SPINK4 modulates inhibition of glycolysis against colorectal cancer progression.

Dysregulation of glycolysis is frequently linked to aggressive tumor activity in colorectal cancer (CRC). Although serine peptidase inhibitor, Kazal type 4 (SPINK4) has been linked to CRC, its exact linkage to glycolytic processes and gene expression remains unclear. Differentially expressed genes (DEGs) were screened from two CRC-related datasets (GSE32323 and GSE141174), followed by expression and prognostic analysis of SPINK4. In vitro techniques such as flow cytometry, western blotting, transwell assay, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to assess SPINK4 expression in CRC cells. Its effects on apoptosis, glycolysis, and the cell cycle were also investigated. Finally, the impact of SPINK4 overexpression on tumor development was assessed using a xenograft model, while histological and immunohistochemical analyses characterized SPINK4 expression patterns in CRC tissues. SPINK4 expression was downregulated in CRC, correlating with poor patient prognosis. In vitro assays confirmed that overexpression of SPINK4 reduced CRC cell proliferation, invasion, and migration, while its knockdown promoted these processes and caused G1 arrest. SPINK4 also regulated apoptosis by altering caspase activation and Bcl-2 expression. Besides, SPINK4 overexpression altered glycolytic activity, reduced 2-Deoxy-D-glucose (2-DG) absorption, and controlled critical glycolytic enzymes, resulting in alterations in metabolic pathways, whereas SPINK4 knockdown reversed this effect. SPINK4 overexpression significantly reduced tumor volume in vivo, indicating its inhibitory role in carcinogenesis. Moreover, high expression of SPINK4, hexokinase 2 (HK2), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and pyruvate kinase M2 (PKM2) was observed in CRC tissues. As a key inhibitor of glycolytic metabolism in CRC, SPINK4 promises metabolic intervention in CRC therapy due to its impact on tumor growth and cell proliferation.

Chemokines and lymphocyte homing in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4ß7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-ß, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-ß receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.

A Rapid Self-Assembling Peptide Hydrogel for Delivery of TFF3 to Promote Gastric Mucosal Injury Repair.

Self-assembled peptide-based nanobiomaterials exhibit promising prospects for drug delivery applications owing to their commendable biocompatibility and biodegradability, facile tissue uptake and utilization, and minimal or negligible unexpected toxicity. TFF3 is an active peptide autonomously secreted by gastric mucosal cells, possessing multiple biological functions. It acts on the surface of the gastric mucosa, facilitating the repair process of gastric mucosal damage. However, when used as a drug, TFF3 faces significant challenges, including short retention time in the gastric mucosal cavity and deactivation due to degradation by stomach acid. In response to this challenge, we developed a self-assembled short peptide hydrogel, Rqdl10, designed as a delivery vehicle for TFF3. Our investigation encompasses an assessment of its properties, biocompatibility, controlled release of TFF3, and the mechanism underlying the promotion of gastric mucosal injury repair. Congo red/aniline blue staining revealed that Rqdl10 promptly self-assembled in PBS, forming hydrogels. Circular dichroism spectra indicated the presence of a stable ß-sheet secondary structure in the Rqdl10 hydrogel. Cryo-scanning electron microscopy and atomic force microscopy observations demonstrated that the Rqdl10 formed vesicle-like structures in the PBS, which were interconnected to construct a three-dimensional nanostructure. Moreover, the Rqdl10 hydrogel exhibited outstanding biocompatibility and could sustainably and slowly release TFF3. The utilization of the Rqdl10 hydrogel as a carrier for TFF3 substantially augmented its proliferative and migratory capabilities, while concurrently bolstering its anti-inflammatory and anti-apoptotic attributes following gastric mucosal injury. Our findings underscore the immense potential of the self-assembled peptide hydrogel Rqdl10 for biomedical applications, promising significant contributions to healthcare science.

Machine learning and optical coherence tomography-derived radiomics analysis to predict persistent diabetic macular edema in patients undergoing anti-VEGF intravitreal therapy.

