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BACKGROUND: The TNFRSF9 molecule is pivotal in thyroid carcinoma (THCA) development. This study utilizes Pathomics techniques to predict TNFRSF9 expression in THCA tissue and explore its molecular mechanisms. METHODS: Transcriptome data, pathology images, and clinical information from the cancer genome atlas (TCGA) were analyzed. Image segmentation and feature extraction were performed using the OTSU's algorithm and pyradiomics package. The dataset was split for training and validation. Features were selected using maximum relevance minimum redundancy recursive feature elimination (mRMR_RFE) and modeling conducted with the gradient boosting machine (GBM) algorithm. Model evaluation included receiver operating characteristic curve (ROC) analysis. The Pathomics model output a probabilistic pathomics score (PS) for gene expression prediction, with its prognostic value assessed in TNFRSF9 expression groups. Subsequent analysis involved gene set variation analysis (GSVA), immune gene expression, cell abundance, immunotherapy susceptibility, and gene mutation analysis. RESULTS: High TNFRSF9 expression correlated with worsened progression-free interval (PFI) and acted as an independent risk factor [hazard ratio (HR) = 2.178, 95% confidence interval (CI) 1.045-4.538, P = 0.038]. Nine pathohistological features were identified. The GBM Pathomics model demonstrated good prediction efficacy [area under the curve (AUC) 0.819 and 0.769] and clinical benefits. High PS was a PFI risk factor (HR = 2.156, 95% CI 1.047-4.440, P = 0.037). Patients with high PS potentially exhibited enriched pathways, increased TIGIT gene expression, Tregs infiltration (P < 0.0001), and higher rates of gene mutations (BRAF, TTN, TG). CONCLUSIONS: The GBM Pathomics model constructed based on the pathohistological features of H&E-stained sections well predicted the expression level of TNFRSF9 molecules in THCA.
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BACKGROUND & AIMS: Pyogenic liver abscess (PLA) is a common hepatobiliary infection that has been shown to have an increasing incidence, with biliary surgery being identified as a trigger. Our aim was to investigate the clinical characteristics and treatments of PLA patients with and without a history of biliary surgery (BS). METHODS: The study included a total of 353 patients with PLA who received treatment at our hospital between January 2014 and February 2023. These patients were categorized into two groups: the BS group (n = 91) and the non-BS group (n = 262). In the BS group, according to the anastomosis method, they were further divided into bilioenteric anastomoses group (BEA, n = 22) and non-bilioenteric anastomoses group (non-BEA, n = 69). Clinical characteristics were recorded and analyzed. RESULTS: The percentage of PLA patients with BS history was 25.78%. The BS group exhibited elevated levels of TBIL and activated APTT abnormalities (P = 0.009 and P = 0.041, respectively). Within the BS group, the BEA subgroup had a higher prevalence of diabetes mellitus (P < 0.001) and solitary abscesses (P = 0.008) compared to the non-BEA subgroup. Escherichia coli was more frequently detected in the BS group, as evidenced by positive pus cultures (P = 0.021). The BS group exhibited reduced treatment efficacy compared to those non-BS history (P = 0.020). Intriguingly, the BS group received a higher proportion of conservative treatment (45.05% vs. 21.76%), along with reduced utilization of surgical drainage (6.59% vs. 16.41%). CONCLUSIONS: Patients with BS history, especially those who have undergone BEA, have an increased susceptibility to PLA formation without affecting prognosis.
