Targeted drug delivery of engineered mesenchymal stem/stromal-cell-derived exosomes in cardiovascular disease: recent trends and future perspectives.

In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.

An Outbreak of Serogroup Y Meningococcal Meningitis in a Private Secondary Vocational School - Guangzhou City, Guangdong Province, China, 2023.

What is already known about this topic?: The inclusion of meningococcal vaccines in the National Immunization Program (NIP) over several years has significantly reduced the incidence of meningococcal meningitis in China to historic lows. Worldwide, there has been a diversification of meningococcal serogroups, leading to a shift in dominant serogroups in China from serogroup A to serogroups C and B, accompanied by a rise in reports of serogroups Y and W. What is added by this report?: An outbreak of serogroup Y Neisseria meningitidis (Nm) in a secondary vocational school involved a single confirmed severe case and 24 individuals with laboratory-confirmed Nm carriage. Epidemiological investigation revealed that the outbreak was localized to the classroom of the confirmed case. Prolonged close contact within a confined space was identified as a significant risk factor for Nm transmission. The genotype sequence identified was type 1655 (ST-1655), which is categorized under clonal complex 23 (CC-23) and bears resemblance to 8 previously confirmed cases of serogroup Y meningococcal meningitis within Guangdong Province. This suggests that serogroup Y infections continue to sporadically emerge and have become prevalent strains. What are the implications for public health practice?: This outbreak underscores the critical need to enhance surveillance of meningococcal serogroups and population carrier, and advocate for vaccination with MenY-containing vaccines.

Gel polymer electrolytes for rechargeable batteries toward wide-temperature applications.

Rechargeable batteries, typically represented by lithium-ion batteries, have taken a huge leap in energy density over the last two decades. However, they still face material/chemical challenges in ensuring safety and long service life at temperatures beyond the optimum range, primarily due to the chemical/electrochemical instabilities of conventional liquid electrolytes against aggressive electrode reactions and temperature variation. In this regard, a gel polymer electrolyte (GPE) with its liquid components immobilized and stabilized by a solid matrix, capable of retaining almost all the advantageous natures of the liquid electrolytes and circumventing the interfacial issues that exist in the all-solid-state electrolytes, is of great significance to realize rechargeable batteries with extended working temperature range. We begin this review with the main challenges faced in the development of GPEs, based on extensive literature research and our practical experience. Then, a significant section is dedicated to the requirements and design principles of GPEs for wide-temperature applications, with special attention paid to the feasibility, cost, and environmental impact. Next, the research progress of GPEs is thoroughly reviewed according to the strategies applied. In the end, we outline some prospects of GPEs related to innovations in material sciences, advanced characterizations, artificial intelligence, and environmental impact analysis, hoping to spark new research activities that ultimately bring us a step closer to realizing wide-temperature rechargeable batteries.

Pulmonary artery dissection secondary to ventricular septal defect and pulmonary valve stenosis.

The aortic short axis view demonstrated the widening of the pulmonary artery and the membrane-like echo in the pulmonary artery divided it into true lumen and false lumen. And the flow of the ruptured openings on the band-like echo was clearly revealed by Color Doppler.

LncRNA XXYLT1-AS2 promotes tumor progression via autophagy inhibition through ubiquitinated degradation of TFEB in hepatocellular carcinoma

Purpose There is compelling evidence that long-stranded non-coding RNAs (lncRNAs) play an important role in the progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of lncRNA XXYLT1 antisense-2 (XXYLT1-AS2) in HCC progression. Methods Real-time PCR was used to assess the levels of XXYLT1-AS2 in plasma from HCC and normal patients. Cell proliferation, apoptosis, migration, and invasion were monitored, and tumor xenografts were established to investigate the biological functions of XXYLT1-AS2 by gain-of-function and loss-of-function studies in vitro and in vivo, the expression of autophagy biomarkers and transcriptional factor EB (TFEB) was examined by immunoprecipitation, ubiquitination assays, and western blotting. Autophagy inhibitor, 3-methyladenine (3MA), and proteasome inhibitor, MG132, were used to verify the role of autophagy in HCC progression and the effect of XXYLT1-AS2 on TFEB ubiquitination, respectively. Results In this study, we identified that lncRNA XXYLT1-AS2 is highly expressed in HCC plasma and promotes tumor growth in vivo. In functional studies, it was found that silent expression of XXYLT1-AS2 inhibited HCC proliferation, migration, invasion, and activated autophagy of HCC cells, which were attenuated by autophagy inhibitor, 3MA. Mechanistically, XXYLT1-AS2 decreased the protein level of TFEB through promoting its degradation by ubiquitin proteasome pathway. Conclusion XXYLT1-AS2 plays an oncogenic role in HCC progression through inhibition of autophagy via promoting the degradation of TFEB, and thus could be a novel target for HCC treatment (AU)