BACKGROUND: Diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. This study aimed to develop and evaluate an OCT-omics prediction model for assessing anti-vascular endothelial growth factor (VEGF) treatment response in patients with DME. METHODS: A retrospective analysis of 113 eyes from 82 patients with DME was conducted. Comprehensive feature engineering was applied to clinical and optical coherence tomography (OCT) data. Logistic regression, support vector machine (SVM), and backpropagation neural network (BPNN) classifiers were trained using a training set of 79 eyes, and evaluated on a test set of 34 eyes. Clinical implications of the OCT-omics prediction model were assessed by decision curve analysis. Performance metrics (sensitivity, specificity, F1 score, and AUC) were calculated. RESULTS: The logistic, SVM, and BPNN classifiers demonstrated robust discriminative abilities in both the training and test sets. In the training set, the logistic classifier achieved a sensitivity of 0.904, specificity of 0.741, F1 score of 0.887, and AUC of 0.910. The SVM classifier showed a sensitivity of 0.923, specificity of 0.667, F1 score of 0.881, and AUC of 0.897. The BPNN classifier exhibited a sensitivity of 0.962, specificity of 0.926, F1 score of 0.962, and AUC of 0.982. Similar discriminative capabilities were maintained in the test set. The OCT-omics scores were significantly higher in the non-persistent DME group than in the persistent DME group (p < 0.001). OCT-omics scores were also positively correlated with the rate of decline in central subfield thickness after treatment (Pearson's R = 0.44, p < 0.001). CONCLUSION: The developed OCT-omics model accurately assesses anti-VEGF treatment response in DME patients. The model's robust performance and clinical implications highlight its utility as a non-invasive tool for personalized treatment prediction and retinal pathology assessment.

The value of lung function assessment and Testin expression detection in clinicopathological features and prognosis of NSCLC patients.

OBJECTIVE: The aim of this study is to investigate the clinical value and potential prognostic significance of lung function assessment and Testin expression in non-small cell lung cancer (NSCLC) patients. METHODS: The NSCLC patients were classified into three groups according to lung function: group of normal lung function, group of PRISm (preserved ratio impaired spirometry) (FEV1, forced expiratory volume during the first second < 80% predicted and FEV1/FVC (forced vital capacity) ≥ 70%) and group of COPD (chronic obstructive pulmonary disease) (FEV1/FVC < 70%). The pre-operational clinicopathological characteristics of these patients were recorded and the markers of systemic inflammatory response, including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and eosinophils (EOS), were compared between three groups. The expression of Testin in NSCLC samples was detected by IHC and we further explored the correlation between Testin expression and clinicopathological characteristics and prognosis of NSCLC patients. Finally, Cox regression analysis was conducted to study the prognostic factors of NSCLC patients. RESULTS: Of the 158 NSCLC patients, percentages of normal lung function, PRISm and COPD were 41.4%, 22.8% and 36.1%, respectively. Patients with tumor in the left lung were more likely to have pulmonary dysfunction (PRISm and COPD) than the right lung. The markers of systemic inflammatory response showed differences to various degree in the three groups and NSCLC patients with PRISm or COPD presented more unfavorable prognosis than patients with normal function. The expression of Testin correlated with lymph node metastasis, TNM stage and tumor invasion of NSCLC patients. Moreover, patients with low Testin expression exhibited poorer disease-free survival and overall survival than those with high Testin expression. In Cox regression analysis, we found that PRISm, COPD and Testin expression served as prognostic factors in NSCLC patients. CONCLUSIONS: The presence of COPD or PRISm influenced systemic inflammatory response and prognosis of NSCLC patients. Testin expression correlated with clinicopathological features and could be potentially used as a prognostic marker in NSCLC.

Diagnostic value of HPV E6/E7 mRNA in screening for cervical intraepithelial neoplasia grade 2 or worse: A systematic review and meta­analysis.