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Biliary Tract Surgical Procedures , Liver Abscess, Pyogenic , Humans , Liver Abscess, Pyogenic/microbiology , Liver Abscess, Pyogenic/surgery , Male , Female , Middle Aged , Retrospective Studies , Aged , Adult , Anti-Bacterial Agents/therapeutic use , Escherichia coli/isolation & purification , DrainageABSTRACT
Immunoglobulin A vasculitis (IgAV) is the most common vasculitis of childhood. Disordered immune responses play important roles in its pathogenesis, but the comprehensive immune profile of the disease and the underlying mechanisms are still largely unknown. Here we found a potential disease biomarker cold inducible RNA binding protein (CIRP) in our pediatric IgAV cohort. Serum CIRP level in these patients were elevated and positively correlated with the increased early memory (CD45RA+CD62L+CD95+) T cells revealed using multicolor flow cytometry. Immune phenotyping of the patients showed they had more activated T cells with higher IL6Ra expression. T cell culture experiment showed CIRP further activated both human CD4+ and CD8+ T cells as indicated by increased perforin secretion and phosphorylation of STAT3. Blockade of IL6Rα attenuated CIRP-induced T cell toxicity in vitro. RNA-sequencing data further supported CIRP stimulation promoted human T cell activation and migration, fueled inflammation through the JAK-STAT signaling pathway. Therefore, IL6Ra-mediated T cell activation by extracellular CIRP may contribute to pathogenesis of IgAV in children, both CIRP and IL6Ra could be new therapeutic targets for IgAV.
Subject(s)
Lymphocyte Activation , RNA-Binding Proteins , Receptors, Interleukin-6 , STAT3 Transcription Factor , Adolescent , Child , Female , Humans , Male , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Hepatitis A Virus Cellular Receptor 2 , IgA Vasculitis/immunology , IgA Vasculitis/pathology , IgA Vasculitis/metabolism , Lymphocyte Activation/immunology , Receptors, Interleukin-6/metabolism , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/immunology , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/immunology , Signal Transduction , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Aim: Pituitary stalk interruption syndrome is a relatively rare disease. Patients with this disease usually have different degrees of short stature in adulthood. The purpose of this case report is to highlight a special case of unusually elongated limbs with excessive height growth and congenital absence of uterus and ovary, so as to improve clinicians understanding of the atypical manifestations of pituitary stalk interruption syndrome and provide reference for the clinical diagnosis and treatment of the disease. Case Presentation: The 30-year-old female patient exhibited disproportionate growth in height, with a significant increase from 140 cm at the age of 16 to 180 cm currently. Physical examination revealed widened bilateral eye fissures, underdeveloped secondary sexual characteristics, and absence of menstruation. The patient 's parents are cousins, belonging to consanguineous marriage. The patient 's hypoglycemia provocation test suggested the lack of growth hormone and cortisol. Gonadorelin provocation test suggested hypogonadism, and thyroid function test showed hypothyroidism. Pituitary MRI plain scan and enhancement suggested pituitary stalk interruption syndrome, and abdominal and urinary color Doppler ultrasound suggested no echo of uterus and bilateral appendages in the pelvic cavity. The karyotype of peripheral blood was 45, X[3] / 46, XX [117]. The patient was diagnosed with pituitary stalk interruption syndrome, congenital uterine and ovarian deficiency, bone overgrowth, hypothyroidism and secondary osteoporosis. During hospitalization, the symptoms were improved and discharged after hormone replacement therapy such as physiological dose of glucocorticoid, estradiol valerate tablets and levothyroxine sodium tablets. Now the patient is still in our hospital endocrinology outpatient follow-up, no special discomfort. Conclusion: The patient had special clinical manifestations and was clinically confirmed as pituitary stalk interruption syndrome. The patient 's height continues to grow in the absence of growth hormone in the body, and its mechanism remains to be further studied.
