Regulating epithelial-mesenchymal plasticity from 3D genome organization.

Epithelial-mesenchymal transition (EMT) is a dynamic process enabling polarized epithelial cells to acquire mesenchymal features implicated in development and carcinoma progression. As our understanding evolves, it is clear the reversible execution of EMT arises from complex epigenomic regulation involving histone modifications and 3-dimensional (3D) genome structural changes, leading to a cascade of transcriptional events. This review summarizes current knowledge on chromatin organization in EMT, with a focus on hierarchical structures of the 3D genome and chromatin accessibility changes.

[Clinical study on the incidence of femoral head posterior tilt angle in non-displaced femoral neck fractures].

OBJECTIVE: To investigate the occurrence of posterior femoral head tilt after clinical non-displaced femoral neck fracture, and to provide a reference basis for clinical surgery and improvement of disease prognosis. METHODS: Total of 165 patients with non-displaced femoral neck fractures of Garden typeⅠandⅡfrom January 2018 to June 2022 were selected as study subjects including 48 males and 117 females, with an average age of (71.5±8.5) years old ranging from 53 to 89, involving 97 cases of typeⅠand 68 of typeⅡ. On the patient's preoperative sagittal or axial CT film of the hip, the angle formed by the radius line of the femoral head and the midline of the femoral neck was used as the posterior tilt angle of the femoral head (α), and the posterior tilt femoral head angle was measured using the method proposed by Palm. The measured data were divided into 6 groups:α<0°, 0°<α< 5°, 5°≤α<10°, 10°≤α<15°, 15°≤α<20°, α≥20°, and the incidence of different ranges of posterior tilt angle was compared. The sex composition ratio of 165 patients were analyzed and compared, and the age of 65 was used as the cut-off point to compare the incidence of fractures between genders. Patients were divided into the posterior tilt <20° group for 135 cases and the posterior tilt ≥20°group for 30 cases according to the preoperative posterior tilt angle, the differences between two groups in terms of gender and age were analyzed. RESULTS: Among 165 patients with non-displaced femoral neck fractures, 143 cases with poaterior tilt of the femoral head occurred with an incidence of 86.7%. Posterior tilt 0°<α<5° accounted for 36 cases with an incidence of 21.8%;5°≤α<10° accounted for 40 cases with an incidence of 24.2%;10°≤α<15° accounted for 27 cases with an incidence of 16.4%;15°≤α<20° accounted for 10 cases with an incidence of 6.1%;posterior tilt angle α≥20° accounted for 30 cases, the incidence was 18.2%, of which the maximum posterior tilt angle was 42.7°. Statistical analysis showed that the percentage of fractures in the 165 patients selected for this study was significantly higher in female than in male, and that the female group was more likely to have fractures before the age of 65 years compared to the male group. However, gender, age and fracture subtypes (GardenⅠ, Ⅱ) were not influential factors for femoral neck fractures with a preoperative posterior femoral head tilt angle >20°(P>0.05). CONCLUSION: The incidence of femoral head posterior tile in non-displaced femoral neck fractures is relatively high, in which severe posterior tile occurs, and the femoral head posterior tile angle≥20° can reach 18.2%. In patients with closed reduction internal fixation, the fracture end needs to be repositioned as much as possible to reduce the risk of postoperative avascular necrosis of the femoral head. In order to prevent femoral neck fractures, special attention should be paid to anti-osteoporosis treatment for female. Preoperative assessment of posterior tilt is critical for patients of different ages, genders and fracture subtypes (GardenⅠ, Ⅱ).

Albumin-bilirubin grade as a predictor of survival in hepatocellular carcinoma patients with thrombocytopenia.