Histology is considered the gold standard for diagnosing the pathological progress of cervical cancer development, while cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) is the cutoff for intervention in clinical practice. The diagnostic value of human papillomavirus (HPV) E6/E7 mRNA in screening for CIN2+ has not been systematically summarized. A meta-analysis was conducted as part of the present study conducted to explore the diagnostic value of HPV E6/E7 mRNA in screening for CIN2+, aiming to provide a new marker for earlier clinical diagnosis of cervical cancer. The PubMed, Embase and Cochrane Library databases were searched from inception to May 2023. Studies reporting the true positive, false positive, true negative and false negative values in differentiating between CIN2+ and CIN2- were included, while duplicate publications, studies without full text, incomplete information or inability to conduct data extraction, animal experiments, reviews and systematic reviews were excluded. STATA software was used to analyze the data. A total of 2,224 patients were included of whom there were 1,274 patients with CIN2+ and 950 patients with CIN2-. The pooled sensitivity and specificity of the studies overall were 0.89 (95% CI, 0.84-0.92) and 0.59 (95% CI, 0.46-0.71), respectively; the positive likelihood ratio (LR) and the negative LR of the studies overall were 2.31 (95% CI, 1.61-3.32) and 0.21 (95% CI, 0.14-0.30), respectively. The pooled diagnostic odds ratio of the studies overall was 11.53 (95% CI, 6.85-19.36). Additionally, the area under the curve was 0.88. The analysis indicated that HPV E6/E7 mRNA has high diagnostic efficacy for CIN2+. HPV E6/E7 mRNA is highly sensitive in the diagnosis of CIN2+, which helps to reduce the rate of missed diagnoses. However, lower specificity may lead to a higher number of misdiagnoses in healthy patients.

Skin mottling score assesses peripheral tissue hypoperfusion in critically ill patients following cardiac surgery.

BACKGROUND: Skin mottling is a common manifestation of peripheral tissue hypoperfusion, and its severity can be described using the skin mottling score (SMS). This study aims to evaluate the value of the SMS in detecting peripheral tissue hypoperfusion in critically ill patients following cardiac surgery. METHODS: Critically ill patients following cardiac surgery with risk factors for tissue hypoperfusion were enrolled (n = 373). Among these overall patients, we further defined a hypotension population (n = 178) and a shock population (n = 51). Hemodynamic and perfusion parameters were recorded. The primary outcome was peripheral hypoperfusion, defined as significant prolonged capillary refill time (CRT, > 3.0 s). The characteristics and hospital mortality of patients with and without skin mottling were compared. The area under receiver operating characteristic curves (AUROC) were used to assess the accuracy of SMS in detecting peripheral hypoperfusion. Besides, the relationships between SMS and conventional hemodynamic and perfusion parameters were investigated, and the factors most associated with the presence of skin mottling were identified. RESULTS: Of the 373-case overall population, 13 (3.5%) patients exhibited skin mottling, with SMS ranging from 1 to 5 (5, 1, 2, 2, and 3 cases, respectively). Patients with mottling had lower mean arterial pressure, higher vasopressor dose, less urine output (UO), higher CRT, lactate levels and hospital mortality (84.6% vs. 12.2%, p < 0.001). The occurrences of skin mottling were higher in hypotension population and shock population, reaching 5.6% and 15.7%, respectively. The AUROC for SMS to identify peripheral hypoperfusion was 0.64, 0.68, and 0.81 in the overall, hypotension, and shock populations, respectively. The optimal SMS threshold was 1, which corresponded to specificities of 98, 97 and 91 and sensitivities of 29, 38 and 67 in the three populations (overall, hypotension and shock). The correlation of UO, lactate, CRT and vasopressor dose with SMS was significant, among them, UO and CRT were identified as two major factors associated with the presence of skin mottling. CONCLUSION: In critically ill patients following cardiac surgery, SMS is a very specific yet less sensitive parameter for detecting peripheral tissue hypoperfusion.