A Multi-Objective Sine Cosine Algorithm Based on a Competitive Mechanism and Its Application in Engineering Design Problems.

There are a lot of multi-objective optimization problems (MOPs) in the real world, and many multi-objective evolutionary algorithms (MOEAs) have been presented to solve MOPs. However, obtaining non-dominated solutions that trade off convergence and diversity remains a major challenge for a MOEA. To solve this problem, this paper designs an efficient multi-objective sine cosine algorithm based on a competitive mechanism (CMOSCA). In the CMOSCA, the ranking relies on non-dominated sorting, and the crowding distance rank is utilized to choose the outstanding agents, which are employed to guide the evolution of the SCA. Furthermore, a competitive mechanism stemming from the shift-based density estimation approach is adopted to devise a new position updating operator for creating offspring agents. In each competition, two agents are randomly selected from the outstanding agents, and the winner of the competition is integrated into the position update scheme of the SCA. The performance of our proposed CMOSCA was first verified on three benchmark suites (i.e., DTLZ, WFG, and ZDT) with diversity characteristics and compared with several MOEAs. The experimental results indicated that the CMOSCA can obtain a Pareto-optimal front with better convergence and diversity. Finally, the CMOSCA was applied to deal with several engineering design problems taken from the literature, and the statistical results demonstrated that the CMOSCA is an efficient and effective approach for engineering design problems.

Contribution of Matrix Metalloproteinase-2 Genotypes to Taiwan Pterygium Risk.

BACKGROUND/AIM: In the literature, the studies about the role of matrix metalloproteinase-2 (MMP-2) in pterygium diagnosis are mainly based on its protein expression. The role of MMP-2 variants has never been examined. The aim of this study was to examine the association of MMP-2 genotypes with pterygium risk. MATERIALS AND METHODS: MMP-2 rs243865 and rs2285053 were genotyped in 140 pterygium cases and 280 non-pterygium controls by typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping technology. RESULTS: The genotypic frequency of MMP-2 rs243865 CC, CT and TT were 86.4%, 12.9% and 0.7% in the pterygium group and 81.1%, 17.1% and 1.8% in the non-pterygium group (p for trend=0.3389). The variant CT and TT carriers had a 0.70- and 0.38-fold pterygium risk (95%CI=0.39-1.26 and 0.04-3.25, p=0.2982 and 0.6686, respectively). As for MMP-2 rs2285053, the genotypic frequency of CC, CT and TT were 67.1%, 28.6% and 4.3% in the pterygium group, non-significantly different from those in non-pterygium group (p for trend=0.7081). The CT and TT carriers had a 0.88- and 0.71-fold pterygium risk (95%CI=0.56-1.38 and 0.27-1.88, p=0.6612 and 0.6456, respectively). The allelic analysis results showed that MMP-2 rs243865 variant T allele was not associated with pterygium risk (7.1% versus 10.4%, OR=0.67, 95%CI=0.39-1.13, p=0.1649). As for MMP-2 rs2285053, the T allele was not associated with pterygium risk either (18.6% versus 21.1%, OR=0.85, 95%CI=0.59-1.23, p=0.4136). CONCLUSION: The genotypes at MMP-2 rs243865 or rs2285053 played minor role in determining individual susceptibility for pterygium among Taiwanese.

Extraction, structural characterization and immunoactivity of glucomannan type polysaccahrides from Lilium brownii var. viridulum Baker.