BACKGROUND: The models for assessing liver function, mainly the Child-Pugh (CP), albuminbilirubin (ALBI), and platelet-ALBI (PALBI) classifications, have been validated for use in estimating the prognosis of hepatocellular carcinoma (HCC) patients. However, thrombocytopenia is a common finding and may influence the prognostic value of the three models in HCC. AIM: To investigate and compare the prognostic performance of the above three models in thrombocytopenic HCC patients. METHODS: A total of 135 patients with thrombocytopenic HCC who underwent radical surgery were retrospectively analyzed. Preoperative scores on the CP, ALBI and PALBI classifications were estimated accordingly. Kaplan-Meier curves with log-rank tests and Cox regression models were used to explore the significant factors associated with overall survival (OS) and recurrence-free survival (RFS). RESULTS: The preoperative platelet counts were significantly different among the CP, ALBI and PALBI groups. After a median follow-up of 28 mo, 39.3% (53/135) of the patients experienced postoperative recurrence, and 36.3% (49/135) died. Univariate analysis suggested that α-fetoprotein levels, tumor size, vascular invasion, and ALBI grade were significant predictors of OS and RFS. According to the multivariate Cox regression model, ALBI was identified as an independent prognostic factor. However, CP and PALBI grades were not statistically significant prognostic indicators. CONCLUSION: The ALBI grade, rather than CP or PALBI grade, is a significant prognostic indicator for thrombocytopenic HCC patients.

Platelet count as a predictor of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma: A systematic review and meta-analysis.

Background: Vascular invasion (VI) indicates highly invasive tumor biological behavior and is a major determining factor of poor survival and high risk of metastasis in hepatocellular carcinoma (HCC). Epidemiological evidence of the association between pretherapeutic platelet count (PLT) and the risk of VI and extrahepatic metastasis in HCC remains controversial. Methods: A systematic retrieval was executed in databases of PubMed, Embase, and Web of Science until Dec 2022. Effect size and 95% confidence interval (CI) were extracted or estimated to synthetically investigate the effects of pretherapeutic PLT on VI and extrahepatic metastasis. Meta-analyses were performed by using a random or a fixed effects model. Results: Finally, the current meta-analysis included 15 studies with a total of 12,378 HCC patients. It was shown that, patients with a higher pretherapeutic level of PLT had a significantly increased risk of VI (11 studies,8,759 patients; OR = 1.44, 95%CI: 1.02-2.02) and extrahepatic metastasis (6 studies,8, 951 patients; OR = 2.51, 95% CI: 2.19-2.88) in comparison with patients with a lower PLT. Funnel plots and Begg's tests indicated that there were no significant publication biases. Conclusion: This meta-analysis shows that pretherapeutic elevated PLT is associated with an increased risk of VI and extrahepatic metastasis in HCC.

"Five steps four quadrants" modularized en bloc dissection technique for accessing hepatic hilum lymph nodes in laparoscopic pancreaticoduodenectomy.

BACKGROUND: Although en bloc dissection of hepatic hilum lymph nodes has many advantages in radical tumor treatment, the feasibility and safety of this approach for laparoscopic pancreaticoduodenectomy (LPD) require further clinical evaluation and investigation. AIM: To explore the application value of the "five steps four quadrants" modularized en bloc dissection technique for accessing hepatic hilum lymph nodes in LPD patients. METHODS: A total of 52 patients who underwent LPD via the "five steps four quadrants" modularized en bloc dissection technique for hepatic hilum lymph nodes from April 2021 to July 2023 in our department were analyzed retrospectively. The patients' body mass index (BMI), preoperative laboratory indices, intraoperative variables and postoperative complications were recorded. The relationships between preoperative data and intraoperative lymph node dissection time and blood loss were also analyzed. RESULTS: Among the 52 patients, 36 were males and 16 were females, and the average age was 62.2 ± 11.0 years. There were 26 patients with pancreatic head cancer, 16 patients with periampullary cancer, and 10 patients with distal bile duct cancer. The BMI was 22.3 ± 3.3 kg/m², and the median total bilirubin (TBIL) concentration was 57.7 (16.0-155.7) µmol/L. All patients successfully underwent the "five steps four quadrants" modularized en bloc dissection technique without lymph node clearance-related complications such as postoperative bleeding or lymphatic leakage. Correlation analysis revealed significant associations between preoperative BMI (r = 0.3581, P = 0.0091), TBIL level (r = 0.2988, P = 0.0341), prothrombin time (r = 0.3018, P = 0.0297) and lymph node dissection time. Moreover, dissection time was significantly correlated with intraoperative blood loss (r = 0.7744, P < 0.0001). Further stratified analysis demonstrated that patients with a preoperative BMI ≥ 21.9 kg/m² and a TIBL concentration ≥ 57.7 µmol/L had significantly longer lymph node dissection times (both P < 0.05). CONCLUSION: The "five steps four quadrants" modularized en bloc dissection technique for accessing the hepatic hilum lymph node is safe and feasible for LPD. This technique is expected to improve the efficiency of hepatic hilum lymph node dissection and shorten the learning curve; thus, it is worthy of further clinical promotion and application.