Clinical significance and potential pathogenesis of VCAN in adult non-cystic fibrosis bronchiectasis: a retrospective study.

BACKGROUND: The pathogenesis of adult non-cystic fibrosis (CF) bronchiectasis is complex, and the relevant molecular mechanism remains ambiguous. Versican (VCAN) is a key factor in inflammation through interactions with adhesion molecules. This study constructs a stable panoramic map of mRNA, reveals the possible pathogenesis of bronchiectasis, and provides new ideas and methods for bronchiectasis. METHODS: Peripheral blood and tissue gene expression data from patients with bronchiectasis and normal control were selected by bioinformatics analysis. The expression of VCAN in peripheral blood and bronchial tissues of bronchiectasis were obtained by transcriptome sequencing. The protein expression levels of VCAN in serums were verified by the enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of VCAN in co-culture of Pseudomonas aeruginosa and bronchial epithelial cells were verified by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the biological function of VCAN was detected by the transwell assay. RESULTS: The expression of VCAN was upregulated in the bronchiectasis group by sequencing analysis (P < 0.001). The expression of VCAN in the bronchial epithelial cell line BEAS-2B was increased in P. aeruginosa (P.a), which was co-cultured with BEAS-2B cells (P < 0.05). The concentration of VCAN protein in the serum of patients with bronchiectasis was higher than that in the normal control group (P < 0.05). Transwell experiments showed that exogenous VCAN protein induced the migration of neutrophils (P < 0.0001). CONCLUSIONS: Our findings indicate that VCAN may be involved in the development of bronchiectasis by increasing the migration of neutrophils and play an important role in bronchial pathogenesis.

m 6 A reader IGF2BP1 reduces the sensitivity of nasopharyngeal carcinoma cells to Taxol by upregulation of AKT2.

Taxol is widely used in the treatment of nasopharyngeal carcinoma (NPC); nevertheless, the acquired resistance of NPC to Taxol remains one of the major obstacles in clinical treatment. In this study, we aimed to investigate the role and mechanism of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in Taxol resistance of NPC. Taxol-resistant NPC cell lines were established by exposing to gradually increased concentration of Taxol. Relative mRNA and protein levels were tested using qRT-PCR and western blot, respectively. NPC cell viability and apoptosis were assessed by cell counting kit-8 and flow cytometry analysis, respectively. Cell migration and invasion capacities were measured using transwell assay. Interaction between IGF2BP1 and AKT2 was examined by RNA immunoprecipitation assay. The N6-methyladenosine level of AKT2 was tested using methylated RNA immunoprecipitation-qPCR. IGF2BP1 expression was enhanced in Taxol-resistant NPC cell lines. Knockdown of IGF2BP1 strikingly enhanced the sensitivity of NPC cells to Taxol and repressed the migration and invasion of NPC cells. Mechanistically, IGF2BP1 elevated the expression of AKT2 by increasing its mRNA stability. Furthermore, overexpression of AKT2 reversed the inhibitory roles of IGF2BP1 silence on Taxol resistance and metastasis. Our results indicated that IGF2BP1 knockdown enhanced the sensitivity of NPC cells to Taxol by decreasing the expression of AKT2, implying that IGF2BP1 might be promising candidate target for NPC treatment.

Novel insights into post-marketing adverse events associated with lenvatinib: A comprehensive analysis utilizing the FAERS database.