Homogeneous polysaccharide (LBP) was extracted and purified from the bulblets of Lilium brownii var. viridulum Baker with a molecular weight of 312 kDa. The monosaccharides are composed of mannose and glucose, and the corresponding molar ratios are 0.582 and 0.418, respectively. FT-IR, LC-MS, NMR, GC-MS and HPAEC were used to analyze the functional groups, glycosidic linkages and chemical structure of LBP, which was a 1-4-linked glucomannan and contained a dodecasaccharide repeating units of →4)-ß-D-Manp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-α-D-Glcp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-ß-D-Glcp-(1 â†’ 4)-ß-D-Manp-(1 â†’ 4)-ß-D-Manp-(1 â†’ . In vitro experimental results showed that LBP had noble biocompatibility, and a low dose of 5 µg/mL LBP significantly up-regulated the mRNA expression of TNF-α, iNOS, IL-6, IL-1ß and Toll-like receptors family (TLRs) in RAW 264.7 cells. In conclusion, LBP played an important role in immunomodulation, and further studies on the specific immunomodulatory mechanisms of LBP on RAW 264.7 cells are still needed.

Pharmacokinetics, pharmacodynamics and safety of 15 mg-tolvaptan administered orally for 7 consecutive days to Chinese patients with child-Pugh B cirrhosis.

Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15 mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites. Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15 mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded. Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%). Conclusion: Tolvaptan at a daily dose of 15 mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis. Clinical Trial Registration: https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.

Myxoma with rich blood supply in the left atrium.

Cardiac myxoma is the most common primary benign cardiac tumors, mostly found in the left atrium. It was previously reported that the main component of myxoma was myxoid stroma riched in acid-mucopolysaccharide, the blood vessels in which were sparsely distributed, being characterized as hypovascular tumor by contrast echocardiography (CE) and computed tomography angiography (CTA). There are few reports of myxoma with rich blood supply and we report one in the left atrium.

First-in-Human Safety, Tolerability, and Pharmacokinetics of Single-Dose Kukoamine B Mesylate in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase I Study.

INTRODUCTION: Kukoamine B mesylate (KB) is a mesylate chrysamine B targeting lipopolysaccharides and CpG DNA, two potential treatment targets in sepsis. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase I study was conducted from July 2014 to May 2015 to explore the safety, tolerability, and pharmacokinetics of KB in healthy subjects. This study consisted of a pre-phase (four participants; KB at 0.005 mg/kg) and a dose escalation phase (eight participants/dose group, randomized 6:2 to KB or placebo; KB at 0.02, 0.04, 0.08, 0.12, 0.24, and 0.48 mg/kg). The primary endpoint was safety. RESULTS: Fifty-two participants were enrolled, including four in the pre-phase and 48 in the dose escalation phase. Among the 40 participants who received KB, 12 (30.0%) experienced adverse events (AEs), while two (16.7%) experienced AEs among 12 participants who received the placebo. The most common AEs in the KB group were headache (5.0%), influenza (5.0%) and positive white blood cell in urine (5.0%). After the administration of KB, the mean plasma elimination half was around 1.61-4.24 h. The relationship between the KB plasma exposure of KB and the administered dose was not linear. The percentage of cumulative urinary excretion of KB was similar among the different dose groups (21.7-35.2%) and the urinary excretion of KB decreased significantly about 8 h after administration. CONCLUSIONS: Single-dose KB demonstrated favorable safety and tolerability in healthy subjects at the dose level of 0.005-0.48 mg/kg. KB exhibited a non-linear pharmacokinetic profile with a half-life of about 1.61-4.24 h, which mainly distributed in plasma. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02219971.

Imaging of pulmonary artery sling: Prenatal and postnatal imaging findings.

During the fetal period, the pulmonary artery bifurcation revealed the absence of the left pulmonary artery. Instead, an anomalous artery originated from the right pulmonary artery, coursing posteriorly the trachea to the left lung. The diagnosis of PAS was established following prenatal ultrasound screening, which was subsequently confirmed by postnatal echocardiography and CT after delivery.

Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity.

Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with four different longevity mechanisms. We discovered the lysosomal recruitment of AMP-activated protein kinase and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we further elucidated lysosomal heterogeneity across tissues as well as the increased enrichment of the Ragulator complex on Cystinosin-positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity across multiple scales and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk, and organism longevity.

