Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of HSC.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a reversible stage of liver disease accompanied by inflammatory cell infiltration. Neutrophils extrude a meshwork of chromatin fibers to establish neutrophil extracellular traps (NETs), which play important roles in inflammatory response regulation. Our previous work demonstrated that NETs promote HCC in MASH. However, it is still unknown if NETs play a role in the molecular mechanisms of liver fibrosis. APPROACH AND RESULTS: Following 12 weeks of Western diet/carbon tetrachloride, MASH fibrosis was identified in C57BL/6 mice with increased NET formation. However, NET depletion using DNase I treatment or mice knocked out for peptidyl arginine deaminase type IV significantly attenuated the development of MASH fibrosis. NETs were demonstrated to induce HSCs activation, proliferation, and migration through augmented mitochondrial and aerobic glycolysis to provide additional bioenergetic and biosynthetic supplies. Metabolomic analysis revealed markedly an altered metabolic profile upon NET stimulation of HSCs that were dependent on arachidonic acid metabolism. Mechanistically, NET stimulation of toll-like receptor 3 induced cyclooxygenase-2 activation and prostaglandin E2 production with subsequent HSC activation and liver fibrosis. Inhibiting cyclooxygenase-2 with celecoxib reduced fibrosis in our MASH model. CONCLUSIONS: Our findings implicate NETs playing a critical role in the development of MASH hepatic fibrosis by inducing metabolic reprogramming of HSCs through the toll-like receptor 3/cyclooxygenase-2/cyclooxygenase-2 pathway. Therefore, NET inhibition may represent an attractive treatment target for MASH liver fibrosis.

Identification and molecular characterization of a novel totivirus from Mangifera indica.

In this study, we determined the complete genome sequence of a novel totivirus, tentatively named "Mangifera indica totivirus 1" (MiTV1), identified in 'Apple' mango in China. The double-stranded RNA genome of MiTV1 is 4800 base pairs (bp) in length and contains two open reading frames (ORFs) encoding a putative coat protein (CP) and an RNA-dependent RNA polymerase (RdRp). Phylogenetic analysis based on RdRp and CP amino acid sequences showed that MiTV1 is closely related to members of the genus Totivirus in the family Totiviridae. To our knowledge, this is the first report of a totivirus found in Mangifera indica.

IDDB: a comprehensive resource featuring genes, variants and characteristics associated with infertility.

Infertility is a complex multifactorial disease that affects up to 10% of couples across the world. However, many mechanisms of infertility remain unclear due to the lack of studies based on systematic knowledge, leading to ineffective treatment and/or transmission of genetic defects to offspring. Here, we developed an infertility disease database to provide a comprehensive resource featuring various factors involved in infertility. Features in the current IDDB version were manually curated as follows: (i) a total of 307 infertility-associated genes in human and 1348 genes associated with reproductive disorder in 9 model organisms; (ii) a total of 202 chromosomal abnormalities leading to human infertility, including aneuploidies and structural variants; and (iii) a total of 2078 pathogenic variants from infertility patients' samples across 60 different diseases causing infertility. Additionally, the characteristics of clinically diagnosed infertility patients (i.e. causative variants, laboratory indexes and clinical manifestations) were collected. To the best of our knowledge, the IDDB is the first infertility database serving as a systematic resource for biologists to decipher infertility mechanisms and for clinicians to achieve better diagnosis/treatment of patients from disease phenotype to genetic factors. The IDDB is freely available at http://mdl.shsmu.edu.cn/IDDB/.

MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance.