BCL6 attenuates hyperoxia-induced lung injury by inhibiting NLRP3-mediated inflammation in fetal mouse.

BACKGROUND: The transcriptional repressor B-cell lymphoma 6 (BCL6) has been reported to inhibit inflammation. So far, experimental evidence for the role of BCL6 in bronchopulmonary dysplasia (BPD) is lacking. Our study investigated the roles of BCL6 in the progression of BPD and its downstream mechanisms. METHODS: Hyperoxia or lipopolysaccharide (LPS) was used to mimic the BPD mouse model. To investigate the effects of BCL6 on BPD, recombination adeno-associated virus serotype 9 expressing BCL6 (rAAV9-BCL6) and BCL6 inhibitor FX1 were administered in mice. The pulmonary pathological changes, inflammatory chemokines and NLRP3-related protein were observed. Meanwhile, BCL6 overexpression plasmid was used in human pulmonary microvascular endothelial cells (HPMECs). Cell proliferation, apoptosis, and NLRP3-related protein were detected. RESULTS: Either hyperoxia or LPS suppressed pulmonary BCL6 mRNA expression. rAAV9-BCL6 administration significantly inhibited hyperoxia-induced NLRP3 upregulation and inflammation, attenuated alveolar simplification and dysregulated angiogenesis in BPD mice, which were characterized by decreased mean linear intercept, increased radical alveolar count and alveoli numbers, and the upregulated CD31 expression. Meanwhile, BCL6 overexpression promoted proliferation and angiogenesis, inhibited apoptosis and inflammation in hyperoxia-stimulated HPMECs. Moreover, administration of BCL6 inhibitor FX1 arrested growth and development. FX1-treated BPD mice exhibited exacerbation of alveolar pathological changes and pulmonary vessel permeability, with upregulated mRNA levels of pro-inflammatory cytokines and pro-fibrogenic factors. Furthermore, both rAAV9-BCL6 and FX1 administration exerted a long-lasting effect on hyperoxia-induced lung injury (≥4 wk). CONCLUSIONS: BCL6 inhibits NLRP3-mediated inflammation, attenuates alveolar simplification and dysregulated pulmonary vessel development in hyperoxia-induced BPD mice. Hence, BCL6 may be a target in treating BPD and neonatal diseases.

Lactiplantibacillus plantarum and Saccharomyces cerevisiae-Fermented Coconut Water Alleviates Dextran Sodium Sulfate-Induced Enteritis in Wenchang Chicken: A Gut Microbiota and Metabolomic Approach.

In order to investigate the potential mechanisms of probiotic-fermented coconut water in treating enteritis, this study conducted a comprehensive analysis of the effects of probiotic intervention on the recovery from Dextran Sodium Sulfate-induced acute enteritis in Wenchang chicks. The analysis encompassed the assessment of growth performance, serum indicators, intestinal tissue structure, and metagenomic and metabolomic profiles of cecal contents in 60 Wenchang chicks subjected to intervention. This approach aimed to elucidate the impact of probiotic intervention on the recovery process from acute enteritis at both the genetic and metabolic levels in the avian model. The results revealed that intervention with Saccharomyces cerevisiae Y301 improved the growth rate of chicks. and intervention with Lactiplantibacillus plantarum MS2c regulated the glycerophospholipid metabolism pathway and reshaped the gut microbiota structure in modeling chicks with acute enteritis, reducing the abundance of potentially pathogenic bacteria from the Alistipes and increasing the abundance of potentially beneficial species from the Christensenellaceae. This intervention resulted in the production of specific gut metabolites, including Gentamicin C and polymyxin B2, recognized for their therapeutic effects on acute enteritis. The combined intervention of S. cerevisiae Y301 and L. plantarum MS2c not only enhanced growth performance but also mitigated intestinal wall damage and increased the abundance of gut metabolites such as gentamicin C and polymyxin B2, thereby mitigating symptoms of enteritis. Furthermore, this combined intervention reduced the levels of serum immune markers, including IL-10, IL-6, TNF-α, IFN-γ, and D-lactic acid, thus mitigating intestinal epithelial cell damage and promoting acute enteritis recovery. This study provides crucial insights into the mechanisms of action of probiotics and probiotic-fermented coconut water in acute enteritis recovery, offering new perspectives for sustainable farming practices for Wenchang chicken.

Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.

BACKGROUND: Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype. METHODS: We integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells and public clinical datasets to identify key protein kinases implicated in temozolomide resistance. RNAseq, apoptosis assays, and comet assays were used to examine the role of p38MAPK signaling and adaptive chemoresistance in mesenchymal cells. The efficacy of dual p38MAPK and MEK/ERK inhibition using ralimetinib (selective orally active p38MAPK inhibitor; phase I/II for glioblastoma) and binimetinib (approved MEK1/2 inhibitor for melanoma; phase II for high-grade glioma) in primary and recurrent mesenchymal tumors was evaluated using an intracranial patient-derived tumor xenograft model, focusing on survival analysis. RESULTS: Our transcriptomic-kinomic integrative analysis revealed p38MAPK as the prime target whose gene signature enables patient stratification based on their molecular subtypes and provides prognostic value. Repurposed p38MAPK inhibitors synergize favorably with temozolomide to promote intracellular retention of temozolomide and exacerbate DNA damage. Mesenchymal cells exhibit adaptive chemoresistance to p38MAPK inhibition through a pH-/calcium-mediated MEK/ERK pathway. Dual p38MAPK and MEK inhibition effectively maintain temozolomide sensitivity in primary and recurrent intracranial mesenchymal glioblastoma xenografts. CONCLUSIONS: Temozolomide resistance in mesenchymal glioblastoma is associated with p38MAPK activation. Adaptive chemoresistance in p38MAPK-resistant cells is mediated by MEK/ERK signaling. Adjuvant therapy with dual p38MAPK and MEK inhibition prolongs temozolomide sensitivity, which can be developed into a precision therapy for the mesenchymal subtype.

Exploring the biotic and abiotic drivers influencing nata de coco production by Komagataeibacter nataicola in pre-fermented coconut water.

In China and Southeast Asia, pre-fermented coconut water is commonly used for the production of nata de coco, a jelly-like fermented food that consists of bacterial cellulose (BC). The inherent natural fermentation process of coconut water introduces uncontrollable variables, which can lead to unstable yields during BC production. This study involved the collection of spontaneously pre-fermented coconut water over a five-month production cycle. The aim was to evaluate the microbiota and metabolite profile, as well as determine its impact on BC synthesis by Komagataeibacter nataicola. Significant variations in the microbial community structure and metabolite profile of pre-fermented coconut water were observed across different production months, these variations had significant effects on BC synthesis by K. nataicola. A total of 52 different bacterial genera and 32 different fungal genera were identified as potential biotic factors that can influence BC production. Additionally, several abiotic factors, including lactate (VIP = 4.92), mannitol (VIP = 4.22), ethanol (VIP = 2.67), and ascorbate (VIP = 1.61), were found to be potential driving forces affecting BC synthesis by K. nataicola. Upon further analysis, the correlation network indicated that 14 biotic factors had a significant contribution to BC production in three strains of K. nataicola. These factors included 8 bacterial genera, such as Limosilactobacillus and Lactiplantibacillus, and 6 fungal genera, such as Meyerozyma and Ogataea. The abiotic factors lactate, mannitol, and ethanol showed a positive correlation with the BC yield. This study provides significant insights into controlling the fermentation processes of pre-fermented coconut water in industrial settings.

CDC123 promotes Hepatocellular Carcinoma malignant progression by regulating CDKAL1.

The cell proliferation protein 123 (CDC123) is involved in the synthesis of the eukaryotic initiation factor 2 (eIF2), which regulates eukaryotic translation. Although CDC123 is considered a candidate oncogene in breast cancer, its expression and role in Hepatocellular Carcinoma (HCC) remain unknown. Herein, we obtained the CDC123 RNA-seq and clinical prognostic data from the TCGA database. The mRNA level revealed that CDC123 was highly expressed in HCC patients, and Kaplan-Meier analysis implied better prognoses in HCC patients with low CDC123 expression (P < 0.001). The multivariate Cox analysis revealed that the CDC123 level was an independent prognostic factor (P < 0.001). We further confirmed a high CDC123 expression in HCC cell lines. Additionally, we found that CDC123 knockdown in HCC cell lines significantly inhibited cellular proliferation, invasion, and migration. Moreover, CDC123 was co-expressed with the CDK5 Regulatory Subunit-Associated Protein 1 Like 1 (CDKAL1), whose mRNA level was decreased after silencing CDC123. Therefore, we hypothesized that CDC123 promotes HCC progression by regulating CDKAL1.