Purpose: The primary aim of this study was to closely monitor and identify adverse events (AEs) linked to lenvatinib, a pharmacotherapeutic agent employed for the management of renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. The ultimate goal was to optimize patient safety and provide evidence-based guidance for the appropriate utilization of this medication. Methods: A comprehensive collection and analysis of reports from the FDA Adverse Event Reporting System (FAERS) database was conducted, encompassing the period from the first quarter of 2015 to the first quarter of 2023. Disproportionality analysis, employing robust algorithms including ROR, PRR, BCPNN, and EBGM was employed for effective data mining to quantify signals associated with lenvatinib-related AEs. Results: Among the collected reports, a total of 15,193 cases were identified where lenvatinib was the "primary suspected (PS)" drug, resulting in 50,508 lenvatinib-induced AEs. An analysis was conducted to examine the occurrence of lenvatinib-induced adverse drug reactions (ADRs) across 26 organ systems. The findings revealed the presence of expected ADRs, including diarrhea, vomiting, stomatitis, hepatic encephalopathy, decreased appetite, dehydration, decreased weight, and electrolyte imbalances, which were consistent with the information provided in the drug labels. Furthermore, unexpected significant ADRs were observed at the preferred terms (PT) level, such as interstitial lung disease, pneumothorax, hypophysitis, failure to thrive, polycythemia, hypopituitarism, spontaneous pneumothorax, pulmonary cavitation, and limbic encephalitis. These findings indicated the potential occurrence of adverse effects that are currently not documented in the drug instructions. Conclusions: This study has successfully detected novel and unforeseen signals pertaining to ADRs associated with the administration of lenvatinib, thereby contributing significant insights into the intricate correlation between ADRs and the utilization of lenvatinib. The outcomes of this investigation underscore the utmost significance of continuous monitoring and vigilant surveillance in order to promptly identify and effectively manage AEs, consequently enhancing overall patient safety and well-being in the context of lenvatinib therapy.

Identification and validation of prognostic and immunotherapeutic responses in esophageal squamous carcinoma based on hypoxia phenotype-related genes.

The study aimed to investigate the clinical significance of the interaction between hypoxia and the immune system in esophageal squamous cell carcinoma (ESCC) microenvironment. A comprehensive evaluation of 13 hypoxia phenotype-related genes (HPRs) was conducted using data from TCGA-ESCC and two GEO cohorts. Three distinct HPRclusters were identified, and the HPRscore was established as an independent prognostic factor (p = 0.001), with higher scores indicating poorer prognosis. The HPRscore was validated in various immunotherapy cohorts, demonstrating its efficacy in evaluating immunotherapy and chemotherapy outcomes. Additionally, phenome-wide association study (PheWAS) analysis showed that PKP1 had no significant correlation with other traits at the gene level. PKP1 was identified as a potential prognostic marker for ESCC, with upregulated expression observed in ESCC patients. In vitro experiments showed that the knockdown of PKP1 inhibited ESCC cell proliferation and migration. These findings suggest that the novel HPRscore and PKP1 may serve as prognostic tools and therapeutic targets for ESCC patients.

Interleukin-10: a novel metabolic inducer of macrophage differentiation and subsequently contributing to improved pregnancy outcomes of mice by orchestrating oxidative phosphorylation metabolism.

Metabolism regulates the phenotype and function of macrophages. After recruitment to local tissues, monocytes are influenced by the local microenvironment and differentiate into various macrophages depending on different metabolic pathways. However, the metabolic mechanisms underlying decidual macrophage differentiation remain unknown. Interleukin-10 (IL-10) is an important decidual macrophage inducer and promotes oxidative phosphorylation (OXPHOS) of bone marrow-derived macrophages. In this study, we mainly investigate the metabolic changes involved in IL-10 generated macrophages from monocytes using in vitro models. We demonstrate that exposure of monocytes (either peripheral or THP-1) to IL-10 altered the phenotype and function of resultant macrophages that is linked with OXPHOS changes. IL-10 enhanced the mitochondrial complex I and III activity of THP-1 cell-differentiated macrophages and increased the mitochondrial membrane potential, intracellular adenosine triphosphate, and reactive oxygen species levels. OXPHOS blockage with oligomycin changed the cell morphology of IL-10-generated macrophages and the expression levels of cytokines, such as transforming growth factor beta, tumor necrosis factor-alpha, interferon gamma, and IL-10, apart from changes in the expression level of the surface markers CD206, CD209, and CD163. Moreover, in vivo IL-10 administration reduced the lipopolysaccharide (LPS)-induced embryo resorption rate, and this effect was diminished when OXPHOS was inhibited, demonstrating that OXPHOS is important for the improved pregnancy outcomes of IL-10 in LPS-induced abortion-prone mice. Our findings provide deep insights into the roles of IL-10 in macrophage biology and pregnancy maintenance. Nevertheless, the direct evidence that OXPHOS is involved in decidual macrophage differentiation or not needs further investigations.