CD4+CD25+ regulatory T (Treg) cells and Th17 cells play important roles in the progression of metabolic-associated fatty liver disease (MAFLD). However, the contribution of monokine induced by interferon-gamma (MIG)/CXCL9 to the Treg/Th17 imbalance in MAFLD is only partially understood. In the present study, we detected increased levels of MIG/CXCL9 and a Treg/Th17 imbalance in the setting of metabolic-associated steatohepatitis (MASH). Recombinant adeno-associated virus-mediated gene transfer and silencing of MIG/CXCL9 expression in mice alleviated MASH and increased the Treg/Th17 ratio. Furthermore, the percentage of Th17 cells, but not Treg cells, differentiated from splenic CD4+ T cells was significantly increased by administration of MIG/CXCL9. MIG/CXCL9 also promoted Th17 cell proliferation, and its effects were dose dependent. Levels of phosphorylated c-Jun N-terminal kinase (JNK) decreased dramatically when MIG/CXCL9 was inhibited in a murine MASH model. In cultured Treg cells, phosphorylated JNK levels decreased dose-dependently in response to MIG/CXCL9 inhibition, but increased in cultured Th17 cells. This effect was blocked in the presence of a JNK inhibitor. These findings underline the fundamental importance of MIG/CXCL9 in maintaining the Treg/Th17 balance in MAFLD and provide the foundations for a novel approach to preventing and treating MAFLD.

Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Regulatory T-cells (Tregs) impair cancer immunosurveillance by creating an immunosuppressive environment that fosters tumor cell survival. Our previous findings demonstrated that neutrophil extracellular traps (NETs), which are involved both in innate and adaptive immunity, are abundant in livers affected by non-alcoholic steatohepatitis (NASH). However, how NETs interact with Tregs in the development of NASH-associated hepatocellular carcinoma (NASH-HCC) is not known. METHODS: A choline-deficient, high-fat diet+diethylnitrosamine mouse model and the stelic animal model were utilized for NASH-HCC and a western diet mouse model was used for NASH development. Treg depletion was achieved using FoxP3-DTR mice. RNA sequencing was used to explore the mechanism by which NETs could regulate Treg differentiation. Bioenergetic analyses of naïve CD4+ T-cells were assessed by Seahorse. RESULTS: Although the absolute number of CD4+ T-cells is lower in NASH livers, the Treg subpopulation is selectively increased. Depleting Tregs dramatically inhibits HCC initiation and progression in NASH. There is a positive correlation between increased NET and hepatic Treg levels. RNA sequencing data reveals that NETs impact gene expression profiles in naïve CD4+ T-cells, with the most differentially expressed genes being those involved in mitochondrial oxidative phosphorylation. By facilitating mitochondrial respiration, NETs can promote Treg differentiation. Metabolic reprogramming of naïve CD4+ T-cells by NETs requires toll-like receptor 4. Blockade of NETs in vivo using Pad4-/- mice or DNase I treatment reduces the activity of Tregs. CONCLUSIONS: Tregs can suppress immunosurveillance in the premalignant stages of NASH. NETs facilitate the crosstalk between innate and adaptive immunity in NASH by promoting Treg activity through metabolic reprogramming. Therapies targeting NETs and Treg interactions could offer a potential strategy for preventing HCC in patients with NASH. LAY SUMMARY: Regulatory T-cells (Tregs) can promote tumor development by suppressing cancer immunosurveillance, but their role in carcinogenesis during non-alcoholic steatohepatitis (NASH) progression is unknown. Herein, we discovered that selectively increased intrahepatic Tregs can promote an immunosuppressive environment in NASH livers. Neutrophil extracellular traps (NETs) link innate and adaptive immunity by promoting Treg differentiation via metabolic reprogramming of naïve CD4+ T-cells. This mechanism could be targeted to prevent liver cancer in patients with NASH.

NH4I-promoted oxidative formation of benzothiazoles and thiazoles from arylacetic acids and phenylalanines with elemental sulfur.

A NH4I/K3PO4-based catalytic system has been established to enable oxidative formation of thiazole compounds from arylacetic acids and phenylalanines with elemental sulfur. While the three-component reaction of anilines or ß-naphthylamines with arylacetic acids and elemental sulfur affords benzo[2,1-d]thiazoles and naphtho[2,1-d]thiazoles, the annulation of phenylalanines with elemental sulfur produces 2-benzyl and 2-benzoylthiazoles. This work well complements previous three-component annulations of benzothiazoles from other coupling partners.

Integration of Bimetallic Electronic Synergy with Oxide Site Isolation Improves the Selective Hydrogenation of Acetylene.