Nrf2/PHB2 alleviates mitochondrial damage and protects against Staphylococcus aureus-induced acute lung injury.

Staphylococcus aureus (SA) is a major cause of sepsis, leading to acute lung injury (ALI) characterized by inflammation and oxidative stress. However, the role of the Nrf2/PHB2 pathway in SA-induced ALI (SA-ALI) remains unclear. In this study, serum samples were collected from SA-sepsis patients, and a SA-ALI mouse model was established by grouping WT and Nrf2-/- mice after 6 h of intraperitoneal injection. A cell model simulating SA-ALI was developed using lipoteichoic acid (LTA) treatment. The results showed reduced serum Nrf2 levels in SA-sepsis patients, negatively correlated with the severity of ALI. In SA-ALI mice, downregulation of Nrf2 impaired mitochondrial function and exacerbated inflammation-induced ALI. Moreover, PHB2 translocation from mitochondria to the cytoplasm was observed in SA-ALI. The p-Nrf2/total-Nrf2 ratio increased in A549 cells with LTA concentration and treatment duration. Nrf2 overexpression in LTA-treated A549 cells elevated PHB2 content on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division. Bioinformatic analysis and dual-luciferase reporter assay confirmed direct binding of Nrf2 to the PHB2 promoter, resulting in increased PHB2 expression. In conclusion, Nrf2 plays a role in alleviating SA-ALI by directly regulating PHB2 transcription and maintaining mitochondrial function in lung cells.

[Research progress of caput femoris posterior tilt and its impact on prognosis in nondisplaced femoral neck fractures].

There are still many unresolved problems in the treatment and prognosis of nondisplaced femoral neck fractures, such as nonunion and avascular necrosis of the caput femoris .In order to reduce the risk of various complications after non-displaced femoral neck fractures, the caput femoris posterior tilt of femoral neck fractures and its impact on prognosis have attracted more and more attention. A large number of scholars' studies have found that when the posterior tilt exceeds 20°, the risk of internal fixation failure increases significantly. Based on this concept, we can choose to use primary artificial joint replacement instead of three-screw internal fixation according to the different posterior tilt angles of patients to reduce the incidence of postoperative complications. At the same time, our analysis found that comminution of the posterior segment of the femoral neck would lead to an increase in the posterior inclination angles. The purpose of this review was to investigate the relationship between caput femoris posterior tilt of femoral neck fractures and surgical outcome, and to introduce a new method for measuring caput femoris posterior tilt of the femoral neck.

FOXA1/MND1/TKT axis regulates gastric cancer progression and oxaliplatin sensitivity via PI3K/AKT signaling pathway.

BACKGROUND: Drug resistance is a main factor affecting the chemotherapy efficacy of gastric cancer (GC), in which meiosis plays an important role. Therefore, it is urgent to explore the effect of meiosis related genes on chemotherapy resistance. METHODS: The expression of meiotic nuclear divisions 1 (MND1) in GC was detected by using TCGA and clinical specimens. In vitro and in vivo assays were used to investigate the effects of MND1. The molecular mechanism was determined using luciferase reporter assay, CO-IP and mass spectrometry (MS). RESULTS: Through bioinformatics, we found that MND1 was highly expressed in platinum-resistant samples. In vitro experiments showed that interference of MND1 significantly inhibited the progression of GC and increased the sensitivity to oxaliplatin. MND1 was significantly higher in 159 GC tissues in comparison with the matched adjacent normal tissues. In addition, overexpression of MND1 was associated with worse survival, advanced TNM stage, and lower pathological grade in patients with GC. Further investigation revealed that forkhead box protein A1 (FOXA1) directly binds to the promoter of MND1 to inhibit its transcription. CO-IP and MS assays showed that MND1 was coexpressed with transketolase (TKT). In addition,TKT activated the PI3K/AKT signaling axis and enhanced the glucose uptake and lactate production in GC cells. CONCLUSIONS: Our results confirm that FOXA1 inhibits the expression of MND1, which can directly bind to TKT to promote GC progression and reduce oxaliplatin sensitivity through the PI3K/AKT signaling pathway.

