Novel genetic variants in the NLRP3 inflammasome-related PANX1 and APP genes predict survival of patients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: The nod-like receptor protein 3 (NLRP3) is one of the most characterized inflammasomes involved in the pathogenesis of several cancers, including hepatocellular carcinoma (HCC). However, the effects of genetic variants in the NLRP3 inflammasome-related genes on survival of hepatitis B virus (HBV)-related HCC patients are unclear. METHODS: We performed multivariable Cox proportional hazards regression analysis to evaluate associations between 299 single-nucleotide polymorphisms (SNPs) in 16 NLRP3 inflammasome-related genes and overall survival (OS) of 866 patients with HBV-related HCC. We further performed expression quantitative trait loci (eQTL) analysis using the data from the GTEx project and 1000 Genomes projects, and performed differential expression analysis using the TCGA dataset to explore possible molecular mechanisms underlying the observed associations. RESULTS: We found that two functional SNPs (PANX1 rs3020013 A > G and APP rs9976425 C > T) were significantly associated with HBV-related HCC OS with the adjusted hazard ratio (HR) of 0.83 [95% confidence interval (CI) = 0.73-0.95, P = 0.008], and 1.26 (95% CI = 1.02-1.55, P = 0.033), respectively. Moreover, the eQTL analysis revealed that the rs3020013 G allele was correlated with decreased mRNA expression levels of PANX1 in both normal liver tissues (P = 0.044) and whole blood (P < 0.001) in the GTEx dataset, and PANX1 mRNA expression levels were significantly higher in HCC samples and associated with a poorer survival of HCC patients. However, we did not observe such correlations for APP rs9976425. CONCLUSIONS: These results indicated that SNPs in the NLRP3 inflammasome-related genes may serve as potential biomarkers for HBV-related HCC survival, once replicated by additional larger studies.

Delta-like noncanonical notch ligand 2 regulates the proliferation and differentiation of sheep myoblasts through the Wnt/ß-catenin signaling pathway.

This study delved into the role of delta-like noncanonical notch ligand 2 (DLK2) in the cell cycle, proliferation, apoptosis, and differentiation of myoblasts, as well as its interaction with the classical Wnt/ß-catenin signaling pathway in regulating myoblast function. The research revealed that upregulation of DLK2 in myoblasts during the proliferation phase enhanced myoblast proliferation, facilitated cell cycle progression, and reduced apoptosis. Conversely, downregulation of DLK2 expression using siRNA during the differentiation phase promoted myoblast hypertrophy and fusion, suppressed the expression of muscle fiber degradation factors, and expedited the differentiation process. DLK2 regulates myoblasts function by influencing the expression of various factors associated with the Wnt/ß-catenin signaling pathway, including CTNNB1, FZD1, FZD6, RSPO1, RSPO4, WNT4, WNT5A, and adenomatous polyposis coli. In essence, DLK2, with the involvement of the Wnt/ß-catenin signaling pathway, plays a crucial regulatory role in the cell cycle, proliferation, apoptosis, and differentiation of myoblasts.

Lectin microarray based glycan profiling of exosomes for dynamic monitoring of colorectal cancer progression.

BACKGROUND: Exosomes, as emerging biomarkers in liquid biopsies in recent years, offer profound insights into cancer diagnostics due to their unique molecular signatures. The glycosylation profiles of exosomes have emerged as potential biomarkers, offering a novel and less invasive method for cancer diagnosis and monitoring. Colorectal cancer (CRC) represents a substantial global health challenge and burden. Thus there is a great need for the aberrant glycosylation patterns on the surface of CRC cell-derived exosomes, proposing them as potential biomarkers for tumor characterization. RESULTS: The interactions of 27 lectins with exosomes from three CRC cell lines (SW480, SW620, HCT116) and one normal colon epithelial cell line (NCM460) have been analyzed by the lectin microarray. The result indicates that Ulex Europaeus Agglutinin I (UEA-I) exhibits high affinity and specificity towards exosomes derived from SW480 cells. The expression of glycosylation related genes within cells has been analyzed by high-throughput quantitative polymerase chain reaction (HT-qPCR). The experimental result of HT-qPCR is consistent with that of lectin microarray. Moreover, the limit of detection (LOD) of UEA-I microarray is calculated to be as low as 2.7 × 105 extracellular vehicles (EVs) mL-1 (three times standard deviation (3σ) of blank sample). The UEA-I microarray has been successfully utilized to dynamically monitor the progression of tumors in mice-bearing SW480 CRC subtype, applicable in tumor sizes ranging from 2 mm to 20 mm in diameter. SIGNIFICANCE: The results reveal that glycan expression pattern of exosome is linked to specific CRC subtypes, and regulated by glycosyltransferase and glycosidase genes of mother cells. Our findings illuminate the potential of glycosylation molecules on the surface of exosomes as reliable biomarkers for diagnosis of tumor at early stage and monitoring of cancer progression.