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Acute pancreatitis (AP) continues to pose a major challenge as targeted therapeutic interventions are absent. Mitochondrial dysfunction and inflammasome-dependent pyroptosis are involved in the pathogenic mechanisms of AP. CIRP is a stress-response protein and a damage-associated molecular pattern (DAMP) molecule. In our previous studies, we discovered that excessive CIRP can directly damage pancreatic acinar cells. Nonetheless, the precise involvement of CIRP in AP is still unexplored. The primary aim of this study was to examine the potential involvement of CIRP in the development of pyroptosis and mitochondrial dysfunction in AP. To study this, an L-arginine-induced AP mouse model was used. Our results showed that Caspase-1-mediated pyroptosis and mitochondria-derived reactive oxygen species (ROS) were crucial factors in the occurrence of tissue damage and inflammation in AP. A substantial increase in the CIRP serum levels was observed in AP mice. Blocking CIRP by either CIRP gene knockout or systemic administration of C23, a competing inhibitor of CIRP, reduced ROS accumulation and pyroptosis in AP mice. These effects were associated with attenuated pancreatic injury and inflammation. In addition, CIRP-triggered mitochondrial dysfunction, autophagy impairment, and pyroptosis in pancreatic acinar cells were prevented by TAK242, an inhibitor of CIRP receptor TLR4. In conclusion, CIRP can induce mitochondrial dysfunction and pyroptosis in pancreatic acinar cells, and blocking CIRP may be a valuable approach to treating patients with AP.
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BACKGROUND: Liver injury is common in severe acute pancreatitis (SAP). Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes, which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis. Our previous study found that milk fat globule epidermal growth factor 8 (MFG-E8) alleviates acinar cell damage during SAP via binding to αvß3/5 integrins. MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy. AIM: To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux. METHODS: SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50 µg/kg cerulein plus lipopolysaccharide. mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAP-induced liver injury. Cilengitide, a specific αvß3/5 integrin inhibitor, was used to investigate the possible mechanism of MFG-E8. RESULTS: The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice, enhanced autophagy flux in hepatocyte, and worsened the degree of ferroptosis. Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner. Mechanistically, MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells. Cilengitide abolished MFG-E8's beneficial effects in SAP-induced liver injury. CONCLUSION: MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury. MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrin αVß3/5.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Ferroptosis , Glycolipids , Glycoproteins , Lipid Droplets , Pancreatitis , Mice , Animals , Factor VIII , Pancreatitis/chemically induced , Pancreatitis/complications , Acute Disease , Hepatocytes/metabolism , Autophagy , EGF Family of Proteins , Milk Proteins/metabolism , Milk Proteins/pharmacologyABSTRACT
Pancreatic cancer is an extremely malignant tumor, and only a few clinical treatment options exist. MFG-E8 and kindlin-2 all play an important role in cancer progression. However, the specific mechanism occurring between MFG-E8, kindlin-2 and the migration and invasion of pancreatic cancer cells remains unelucidated. To unravel the specific mechanism, this study assessed the potential association between MFG-E8 and kindlin-2 as well as the involvement of MFG-E8 in pancreatic cancer using two pancreatic cancer cell lines (MiaPaCa-2 and PANC-1). Pancreatic cancer cells were treated with 0, 250, and 500 ng/ml MFG-E8, and the effects of MFG-E8 on the migration, invasion, and anoikis of pancreatic cancer cells were observed. To investigate the role of kindlin-2 in pancreatic cancer, kindlin-2-shRNAi was transfected to knock down its expression level in the two pancreatic cancer cell lines. Furthermore, cilengitide, a receptor blocker of MFG-E8, was used to explore the relationship between MFG-E8, kindlin-2, and pancreatic cancer progression. Our findings demonstrated that MFG-E8 promotes the migration and invasion of pancreatic cancer cells and induces cell anoikis resistance in a dose-dependent manner, which was effectively counteracted by cilengitide, a receptor blocker. Additionally, the knockdown of kindlin-2 expression nullified the effect of MFG-E8 on the migration and invasion of pancreatic cancer cells. Consequently, this study provides insights into the specific mechanism underlying the interplay between MFG-E8 and kindlin-2 in the progression of pancreatic cancer cells.
Subject(s)
Anoikis , Pancreatic Neoplasms , Humans , Cell Line , Pancreas , Pancreatic Neoplasms/genetics , Epithelial-Mesenchymal TransitionABSTRACT
BACKGROUND & AIMS: Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. METHODS: Hepatocyte-specific Sry knock-in (KI), Sry knockout (KO), and Sry KI with platelet-derived growth factor receptor α (Pdgfrα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. RESULTS: Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex-matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfrα expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfrα KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. CONCLUSIONS: SRY is a strong pro-fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease. IMPACT AND IMPLICATION: We identified that a male-specific gene, sex-determining region Y gene (SRY), is a strong pro-fibrotic gene that accounts for the sex disparity observed in liver fibrosis. As such, SRY might be an appropriate target for surveillance and treatment of liver fibrosis in a sex-specific manner. Additionally, SRY might be a key player in the sexual dimorphism observed in hepatic pathophysiology more generally.