Semi-hydrogenation of acetylene to ethylene is an important process to purify ethylene streams in industry. However, among current approaches reported in the literature, high ethylene selectivity has been generally achieved at the expense of activity. Herein, we show that a Ga2 O3 coating of Ag@Pd core-shell bimetallic nanoparticle catalysts, allows improvement of the ethylene selectivity to a much greater extent than the coating of monometallic Pd nanoparticles, while preserving a remarkable intrinsic activity, approximately 50 times higher than the benchmark catalyst of Pd1 Ag single-atom alloys (SAAs). Importantly, the resulting catalyst also shows excellent long-term stability, by suppressing coke formation efficiently. Spectroscopic characterization reveals that weakened ethylene adsorption by bimetallic electronic synergy, and oxide site isolation are both essential for the high ethylene selectivity and high-coking resistance. H-D exchange measurements further show that the Ga2 O3 -coated Ag@Pd catalyst possesses a much higher activity of H2 activation than that of Pd1 Ag SAAs, thus boosting the hydrogenation activity at the same time.

The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China.

The outbreak of 2019 novel coronavirus (COVID-19) infection emerged in Wuhan, China, in December 2019. Since then the novel coronavirus pneumonia disease has been spreading quickly and many countries and territories have been affected, with major outbreaks in China, South Korea, Italy, and Iran. Influenza virus has been known as a common pathogen in winter and it can cause pneumonia. It was found clinically that very few patients were diagnosed with both COVID-19 and influenza virus. A total of 5 of the 115 patients confirmed with COVID-19 were also diagnosed with influenza virus infection, with three cases being influenza A and two cases being influenza B. In this study, we describe the clinical characteristics of those patients who got infected with COVID-19 as well as influenza virus. Common symptoms at onset of illness included fever (five [100%] patients), cough (five [100%] patients), shortness of breath (five [100%] patients), nasal tampon (three [60%] patients), pharyngalgia (three [60%] patients), myalgia (two [40%] patients), fatigue (two [40%] patients), headache (two [40%] patients), and expectoration (two [40%] patients). The laboratory results showed that compared to the normal values, the patients' lymphocytes were reduced (four [80%] patients), and liver functions alanine aminotransferase and aspartate aminotransferase (two [40%] patients and two [40%] patients) and C-reactive protein (four [80%] patients) were increased when admitted to hospital. They stayed in the hospital for 14, 30, 17, 12, and 19 days (28.4 ± 7.02), respectively. The main complications for the patients were acute respiratory distress syndrome (one [20%] patients), acute liver injury (three [60%] patients), and diarrhea (two [40%] patients). All patients were given antiviral therapy (including oseltamivir), oxygen inhalation, and antibiotics. Three patients were treated with glucocorticoids including two treated with oral glucocorticoids. One of the five patients had transient hemostatic medication for hemoptysis. Fortunately, all patients did not need intensive care unit and were discharged from the hospital without death. In conclusion, those patients with both COVID-19 and influenza virus infection did not appear to show a more severe condition because based on the laboratory findings, imaging studies, and patient prognosis, they showed similar clinical characteristics as those patients with COVID-19 infection only. However, it is worth noting that the symptoms of nasal tampon and pharyngalgia may be more prone to appear for those coinfection patients.

Synthesis of polysubstituted pyridines from oxime acetates using NH4I as a dual-function promoter.

Pyridine formation with oxime acetates as the building blocks under metal-free conditions is described. Ammonium iodide has proved to be a highly efficient promoter for oxime N-O bond reduction and subsequent condensation reactions, whereby it played a dual-function role in the transformation. While the three-component reaction of oxime acetates, benzaldehydes, and 1,3-dicarbonyls proceeded well with the assistance of a stoichiometric amount of ammonium iodide, the condensation of oximes and acroleins was enabled by using a catalytic initiator to afford substituted pyridines. By this protocol, substituted pyridine products were generated in moderate to excellent yields with tolerance towards a broad range of functional groups.

Sirtuin 6 promotes transforming growth factor-ß1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence.