Development and validation of a lung metastases-predicting nomogram for intermediate- to high-risk differentiated thyroid carcinoma patients.

Aim: This research aimed to construct a clinical model for forecasting the likelihood of lung metastases in differentiated thyroid carcinoma (DTC) with intermediate- to high-risk. Methods: In this study, 375 DTC patients at intermediate to high risk were included. They were randomly divided into a training set (70%) and a validation set (30%). A nomogram was created using the training group and then validated in the validation set using calibration, decision curve analysis (DCA) and receiver operating characteristic (ROC) curve. Results: The calibration curves demonstrated excellent consistency between the predicted and the actual probability. ROC analysis showed that the area under the curve in the training cohort was 0.865 and 0.845 in the validation cohort. Also, the DCA curve indicated that this nomogram had good clinical utility. Conclusion: A user-friendly nomogram was constructed to predict the lung metastases probability with a high net benefit.

[Box: see text].

Analysis of 3D pathology samples using weakly supervised AI.

Human tissue, which is inherently three-dimensional (3D), is traditionally examined through standard-of-care histopathology as limited two-dimensional (2D) cross-sections that can insufficiently represent the tissue due to sampling bias. To holistically characterize histomorphology, 3D imaging modalities have been developed, but clinical translation is hampered by complex manual evaluation and lack of computational platforms to distill clinical insights from large, high-resolution datasets. We present TriPath, a deep-learning platform for processing tissue volumes and efficiently predicting clinical outcomes based on 3D morphological features. Recurrence risk-stratification models were trained on prostate cancer specimens imaged with open-top light-sheet microscopy or microcomputed tomography. By comprehensively capturing 3D morphologies, 3D volume-based prognostication achieves superior performance to traditional 2D slice-based approaches, including clinical/histopathological baselines from six certified genitourinary pathologists. Incorporating greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, further emphasizing the value of capturing larger extents of heterogeneous morphology.

Towards a general-purpose foundation model for computational pathology.

Quantitative evaluation of tissue images is crucial for computational pathology (CPath) tasks, requiring the objective characterization of histopathological entities from whole-slide images (WSIs). The high resolution of WSIs and the variability of morphological features present significant challenges, complicating the large-scale annotation of data for high-performance applications. To address this challenge, current efforts have proposed the use of pretrained image encoders through transfer learning from natural image datasets or self-supervised learning on publicly available histopathology datasets, but have not been extensively developed and evaluated across diverse tissue types at scale. We introduce UNI, a general-purpose self-supervised model for pathology, pretrained using more than 100 million images from over 100,000 diagnostic H&E-stained WSIs (>77 TB of data) across 20 major tissue types. The model was evaluated on 34 representative CPath tasks of varying diagnostic difficulty. In addition to outperforming previous state-of-the-art models, we demonstrate new modeling capabilities in CPath such as resolution-agnostic tissue classification, slide classification using few-shot class prototypes, and disease subtyping generalization in classifying up to 108 cancer types in the OncoTree classification system. UNI advances unsupervised representation learning at scale in CPath in terms of both pretraining data and downstream evaluation, enabling data-efficient artificial intelligence models that can generalize and transfer to a wide range of diagnostically challenging tasks and clinical workflows in anatomic pathology.

Coxsackie B virus-induced myocarditis in a patient with a history of lymphoma: A case report and review of literature.