Tannic Acid-Modified Decellularized Tendon Scaffold with Antioxidant and Anti-Inflammatory Activities for Tendon Regeneration.

Tendon regeneration is greatly influenced by the oxidant and the inflammatory microenvironment. Persistent inflammation during the tendon repair can cause matrix degradation, tendon adhesion, and excessive accumulation of reactive oxygen species (ROS), while excessive ROS affect extracellular matrix remodeling and tendon integration. Herein, we used tannic acid (TA) to modify a decellularized tendon slice (DTS) to fabricate a functional scaffold (DTS-TA) with antioxidant and anti-inflammatory properties for tendon repair. The characterizations and cytocompatibility of the scaffolds were examined in vitro. The antioxidant and anti-inflammatory activities of the scaffold were evaluated in vitro and further studied in vivo using a subcutaneous implantation model. It was found that the modified DTS combined with TA via hydrogen bonds and covalent bonds, and the hydrophilicity, thermal stability, biodegradability, and mechanical characteristics of the scaffold were significantly improved. Afterward, the results demonstrated that DTS-TA could effectively reduce inflammation by increasing the M2/M1 macrophage ratio and interleukin-4 (IL-4) expression, decreasing the secretion of interleukin-6 (IL-6) and interleukin-1ß (IL-1ß), as well as scavenging excessive ROS in vitro and in vivo. In summary, DTS modified with TA provides a potential versatile scaffold for tendon regeneration.

Ginseng fermentation solution affects the gut microbiota in zebrafish with alcoholic liver disease via PI3K/Akt pathway.

BACKGROUND: Ginsenosides have received increased amounts of attention due to their ability to modulate the intestinal flora, which may subsequently alleviate alcoholic liver disease (ALD). The effects of ginseng fermentation solution (GFS) on the gut microbiota and metabolism in ALD patients have not been explored. PURPOSE: This research aimed to explore the regulatory effect of GFS on ALD both in vitro and in vivo. METHOD: This study assessed the anti-ALD efficacy of GFS using an LO2 cell model and a zebrafish model. Untargeted metabolomics was used for differentially abundant metabolite analysis, and high-throughput 16S rRNA sequencing was used to examine the effect of GFS on ALD. RESULTS: The LO2 cell line experiments demonstrated that GFS effectively mitigated alcohol-induced oxidative stress and reduced apoptosis by upregulating PI3K and Bcl-2 expression and decreasing the levels of malondialdehyde, total cholesterol, and triglycerides. In zebrafish, GFS improved morphological and physiological parameters and diminished oxidative stress-induced ALD. Meanwhile, the results from Western blotting indicated that GFS enhanced the expression of PI3K, Akt, and Bcl-2 proteins while reducing Bax protein expression, thereby ameliorating the ALD model in zebrafish. Metabolomics data revealed significant changes in a total of 46 potential biomarkers. Among them, metabolites such as prostaglandin F2 alpha belong to arachidonic acid metabolism. In addition, GFS also partly reversed the imbalance of gut microbiota composition caused by alcohol. At the genus level, alcohol consumption elevated the presence of Flectobacillus, Curvibacter, among others, and diminished Elizabethkingia within the intestinal microbes of zebrafish. Conversely, GFS reversed these effects, notably enhancing the abundance of Proteobacteria and Archaea. Correlation analyses further indicated a significant negative correlation between prostaglandin F2 alpha, 11,14,15-THETA, Taurocholic acid and Curvibacter. CONCLUSION: This study highlights a novel mechanism by which GFS modulates anti-ALD activity through the PI3K/Akt signalling pathway by influencing the intestinal flora-metabolite axis. These results indicate the potential of GFS as a functional food for ALD treatment via modulation of the gut flora.

