temporary interruption of cerebral blood flow ischemia followed by the restoration of reperfusion, which is the main cause of post-stroke brain injury. A traditional Chinese herbal preparation called Tongqiao Huoxue Decoction (TQHX) has shown promise in reducing CIRI in rats. However, the mechanism of this herbal preparation for CIRI remains unclear. PURPOSE: This study aimed to evaluate the therapeutic effect of TQHX extract on rats with CIRI and to further explore the underlying mechanisms. METHODS: The active ingredients of TQHX extract were quantified by the high-performance liquid chromatography (HPLC) condition. We conducted thorough investigations to assess the effects of TQHX on CIRI and ferroptosis using oxygen-glucose deprivation/reperfusion (OGD/R)-treated PC12 cells as an in vitro model and transient middle cerebral artery occlusion (tMCAO) animals as an in vivo model. The neurological score assessment was performed to evaluate the neuroprotective effects of TQHX extract on tMCAO rats. Using histologic methods to study the extent of cerebral infarction, blood-brain barrier, and rat brain tissue. We examined the impact of TQHX on ferroptosis-related markers of Fe2+, superoxide dismutase (SOD), reactive oxygen species (ROS), and malondialdehyde (MDA) in the brain tissue. In addition, the expression of key proteins and markers of ferroptosis, as well as key factors associated with Acyl-CoA synthetase long-chain family member 4 (ACSL4) were detected by Western blot and quantitative real-time PCR (RT-qPCR). RESULTS: TQHX extract could decrease the Longa score and extent of cerebral infarction of tMCAO rats, which exerted the function of neuroprotection. Additionally, TQHX treatment efficiently decreased levels of MDA and ROS while increasing the expression of SOD and ferroptosis-related proteins including ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) at the transcription and translation level. Meanwhile, TQHX provided strong protection against oxidative stress and ferritin accumulation by increasing the ubiquitination and degradation of ACSL4. The injection of OE-ACSL4 reversed the effects of TQHX on neuroprotection and ferroptosis inhibition in PC12 cells. The injection of shACSL4 reversely validate the crucial role of ACSL4 in CIRI rat treatment. CONCLUSION: This work shows that TQHX promotes the ubiquitination-mediated degradation of ACSL4, which improves oxidative stress and inhibits the beginning of ferroptosis in cells. TQHX provides a possible path for additional research in CIRI therapies, advancing translational investigations.

miRNAs Influence m6A RNA Methylation through FTO and IGF2BP2 in Pressure Overload-Induced Heart Failure.

BACKGROUND: N6-adenosine methylation (m6A) is a prevalent RNA modification associated with heart failure, alongside aberrant miRNA expression. Despite indications of miRNAs regulating m6A modification, their specific influence on m6A in heart failure remains unclear. METHODS: The initial analysis utilized transcriptome and methylation sequencing data from GSE131296 in mice to identify key m6A methylation enzymes in heart failure and construct an associated network. Integration of miRNA sequencing data from GSE231700 revealed miRNAs influencing m6A methylation enzymes, contributing to the formation of a comprehensive network. Furthermore, differential miRNA levels in human serum were assessed via qPCR, and the expression of m6A methyltransferases in the heart was confirmed using proteomic databases. RESULTS: In pressure overload-induced heart failure mice, 217 mRNAs showed differential expression, with FTO and IGF2BP2 identified as m6A methylation enzymes. Subsequent methylation sequencing revealed 884 highly-methylated and 178 lowly-methylated peaks, establishing a network linking Fto and Igf2bp2 with these peaks. Additionally, miRNA sequencing identified 156 differentially expressed miRNAs, including let-7b-5p and miR-23b-3p, predicted as m6Aregulating miRNAs, both elevated in heart failure patients. CONCLUSION: miR-23b-3p and let-7b-5p are identified as potential regulators of RNA methylation in heart failure, acting via FTO and IGF2BP2, offering new insights into the role of miRNA-mediated RNA methylation and its potential therapeutic avenues for heart failure.

Effects of foliar selenium, biochar, and pig manure on cadmium accumulation in rice grains and assessment of health risk.