INTRODUCTION: In rare occasions, coxsackievirus infections can cause serious illness, such as encephalitis and myocarditis. The immunotherapies of cancer could increase the risk of myocarditis, especially when applying immune checkpoint inhibitors. Herein, we report a rare case of Coxsackie B virus-induced myocarditis in a patient with a history of lymphoma. CASE PRESENTATION: A 32-year-old woman was admitted to the hospital with recurrent fever for more than 20 days, and she had a history of lymphoma. Before admission, the positron emission tomography/computed tomography result indicated that the patient had no tumor progression, and she was not considered the cancer-related fever upon arriving at our hospital. Patient's red blood cell, platelet count, and blood pressure were decreased. In addition, she had sinus bradycardia and 3 branch blocks, which was consistent with acute high lateral and anterior wall myocardial infarction. During hospitalization, the patient had recurrent arrhythmia, repeated sweating, poor mentation, dyspnea, and Coxsackie B virus were detected in patient's blood samples by pathogen-targeted next-generation sequencing. The creatine kinase, creatine kinase MB, and N-terminal pro-brain natriuretic peptide were persistently elevated. Consequently, the patient was diagnosed with viral myocarditis induced by Coxsackie B virus, and treated with acyclovir, gamma globulin combined with methylprednisolone shock therapy, trimetazidine, levosimendan, sildenan, continuous pump pressors with m-hydroxylamine, entecavir, adefovir, glutathione, pantoprazole, and low-molecular-weight heparin. Her symptoms worsened and died. CONCLUSION: We reported a case with a history of lymphoma presented with fever, myocardial injury, who was ultimately diagnosed with Coxsackie B virus-induced myocarditis. Moreover, pathogen-targeted next-generation sequencing indeed exhibited higher sensitivity compared to mNGS in detecting Coxsackie B virus.

Genetic variants in m5C modification genes are associated with survival of patients with HBV-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high mortality rate. The 5-methylcytosine (m5C), a type of RNA modification, plays crucial regulatory roles in HCC carcinogenesis, metastasis, and prognosis. However, a few studies have investigated the effect of genetic variants in m5C modification genes on survival of patients with hepatitis B virus (HBV)-related HCC. In the present study, we evaluated associations between 144 SNPs in 15 m5C modification genes and overall survival (OS) in 866 patients with the HBV-related HCC. Expression quantitative trait loci (eQTL) analysis and differential expression analysis were conducted to investigate biological mechanisms. As a result, we identified that two SNPs (NSUN7 rs2437325 A > G and TRDMT1 rs34434809 G > C) were significantly associated with HBV-related HCC OS with adjusted allelic hazards ratios of 1.25 (95% confidence interval = 1.05-1.48 and P = 0.011) and 1.19 (1.02-1.38 and P = 0.027), respectively, with a trend of combined risk genotypes (Ptrend < 0.001). Moreover, the results of eQTL analyses showed that both NSUN7 rs2437325 G and TRDMT1 rs34434809 C alleles were associated with a reduced mRNA expression level in 208 normal liver tissues (P = 0.007 and P < 0.001, respectively). Taken together, genetic variants in the m5C modification genes may be potential prognostic biomarkers of HBV-related HCC after hepatectomy, likely through mediating the mRNA expression of corresponding genes.

Taurohyocholic acid acts as a potential predictor of the efficacy of tyrosine kinase inhibitors combined with programmed cell death-1 inhibitors in hepatocellular carcinoma.

Background and aims: Tyrosine kinase inhibitors (TKIs) combined with programmed cell death protein-1 (PD-1) have significantly improved survival in patients with unresectable hepatocellular carcinoma (uHCC), but effective biomarkers to predict treatment efficacy are lacking. Peripheral blood bile acids (BAs) are associated with tumor response to therapy, but their roles in HCC remain unclear. Methods: This retrospective study included HCC patients who received first-line TKIs combined with PD-1 inhibitors treatment (combination therapy) in our clinical center from November 2020 to June 2022. The aim of this study was to analyze the changes in plasma BA profiles before and after treatment in both the responding group (Res group) and the non-responding group (Non-Res group). We aimed to explore the potential role of BAs in predicting the response to combination therapy in HCC patients. Results: Fifty-six patients with HCC who underwent combination therapy were included in this study, with 28 designated as responders (Res group) and 28 as non-responders (Non-Res group). There were differences in plasma BA concentrations between the two groups before systemic therapy. Plasma taurohyocholic acid (THCA) levels in the Res group were significantly lower than those in the Non-Res group. Patients with low levels of THCA exhibited superior median progression-free survival (7.6 vs. 4.9 months, p = 0.027) and median overall survival (23.7 vs. 11.6 months, p = 0.006) compared to those of patients with high levels of THCA. Conclusion: Peripheral blood BA metabolism is significantly correlated with combination therapy response and survival in patients with HCC. Our findings emphasize the potential of plasma BAs as biomarkers for predicting combination therapy outcomes and offering novel therapeutic targets for modulating responses to systemic cancer therapy.