Subject(s)
Hepatic Stellate Cells , Hepatocytes , Liver Cirrhosis , Mice, Knockout , Sex-Determining Region Y Protein , Animals , Male , Female , Mice , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/physiopathology , Humans , Hepatocytes/metabolism , Sex-Determining Region Y Protein/genetics , Sex-Determining Region Y Protein/metabolism , Hepatic Stellate Cells/metabolism , Sex Characteristics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Carbon Tetrachloride/toxicity , Carbon Tetrachloride/adverse effects , Cholestasis/genetics , Cholestasis/metabolism , Cholestasis/physiopathology , Disease Models, AnimalABSTRACT
The incidences of thyroid cancer and diabetes are rapidly increasing worldwide. The relationship between thyroid cancer and diabetes is a popular topic in medicine. Increasing evidence has shown that diabetes increases the risk of thyroid cancer to a certain extent. This mechanism may be related to genetic factors, abnormal thyroid-stimulating hormone secretion, oxidative stress injury, hyperinsulinemia, elevated insulin-like growth factor-1 levels, abnormal secretion of adipocytokines, and increased secretion of inflammatory factors and chemokines. This article reviews the latest research progress on the relationship between thyroid cancer and diabetes, including the association between diabetes and the risk of developing thyroid cancer, its underlying mechanisms, and potential anti-thyroid cancer effects of hypoglycemic drugs. It providing novel strategies for the prevention, treatment, and improving the prognosis of thyroid cancer.
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Nanosecond pulsed laser induced photoporation has gained increasing attention from scholars as an effective method for delivering the membrane-impermeable extracellular materials into living cells. Compared with femtosecond laser, nanosecond laser has the advantage of high throughput and low costs. It also has a higher delivery efficiency than continuous wave laser. Here, we provide an extensive overview of current status of nanosecond pulsed laser induced photoporation, covering the photoporation mechanism as well as various factors that impact the delivery efficiency of photoporation. Additionally, we discuss various techniques for achieving photoporation, such as direct photoporation, nanoparticles-mediated photoporation and plasmonic substrates mediated photoporation. Among these techniques, nanoparticles-mediated photoporation is the most promising approach for potential clinical application. Studies have already been reported to safely destruct the vitreous opacities in vivo by nanosecond laser induced vapor nanobubble. Finally, we discuss the potential of nanosecond laser induced phototoporation for future clinical applications, particularly in the areas of skin and ophthalmic pathologies. We hope this review can inspire scientists to further improve nanosecond laser induced photoporation and facilitate its eventual clinical application.
