Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids.

The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable in vitro models that can mimic hBBB development and function. Here, we constructed hBBB assembloids from brain and blood vessel organoids derived from human pluripotent stem cells. We validated the acquisition of blood-brain barrier (BBB)-specific molecular, cellular, transcriptomic, and functional characteristics and uncovered an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids. When we used patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), we found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernoma tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic the core properties of the hBBB and identify a potentially underlying cause of CCMs.

Magnetic resonance imaging-based prediction models for differentiating intraspinal schwannomas from meningiomas: classification and regression tree and random forest analysis.

Background: Due to the variations in surgical approaches and prognosis between intraspinal schwannomas and meningiomas, it is crucial to accurately differentiate between the two prior to surgery. Currently, there is limited research exploring the implementation of machine learning (ML) methods for distinguishing between these two types of tumors. This study aimed to establish a classification and regression tree (CART) model and a random forest (RF) model for distinguishing schwannomas from meningiomas. Methods: We retrospectively collected 88 schwannomas (52 males and 36 females) and 51 meningiomas (10 males and 41 females) who underwent magnetic resonance imaging (MRI) examinations prior to the surgery. Simple clinical data and MRI imaging features, including age, sex, tumor location and size, T1-weighted images (T1WI) and T2-weighted images (T2WI) signal characteristics, degree and pattern of enhancement, dural tail sign, ginkgo leaf sign, and intervertebral foramen widening (IFW), were reviewed. Finally, a CART model and RF model were established based on the aforementioned features to evaluate their effectiveness in differentiating between the two types of tumors. Meanwhile, we also compared the performance of the ML models to the radiologists. The receiver operating characteristic (ROC) curve, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to evaluate the models and clinicians' discrimination performance. Results: Our investigation reveals significant variations in ten out of 11 variables in the training group and five out of 11 variables in the test group when comparing schwannomas and meningiomas (P<0.05). Ultimately, the CART model incorporated five variables: enhancement pattern, the presence of IFW, tumor location, maximum diameter, and T2WI signal intensity (SI). The RF model combined all 11 variables. The CART model, RF model, radiologist 1, and radiologist 2 achieved an area under the curve (AUC) of 0.890, 0.956, 0.681, and 0.723 in the training group, and 0.838, 0.922, 0.580, and 0.659 in the test group, respectively. Conclusions: The RF prediction model exhibits more exceptional performance than an experienced radiologist in discriminating intraspinal schwannomas from meningiomas. The RF model seems to be better in discriminating the two tumors than the CART model.

Renal interstitial fibrotic assessment using non-Gaussian diffusion kurtosis imaging in a rat model of hyperuricemia.

BACKGROUND: To investigate the feasibility of Diffusion Kurtosis Imaging (DKI) in assessing renal interstitial fibrosis induced by hyperuricemia. METHODS: A hyperuricemia rat model was established, and the rats were randomly split into the hyperuricemia (HUA), allopurinol (AP), and AP + empagliflozin (AP + EM) groups (n = 19 per group). Also, the normal rats were selected as controls (CON, n = 19). DKI was performed before treatment (baseline) and on days 1, 3, 5, 7, and 9 days after treatment. The DKI indicators, including mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) of the cortex (CO), outer stripe of the outer medulla (OS), and inner stripe of the outer medulla (IS) were acquired. Additionally, hematoxylin and eosin (H&E) staining, Masson trichrome staining, and nuclear factor kappa B (NF-κB) immunostaining were used to reveal renal histopathological changes at baseline, 1, 5, and 9 days after treatment. RESULTS: The HUA, AP, and AP + EM group MKOS and MKIS values gradually increased during this study. The HUA group exhibited the highest MK value in outer medulla. Except for the CON group, all the groups showed a decreasing trend in the FA and MD values of outer medulla. The HUA group exhibited the lowest FA and MD values. The MKOS and MKIS values were positively correlated with Masson's trichrome staining results (r = 0.687, P < 0.001 and r = 0.604, P = 0.001, respectively). The MDOS and FAIS were negatively correlated with Masson's trichrome staining (r = -626, P < 0.0014 and r = -0.468, P = 0.01, respectively). CONCLUSION: DKI may be a non-invasive method for monitoring renal interstitial fibrosis induced by hyperuricemia.