[Acute cerebral infarction following extracorporeal membrane oxygenation treatment in patients with cardiogenic shock: 2 cases report and review of the literature].

OBJECTIVE: To explore the diagnosis and treatment of acute cerebral infarction following extracorporeal membrane oxygenation (ECMO) therapy in patients with cardiogenic shock to review the literature. METHODS: The clinical data of two patients with cardiogenic shock treated with veno-arterial ECMO (VA-ECMO) complicated with acute cerebral infarction admitted to department of intensive care unit (ICU) of Affiliated Hospital of Guizhou Medical University were retrospectively analyzed and the treatment experience was shared. RESULTS: Case 1 was a 46-year-old male patient who was admitted to the hospital on September 16, 2021, due to "repeated chest tightness, shortness of breath, syncope for 2+ years, and worsened for 15 days. Coronary artery angiography showed 3-vessel coronary artery disease lesions. On October 15, 2021, coronary artery bypass grafting (CABG), pericardial fenestration and drainage, thoracic closed drainage, femoral bypass, thoracotomy exploration, and sternal internal fixation were performed under support of extracorporeal circulation. After surgery, the heart rate was 180-200 bpm, the blood pressure could not be maintained, and the improvement was not obvious after active drug treatment. The right femoral artery and femoral vein were intubated, VA-ECMO support treatment was performed, and the patient was transferred to the ICU. Intra-aortic balloon pump (IABP) was treated on the day of transfer because the circulation could not be maintained. Due to acute cerebral infarction in the left hemisphere and right parieto-occipital lobe, subfalcine herniation, tentorial herniation, the patient ultimately died after withdrawing from ECMO. Case 2 was a 43-year-old male patient who was admitted to the hospital on June 29, 2021, with "fever for 8 days and vomiting for 4 days". Bedside ultrasound showed cardiac enlargement and diffuse wall motion reduction in the left and right ventricles. On June 30, 2021, the patient underwent catheterization through the right femoral artery and femoral vein, VA-ECMO support, and was transferred to ICU for treatment. Acute cerebral infarction on both sides of the cerebellum occurred, and after treatment, the patient was discharged with mild impairment of daily living ability. CONCLUSIONS: Strengthen monitoring of anticoagulation; regular neurological examination of patients undergoing ECMO therapy; ECMO under light sedation or awake can be performed if the condition permitsif the condition permits, perform light sedation or awake ECMO, which helpful for the early detection of nervous system injury.

The diagnostic value of fluorescence in situ hybridization in secondary electroresection of bladder cancer.

OBJECTIVE: To investigate the utility of fluorescence in situ hybridization (FISH) in secondary electroresection of bladder cancer. METHODS: From January 2016 to April 2022, bladder cancer patients who had undergone secondary electroresection in Tongji Hospital and had preoperative urine FISH were recruited, and the positive rate, accuracy, sensitivity, specificity, genetic material changes and predictive power on malignancy degree of FISH in the secondary electroresection of bladder cancer were examined. RESULTS: Twenty-six patients with bladder cancer were included in this study, and 8 were confirmed by secondary electroresection, including 6 cases positive for FISH positive and 2 negative for FISH. Besides, among the subjects, 18 were without tumor recurrence, including 1 case with positive FISH results and 17 with negative FISH results. Tumor recurrence was diagnosed in 85.71% (6/7) of FISH-positive patients in secondary electroresection while only 10.53% (2/19) of FISH-negative patients were found to develop tumor recurrence in the secondary electroresection. The sensitivity of FISH for the detection of bladder cancer before secondary electroresection was 75%, with a specificity of 94.44%, and an accuracy of 88.46%. A 6-month follow-up revealed that 2 of the 8 recurrent patients underwent radical resection of bladder cancer, and the remaining 6 patients had no recurrence, as confirmed by regular bladder perfusion and microscopy. In the 18 non-recurrent patients during secondary electroresection, no recurrence developed. CONCLUSIONS: Urine FISH can achieve a high detection rate and specificity for secondary electroresection of bladder cancer. If a bladder cancer patient who are indicated for secondary electroresection is negative for urine FISH, the recurrence rate after secondary electroresection will be low, and the cystoscopy can be performed before deciding whether to perform secondary electroresection.