Sirtuin 6 (SIRT6) can function as a tumor suppressor by suppressing aerobic glycolysis and apoptosis resistance. However, the negative effect of SIRT6 on cellular senescence implies that it may also have the potential to promote tumor development. Here we report that the upregulation of SIRT6 expression was required for transforming growth factor (TGF)-ß1 and H2O2/HOCl reactive oxygen species (ROS) to promote the tumorigenicity of hepatocellular carcinoma (HCC) cells. Transforming growth factor-ß1/H2O2/HOCl could upregulate SIRT6 expression in HCC cells by inducing the sustained activation of ERK and Smad pathways. Sirtuin 6 in turn abrogated the inducing effect of TGF-ß1/H2O2/HOCl on cellular senescence of HCC cells, and was required for the ERK pathway to efficiently suppress the expression of p16 and p21. Sirtuin 6 altered the effect of Smad and p38 MAPK pathways on cellular senescence, and contributed to the inhibitory effect of the ERK pathway on cellular senescence. However, SIRT6 was inefficient in antagonizing the promoting effect of TGF-ß1/H2O2 HOCl on aerobic glycolysis and anoikis resistance. Intriguingly, if SIRT6 expression was inhibited, the promoting effect of TGF-ß1/H2O2/HOCl on aerobic glycolysis and anoikis resistance was not sufficient to enhance the tumorigenicity of HCC cells. Suppressing the upregulation of SIRT6 enabled TGF-ß1/H2O2/HOCl to induce cellular senescence, thereby abrogating the enhancement of HCC cell tumorigenicity by TGF-ß1/H2O2/HOCl. These results suggest that SIRT6 is required for TGF-ß1/H2O2/HOCl to enhance the tumorigenicity of HCC cells, and that targeting the ERK pathway to suppress the upregulation of SIRT6 might be a potential approach in comprehensive strategies for the therapy of HCC.

Deep Learning-Based Detect-Then-Track Pipeline for Treatment Outcome Assessments in Immunotherapy-Treated Liver Cancer.

Accurate treatment outcome assessment is crucial in clinical trials. However, due to the image-reading subjectivity, there exist discrepancies among different radiologists. The situation is common in liver cancer due to the complexity of abdominal scans and the heterogeneity of radiological imaging manifestations in liver subtypes. Therefore, we developed a deep learning-based detect-then-track pipeline that can automatically identify liver lesions from 3D CT scans then longitudinally track target lesions, thereby providing the evaluation of RECIST treatment outcomes in liver cancer. We constructed and validated the pipeline on 173 multi-national patients (344 venous-phase CT scans) consisting of a public dataset and two in-house cohorts of 28 centers. The proposed pipeline achieved a mean average precision of 0.806 and 0.726 of lesion detection on the validation and test sets. The model's diameter measurement reliability and consistency are significantly higher than that of clinicians (p = 1.6 × 10-4). The pipeline can make precise lesion tracking with accuracies of 85.7% and 90.8% then finally yield the RECIST accuracies of 82.1% and 81.4% on the validation and test sets. Our proposed pipeline can provide precise and convenient RECIST outcome assessments and has the potential to aid clinicians with more efficient therapeutic decisions.

The influence of psychological change factors of tennis training strategy using optimized recurrent neural network and artificial intelligence.

Due to the specialization of tennis technical training, the teaching focus of tennis teaching has gradually shifted to the psychological skills training of tennis players. This work addresses the impact of psychological factors on tennis players' insufficient concentration in teaching and training on match results. It discusses the psychological changes' influencing factors in tennis training strategies and analyzes the current psychological changes that are easy to occur in tennis teaching. The Recurrent Neural Network (RNN) can simulate the human brain's information processing and learning process to establish models to study human psychological changes. To explore the influence of psychological changes on tennis training, artificial intelligence technology is combined to optimize the performance of RNN, and a prediction model of psychological distress in tennis training is constructed. Additionally, a questionnaire is applied to compare the sports state of tennis players before and after the psychological regulation intervention. The findings demonstrate that following psychological regulation, 73 % of players perform as usual, 20 % present exceptionally well, and 7 % do not perform as well as usual. These results indicate an improvement compared to previous performances, highlighting the efficacy of psychological regulation supported by optimized RNN under AI assistance. This study aims to foster a consistently positive psychological state among tennis players during daily training and competitions, ensuring that their competitive performance levels remain normal or even exceed their usual standards.