Subject(s)
Lasers , Nanoparticles , Light , SkinSubject(s)
Esophageal Neoplasms , Silicosis , Situs Inversus , Humans , Situs Inversus/complications , Situs Inversus/diagnostic imaging , Esophageal Neoplasms/complications , Esophageal Neoplasms/diagnostic imaging , Esophageal Neoplasms/surgery , Silicosis/complications , Silicosis/diagnostic imagingSubject(s)
Adenoma, Acidophil , Pituitary Neoplasms , Thyroid Dysgenesis , Thyroid Neoplasms , Humans , LungABSTRACT
Magnetic anastomosis substantially shortens the duration of vascular anastomosis. We aimed to apply magnetic anastomosis technology (MAT) to donor liver implantations in pig orthotopic liver transplantation (OLT). Twenty healthy adult pigs were randomly divided into donors and recipients, and major vascular anastomosis was performed using MAT during OLT. Recipient liver and kidney function was measured pre-surgery and 12, 24 and 72 h post-surgery. Vascular anastomoses examinations were performed using ultrasound or angiography weekly post-surgery, and pathological examinations of vascular anastomoses were performed during autopsy after animal euthanasia. All recipients survived 24 h after surgery, which is considered as successful transplantation. Anhepatic duration was only 13 min, and no anastomotic obstruction or stenosis, magnetic displacement and anastomotic angulation, or distortion was found upon postoperative examinations of major liver vasculature. Aspartate aminotransferase, alanine aminotransferase, and total bilirubin serum levels increased considerably postoperatively. The follow-up period for this study was 1 year, and the median survival time of all recipients was 115 d (interquartile range = 11-180 d). The main causes of death were liver failure, immune rejection, infection, and arterial anastomotic bleeding. Moreover, vascular anastomoses healed well with a survival time of more than two weeks. We developed a novel magnetic device to create a fast and safe technique to perform major vascular anastomoses in pig liver transplantations. Additionally, the liver graft implantation using MAT considerably shortened the recipient warm ischemia time, which will reduce the extent of ischemia-reperfusion injury. We conclude that MAT is an effective method for donor liver fast implantation in OLT in pigs.
Subject(s)
Liver Transplantation , Animals , Anastomosis, Surgical/methods , Liver/surgery , Liver Transplantation/methods , Living Donors , Magnetic Phenomena , Swine , Models, Animal , Random AllocationABSTRACT
Traditional drug-based treatments for inflammatory bowel disease (IBD) have significant limitations due to their potential off-target systemic side-effects. Currently, there is a lack of understanding on how to effectively address excessive oxidative stress, dysregulated immune homeostasis, and microbiota dysbiosis within the IBD microenvironment. Herein, we introduce a nanotherapeutic approach, named LBL-CO@MPDA, for IBD treatment. LBL-CO@MPDA is an orally administered formulation that supplies carbon monoxide (CO) for therapeutic purposes. To create the LBL-CO@MPDA nanocomposite, we developed a layer by layer (LBL) self-assembly strategy where we coated chitosan/alginate polyelectrolytes onto the surface of CO prodrug-loaded mesoporous polydopamine nanoparticles (CO@MPDA). Benefiting from the negatively charged surface of the LBL coating, it allows for targeted accumulation of LBL-CO@MPDA specifically onto the positively charged inflamed colon lesions through electrostatic interactions. Furthermore, in the oxidative microenvironment of the inflamed colon, the nanotherapeutic system releases CO in a responsive manner. Interestingly, CO@MPDA ameliorates inflammatory conditions by MPDA-mediated ROS-scavenging and CO-mediated immunomodulation. CO-supplying activates heme oxygenase-1, leading to macrophage M2 polarization via the Notch/Hes1/Stat3 signaling pathway, while suppressing the inflammatory response by down-regulating the p38 MAPK and NF-κB (p50/p65) signaling pathways. In the mice model of dextran sulfate sodium (DSS)-induced IBD, LBL-CO@MPDA effectively reverses the pro-inflammatory microenvironment and restores gut barrier functions through multiple mechanisms, including scavenging oxidative stress, restoring immune homeostasis, and modulating the gut microbiota. Collectively, our findings highlight the promising potential of this innovative nanotherapeutic strategy for the targeted treatment of IBD.