[Risk factors for neonatal asphyxia and establishment of a nomogram model for predicting neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture: a multicenter study]. / æ¹–åŒ—æ©æ–½åœŸå®¶æ—è‹—æ—è‡ªæ²»å·žæ–°ç”Ÿå„¿çª’æ¯å±é™©å› ç´ åˆ†æžåŠåˆ—çº¿å›¾é¢„æµ‹æ¨¡åž‹çš„æž„å»ºï¼šä¸€é¡¹å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the risk factors for neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture and establish a nomogram model for predicting the risk of neonatal asphyxia. METHODS: A retrospective study was conducted with 613 cases of neonatal asphyxia treated in 20 cooperative hospitals in Enshi Tujia and Miao Autonomous Prefecture from January to December 2019 as the asphyxia group, and 988 randomly selected non-asphyxia neonates born and admitted to the neonatology department of these hospitals during the same period as the control group. Univariate and multivariate analyses were used to identify risk factors for neonatal asphyxia. R software (4.2.2) was used to establish a nomogram model. Receiver operator characteristic curve, calibration curve, and decision curve analysis were used to assess the discrimination, calibration, and clinical usefulness of the model for predicting the risk of neonatal asphyxia, respectively. RESULTS: Multivariate logistic regression analysis showed that minority (Tujia), male sex, premature birth, congenital malformations, abnormal fetal position, intrauterine distress, maternal occupation as a farmer, education level below high school, fewer than 9 prenatal check-ups, threatened abortion, abnormal umbilical cord, abnormal amniotic fluid, placenta previa, abruptio placentae, emergency caesarean section, and assisted delivery were independent risk factors for neonatal asphyxia (P<0.05). The area under the curve of the model for predicting the risk of neonatal asphyxia based on these risk factors was 0.748 (95%CI: 0.723-0.772). The calibration curve indicated high accuracy of the model for predicting the risk of neonatal asphyxia. The decision curve analysis showed that the model could provide a higher net benefit for neonates at risk of asphyxia. CONCLUSIONS: The risk factors for neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture are multifactorial, and the nomogram model based on these factors has good value in predicting the risk of neonatal asphyxia, which can help clinicians identify neonates at high risk of asphyxia early, and reduce the incidence of neonatal asphyxia.

Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma Using an Advanced Human In Vitro Model of the Blood-Brain Barrier and Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain cancer in adults with a dismal prognosis. Temozolomide (TMZ) is the first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment, particularly the blood-brain barrier (BBB), is unknown. Here, the authors investigate these using a complex in vitro model for GBM and its surrounding BBB. The model recapitulates important clinical features such as a dense tumor core with tumor cells that invade along the perivascular space; and a perfusable BBB with a physiological permeability and morphology that is altered in the presence of a tumor spheroid. It is demonstrated that TMZ sensitivity decreases with increasing cancer cell spatial organization, and that the BBB can contribute to TMZ resistance. Proteomic analysis with next-generation low volume sample workflows of these cultured microtissues revealed potential clinically relevant proteins involved in tumor aggressiveness and TMZ resistance, demonstrating the utility of complex in vitro models for interrogating the tumor microenvironment and therapy validation.

Multiplexed RNA profiling by regenerative catalysis enables blood-based subtyping of brain tumors.

Current technologies to subtype glioblastoma (GBM), the most lethal brain tumor, require highly invasive brain biopsies. Here, we develop a dedicated analytical platform to achieve direct and multiplexed profiling of circulating RNAs in extracellular vesicles for blood-based GBM characterization. The technology, termed 'enzyme ZIF-8 complexes for regenerative and catalytic digital detection of RNA' (EZ-READ), leverages an RNA-responsive transducer to regeneratively convert and catalytically enhance signals from rare RNA targets. Each transducer comprises hybrid complexes - protein enzymes encapsulated within metal organic frameworks - to configure strong catalytic activity and robust protection. Upon target RNA hybridization, the transducer activates directly to liberate catalytic complexes, in a target-recyclable manner; when partitioned within a microfluidic device, these complexes can individually catalyze strong chemifluorescence reactions for digital RNA quantification. The EZ-READ platform thus enables programmable and reliable RNA detection, across different-sized RNA subtypes (miRNA and mRNA), directly in sample lysates. When clinically evaluated, the EZ-READ platform established composite signatures for accurate blood-based GBM diagnosis and subtyping.