3D-printed PCL framework assembling ECM-inspired multi-layer mineralized GO-Col-HAp microscaffold for in situ mandibular bone regeneration.

BACKGROUND: In recent years, natural bone extracellular matrix (ECM)-inspired materials have found widespread application as scaffolds for bone tissue engineering. However, the challenge of creating scaffolds that mimic natural bone ECM's mechanical strength and hierarchical nano-micro-macro structures remains. The purposes of this study were to introduce an innovative bone ECM-inspired scaffold that integrates a 3D-printed framework with hydroxyapatite (HAp) mineralized graphene oxide-collagen (GO-Col) microscaffolds and find its application in the repair of mandibular bone defects. METHODS: Initially, a 3D-printed polycaprolactone (PCL) scaffold was designed with cubic disks and square pores to mimic the macrostructure of bone ECM. Subsequently, we developed multi-layer mineralized GO-Col-HAp microscaffolds (MLM GCH) to simulate natural bone ECM's nano- and microstructural features. Systematic in vitro and in vivo experiments were introduced to evaluate the ECM-inspired structure of the scaffold and to explore its effect on cell proliferation and its ability to repair rat bone defects. RESULTS: The resultant MLM GCH/PCL composite scaffolds exhibited robust mechanical strength and ample assembly space. Moreover, the ECM-inspired MLM GCH microscaffolds displayed favorable attributes such as water absorption and retention and demonstrated promising cell adsorption, proliferation, and osteogenic differentiation in vitro. The MLM GCH/PCL composite scaffolds exhibited successful bone regeneration within mandibular bone defects in vivo. CONCLUSIONS: This study presents a well-conceived strategy for fabricating ECM-inspired scaffolds by integrating 3D-printed PCL frameworks with multilayer mineralized porous microscaffolds, enhancing cell proliferation, osteogenic differentiation, and bone regeneration. This construction approach holds the potential for extension to various other biomaterial types.

Neutrophil Targeting Platform Reduces Neutrophil Extracellular Traps for Improved Traumatic Brain Injury and Stroke Theranostics.

Traumatic brain injuries (TBI) and stroke are major causes of morbidity and mortality in both developing and developed countries. The complex and heterogeneous pathophysiology of TBI and cerebral ischemia-reperfusion injury (CIRI), in addition to the blood-brain barrier (BBB) resistance, is a major barrier to the advancement of diagnostics and therapeutics. Clinical data showed that the severity of TBI and stroke is positively correlated with the number of neutrophils in peripheral blood and brain injury sites. Furthermore, neutrophil extracellular traps (NETs) released by neutrophils correlate with worse TBI and stroke outcomes by impairing revascularization and vascular remodeling. Therefore, targeting neutrophils to deliver NETs inhibitors to brain injury sites and reduce the formation of NETs can be an optimal strategy for TBI and stroke therapy. Herein, the study designs and synthesizes a reactive oxygen species (ROS)-responsive neutrophil-targeting delivery system loaded with peptidyl arginine deiminase 4 (PAD4) inhibitor, GSK484, to prevent the formation of NETs in brain injury sites, which significantly inhibited neuroinflammation and improved neurological deficits, and improved the survival rate of TBI and CIRI. This strategy may provide a groundwork for the development of targeted theranostics of TBI and stroke.

Undifferentiated sarcomatoid carcinoma of the pancreas-a single-institution experience with 23 cases.