Association of healthy lifestyle with self-reported sleep disordered breathing: A cross-sectional study.

Some healthy lifestyle components have been linked with sleep disordered breathing (SDB), yet little is known about the relationship between comprehensive lifestyle factors and SDB. This study aimed to examine the healthy lifestyle with SDB in community-dwelling adults. We conducted a cross-sectional analysis of the Suzhou Food Consumption and Health Survey in China between 2018 and 2020. The healthy lifestyle index (HLI) was created by combining smoking, alcohol drinking, diet, physical activity, and body mass index (BMI). Its association with SDB was assessed by multiple logistic regression analysis. Subgroup analysis and sensitivity analysis were conducted to assess the robustness of our results. The final analysis included 3788 participants (2859 without SDB and 929 with SDB). In multivariable-adjusted analyses, non-smoking (OR: 0.58, 95 % CI: 0.47-0.71), non-drinking (OR: 0.55, 95 % CI: 0.45-0.68), healthy diet (OR: 0.79, 95 % CI: 0.65-0.95), and healthy BMI (OR: 0.72, 95 % CI: 0.6-0.86) were associated with SDB. Compared with participants with HLI score of 0-1, participants with HLI score of 2, 3, 4, and 5 had OR of 0.68 (95 % CI: 0.51-0.91), 0.49 (95 % CI: 0.37-0.64), 0.29 (95 % CI: 0.21-0.38), and 0.22 (95 % CI: 0.15-0.33), respectively, after adjustment for confounding factors (P-trend<0.001). An inverse dose-response relationship between HLI and SDB was also observed. The association was similar in subgroups stratified by sex, marital status, diabetes and dyslipidemia. A higher score of HLI was associated with reduced odds of SDB in Chinese adults. Our findings suggest the potential of addressing five modifiable lifestyle factors for the prevention of SDB.

CT-based multimodal deep learning for non-invasive overall survival prediction in advanced hepatocellular carcinoma patients treated with immunotherapy.

OBJECTIVES: To develop a deep learning model combining CT scans and clinical information to predict overall survival in advanced hepatocellular carcinoma (HCC). METHODS: This retrospective study included immunotherapy-treated advanced HCC patients from 52 multi-national in-house centers between 2018 and 2022. A multi-modal prognostic model using baseline and the first follow-up CT images and 7 clinical variables was proposed. A convolutional-recurrent neural network (CRNN) was developed to extract spatial-temporal information from automatically selected representative 2D CT slices to provide a radiological score, then fused with a Cox-based clinical score to provide the survival risk. The model's effectiveness was assessed using a time-dependent area under the receiver operating curve (AUC), and risk group stratification using the log-rank test. Prognostic performances of multi-modal inputs were compared to models of missing modality, and the size-based RECIST criteria. RESULTS: Two-hundred seven patients (mean age, 61 years ± 12 [SD], 180 men) were included. The multi-modal CRNN model reached the AUC of 0.777 and 0.704 of 1-year overall survival predictions in the validation and test sets. The model achieved significant risk stratification in validation (hazard ratio [HR] = 3.330, p = 0.008), and test sets (HR = 2.024, p = 0.047) based on the median risk score of the training set. Models with missing modalities (the single-modal imaging-based model and the model incorporating only baseline scans) can still achieve favorable risk stratification performance (all p < 0.05, except for one, p = 0.053). Moreover, results proved the superiority of the deep learning-based model to the RECIST criteria. CONCLUSION: Deep learning analysis of CT scans and clinical data can offer significant prognostic insights for patients with advanced HCC. CRITICAL RELEVANCE STATEMENT: The established model can help monitor patients' disease statuses and identify those with poor prognosis at the time of first follow-up, helping clinicians make informed treatment decisions, as well as early and timely interventions. KEY POINTS: An AI-based prognostic model was developed for advanced HCC using multi-national patients. The model extracts spatial-temporal information from CT scans and integrates it with clinical variables to prognosticate. The model demonstrated superior prognostic ability compared to the conventional size-based RECIST method.