MiR-155-5p Attenuates Vascular Smooth Muscle Cell Oxidative Stress and Migration via Inhibiting BACH1 Expression.

The malfunction of vascular smooth muscle cells (VSMCs) is an initiating factor in the pathogenesis of pathological vascular remodeling, including hypertension-related vascular lesions. MicroRNAs (miRNAs) have been implicated in the pathogenesis of VSMC proliferation and migration in numerous cases of cardiovascular remodeling. The evidence for the regulatory role of miR-155-5p in the development of the cardiovascular system has been emerging. However, it was previously unclear whether miR-155-5p participated in the migration of VSMCs under hypertensive conditions. Thus, we aimed to define the exact role and action of miR-155-5p in VSMC migration by hypertension. Here, we detected that the level of miR-155-5p was lower in primary VSMCs from spontaneously hypertensive rats (SHRs). Its overexpression attenuated, while its depletion accelerated, the migration and oxidative damage of VSMCs from SHRs. Our dual-luciferase reporter assay showed that miRNA-155-5p directly targeted the 3'-untranslated region (3'-UTR) of BTB and CNC homology 1 (BACH1). The miR-155-5p mimic inhibited BACH1 upregulation in SHR VSMCs. By contrast, the deletion of miR-155-5p further elevated the upregulation of BACH1 in SHR-derived VSMCs. Importantly, the overexpression of miR-155-5p and knockdown of BACH1 had synergistic effects on the inhibition of VSMCs in hypertension. Collectively, miR-155-5p attenuates VSMC migration and ameliorates vascular remodeling in SHRs, via suppressing BACH1 expression.

4-OI ameliorates bleomycin-induced pulmonary fibrosis by activating Nrf2 and suppressing macrophage-mediated epithelial-mesenchymal transition.

OBJECTIVES: Pulmonary fibrosis (PF) is a chronic and refractory interstitial lung disease with limited therapeutic options. 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, has been shown to have anti-oxidative and anti-inflammatory properties. However, the effect and the underlying mechanism of 4-OI on PF are still unknown. METHODS: WT or Nrf2 knockout (Nrf2-/-) mice were intratracheally injected with bleomycin (BLM) to establish PF model and then treated with 4-OI. The mechanism study was performed by using RAW264.7 cells, primary macrophages, and conditional medium-cultured MLE-12 cells. RESULTS: 4-OI significantly alleviated BLM-induced PF and EMT process. Mechanism studies have found that 4-OI can not only directly inhibit EMT process, but also can reduce the production of TGF-ß1 by restraining macrophage M2 polarization, which in turn inhibits EMT process. Moreover, the effect of 4-OI on PF and EMT depends on Nrf2. CONCLUSION: 4-OI ameliorates BLM-induced PF in an Nrf2-dependent manner, and its role in alleviating PF is partly due to the direct inhibition on EMT, and partly through indirect inhibition of M2-mediated EMT. These findings suggested that 4-OI has great clinical potential to develop as a new anti-fibrotic agent for PF therapy.

Facet modulation of nickel-ruthenium nanocrystals for efficient electrocatalytic hydrogen evolution.

Constructing highly active electrocatalysts towards hydrogen evolution reaction (HER) in both alkaline and acidic media is essential for achieving a sustainable energy economy. Here, a facile ethylene glycol reduction strategy was employed to design the nickel-ruthenium nanocrystals (Ni-Ru NC) with an exposed highly active Ru (101) facet as an efficient electrocatalyst for HER. Testings show Ni-Ru NC outperforms the benchmark catalyst Pt/C by delivering extraordinarily low overpotentials of 21.1 and 70.9 mV to drive 10 mA cm-2 in acidic and alkaline solutions, respectively. The results of experimental and theoretical studies suggest that Ni can modulate the electronic structure of the Ru NC and optimize the hydrogen adsorption free energy on Ru's surface, which accelerates the charge transfer kinetics and enhances the HER performance. The study support the potential application of facet-modulated Ru-based HER eleccatalyst in an alkaline environment.