Addressing cadmium (Cd) contamination in agricultural lands is crucial, given its health implications and accumulation in crops. This study used pot experiments to evaluate the impact of foliar selenium spray (Se) (0.40 mM), corn straw biochar (1%), and pig manure (1%) on the growth of rice plants, the accumulation of Cd in rice grain, and to examine their influence on health risk indices associated with Cd exposure. The treatments were designated as follows: a control group without any amendment (CK), biochar (T1), pig manure (T2), Se (T3), Se and biochar (T4), Se and pig manure (T5), and Se along with biochar and pig manure (T6). Our results indicated that the treatments affected soil pH and redox potential and improved growth and the nitrogen and phosphorus content in rice plants. The soil-plant analysis development (SPAD) meter readings of leaves during the tillering stage indicated a 5.27%-15.86% increase in treatments T2 to T6 compared to CK. The flag leaves of T2 exhibited increases of 12.06%-38.94% for electrolyte leakage and an 82.61%-91.60% decline in SOD compared to treatments T3 to T6. Treatments T1 to T6 increased protein content; however, amylose content was significantly reduced in T6. Treatment T6 recorded the lowest Cd concentration in rice grains (0.018 mg/kg), while T2 recorded the highest (0.051 mg/kg). The CK treatment group showed a grain Cd content reduction of 29.30% compared to T2. The assessment of acceptable daily intake, hazard quotient, and carcinogenic risk revealed an ascending order as follows: T6 < T3 < T5 < T4 < T1 < CK < T2. In conclusion, the application of treatment T6 demonstrates the potential to lower oxidative stress, enhance production, reduce cancer risk, and ensure the safe cultivation of rice in environments affected by Cd contamination.

Risk factors associated with functional decline in older hospital survivors with acute lower respiratory tract infections: a prospective cohort study.

OBJECTIVE: To evaluate the dynamics of basic activity of daily living (BADL) in older patients with acute lower respiratory tract infections (LRTIs) during acute phase and to investigate risk factors associated with decreased physical function at discharge. METHODS: We conducted a prospective cohort study of patients aged 65 years and older who were hospitalized for acute LRTIs between April 15, 2020 and January 15, 2023. All patients received geriatric assessment at admission, including emotion, cognition, frailty, physical function status and so on. The BADL was also evaluated by the Barthel Index (BI) at two weeks before admission by recall (baseline status), at admission and at discharge. Based on the BI grades at baseline and at discharge, patients were classified into two groups: ADL decline and no ADL decline. Multivariable adjusted logistic regression models were used to evaluate the risk factors of decreased physical function. RESULTS: A total of 364 older survivors with LRTIs were included in the analysis. The median age was 74 years (IQR 61.0-82.0), 231 (62.6%) were male, the median length of stay was 10 days. In the geriatric assessment, 139 patients (38.2%) were classified as frailty, 137 patients (37.6%) experienced insomnia, 60 patients (16.5%) exhibited cognitive impairments, and 37 patients (10.2%) were defined as malnutrition. Additionally, 30 patients (8.2%) dealt with emotional disorders. On average, patients were taking 3 medications, and Charlson Comorbidity Index score was 4. 72 patients (19.8%) had function decline at discharge. In the multivariable analysis, frailty status had an odds ratio of 4.25 (95% CI 1.31-19.26) for decreased physical function and cognitive impairment had an odds ratio of 2.58 (95% CI 1.27-5.19). CONCLUSIONS: About 20% older patients with LRTIs experienced functional decline at discharge. Compared to age, severity of diseases and length of stay, frailty and cognitive impairment performed better at predicting the function decline. The apply of geriatric assessment may contribute to enhance the quality of management and treatment for patients with the older with LRTIs.

Gyroid Liquid Crystals as Quasi-Solid-State Electrolytes Toward Ultrastable Zinc Batteries.

The potential for optimizing ion transport through triply periodic minimal surface (TPMS) structures renders promising electrochemical applications. In this study, as a proof-of-concept, we extend the inherent efficiency and mathematical beauty of TPMS structures to fabricate liquid-crystalline electrolytes with high ionic conductivity and superior structural stability for aqueous rechargeable zinc-ion batteries. The specific topological configuration of the liquid-crystalline electrolytes, featuring a Gyroid geometry, enables the formation of a continuous ion conduction pathway enriched with confined water. This, in turn, promotes the smooth transport of charge carriers and contributes to high ionic conductivity. Meanwhile, the quasi-solid hydrophobic phase assembled by hydrophobic alkyl chains exhibits notable rigidity and toughness, enabling uniform and compact dendrite-free Zn deposition. These merits synergistically enhance the overall performance of the corresponding full batteries. This work highlights the distinctive role of TPMS structures in developing high-performance, liquid-crystalline electrolytes, which can provide a viable route for the rational design of next-generation quasi-solid-state electrolytes.