BACKGROUND: The clinical course and surgical outcomes of undifferentiated sarcomatoid carcinoma of the pancreas (USCP) remain poorly characterized owing to its rarity. This study aimed to describe the histology, clinicopathologic features, perioperative outcomes, and overall survival (OS) of 23 resected USCP patients. METHODS: We retrospectively described the histology, clinicopathologic features, perioperative outcomes and OS of patients who underwent pancreatectomy with a final diagnosis of USCP in a single institution. RESULTS: A total of 23 patients were included in this study. Twelve patients were male, the median age at diagnosis was 61.5 ± 13.0 years (range: 35-89). Patients with USCP had no specific symptoms and characteristic imaging findings. The R0 resection was achieved in 21 cases. The En bloc resection and reconstruction of mesenteric-portal axis was undertaken in 9 patients. There were no deaths attributed to perioperative complications in this study. The intraoperative tumor-draining lymph nodes (TDLNs) dissection was undergone in 14 patients. The 1-, 3- and 5-year survival rates were 43.5%, 4.8% and 4.8% in the whole study, the median survival was 9.0 months. Only 1 patient had survived more than 5 years and was still alive at last follow-up. The presence of distant metastasis (p = 0.004) and the presence of pathologically confirmed mesenteric-portal axis invasion (p = 0.007) was independently associated with poor OS. CONCLUSIONS: USCP was a rare subgroup of pancreatic malignancies with a bleak prognosis. To make a diagnose of USCP by imaging was quite difficult because of the absence of specific manifestations. Accurate diagnosis depended on pathological biopsy, and the IHC profile of USCP was mainly characterized by co-expression of epithelial and mesenchymal markers. A large proportion of patients have an early demise, especially for patients with distant metastasis and pathologically confirmed mesenteric-portal axis invasion. Long-term survival after radical resection of USCPs remains rare.

How do information and communication technology, human capital and renewable energy affect CO2 emission; New insights from BRI countries.

If nations want to attain sustainable development with the exponential growth of information and communication technology (ICT) around the world, they must understand the connection between ICT and carbon emissions. Therefore, this study has used panel data from 64 ''Belt and Road Initiative economies between 2000 and 2021 while finding the impact of ICT, renewable energy consumption (REC), human capital (HC) and economic growth (EG) on CO2 emissions. This study employs the Augmented Mean Group (AMG) estimator, Mean Group (MG) estimator and the Dumitrescu-Hurlin panel causality. The findings indicate that the use of ICT, HC and the REC are inversely related to CO2 emissions, whereas EG is positively associated to CO2 emissions and hence poses a danger to environmental sustainability. In addition, the interaction term of EG with ICT, REC and HC has negative impact on CO2 emissions in BRI economies. Intriguingly, the results reveal that ICT and CO2 emissions has inverted U-shape relationship in BRI economies. Furthermore, the causality results show that ICT, REC, and human capital are all cause and effect linkages that affect CO2 emissions in both directions. In order to reduce energy utilization and boost economic growth, the findings stress the importance of implementing cutting-edge ICT and REC in the industrial sector.

Using intravoxel incoherent motion imaging to evaluate uric acid-induced renal injury and efficacy after treatment.

OBJECTIVES: To validate the feasibility of intravoxel incoherent motion imaging (IVIM) for monitoring renal injury and uric acid-lowering efficacy in a rat model of hyperuricaemia. METHODS: A total of 92 rats were analysed and categorized into 4 groups: control (CON), hyperuricaemia (HUA), allopurinol intervention (ALL), and combined intervention (COM). Eight rats were randomly selected from each group and underwent IVIM scanning on days 0, 1, 3, 5, 7, and 9. Quantitative magnetic resonance values (D, D*, and f values) measured from the different renal anatomical regions. Quantitative histopathological analysis was performed to assess renal tubular injury using neutrophil gelatinase-associated lipocalin (NGAL), and renal fibrosis using alpha-smooth-muscle-actin (α-SMA). Pearson's correlation analysis was used to determine the correlation between IVIM-derived parameters and the expression of NGAL and α-SMA. RESULTS: The D values of the HUA, ALL, and COM groups generally showed a downward trend over time, and this fluctuation was most significant in the HUA group. The D values showed significant intergroup differences at each point, whereas only a few discrepancies were found in the D* and f values. In addition, the renal D value was negatively correlated with the positive staining rates for NGAL and α-SMA (P < .05), except for the lack of correlation between Dos and α-SMA (P > .05). CONCLUSION: IVIM could be a noninvasive and potential assessment modality for the evaluation of renal injury induced by hyperuricaemia and its prognostic efficacy. ADVANCES IN KNOWLEDGE: IVIM could be a surrogate manner in monitoring renal damage induced by hyperuricaemia and its treatment evaluation.

Association of Muscle Fat Content and Muscle Mass With Impaired Lung Function in Young Adults With Obesity: Evaluation With MRI.