Identification of WUSCHEL-related homeobox gene and truncated small peptides in transformation efficiency improvement in Eucalyptus.

BACKGROUND: The WUSCHEL-related Homeobox (WOX) genes, which encode plant-specific homeobox (HB) transcription factors, play crucial roles in regulating plant growth and development. However, the functions of WOX genes are little known in Eucalyptus, one of the fastest-growing tree resources with considerable widespread cultivation worldwide. RESULTS: A total of nine WOX genes named EgWOX1-EgWOX9 were retrieved and designated from Eucalyptus grandis. From the three divided clades marked as Modern/WUS, Intermediate and Ancient, the largest group Modern/WUS (6 EgWOXs) contains a specific domain with 8 amino acids: TLQLFPLR. The collinearity, cis-regulatory elements, protein-protein interaction network and gene expression analysis reveal that the WUS proteins in E. grandis involve in regulating meristems development and regeneration. Furthermore, by externally adding of truncated peptides isolated from WUS specific domain, the transformation efficiency in E. urophylla × E. grandis DH32-29 was significant enhanced. The transcriptomics data further reveals that the use of small peptides activates metabolism pathways such as starch and sucrose metabolism, phenylpropanoid biosynthesis and flavonoid biosynthesis. CONCLUSIONS: Peptides isolated from WUS protein can be utilized to enhance the transformation efficiency in Eucalyptus, thereby contributing to the high-efficiency breeding of Eucalyptus.

Association between dietary zinc intake and Helicobacter pylori seropositivity in US adults: National Health and Nutrition Examination Survey.

Purpose: Helicobacter pylori infection is a well-established etiological factor for gastric inflammation and a significant risk factor for the development of gastric cancer. However, the precise relationship between dietary zinc intake and seropositivity for Helicobacter pylori remains uncertain. Methods: This cross-sectional observational study utilized data from the United States National Health and Nutrition Examination Survey conducted between 1999 and 2000. The study cohort comprised 2,884 adults aged 20 years or older who provided comprehensive 24-h dietary recall data. The presence of Helicobacter pylori infection was confirmed using serum analysis and lgG protein enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression models and generalized additive model (GAM) were employed to explore the potential association between dietary zinc intake and Helicobacter pylori seropositivity. Results: Additionally, subgroup analysis was performed to evaluate the robustness of the primary findings. Of the 1,281 participants, 47.8% were male and the average age was 49.5 years. In the fully adjusted model, a statistically significant inverse association between dietary zinc intake and Helicobacter pylori seropositivity was observed [quartile variable, Q4 vs. Q1, odds ratio (OR): 0.72, 95% confidence interval (CI): 0.57-0.91, p = 0.007]. Furthermore, the relationship between dietary zinc intake and Helicobacter pylori seropositivity exhibited an L-shaped pattern, indicating a saturation effect. The results of sensitivity analysis remained consistent and reliable. Conclusion: Therefore, this study suggests that higher dietary zinc intake may be associated with a lower prevalence of Helicobacter pylori seropositivity. Notably, this association follows an L-shaped pattern, with a threshold point estimated at 24.925 mg/day.