LATS1/YAP1 Axis Controls Bone Regeneration on Distraction Osteogenesis by Activating Wnt/ß-Catenin.

The Hippo signaling pathway inhibits cell growth, and its components and functions are highly conserved in mammals. LATS1 is a core component of the Hippo signaling pathway associated with lymphatic invasion, astrogliosis, apoptosis, and autophagy. Nevertheless, the role of Hippo/LATS1 in osteogenesis remains unclear. In this study, we used ribonucleic acid (RNA) lentiviruses to inhibit the expression of Lats1 in bone marrow-derived stem cells (BMSCs) and distraction osteogenic regions in rats. Increased osteogenic, proliferative, and migratory abilities of BMSCs were observed in Lats1-inhibited BMSCs, while these phenotypes were partially reversed by YAP1 inhibition. In vivo, we found that the LATS1/YAP1 axis promoted osteogenesis during distraction osteogenesis (DO). ß-catenin was positively correlated with YAP1 expression in vivo and in vitro. When YAP1 was strongly positive in the nucleus, ß-catenin expression was upregulated; when YAP1 expression was inhibited by verteporfin, ß-catenin was not expressed in the nucleus. These findings suggest that the LATS1/YAP1 signaling axis promotes DO by activating the Wnt/ß-catenin signaling pathway. This study provides insights into the molecular mechanism of osteogenesis and a potential therapeutic strategy for bone regeneration in DO by associating with LATS1/YAP1-ß-catenin.

Bacteria debridement efficacy of two sonic root canal irrigant activation systems.

OBJECTIVE: To evaluate the bacteria debridement efficacy of two generations of sonic root canal irrigant activation systems: EndoActivator (Dentsply Sirona), the first generation, and SmartLite Pro EndoActivator, the second generation. METHODS: Instrumented, autoclaved, single-rooted human premolars were inoculated with Enterococcus faecalis (ATCC-29212) for 21 days. The bacteria biofilm-containing teeth were randomly divided into 5 groups (N=8): Group 1: Syringe-side-vented needle (S-N) delivery of saline for 1 min; Group 2: S-N delivery of 2% NaOCl for 1 min; Group 3: S-N delivery of 2% NaOCl for 5 min; Group 4: EndoActivator activation of 2% NaOCl for 1 min; Group 5: SmartLite Pro EndoActivator activation of 2% NaOCl for 1 min. The teeth were evaluated for bacterial reduction using CFU counts, and the percentages of dead bacteria within the dentinal tubules using confocal laser scanning microscopy. RESULTS: Activation of NaOCl with EndoActivator or SmartLite Pro EndoActivator significantly reduced the overall intracanal bacterial load, compared with S-N irrigant delivery (P<0.05), with no significant difference between the two agitation devices (P>0.05). Nevertheless, S-N delivery of 2% NaOCl for 5 min produced better bacteria debridement than either sonic agitation system. Different degrees of bacteria kill were identified in the coronal-middle portions and apical portion of the canal space. CONCLUSION: Delivery time of NaOCl affects the efficacy of bacteria disinfection. Activation for 1 min with the EndoActivator or SmartLite Pro EndoActivator demonstrated comparable canal wall biofilm and intracanal bacteria reduction efficacy when 2% NaOCl was used as irrigant for disinfecting E. faecalis in single-rooted teeth. CLINICAL SIGNIFICANCE: Although the sonic root canal irrigant activation devices investigated do not completely eliminate live bacteria biofilms from the canal space, they help reduce bacteria load during irrigant activation.

LncRNA XXYLT1-AS2 promotes tumor progression via autophagy inhibition through ubiquitinated degradation of TFEB in hepatocellular carcinoma.