Subject(s)
Carbon Monoxide , Inflammatory Bowel Diseases , Mice , Animals , Carbon Monoxide/pharmacology , Inflammatory Bowel Diseases/drug therapy , Colon/metabolism , Oxidative Stress , Mice, Inbred C57BLSubject(s)
Adenocarcinoma of Lung , Adenocarcinoma , Lung Neoplasms , Neoplasms, Multiple Primary , Thymoma , Thymus Neoplasms , Humans , Thymoma/diagnostic imaging , Thymoma/surgery , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/surgery , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/surgery , Lung Neoplasms/pathology , Thymus Neoplasms/diagnostic imaging , Thymus Neoplasms/surgery , Neoplasms, Multiple Primary/diagnosis , Neoplasms, Multiple Primary/surgery , Neoplasms, Multiple Primary/pathologyABSTRACT
OBJECTIVE: This study aimed to summarize and analyze the characteristics of pulmonary sequestration to improve our understanding of this disease. METHODS: Between January 2019 and April 2023, the clinical data of 13 patients with pulmonary sequestration underwent surgical treatment at the First Affiliated Hospital of Gannan Medical University. RESULTS: The male-to-female ratio was 4:9, the age was 0.5 to 60 years, and the average age was 38 ± 19 years. There were 10 and 3 cases of intralobar and extralobar pulmonary sequestration, respectively. Chest enhanced computed tomography (CT) and three-dimensional vascular reconstruction showed that the abnormal blood vessels were derived from the descending thoracic aorta in nine cases and from other blood vessels in four cases. Three patients underwent thoracoscopic lobectomy, two underwent thoracoscopic segmentectomy, and eight underwent thoracoscopic wedge resection. All the patients successfully completed the surgery and were discharged postoperatively. CONCLUSIONS: Some patients with pulmonary sequestration exhibit no obvious symptoms. Patients with clinical symptoms are easily confused for pneumonia, bronchial cysts, lung abscesses, and lung tumors; therefore, patients with pulmonary sequestration are prone to missed diagnosis and misdiagnosis. Currently, enhanced chest CT combined with three-dimensional vascular reconstruction can accurately show the course, branches, and relationship with the mass of the feeding artery. Routine pathological examination is helpful to further clarify the diagnosis of pulmonary sequestration. Minimally invasive thoracoscopic surgery is the preferred treatment for patients with pulmonary sequestration. Surgical resection is safe and feasible, and satisfactory results are typically obtained.
Subject(s)
Bronchopulmonary Sequestration , Humans , Male , Female , Young Adult , Adult , Middle Aged , Infant , Child, Preschool , Child , Adolescent , Bronchopulmonary Sequestration/diagnostic imaging , Bronchopulmonary Sequestration/surgery , Retrospective Studies , Thoracic Surgery, Video-Assisted/methods , Prognosis , Tomography, X-Ray ComputedABSTRACT
Background and Aims: N6-methyladenosine (m6A) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various biological processes. However, its roles in fulminant hepatitis remain largely unknown. In the current study, YTHDF1 expression was found to be significantly downregulated in the livers among patients, as well as murine models with fulminant hepatitis versus normal controls. Thus, we hypothesized that YTHDF1 protects against fulminant hepatitis and investigated the underlying molecular mechanisms. Methods: Fulminant hepatitis was induced by D-GalN/LPS in conventional YTHDF1 knockout (YTHDF1-/-) mice, hepatocyte-specific YTHDF1 overexpression (AAV8- YTHDF1) mice, and corresponding control mice. Primary hepatocytes were cultured and subjected to LPS insult in vitro. Hepatic histology, cell death, oxidative stress and mitochondrial function were examined to assess liver damage. The molecular mechanisms of YTHDF1 function were explored using multi-omics analysis. Results: Ablation of YTHDF1 exacerbated hepatic apoptosis and reactive oxygen species (ROS) production and increased the number of aberrant mitochondria, while YTHDF1 overexpression resulted in the opposite effects. Multiomics analysis identified MFG-E8 as the direct target of YTHDF1. YTHDF1 augmented the translation of MFG-E8 in an m6A-dependent manner without effect on its mRNA expression, thereby restoring mitochondrial function. Additionally, administration of MFG-E8 almost completely reversed the YTHDF1 deficiency-mediated exacerbation of liver injury. Conclusions: The current study suggested that the m6A reader YTHDF1 alleviates cell death, enhances antioxidant capacity and restores mitochondrial function in fulminant hepatitis by promoting MFG-E8 protein translation in an m6A-dependent manner.