Exosomal MALAT1 promotes the proliferation of esophageal squamous cell carcinoma through glyoxalase 1-dependent methylglyoxal removal.

In previous study we characterized the oncogenic role of long non-coding RNA MALAT1 in esophageal squamous cell carcinoma (ESCC), but the detailed mechanism remains obscure. Here we identified glyoxalase 1 (GLO1) as the most possible executor of MALAT1 by microarray screening. GLO1 is responsible for degradation of cytotoxic methylglyoxal (MGO), which is by-product of tumor glycolysis. Accumulated MGO may lead to glycation of DNA and protein, resulting in elevated advanced glycation end products (AGEs), while glyoxalase 1 detoxify MGO to alleviate its cytotoxic effect to tumor cells. GLO1 interfering led to accumulation of AGEs and following activation of DNA injury biomarkers, which lead to cell cycle arrest and growth inhibition. In silico analysis based on online database revealed abundant enrichment of histone acetylation marker H3K27ac in GLO1 promotor, and acetyltransferase inhibitor C646 declined GLO1 expression. Acetyltransferase KAT2B, which was also identified as a target of MALAT, mediated histone lysine acetylation of GLO1 promotor, which was confirmed by ChIP-qPCR experiment. Shared binding sites of miR-206 were found on MALAT1 and KAT2B mRNA. Dual-luciferase reporter assays confirmed interaction within MALAT1-miR-206-GLO1. Finally, we identified MALAT1 encapsuled by exosome from donor cells, and transferred malignant behaviors to recipient cells. The secreted exosomes may enter circulation, and serum MALAT1 level combined with traditional tumor markers showed potential power for ESCC diagnosis.

High-speed imaging of supersaturated cavitation clouds and the vibration modes of the radiation surface of high-power transducers.

The vibration mode of the radiation surface of transducer (or structure of supersaturated cavitation cloud in thin liquid) is investigated experimentally by high-speed photography. The classification of saturated, supersaturated and undersaturated cavitation clouds was proposed, and a comparison was made between saturated and supersaturated cavitation cloud structures in liquid thin layers. The characteristics and formation mechanism of supersaturated cavitation cloud structure were investigated. Based on the close correspondence and rapid response between the distribution of supersaturated cavitation clouds and vibration modes of radiation surface, a new approach is proposed to measure the vibration mode of transducer operating at high power and large amplitude in real time.

Desirable Strong and Tough Adhesive Inspired by Dragonfly Wings and Plant Cell Walls.

The production of wood-based panels has a significant demand for mechanically strong and flexible biomass adhesives, serving as alternatives to nonrenewable and toxic formaldehyde-based adhesives. Nonetheless, plywood usually exhibits brittle fracture due to the inherent trade-off between rigidity and toughness, and it is susceptible to damage and deformation defects in production applications. Herein, inspired by the microstructure of dragonfly wings and the cross-linking structure of plant cell walls, a soybean meal (SM) adhesive with great strength and toughness was developed. The strategy was combined with a multiple assembly system based on the tannic acid (TA) stripping/modification of molybdenum disulfide (MoS2@TA) hybrids, phenylboronic acid/quaternary ammonium doubly functionalized chitosan (QCP), and SM. Motivated by the microstructure of dragonfly wings, MoS2@TA was tightly bonded with the SM framework through Schiff base and strong hydrogen bonding to dissipate stress energy through crack deflection, bridging, and immobilization. QCP imitated borate chemistry in plant cell walls to optimize interfacial interactions within the adhesive by borate ester bonds, boron-nitrogen coordination bonds, and electrostatic interactions and dissipate energy through sacrificial bonding. The shear strength and fracture toughness of the SM/QCP/MoS2@TA adhesive were 1.58 MPa and 0.87 J, respectively, which were 409.7% and 866.7% higher than those of the pure SM adhesive. In addition, MoS2@TA and QCP gave the adhesive good mildew resistance, durability, weatherability, and fire resistance. This bioinspired design strategy offers a viable and sustainable approach for creating multifunctional strong and tough biobased materials.