PURPOSE: There is compelling evidence that long-stranded non-coding RNAs (lncRNAs) play an important role in the progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of lncRNA XXYLT1 antisense-2 (XXYLT1-AS2) in HCC progression. METHODS: Real-time PCR was used to assess the levels of XXYLT1-AS2 in plasma from HCC and normal patients. Cell proliferation, apoptosis, migration, and invasion were monitored, and tumor xenografts were established to investigate the biological functions of XXYLT1-AS2 by gain-of-function and loss-of-function studies in vitro and in vivo, the expression of autophagy biomarkers and transcriptional factor EB (TFEB) was examined by immunoprecipitation, ubiquitination assays, and western blotting. Autophagy inhibitor, 3-methyladenine (3MA), and proteasome inhibitor, MG132, were used to verify the role of autophagy in HCC progression and the effect of XXYLT1-AS2 on TFEB ubiquitination, respectively. RESULTS: In this study, we identified that lncRNA XXYLT1-AS2 is highly expressed in HCC plasma and promotes tumor growth in vivo. In functional studies, it was found that silent expression of XXYLT1-AS2 inhibited HCC proliferation, migration, invasion, and activated autophagy of HCC cells, which were attenuated by autophagy inhibitor, 3MA. Mechanistically, XXYLT1-AS2 decreased the protein level of TFEB through promoting its degradation by ubiquitin proteasome pathway. CONCLUSION: XXYLT1-AS2 plays an oncogenic role in HCC progression through inhibition of autophagy via promoting the degradation of TFEB, and thus could be a novel target for HCC treatment.

Resveratrol Inhibits Hepatocellular Carcinoma Progression through Regulating Exosome Secretion.

BACKGROUND AND OBJECTIVES: Resveratrol is a promising drug for tumor therapy, but its anti-tumor mechanism remains unclarified. The present study aimed to explore the effect of resveratrol on the secretion of exosomes and the role of resveratrol-induced exosomes in the progression of hepatocellular carcinoma. METHODS: The number and contents of exosomes induced by resveratrol were determined by nanoparticle tracking analysis and high-throughput sequencing in Huh7 cells, respectively. Expression of Rab27a was assessed by western blotting and immunofluorescence. Cell proliferation, migration and epithelial-mesenchymal transition were examined with the stimuli of resveratrol and exosomes, the activity of autophagy and wnt/ß-catenin signaling induced by resveratrol-induced exosomes and knockdown of lncRNA SNHG29 were monitored by western blotting and immunofluorescence. RESULTS: It was found that resveratrol might inhibit the exosome secretion by down-regulating the expression of Rab27a, thereby suppressing the proliferation, migration and epithelial-mesenchymal transition of Huh7 cells. Moreover, resveratrol-induced exosomes could also inhibit the malignant phenotype of Huh7 cells via inhibiting the nuclear translocation of ß-catenin and the activation of autophagy, which lncRNA SNHG29 might mediate. CONCLUSION: Resveratrol inhibits hepatocellular carcinoma progression by regulating exosome secretion and contents.

The role and mechanism of HIF-1α-mediated glypican-3 secretion in hypoxia-induced tumor progression in hepatocellular carcinoma.

OBJECTIVE: To explore the expression and secretion mechanism of glypican-3 (GPC3) in hepatocellular carcinoma (HCC) cells under hypoxic conditions, and its role in tumor progression. METHODS: Huh7 cells with and without the knockdown of hypoxia-inducible factor 1-alpha (HIF-1α) were cultured under 1% O2 for varying durations to induce hypoxia. The expression levels of GPC3, HSP70, CD63, STX11 and SYT7 in the cytoplasm and exosomes of Huh7 cells were evaluated by western blotting and immunofluorescence. GPC3 protein expression was further measured in cells treated with GW4869 under hypoxic conditions. Huh7 cells and human umbilical vein endothelial cells (HUVECs) were cultured with the exosomes extracted from the control and GPC3-knockdown cells, the cell proliferation, migration, epithelial-mesenchymal transition (EMT), invasion, and in vitro angiogenesis were analyzed. Tumor xenografts were established to assess the role of GPC3-deficient exosomes in tumor growth. RESULTS: Hypoxic culture conditions downregulated GPC3, STX11 and SYT7 protein levels in the Huh7 cells and upregulated GPC3 mRNA, and also increased GPC3 protein expression in the exosomes. HIF-1α knockdown, as well as treatment with GW4869, upregulated GPC3 protein in the Huh7 cells grown under 1% O2, but downregulated exosomal GPC3. Furthermore, exosomes derived from the GPC3-knockdown cells inhibited the proliferation and migration of Huh7 cells, decreased the expression of N-cadherin, vimentin, ß-catenin, c-Myc and cyclin D1, and increased that of E-cadherin. Likewise, the GPC3-deficient exosomes also suppressed the invasion and tube formation ability of the HUVECs compared to that of control cells. Consistent with the in vitro results, the GPC3-deficient exosomes also repressed tumor growth in vivo. CONCLUSION: Hypoxia promoted secretion of exosomal GPC3 through the activation of HIF-1α. GPC3-deficient exosomes inhibited the proliferation, migration and EMT of HCC cells via the Wnt/ß-catenin signaling pathway, and suppressed the angiogenic potential of HUVECs. This provided a novel understanding of the role of exosomal GPC3 in HCC progression.