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Massive Hepatic Necrosis , RNA-Binding Proteins , Animals , Mice , Apoptosis/genetics , Lipopolysaccharides , RNA/genetics , RNA-Binding Proteins/metabolismABSTRACT
Acute liver injury (ALI) in children, which commonly leads to acute liver failure (ALF) with the need for liver transplantation, is a devastating life-threatening condition. As the orchestrated regulation of immune hemostasis in the liver is essential for resolving excess inflammation and promoting liver repair in a timely manner, in this study we focused on the immune inflammation and regulation with the functional involvement of both innate and adaptive immune cells in acute liver injury progression. In the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, it was also important to incorporate insights from the immunological perspective for the hepatic involvement with SARS-CoV-2 infection, as well as the acute severe hepatitis of unknown origin in children since it was first reported in March 2022. Furthermore, molecular crosstalk between immune cells concerning the roles of damage-associated molecular patterns (DAMPs) in triggering immune responses through different signaling pathways plays an essential role in the process of liver injury. In addition, we also focused on DAMPs such as high mobility group box 1 (HMGB1) and cold-inducible RNA-binding protein (CIRP), as well as on macrophage mitochondrial DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in liver injury. Our review also highlighted novel therapeutic approaches targeting molecular and cellular crosstalk and cell-based therapy, providing a future outlook for the treatment of acute liver injury.
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COVID-19 , Hepatitis , Humans , Child , COVID-19/therapy , SARS-CoV-2 , InflammationABSTRACT
Sb-related III-V compounds have recently gained great research interest owing to their excellent optical and electrical characteristics, which provide many possibilities in photonics and electronics. This study investigated the application of InSb films in ultrafast photonics. An InSb film was fabricated on the tapered zone of a microfiber, and its saturation intensity, modulation depth, and non-saturable loss were determined as 119.8 MW cm-2, 23.5%, and 27.3%, respectively. The structure of the electronic band and density of states of InSb were theoretically calculated. Notably, mode-locked and Q-switched fiber lasers were realised by incorporating the InSb-microfiber device into two different Er-doped fiber cavities. In the Q-switching state, the narrowest pulse duration was measured as 1.756 µs with a maximum single-pulse energy of 221.95 nJ and a signal-to-noise ratio of 60 dB. In the mode-locking operation, ultrafast lasers with a high signal-to-noise ratio (70 dB), a pulse width as narrow as 265 fs and a repetition rate of 49.51 MHz were acquired. Besides, the second-harmonic mode-locked state was built with an output power of 13.22 mW. In comparison with the reported laser performance with 2D materials as saturable absorbers, the InSb-based mode-locked and Q-switched fiber lasers proposed herein exhibit better comprehensive performance.
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OBJECTIVE: Traditional uterine manipulator is considered as the main reason for short survival of patients with early-stage cervical cancer during minimally invasive surgery. This study aims to assess the sealing effect of magnetic-sealing uterine manipulators (MUMs) in isolated uteruses. METHODS: The study was performed on isolated uterus from patients with early-stage cervical cancer who underwent open abdominal radical hysterectomy between November 2019 to April 2021. Right-angle forceps closure tests (groups 1 and 3) were defined as control tests. One experimental MUM closure test (group 2) and 2 control tests were respectively carried out in each of the isolated uterus. DNA ploidy analysis system was used to observe exfoliated cells. Statistical analysis was performed using Wilcoxon signed-rank test to assess the sealing effect of MUM. RESULTS: We identified 36 patients. No regional node metastasis was discovered and only one tumor was larger than 4.0 cm in diameter. The mean of exfoliated tumor cells in groups 1, 2, and 3 were 1, 1, and 2, respectively. There was no significant difference in the quantity of exfoliated cells between groups 1 and 3 (p=0.476), so the results of the 2 groups were merged. Subsequently, a significant difference was observed between combined right-angle forceps closure tests and MUM closure tests (p=0.022). CONCLUSION: The sealing effect of MUM was better than that of right-angle forceps. MUM can effectively seal cervical cancer cells in the cup cover, avoiding the dissemination of tumor cells. TRIAL REGISTRATION: Chinese Clinical Trial Register Identifier: ChiCTR1900026012.