Effect of lifestyle intervention on HbA1c levels in overweight and obese adults with type 2 diabetes across ethnicities: A systematic review and meta-analysis of randomized controlled trials.

AIMS: Weight reduction is fundamental for the management and remission of diabetes. We aimed to assess ethnic differences in the effects of lifestyle weight-loss interventions on HbA1c levels in overweight or obese adults with type 2 diabetes mellitus (T2DM). METHODS: We systematically searched PubMed/MEDLINE and Web of Science online databases up to 31 Dec 2022. Randomized controlled trials using lifestyle weight-loss interventions in overweight or obese adults with T2DM were selected. We performed subgroup analyses to explore the heterogeneity across different ethnicities (Asians, White/Caucasians, Black/Africans and Hispanics). A random effects model was applied to calculate weighted mean difference (WMD) with 95% confidence interval (CI). RESULTS: Thirty studies including 7580 subjects from different ethnicities were identified according to the predefined inclusion and exclusion criteria. HbA1c levels were significantly reduced by lifestyle weight-loss intervention. Notably, a significantly beneficial effect on HbA1c was observed in White/Caucasians (WMD = -0.59, 95% CI: -0.90, -0.28, P < 0.001) and Asians (WMD = -0.48, 95% CI: -0.63, -0.33, P < 0.001), but not in the Black/African or Hispanic group (both P > 0.05). The findings remained essentially unchanged in the sensitivity analysis. CONCLUSIONS: Lifestyle weight-loss interventions had distinct beneficial effects on HbA1c levels in different ethnic groups with T2DM, especially in Caucasians and Asians.

Upregulation of SATB1 promotes tumor growth and metastasis in liver cancer.

BACKGROUND: Special AT-rich binding protein-1 (SATB1) reprograms chromatin organization and transcription profiles to promote tumour growth and metastasis. AIMS: This study aimed to confirm the effects of SATB1 on the growth and metastasis of liver cancer and its specific regulation mechanism. METHODS: SATB1 expression was evaluated in human hepatoma tissue, adjacent noncancerous tissue and seven kinds of liver cancer cell lines. Cell cycle, cell proliferation, apoptosis and epithelial-mesenchymal transition (EMT) was investigated after enhanced or silenced expression of SATB1. The regulatory action of SATB1 on the expression of genes that are known to regulate cell cycle progression, apoptosis and EMT and the specific apoptotic pathway on which it acts were further analysed. Nude mice that received subcutaneous implantation were used to study the effects of SATB1 on tumour growth in vivo. RESULTS: Our data show that the high expression of SATB1 was observed in the human hepatocellular carcinoma tissue (26/45) and liver cancer cell lines with high metastatic potential. SATB1 upregulated CDK4 and downregulated p16 (INK) (4A) to promote cell cycle progression and cell proliferation and prevented apoptosis by inhibiting the FADD-caspase-8-caspase-3 death receptor-mediated apoptosis pathway. SATB1 also induced EMT concomitant with increased expression of Snail1, Slug, Twist and vimentin and decreased expression of E-cadherin, tight junction protein ZO-1 and desmoplakin. SATB1 promoted the growth of tumour in vivo. CONCLUSION: These data suggest that the SATB1 gene may play an important role in the development and progression of liver cancer by regulation of genes related to cell cycle progression, apoptosis and EMT.

Role of autophagy in monokine induced by interferon γ (Mig) production during adenovirus-hepatitis B virus infection.

BACKGROUND/AIMS: The aim of this study was to investigate the effect of HBV-induced Mig and role of autophagy in the process. METHODOLOGY: Adxsi-1.3 x HBV plasmid was constructed and identified. The three cell lines (L02, HepG2, SMMC-7721) were infected with adenovirus-HBV. HBsAg and HBeAg were assessed by electrochemiluminescence immunoassay. HBV DNA, HBx, Beclin 1 and Mig expression were detected by quantitative real-Time PCR, western blotting and ELISA. The level of autophagy was evaluated by transmission electron microscope. RESULTS: Human fetal liver cells and hepatocellular carcinoma cells were successfully transfected with overlength HBV genome using an adenovirus vector (Ad-HBV). Ad-HBV induced Mig production and cell autophagy through up-regulation of Beclin 1 expression. We further demonstrated that the increased autophagy extent was in association with HBV-induced Mig expression. CONCLUSIONS: Autophagy may be a crucial intracellular mechanism of Mig induction in response to HBV infection. The results provide new insights into the pathogenesis of HBV.