RATIONALE AND OBJECTIVES: Although low muscle mass is associated with decreased lung function, studies exploring the relationship between muscle fat content and lung function impairment are scarce. This study aimed to evaluate the association of muscle mass and fatty infiltration with lung function in young adults with obesity. MATERIALS AND METHODS: We performed a retrospective cross-sectional study of patients aged 18-45 years with obesity who had impaired pulmonary function (case group, n = 66) and those with normal pulmonary function (control group, n = 198) by matching age, sex, body mass index (BMI), and height to assess whether muscle characteristics differed. Muscle mass and muscle fat content were assessed by MRI using a chemical shift-encoded sequence (IDEAL-IQ). RESULTS: A total of 264 patients were enrolled (124 females; mean age 32.0 years). The case group had lower muscle mass than the control group (p = 0.012), and there was an association between low muscle mass and lung function impairment (odds ratio (OR), 3.74; 95% confidence interval (CI), 1.57-8.93). Furthermore, muscle fat content was significantly higher in cases compared to controls (7.4 (2.7) % vs. 6.2 (2.5) %, p = 0.001). Multiple logistic regression analysis showed that muscle fat content was associated with a higher risk of impaired lung function (OR, 2.10; 95% CI, 1.65-2.66), regardless of adiposity and muscle mass. CONCLUSION: Both muscle fat content and muscle mass are associated with impaired lung function in young adults with obesity.

A fucoidan plant drink reduces Helicobacter pylori load in the stomach: a real-world study.

Background: Helicobacter pylori (Hp) infection is highly prevalent globally and is predominantly managed by antibiotics. Recently, the anti-adhesive, antioxidant, antitoxin, immunomodulatory, anti-coagulant, and anti-infective activities of fucoidan, a polysaccharide extracted from brown seaweeds, have been widely studied, and the results showed promise. Fucoidan has the potential to be utilized in Hp eradication therapy. Our present clinical study was designed to evaluate the efficiency of Lewuyou®, a fucoidan plant drink (FPD) in eradicating Hp in humans. Methods: This multi-center, clinical study was conducted between October 2020 and July 2021. Hp infection was confirmed by urea breath test (UBT). A total of 122 patients with confirmed Hp infection were enrolled; after exclusion of incomplete data, 85 eligible patients (37 males and 48 females aged 20-81 years) were included in the final analysis. FPD (50 mL per vial) was orally administered twice daily for a 4-week cycle, and 41 patients completed an 8-week cycle. Results: No adverse event (AE) was reported in all 122 participants who had consumed FPD. The Hp eradication rate and clearance rate were 77.6% (66/85) and 20.0% (17/85), respectively, after 4 weeks of FPD consumption and 80.5% (33/41) and 26.8 (11/41) , respectively, after 8 weeks of consumption. Conclusions: The 4- and 8-week protocols of FPD consumption were safe and effective at reducing Hp load on the gastric mucosa, with Hp eradicated in the majority of participants.

Physiological Barriers and Strategies of Lipid-Based Nanoparticles for Nucleic Acid Drug Delivery.

Lipid-based nanoparticles (LBNPs) are currently the most promising vehicles for nucleic acid drug (NAD) delivery. Although their clinical applications have achieved success, the NAD delivery efficiency and safety are still unsatisfactory, which are, to a large extent, due to the existence of multi-level physiological barriers in vivo. It is important to elucidate the interactions between these barriers and LBNPs, which will guide more rational design of efficient NAD vehicles with low adverse effects and facilitate broader applications of nucleic acid therapeutics. This review describes the obstacles and challenges of biological barriers to NAD delivery at systemic, organ, sub-organ, cellular, and subcellular levels. The strategies to overcome these barriers are comprehensively reviewed, mainly including physically/chemically engineering LBNPs and directly modifying physiological barriers by auxiliary treatments. Then the potentials and challenges for successful translation of these preclinical studies into the clinic are discussed. In the end, a forward look at the strategies on manipulating protein corona (PC) is addressed, which may pull off the trick of overcoming those physiological barriers and significantly improve the efficacy and safety of LBNP-based NADs delivery.

Upper-critical solution temperature (UCST) polymer functionalized nanomedicine for controlled drug release and hypoxia alleviation in hepatocellular carcinoma therapy.