Immune pathogenesis of idiopathic granulomatous mastitis: from etiology toward therapeutic approaches.

Idiopathic granulomatous mastitis (IGM) is a noncancerous, chronic inflammatory disorder of breast with unknown causes, posing significant challenges to the quality of life due to its high refractoriness and local aggressiveness. The typical symptoms of this disease involve skin redness, a firm and tender breast mass and mastalgia; others may include swelling, fistula, abscess (often without fever), nipple retraction, and peau d'orange appearance. IGM often mimics breast abscesses or malignancies, particularly inflammatory breast cancer, and is characterized by absent standardized treatment options, inconsistent patient response and unknown mechanism. Definite diagnosis of this disease relies on core needle biopsy and histopathological examination. The prevailing etiological theory suggests that IGM is an autoimmune disease, as some patients respond well to steroid treatment. Additionally, the presence of concurrent erythema nodosum or other autoimmune conditions supports the autoimmune nature of the disease. Based on current knowledge, this review aims to elucidate the autoimmune-favored features of IGM and explore its potential etiologies. Furthermore, we discuss the immune-mediated pathogenesis of IGM using existing research and propose immunotherapeutic strategies for managing this condition.

Decreased stress shielding with poly-ether-ether-ketone tibial implant for total knee arthroplasty - A preliminary study using finite element analysis.

In total knee arthroplasty (TKA), the mechanical mismatch between cobalt-chromium (CoCr) alloy tibial implant and bone has been implicated in stress shielding and subsequent implant failure and bone resorption. This study investigates the biomechanical advantages of poly-ether-ether-ketone (PEEK) tibial implant, which exhibit properties analogous to those of the surrounding bone. A finite element analysis (FEA) was employed to assess and compare the biomechanical performances of PEEK and CoCr tibial implants in patients with and without osteoporosis. Four FEA models were constructed with PEEK and CoCr alloy implants in normal and osteoporotic tibias. Based on previous literature and our clinical experience, stresses measurements were taken at 16 points on the tibial plateau and 8 points on the two surfaces which were 10 mm and 20 mm apart from the tibial plateau, with specific regions quantified for stress shielding. The results showed significant differences in stress distribution between PEEK and CoCr implants. The PEEK implants exhibited higher equivalent stresses on the tibial plateau in all models (normal bone: 0.22 ± 0.07 MPa vs. 0.13 ± 0.06 MPa, p < 0.01; osteoporotic bone: 0.39 ± 0.06 MPa vs. 0.17 ± 0.07 MPa, p < 0.01). In non-osteoporotic models, the mean equivalent stresses on proximal tibial surfaces were similarly elevated for PEEK implants (0.29 ± 0.13 MPa vs. 0.21 ± 0.08 MPa, p = 0.02). The CoCr implants demonstrated more stress shielding across all measured regions (tibial plateau: 23.47% vs. 2.73%; surface 1: 15.93% vs. 1.37%; surface 2: 10.71% vs. 6.56%). These disparities were even more pronounced in osteoporotic models in the CoCr group (tibial plateau: 32.50% vs. 8.36%). The maximum equivalent stresses on the tibial plateau further supported this trend (normal bone: 1.02 MPa vs. 0.52 MPa; osteoporotic bone: 1.43 MPa vs. 0.67 MPa). These data confirm the hypothesis that a PEEK tibial implant can reduce peri-prosthetic stress shielding, suggesting that PEEK implants have the capability to distribute loads more uniformly and maintain a closer approximation to physiological conditions.