Hypermethylated CDO1 and CELF4 in cytological specimens as triage strategy biomarkers in endometrial malignant lesions.

Objective: Developing a non-invasive and reliable triage test for endometrial malignant lesions is an important goal, as it could help to reduce the number of invasive diagnostic procedures required and improve patient survival. We aimed to estimate the diagnostic value of DNA methylation levels in cervical cytological samples of endometrial cancer (EC) and endometrial atypical hyperplasia (AH). Methods: A total of 607 women who had indications for endometrial biopsy in the Department of Obstetrics and Gynecology of Cangzhou Central Hospital from October 2022 to April 2023 were enrolled in this study. The cervical exfoliated cells were collected for gene methylation before endometrial biopsy. Clinical information, tumor biomarkers, and endometrial thickness (ET) of transvaginal ultrasonography (TVS) were also collected. With endometrial histopathology as the gold standard, multivariate unconditional logistic regression was applied to analyze the risk factors of endometrial malignant lesions. The role of cysteine dioxygenase type 1 (CDO1) and CUGBP Elav-like family member 4 (CELF4) gene methylation as a triage strategy biomarker in endometrial malignant lesions was specifically explored. Results: Multivariate logistic regression analysis showed that premenopausal ET ≥ 11 mm or postmenopausal ET ≥ 5 mm, CDO1 ΔCt ≤ 8.4, or CELF4 ΔCt ≤ 8.8 were the risk factors for AH and EC, with odds ratios (ORs) (95%CI) of 5.03 (1.83-13.82) and 6.92 (1.10-43.44), respectively (p-values < 0.05). The sensitivity and specificity of CDO1/CELF4 dual-gene methylation assay for AH and EC reached 84.9% (95%CI: 75.3%-94.5%) and 86.6% (95%CI: 83.8%-89.5%), respectively. ET combined with DNA methylation detection further improved the specificity to (94.9%, 95%CI: 93.1%-96.8%). Conclusion: The accuracy of cervical cytology DNA methylation is superior to that of other clinical indicators in the non-invasive examination of endometrial malignant lesions. DNA methylation combined with TVS can further improve the specificity and is a promising biomarker triage strategy in women with suspected endometrial lesions.

Crop sensitivity to waterlogging mediated by soil temperature and growth stage.

Waterlogging constrains crop yields in many regions around the world. Despite this, key drivers of crop sensitivity to waterlogging have received little attention. Here, we compare the ability of the SWAGMAN Destiny and CERES models in simulating soil aeration index, a variable contemporaneously used to compute three distinct waterlogging indices, denoted hereafter as WI Destiny, WIASD1, and WIASD2. We then account for effects of crop growth stage and soil temperature on waterlogging impact by introducing waterlogging severity indices, WI Growth, which accommodates growth stage tolerance, and WI Plus, which accounts for both soil temperature and growth stage. We evaluate these indices using data collected in pot experiments with genotypes "Yang mai 11" and "Zheng mai 7698" that were exposed to both single and double waterlogging events. We found that WI Plus exhibited the highest correlation with yield (-0.82 to -0.86) suggesting that waterlogging indices which integrate effects of temperature and growth stage may improve projections of yield penalty elicited by waterlogging. Importantly, WI Plus not only allows insight into physiological determinants, but also lends itself to remote computation through satellite imagery. As such, this index holds promise in scalable monitoring and forecasting of crop waterlogging.