Recently, bioinspired material such as nanoparticle has been successfully applied in the cancer therapy. However, how to precisely control the drug release from nanomedicine in tumor tissue and overcome the hypoxic microenvironment of tumor tissue is still an important challenge in the development of nanomedicine. In this work, a new type of drug-loaded nanoparticles P(AAm-co-AN)-AuNRs@CeO2-DOX (PA-DOX) was prepared by combining high-efficiency photothermal reagents, critical up-conversion temperature polymer layer and anti-cancer drug doxorubicin (DOX) for the treatment of hepatocellular carcinoma (HCC). In this system, CeO2 can decompose hydrogen peroxide to H2O and O2 alleviate the anaerobic microenvironment of liver cancer cells. As a photothermal reagent, AuNRs@CeO2 can convert near-infrared light into heat energy to achieve local heat to kill cancer cells and ablate solid tumors. In addition, the elevated temperature would enable the polymer layer to undergo a phase transition to release more DOX to achieve a controlled release mechanism, which will open up a new horizon for clinical cancer treatment.

Zimberelimab plus chemotherapy as the first-line treatment of malignant peritoneal mesothelioma: A case report and review of literature.

BACKGROUND: Malignant peritoneal mesothelioma (MPeM) is a rare cancer with a poor prognosis at advanced stage, and the standard first-line treatment for inoperable patients is chemotherapy. Although combining programmed cell death 1 (PD-1) inhibitors with chemotherapy is generally considered safe and effective in several malignant solid tumors, there are few reports regarding initial immunochemotherapy in advanced MPeM. CASE SUMMARY: Here, to our knowledge, we present the first case of a patient with epithelioid subtype MPeM, who was treatment-naïve and benefited from initial PD-1 inhibitor plus standard chemotherapy with a prolonged progression-free survival (PFS) and good tolerance. A 49-year-old man was admitted to our hospital for a persistent burning sensation in the abdomen. Computed tomography revealed a solid mass in the lower abdomen, which was subsequently diagnosed histologically as epithelioid subtype MPeM by core needle biopsy. The patient received eight cycles of pemetrexed 800 mg (day 1), cisplatin 60/50 mg (day 1-2), and zimberelimab (PD-1 inhibitor) 240 mg (day 1) every 3 wk. He achieved significant reduction of peritoneal tumors with remarkable improvement in symptoms. The best tumor response was partial remission with a final PFS of 7 mo. No immune-related adverse event occurred during the combination treatment. CONCLUSION: The outcome of the present case demonstrates the promising anti-tumor activity of immunochemotherapy to treat inoperable MPeM in the future.

Synthesis of a Cd-MOF Fluorescence Sensor and Its Detection of Fe3+, Fluazinam, TNP, and Sulfasalazine Enteric-Coated Tablets in Aqueous Solution.

A Cd-based metal-organic framework (Cd-MOF), named after {[Cd(ttc)(H2O)]·H2O}n (ttc = 1-imidazole-1-yl-2,4,6-benzene-tricarboxylic acid), was synthesized using the solvothermal reaction. The single-crystal structure was determined by single X-ray diffraction analysis, and crystalline characteristics and composition were confirmed by powder X-ray diffraction (PXRD) and thermogravimetric analysis (TG), respectively. Structural analysis showed that the Cd2+ ion is in the seven-coordinated mode, in which ttc2- ion adopts the µ4-η1-η1-η2-η2 coordination mode. It is worth noting that the Cd2+ ion is connected to ttc2- to form a 2D network, and the adjacent 2D network is expanded into a 3D supramolecular network structure through weak hydrogen bonds. The fluorescence sensing experiments indicated that Cd-MOF could not only be used as a fluorescence sensor for Fe3+, fluazinam (FLU), and 2,4,6-trinitrophenolol (TNP) but also for sulfasalazine detection in aqueous solution. To verify the sensitivity of the fluorescent probe, we calculated its detection limit: 5.34 × 10-8 M (Fe3+), 7.8 × 10-8 M (FLU), 1.21 × 10-7 M (TNP), and 2.67 × 10-7 M (SECT). In addition, the quenching mechanism was thoroughly studied.