Synthesis of lenvatinib-loaded upconversion@polydopamine nanocomposites for upconversion luminescence imaging-guided chemo-photothermal synergistic therapy of anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is the most malignant and aggressive of all classifications of thyroid cancer. ATC normally has poor prognosis after classic treatments such as surgery, endocrine therapy, radiotherapy and chemotherapy. Herein, a novel nanocomposite (named as UCNP@PDA@LEN) has been synthesized for chemo-photothermal therapy of ATC, which is based on a NaErF4:Tm3+@NaYbF4@NaYF4:Nd3+ upconverting nanoparticle (UCNP) as the core, a near-infrared light (NIR)-absorbing polydopamine (PDA) as the shell, and lenvatinib (LEN) as a chemotherapeutic drug. The as-prepared multifunctional UCNP@PDA@LEN exhibits excellent photothermal conversion capability (η = 30.7%), good photothermal stability and reasonable biocompatibility. Owing to the high UCL emission and good tumor accumulation ability, the UCL imaging of mouse-bearing ATC (i.e., C643 tumor) has been achieved by UCNP@PDA@LEN. Under 808 nm NIR laser irradiation, the UCNP@PDA@LEN shows a synergistic interaction between photothermal therapy (PTT) and chemotherapy (CT), resulting in strongly suppressed mouse-bearing C643 tumor. The results provide an explicit approach for developing theranostics with high anti-ATC efficiency.

A General-Purpose Self-Supervised Model for Computational Pathology.

Tissue phenotyping is a fundamental computational pathology (CPath) task in learning objective characterizations of histopathologic biomarkers in anatomic pathology. However, whole-slide imaging (WSI) poses a complex computer vision problem in which the large-scale image resolutions of WSIs and the enormous diversity of morphological phenotypes preclude large-scale data annotation. Current efforts have proposed using pretrained image encoders with either transfer learning from natural image datasets or self-supervised pretraining on publicly-available histopathology datasets, but have not been extensively developed and evaluated across diverse tissue types at scale. We introduce UNI, a general-purpose self-supervised model for pathology, pretrained using over 100 million tissue patches from over 100,000 diagnostic haematoxylin and eosin-stained WSIs across 20 major tissue types, and evaluated on 33 representative CPath clinical tasks in CPath of varying diagnostic difficulties. In addition to outperforming previous state-of-the-art models, we demonstrate new modeling capabilities in CPath such as resolution-agnostic tissue classification, slide classification using few-shot class prototypes, and disease subtyping generalization in classifying up to 108 cancer types in the OncoTree code classification system. UNI advances unsupervised representation learning at scale in CPath in terms of both pretraining data and downstream evaluation, enabling data-efficient AI models that can generalize and transfer to a gamut of diagnostically-challenging tasks and clinical workflows in anatomic pathology.

Weakly Supervised AI for Efficient Analysis of 3D Pathology Samples.

Human tissue consists of complex structures that display a diversity of morphologies, forming a tissue microenvironment that is, by nature, three-dimensional (3D). However, the current standard-of-care involves slicing 3D tissue specimens into two-dimensional (2D) sections and selecting a few for microscopic evaluation1,2, with concomitant risks of sampling bias and misdiagnosis3-6. To this end, there have been intense efforts to capture 3D tissue morphology and transition to 3D pathology, with the development of multiple high-resolution 3D imaging modalities7-18. However, these tools have had little translation to clinical practice as manual evaluation of such large data by pathologists is impractical and there is a lack of computational platforms that can efficiently process the 3D images and provide patient-level clinical insights. Here we present Modality-Agnostic Multiple instance learning for volumetric Block Analysis (MAMBA), a deep-learning-based platform for processing 3D tissue images from diverse imaging modalities and predicting patient outcomes. Archived prostate cancer specimens were imaged with open-top light-sheet microscopy12-14 or microcomputed tomography15,16 and the resulting 3D datasets were used to train risk-stratification networks based on 5-year biochemical recurrence outcomes via MAMBA. With the 3D block-based approach, MAMBA achieves an area under the receiver operating characteristic curve (AUC) of 0.86 and 0.74, superior to 2D traditional single-slice-based prognostication (AUC of 0.79 and 0.57), suggesting superior prognostication with 3D morphological features. Further analyses reveal that the incorporation of greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, suggesting that there is value in capturing larger extents of spatially heterogeneous 3D morphology. With the rapid growth and adoption of 3D spatial biology and pathology techniques by researchers and clinicians, MAMBA provides a general and efficient framework for 3D weakly supervised learning for clinical decision support and can help to reveal novel 3D morphological biomarkers for prognosis and therapeutic response.