En Bloc Resection of Primary Large Esophageal Mucosa-Associated Lymphoid Tissue Lymphoma by Endoscopic Submucosal Dissection: A Case Report.

Treatment of mucosa-associated lymphoid tissue (MALT) lymphoma has recently received considerable attention. Here, we report a case of large esophageal MALT lymphoma that was successfully en bloc resected using endoscopic submucosal dissection (ESD). A 77-year-old woman was admitted to our hospital with progressive dysphagia for more than 2 months. Upper gastrointestinal endoscopy revealed a large rounded submucosal mass covered by normal mucosa, located at the lower esophagus. Endoscopic ultrasonography (EUS) showed a well-demarcated hypoechoic mass chiefly located in the esophageal wall, but the layers of the esophageal wall were not clear. ESD was performed for diagnostic and treatment purposes. No complications occurred during or after ESD. The resected specimen measured 4.3 cm × 2.8 cm × 1.5 cm. The histologic findings were diagnostic of esophageal MALT lymphoma. Infiltration of neoplastic cells in the lateral margins of the resected specimen was not observed. However, vertical margins showed an R1 situation and mild damage to the muscularis propria. After 3 months, her dysphagia disappeared. Additional radiation therapy was then administered. After 5 months, the patient was still under surveillance and free of recurrent disease. Resection with ESD of such a large mass of MALT in the esophageal region has rarely been reported before in the literature.

Metabolic reprogramming of immune cells: Shaping the tumor microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a typical inflammation-induced cancer and displays a complex interaction between the tumor microenvironment and tumor development. Immune cells in the HCC microenvironment play both pro- and anti-tumoral roles in HCC progression. An increasing number of findings indicate that metabolic reprogramming is essential for immune cell differentiation and function. In this review, we discuss the metabolic changes of different immune cells and correlate these findings to HCC progression.

Platelet TLR4-ERK5 Axis Facilitates NET-Mediated Capturing of Circulating Tumor Cells and Distant Metastasis after Surgical Stress.

Surgical removal of malignant tumors is a mainstay in controlling most solid cancers. However, surgical insult also increases the risk of tumor recurrence and metastasis. Tissue trauma activates the innate immune system locally and systemically, mounting an inflammatory response. Platelets and neutrophils are two crucial players in the early innate immune response that heals tissues, but their actions may also contribute to cancer cell dissemination and distant metastasis. Here we report that surgical stress-activated platelets enhance the formation of platelet-tumor cell aggregates, facilitating their entrapment by neutrophil extracellular traps (NET) and subsequent distant metastasis. A murine hepatic ischemia/reperfusion (I/R) injury model of localized surgical stress showed that I/R promotes capturing of aggregated circulating tumor cells (CTC) by NETs and eventual metastasis to the lungs, which are abrogated when platelets are depleted. Hepatic I/R also increased deposition of NETs within the lung microvasculature, but depletion of platelets had no effect. TLR4 was essential for platelet activation and platelet-tumor cell aggregate formation in an ERK5-GPIIb/IIIa integrin-dependent manner. Such aggregation facilitated NET-mediated capture of CTCs in vitro under static and dynamic conditions. Blocking platelet activation or knocking out TLR4 protected mice from hepatic I/R-induced metastasis with no CTC entrapment by NETs. These results uncover a novel mechanism where platelets and neutrophils contribute to metastasis in the setting of acute inflammation. Targeted disruption of the interaction between platelets and NETs holds therapeutic promise to prevent postoperative distant metastasis. SIGNIFICANCE: Targeting platelet activation via TLR4/ERK5/integrin GPIIb/IIIa signaling shows potential for preventing NET-driven distant metastasis in patients post-resection.