Minimally invasive surgery versus laparotomy of nonmetastatic pT4a colorectal cancer: a propensity score analysis.

AIM: The aim was to compare short-term and long-term oncological outcomes between minimally invasive surgery (MIS group) and laparotomy (lap group) in nonmetastatic pT4a colorectal cancer (CRC). MATERIALS AND METHODS: The study retrospectively analyzed the outcomes of 634 patients treated with radical operation from January 2015 to December 2021 for nonmetastatic pT4a CRC, with propensity score matching. RESULTS: The conversion rate from the MIS group to laparotomy is 3.5%. Intraoperative blood loss, time to first anal exhaust, defecation and drainage tube removal, and complication rate were significantly less in the MIS group. After 5 years, the outcomes of the MIS group were no inferior to laparotomy outcomes [overall survival (OS): 72.7 vs. 77.8%, P =0.285; disease-free survival (DFS): 72.2 vs. 75.0%, P =0.599]. And multivariate analysis showed that age greater than or equal to 60 years old, lymph node metastasis and the carcinoembryonic antigen levels were independent variables for OS, while lymph node metastasis and CA125 levels were independent variables for DFS. The results of the graph show the relationship between the sum of scores of sex, age, complications, BMI, carcinoembryonic antigen, age, CA125, tumor site, N stage and tumor length diameter and 1-year, 3-year, and 5-year mortality and DFS of patients. Among them, tumor length diameter and N stage are significantly correlated with long-term survival and disease-free of patients. CONCLUSION: MIS is safe and feasible for nonmetastatic pT4a CRC, with the added benefit of accelerated postoperative recovery. In oncology, MIS did not affect OS and DFS.

Well-controlled versus poorly controlled diabetes in patients with obesity: differences in MRI-evaluated pancreatic fat content.

Background: Patients with obesity and poorly controlled type 2 diabetes (T2D) are at high risk of diabetic complications. This study aimed to determine the associations of visceral adipose tissue (VAT), hepatic proton-density fat fraction (PDFF), and pancreatic PDFF with poor glycemic control in patients with obesity and T2D and to evaluate the metabolic effect of bariatric surgery in patients with obesity and poorly controlled diabetes. Methods: In this retrospective cross-sectional study, from July 2019 to March 2021, 151 consecutive obese patients with new-onset T2D (n=28), well-controlled T2D (n=17), poorly controlled T2D (n=32), prediabetes (n=20), or normal glucose tolerance (NGT; n=54) were included. A total of 18 patients with poorly controlled T2D were evaluated before and 12 months after bariatric surgery, and 18 non-obese healthy individuals served as controls. VAT, hepatic PDFF, and pancreatic PDFF were quantified by magnetic resonance imaging (MRI) using a chemical shift-encoded sequence [iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantitation (IDEAL-IQ)]. Univariate analysis and multivariate regression analysis were performed. Results: There were significant differences in VAT, hepatic PDFF, and all pancreatic PDFF between the new-onset T2D, prediabetes, and NGT groups (all P<0.05). Pancreatic tail PDFF was significantly higher in the poorly controlled T2D group than in the well-controlled T2D group (P=0.001). In the multivariate analysis, only pancreatic tail PDFF was significantly associated with increased odds of poor glycemic control [odds ratio (OR) =2.09; 95% confidence interval (CI): 1.11-3.94; P=0.022]. The glycated hemoglobin (HbA1c), hepatic PDFF, and pancreatic PDFF significantly decreased (all P<0.01) after bariatric surgery, and the values were statistically similar to those observed in the non-obese healthy controls. Conclusions: Increased fat in the pancreatic tail is strongly associated with poor glycemic control in patients with obesity and T2D. Bariatric surgery is an effective therapy for poorly controlled diabetes and obesity, which improves glycemic control and decreases ectopic fat deposits.

Targeting cytokine-like protein FAM3D lowers blood pressure in hypertension.