A TGF-ß-dominant chemoresistant phenotype of hepatoblastoma associated with aflatoxin exposure in children.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in patients with HB. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need. APPROACH AND RESULTS: We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multicolor immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors. Among them, the S2A subtype, characterized by strong expression of progenitor ( MYCN , MIXL1 ) and mesenchymal transcription factors ( TWIST1 , TBX5 ), was defined as a new chemoresistant subtype. The S2A subtype showed increased TGF-ß cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-ß of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes HB to upregulate TGF-ß. Furthermore, clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis. CONCLUSIONS: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.

Computed tomography imaging phenotypes of hepatoblastoma identified from radiomics signatures are associated with the efficacy of neoadjuvant chemotherapy.

BACKGROUND: Though neoadjuvant chemotherapy has been widely used in the treatment of hepatoblastoma, there still lacks an effective way to predict its effect. OBJECTIVE: To characterize hepatoblastoma based on radiomics image features and identify radiomics-based lesion phenotypes by unsupervised machine learning, intended to build a classifier to predict the response to neoadjuvant chemotherapy. MATERIALS AND METHODS: In this retrospective study, we segmented the arterial phase images of 137 cases of pediatric hepatoblastoma and extracted the radiomics features using PyRadiomics. Then unsupervised k-means clustering was applied to cluster the tumors, whose result was verified by t-distributed stochastic neighbor embedding (t-SNE). The least absolute shrinkage and selection operator (LASSO) regression was used for feature selection, and the clusters were visually analyzed by radiologists. The correlations between the clusters, clinical and pathological parameters, and qualitative radiological features were analyzed. RESULTS: Hepatoblastoma was clustered into three phenotypes (homogenous type, heterogenous type, and nodulated type) based on radiomics features. The clustering results had a high correlation with response to neoadjuvant chemotherapy (P=0.02). The epithelial ratio and cystic components in radiological features were also associated with the clusters (P=0.029 and 0.008, respectively). CONCLUSIONS: This radiomics-based cluster system may have the potential to facilitate the precise treatment of hepatoblastoma. In addition, this study further demonstrated the feasibility of using unsupervised machine learning in a disease without a proper imaging classification system.

Axitinib targets cardiac fibrosis in pressure overload-induced heart failure through VEGFA-KDR pathway.

Background: There are no specific clinical medications that target cardiac fibrosis in heart failure (HF). Recent studies have shown that tyrosine kinase inhibitors (TKIs) may benefit fibrosis in various organs. However, there is limited research on their application in cardiac fibrosis. Axitinib, an FDA-approved tyrosine kinase inhibitor, was used to evaluate its effects on cardiac fibrosis and function in pressure overload-induced heart failure. Methods: To build a pharmacological network, the pharmacological targets of axitinib were first retrieved from databases and coupled with key heart failure gene molecules for analysis and prediction. To validate the results outlined above, 8-week-old male C57BL/6 J mice were orally administrated of axitinib (30 mg/kg) daily for 8 weeks after Transverse Aortic Constriction (TAC) surgery. Mouse cardiomyocytes and cardiac fibroblasts were used as cell lines to test the function and mechanism of axitinib. Results: We found that the pharmacological targets of axitinib could form a pharmacological network with key genes involved in heart failure. The VEGFA-KDR pathway was found to be closely related to the differential gene expression of human heart-derived primary cardiomyocyte cell lines treated with axitinib, based on analysis of the publicly available dataset. The outcomes of animal experiments demonstrated that axitinib therapy greatly reduced cardiac fibrosis and improved TAC-induced cardiac dysfunction. Further research has shown that the expression of transforming growth factor-ß(TGF-ß) and other fibrosis genes was significantly reduced in vivo and in vitro. Conclusion: Our study provides evidence for the repurposing of axitinib to combat cardiac fibrosis, and offers new insights into the treatment of patients with HF.