Sox10 escalates vascular inflammation by mediating vascular smooth muscle cell transdifferentiation and pyroptosis in neointimal hyperplasia.

Vascular smooth muscle cells (VSMCs) can transdifferentiate into macrophage-like cells in the context of sustained inflammatory injury, which drives vascular hyperplasia and atherosclerotic complications. Using single-cell RNA sequencing, we identify that macrophage-like VSMCs are the key cell population in mouse neointimal hyperplasia. Sex-determining region Y (SRY)-related HMG-box gene 10 (Sox10) upregulation is associated with macrophage-like VSMC accumulation and pyroptosis in vitro and in the neointimal hyperplasia of mice. Tumor necrosis factor α (TNF-α)-induced Sox10 lactylation in a phosphorylation-dependent manner by PI3K/AKT signaling drives transcriptional programs of VSMC transdifferentiation, contributing to pyroptosis. The regulator of G protein signaling 5 (RGS5) interacts with AKT and blocks PI3K/AKT signaling and Sox10 phosphorylation at S24. Sox10 silencing mitigates vascular inflammation and forestalls neointimal hyperplasia in RGS5 knockout mice. Collectively, this study shows that Sox10 is a regulator of vascular inflammation and a potential control point in inflammation-related vascular disease.

Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases.

Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

Safety and efficacy of percutaneous electrocoagulation haemostasis in the treatment of grade IV haemorrhagic cystitis after allogeneic haematopoietic stem cell transplantation in children: a retrospective analysis.

BACKGROUND: To investigate the efficacy and safety of endoscopic electrocoagulation haemostasis via a percutaneous transhepatic approach for the treatment of grade IV haemorrhagic cystitis (HC) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) in children. METHODS: The clinical data of 14 children with severe HC, who were admitted to Hebei Yanda Hospital between July 2017 and January 2020, were analysed retrospectively. There were nine males and five females, with an average age of 8.6 years (range: 3 to 13 years). After an average of 39.6 (7 to 96) days of conservative treatment in the hospital's haematology department, the bladders of all patients were filled with blood clots. A small 2-cm incision was made in the suprapubic area to enter the bladder and quickly clear the blood clots, and a percutaneous transhepatic approach to electrocoagulation and haemostasis was performed. RESULTS: In the 14 children, a total of 16 operations were performed, with an average operation time of 97.1 (31 to 150) min, an average blood clot of 128.1 (80 to 460) mL and an average intraoperative blood loss of 31.9 (20 to 50) mL. There were three cases of postoperative bladder spasm remission after conservative treatment. During the follow-up period of 1 to 31 months, one patient improved after one operation, 11 patients were cured after one operation, and two patients were cured after recurrent haemostasis by secondary electrocoagulation, four of whom died of postoperative non-surgical blood-related diseases and severe lung infections. CONCLUSION: Percutaneous electrocoagulation haemostasis can quickly remove blood clots in the bladders of children after allo-HSCT with grade IV HC. It is a safe and effective minimally invasive treatment.

The Role of MMP-9 and MMP-9 Inhibition in Different Types of Thyroid Carcinoma.

Matrix metalloproteinase-9 (MMP-9), one of the most investigated and studied biomarkers of the MMPs family, is a zinc-dependent proteolytic metalloenzyme whose primary function is degrading the extracellular matrix (ECM). It has been proved that MMP-9 expression elevates in multiple pathological conditions, including thyroid carcinoma. MMP-9 has a detectable higher level in malignant or metastatic thyroid tumor tissues than in normal or benign tissues and acts as an additional marker to distinguish different tumor stages because of its close correlations with clinical features, such as lymph node metastasis, TNM stage, tumor size and so on. Natural and non-natural MMP-9 inhibitors suppress its expression, block the progression of diseases, and play a role in therapy consequently. MMP-9 inhibitory molecules also assist in treating thyroid tumors by suppressing the proliferation, invasion, migration, metastasis, viability, adhesion, motility, epithelial-mesenchymal transition (EMT), and other risk factors of different thyroid cancer cells. In a word, discovering and designing MMP-9 inhibitors provide great therapeutic effects and promising clinical values in various types of thyroid carcinoma.