Current antihypertensive options still incompletely control blood pressure, suggesting the existence of uncovered pathogenic mechanisms. Here, whether cytokine-like protein family with sequence similarity 3, member D (FAM3D) is involved in hypertension etiology is evaluated. A case-control study exhibits that FAM3D is elevated in patients with hypertension, with a positive association with odds of hypertension. FAM3D deficiency significantly ameliorates angiotensin II (AngII)-induced hypertension in mice. Mechanistically, FAM3D directly causes endothelial nitric oxide synthase (eNOS) uncoupling and impairs endothelium-dependent vasorelaxation, whereas 2,4-diamino-6-hydroxypyrimidine to induce eNOS uncoupling abolishes the protective effect of FAM3D deficiency against AngII-induced hypertension. Furthermore, antagonism of formyl peptide receptor 1 (FPR1) and FPR2 or the suppression of oxidative stress blunts FAM3D-induced eNOS uncoupling. Translationally, targeting endothelial FAM3D by adeno-associated virus or intraperitoneal injection of FAM3D-neutralizing antibodies markedly ameliorates AngII- or deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Conclusively, FAM3D causes eNOS uncoupling through FPR1- and FPR2-mediated oxidative stress, thereby exacerbating the development of hypertension. FAM3D may be a potential therapeutic target for hypertension.

Integrated analysis of methylation profiles and transcriptome of Marek's disease virus-infected chicken spleens reveal hypomethylation of CD4 and HMGB1 genes might promote Marek's disease tumorigenesis.

Marek's disease (MD) is a lymphoproliferative neoplastic disease caused by Marek's disease virus (MDV). Previous studies have showed that DNA methylation was involved in MD development, but systematic studies are still lacking. Herein, we performed whole genome bisulfite sequencing (WGBS) and RNA-seq in MDV-infected tumorous spleens (IN), noninfected spleens (NoIN), and survivor (SUR) spleens of chickens to identify the genes playing important roles in MD tumor transformation. We generated the first genome-wide DNA methylation profile of MDV-infected, noninfected, and survivor chickens. Combined the WGBS and RNA-Seq, we found that the expression of 25% differential expression genes (DEGs) were significantly correlated with methylation of CpG sites in their gene bodies or promoters. Further, we focused on the DEGs with differentially methylated regions (DMRs) on genes' body and promoter, and it showed the expression of 60% DEGs were significantly correlated with methylation of CpG sites in DMRs. Finally, we identified 8 genes, including CD4, CTLA4, DTL, HMGB1, LGMN, NUP210, RAD52, and ZAP70, and their expression was negatively correlated with methylation of DMRs in their promoters in both IN vs. NoIN and IN vs. SUR. These 8 genes showed specifically high expression in IN groups and clustered in module turquoise analyzed by WGCNA. Out of 8 genes, CD4 and HMGB1 were drop in QTLs associated with MD resistance. Thus, we overexpressed the 2 genes to simulate their high expression in the IN group and found they significantly promoted MDCC-MSB-1 cell proliferation, which revealed they might play promoting roles in MD tumorigenesis in IN due to their high expression induced by hypomethylation.

Hollow MnO2-Based Nanoprobes for Enhanced Photothermal/Photodynamic /Chemodynamic Co-Therapy of Hepatocellular Carcinoma.

PURPOSE: The effect of monotherapy in cancer is frequently influenced by the tumor's unique hypoxic microenvironment, insufficient drug concentration at the treatment site, and tumour cells' increased drug tolerance. In this work, we expect to design a novel therapeutic nanoprobe with the ability to solve these problems and improve the efficacy of antitumor therapy. METHODS: We have prepared a hollow manganese dioxide nanoprobes loaded with photosensitive drug IR780 for the photothermal/photodynamic/chemodynamic co-therapy of liver cancer. RESULTS: The nanoprobe demonstrates efficient thermal transformation ability under a single laser irradiation, and under the synergistic influence of photo heat, accelerates the Fenton/ Fenton-like reaction efficiency based on Mn2+ ions to produce more ·OH under the synergistic effect of photo heat. Moreover, the oxygen released under the degradation of manganese dioxide further promotes the ability of photosensitive drugs to produce singlet oxygen (ROS). The nanoprobe has been found to efficiently destroy tumour cells in vivo and in vitro experiments when used in combination with photothermal/photodynamic/ chemodynamic modes of treatment under laser irradiation. CONCLUSION: In all, this research shows that a therapeutic strategy based on this nanoprobe could be a viable alternative for cancer treatment in the near future.