Hypersensitive C-reactive protein as a potential indicator for predicting left ventricular hypertrophy in elderly community-dwelling patients with hypertension.

BACKGROUND: The aim of this study was to investigate the relationship between Hypersensitive C-reactive protein (hs-CRP) and left ventricular hypertrophy (LVH) in elderly community-dwelling patients with hypertension. METHODS: A cross-sectional study was conducted, involving the recruitment of 365 elderly hypertensive residents ≥ 65 years of age from five communities. The participants were divided into two groups: an LVH group (n = 134) and a non-LVH group (n = 231), based on the left ventricular mass index (LVMI) determined by echocardiography. Spearman correlation analysis was used to assess the relationship between hs-CRP and LVH. Univariate and Multivariate analysis was performed to detect variables associated with LVH. The diagnostic value of hs-CRP for LVH was expressed as the area under the receiver operating characteristic (ROC) curve. RESULTS: The incidence of LVH in elderly hypertension patients in the community was 36.7%. The hs-CRP levels were significantly higher in subjects with LVH compared to those without LVH (1.9 [0.8, 2.9] vs. 0.7 [0.4, 1.4], P = 0.002). Spearman correlation analysis demonstrated a positive correlation between hs-CRP and LVMI (r = 0.246, P < 0.001), as well as with IVST (r = 0.225, P < 0.001) and LVPWT (r = 0.172, P = 0.001). Among elderly hypertensive residents in the community, the cut-off value of hs-CRP for diagnosing LVH was 1.25 mg/L (sensitivity: 57.5%; specificity: 78.4%), and the area under the ROC curve for hs-CRP to predict LVH was 0.710 (95%CI: 0.654-0.766; P < 0.001). In the final model, hs-CRP ≥ 1.25 mg/L (OR = 3.569; 95%CI, 2.153-5.916; P<0.001) emerged as an independent risk factor for LVH. This association remained significant even after adjusting for various confounding factors (adjusted OR = 3.964; 95%CI, 2.323-6.765; P < 0.001). CONCLUSIONS: This community-based cohort of elderly hypertensive individuals demonstrates a strong association between hs-CRP levels and the presence of LVH. The hs-CRP ≥ 1.25 mg/L may serve as an independent predictor for LVH in hypertensive subjects and exhibit good diagnostic efficacy for LVH.

Intratumoral erythroblastic islands restrain anti-tumor immunity in hepatoblastoma.

Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1+ macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB.

Investigation of the Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule-1 in Diabetic Retinopathy.

PURPOSE: Diabetic retinopathy (DR) has become a major cause of blindness with increased prevalence of diabetic mellitus. Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) plays a part in pathological neovascularization. This study aimed to investigate the role of CEACAM1 in the progression of DR. METHODS: Aqueous and vitreous samples were collected from proliferative or non-proliferative DR and the control group. Multiplex fluorescent bead-based immunoassays were used to detect the levels of Cytokines. Expression of CEACAM1, VEGF, VEGF receptor 2 (VEGFR2) and hypoxia-induced factor-1α (HIF-1α) were detected in human retinal microvascular endothelial cells (HRECs). RESULTS: CEACAM1 and VEGF levels were significantly upregulated in PDR group and positively correlated with PDR progression. Expression CEACAM1 and VEGFR2 were increased in HRECs under hypoxic conditions. The HIF-1α/VEGFA/VEGFR2 pathway was blocked by CEACAM1 siRNA in vitro. CONCLUSIONS: CEACAM1 might play a role in the pathology of PDR. CEACAM1 might be a therapeutic target for retinal neovasculariztion.

Spatial Decoupling of Redox Chemistry for Efficient and Highly Selective Amine Photoconversion to Imines.

Light-driven primary amine oxidation to imines integrated with H2 production presents a promising means to simultaneous production of high-value-added fine chemicals and clean fuels. Yet, the effectiveness of this strategy is generally limited by the poor charge separation of photocatalysts and uncontrolled hydrogenation of imines to secondary amines. Herein, a spatial decoupling strategy is proposed to isolate redox chemistry at distinct sites of photocatalysts, and CoP core-ZnIn2S4 shell (CoP@ZnIn2S4) coaxial nanorods are assembled as the proof-of-concept photocatalyst. Directional and ultrafast carrier separation occurs between the CoP core and the ZnIn2S4 shell, as confirmed by in situ X-ray photoelectron spectroscopy, surface photovoltage spectroscopy, and transient absorption spectroscopy analyses. Toward the photoconversion of model substrate benzylamine to N-benzylbenzaldimine, CoP@ZnIn2S4 exhibits a 48-time higher production rate and >99% selectivity when compared to ZnIn2S4 (ca. 20% selectivity), and the detailed reaction mechanism has been verified by in situ diffuse reflectance infrared Fourier transform spectroscopy.

Ex vivo tumor dissection followed by kidney autotransplantation in bilateral wilms tumor.

Introduction: Successful management of bilateral Wilm's tumor (BWT) involves a radical resection while preserving enough normal kidney tissue. Nephron-sparing surgery often results in an R1/R2 resection with a high recurrence rate in children with huge or multiple tumors, or tumors proximity to the renal hilum. In contrast, kidney autotransplantation can completely resect the tumor while maintaining homeostasis and preserving the patient's healthy kidney tissues. Methods: We summarized the clinical data of 8 synchronous BWT patients who underwent kidney autotransplantation at the First Affiliated Hospital of Sun Yat-sen University from 2018 to 2020. Ex vivo tumor resection and kidney autotransplantions were performed on 11 kidneys. The baseline characteristics, perioperative management, and survival status were reported. Results: Nephron-sparing surgeries were performed on 5 kidneys in vivo. Among all the 8 patients, six of them (75%) received staged operation and the other 2 patients (25%) received single-stage operation. No residual tumors were found on the postoperative imaging in all the 8 patients. In total, 6 (75%) patients occurred complications after the autotransplantation, among which, 2 (33.3%) patients had complication of Clavien-Dindo grade IIIa, and 4 (66.7%) patients had complication of grade < 3. During the 38 months of follow-up, 87.5% (7/8) of patients were tumor-free survival with normal renal function. One patient died from renal failure without tumor recurrence. Discussion: Therefore, our study indicated that autologous kidney transplantation can be an option for patients with complex BWT if the hospital's surgical technique and perioperative management conditions are feasible.

Suppression of porcine hemagglutinating encephalomyelitis virus replication by resveratrol.

BACKGROUND: Porcine hemagglutinating encephalomyelitis virus (PHEV), a member of the genus Betacoronavirus, is the causative agent of neurological disease in pigs. No effective therapeutics are currently available for PHEV infection. Resveratrol has been shown to exert neuroprotective and antiviral effects. Here resveratrol was investigated for its ability to inhibit PHEV replication in nerve cells and central nervous system tissues. METHODS: Anti-PHEV effect of resveratrol was evaluated using an in vitro cell-based PHEV infection model and employing a mouse PHEV infection model. The collected cells or tissues were used for quantitative PCR analysis, western blot analysis, or indirect immunofluorescence assay. The supernatants were collected to quantify viral loads by TCID50 assay in vitro. EC50 and CC50 were determined by dose-response experiments, and the ratio (EC50/CC50) was used as a selectivity index (SI) to measure the antiviral versus cytotoxic activity. RESULTS: Our results showed that resveratrol treatment reduced PHEV titer in a dose-dependent manner, with a 50% inhibition concentration of 6.24 µM. A reduction of > 70% of viral protein expression and mRNA copy number and a 19-fold reduction of virus titer were achieved when infected cells were treated with 10 µM resveratrol in a pre-treatment assay. Quantitative PCR analysis and TCID50 assay results revealed that the addition of 10 µM resveratrol to cells after adsorption of PHEV significantly reduced 56% PHEV mRNA copy number and eightfold virus titer. 10 µM resveratrol treatment reduced 46% PHEV mRNA copy number and fourfold virus titer in virus inactivation assay. Moreover, the in vivo data obtained in this work also demonstrated that resveratrol inhibited PHEV replication, and anti-PHEV activities of resveratrol treatment via intranasal installation displayed better than oral gavage. CONCLUSION: These results indicated that resveratrol exerted antiviral effects under various drug treatment and virus infection conditions in vitro and holds promise as a treatment for PHEV infection in vivo.