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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.
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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.
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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.
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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.
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Índice de Masa Corporal , Estilo de Vida Saludable , Autoinforme , Síndromes de la Apnea del Sueño , Humanos , Estudios Transversales , Masculino , Femenino , Síndromes de la Apnea del Sueño/epidemiología , Persona de Mediana Edad , China/epidemiología , Consumo de Bebidas Alcohólicas/epidemiología , Ejercicio Físico , Adulto , Fumar/epidemiología , Encuestas Epidemiológicas , Factores de Riesgo , AncianoRESUMEN
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.
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Mangifera , Totivirus , Totivirus/genética , Mangifera/genética , Filogenia , Secuencia de Aminoácidos , ARN Bicatenario , ARN Polimerasa Dependiente del ARN/genética , Sistemas de Lectura Abierta , Genoma Viral , ARN Viral/genéticaRESUMEN
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.
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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.
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Diabetes Mellitus Tipo 2 , Sobrepeso , Adulto , Humanos , Sobrepeso/terapia , Diabetes Mellitus Tipo 2/terapia , Hemoglobina Glucada , Etnicidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Obesidad/terapia , Estilo de Vida , Pérdida de PesoRESUMEN
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.
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Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors.
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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.
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Quimiocina CXCL9/metabolismo , Interferón gamma/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Síndrome Metabólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/patología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Proliferación Celular , Quimiocina CXCL9/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , FosforilaciónRESUMEN
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.
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Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/inmunología , Hígado/patología , Microambiente Tumoral/inmunología , Inmunidad Adaptativa , Carcinogénesis/inmunología , Carcinogénesis/patología , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Hígado/inmunología , Neoplasias Hepáticas/patología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
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.
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Carcinogénesis , Trampas Extracelulares/metabolismo , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Linfocitos T/metabolismo , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/antagonistas & inhibidores , Ratones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Ohio , Estadísticas no ParamétricasRESUMEN
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.
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Pre-operative exercise therapy improves outcomes for many patients who undergo surgery. Despite the well-known effects on tolerance to systemic perturbation, the mechanisms by which pre-operative exercise protects the organ that is operated on from inflammatory injury are unclear. Here, we show that four-week aerobic pre-operative exercise significantly attenuates liver injury and inflammation from ischaemia and reperfusion in mice. Remarkably, these beneficial effects last for seven more days after completing pre-operative exercising. We find that exercise specifically drives Kupffer cells toward an anti-inflammatory phenotype with trained immunity via metabolic reprogramming. Mechanistically, exercise-induced HMGB1 release enhances itaconate metabolism in the tricarboxylic acid cycle that impacts Kupffer cells in an NRF2-dependent manner. Therefore, these metabolites and cellular/molecular targets can be investigated as potential exercise-mimicking pharmaceutical candidates to protect against liver injury during surgery.
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Metabolismo Energético , Inmunidad Innata , Macrófagos del Hígado/inmunología , Macrófagos del Hígado/metabolismo , Ejercicio Preoperatorio , Animales , Resistencia a la Enfermedad , Inflamación/inmunología , Inflamación/metabolismo , Isquemia/inmunología , Isquemia/metabolismo , RatonesRESUMEN
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.
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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.
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Plaquetas/inmunología , Trampas Extracelulares/metabolismo , Hígado/lesiones , Neoplasias Pulmonares/secundario , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Células Neoplásicas Circulantes/metabolismo , Neutrófilos/inmunología , Daño por Reperfusión/metabolismo , Receptor Toll-Like 4/deficiencia , Animales , Plaquetas/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Recurrencia Local de Neoplasia , Neutrófilos/metabolismo , Transducción de Señal/genética , Receptor Toll-Like 4/genéticaRESUMEN
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/.
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Aberraciones Cromosómicas , Bases de Datos Factuales , Enfermedades del Sistema Endocrino/genética , Infertilidad Femenina/genética , Infertilidad Masculina/genética , Mutación , Animales , Mapeo Cromosómico , Modelos Animales de Enfermedad , Enfermedades del Sistema Endocrino/metabolismo , Enfermedades del Sistema Endocrino/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Genoma Humano , Humanos , Infertilidad Femenina/metabolismo , Infertilidad Femenina/patología , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Internet , Masculino , Oocitos/metabolismo , Oocitos/patología , Programas Informáticos , Espermatozoides/metabolismo , Espermatozoides/patologíaRESUMEN
Liver metastasis is the main cause of colorectal cancer (CRC)-related death. Neutrophil extracellular traps (NETs) play important roles in CRC progression. Deoxyribonuclease I (DNase I) has been shown to alter NET function by cleaving DNA strands comprising the NET backbone. Moreover, DNase I displays high antimetastatic activity in multiple tumor models. To circumvent long-term daily administrations of recombinant DNase I, we have developed an adeno-associated virus (AAV) gene therapy vector to specifically express DNase I in the liver. In this study, we demonstrate AAV-mediated DNase I liver gene transfer following a single intravenous injection suppresses the development of liver metastases in a mouse model of CRC liver metastasis. Increased levels of neutrophils and NET formation in tumors are associated with poor prognosis in many patients with advanced cancers. Neutrophil infiltration and NET formation were inhibited in tumor tissues with AAV-DNase I treatment. This approach restored local immune responses at the tumor site by increasing the percentage of CD8+ T cells while keeping CD4+ T cells similar between AAV-DNase I and AAV-null treatments. Our data suggest that AAV-mediated DNase I liver gene transfer is a safe and effective modality to inhibit metastasis and represents a novel therapeutic strategy for CRC.
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Neoplasias Colorrectales/patología , Desoxirribonucleasa I/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Inmunidad Adaptativa , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Desoxirribonucleasa I/inmunología , Dependovirus/genética , Trampas Extracelulares/genética , Trampas Extracelulares/inmunología , Femenino , Expresión Génica , Técnicas de Transferencia de Gen , Terapia Genética , Células Hep G2 , Humanos , Inmunidad Innata , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
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.
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COVID-19/diagnóstico , COVID-19/epidemiología , Coinfección , Gripe Humana/diagnóstico , Gripe Humana/epidemiología , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Biomarcadores , COVID-19/complicaciones , COVID-19/virología , China/epidemiología , Comorbilidad , Manejo de la Enfermedad , Humanos , Gripe Humana/complicaciones , Gripe Humana/virología , Evaluación del Resultado de la Atención al Paciente , Neumonía Viral/etiología , Vigilancia en Salud Pública , Evaluación de Síntomas , Tomografía Computarizada por Rayos XRESUMEN
The prevalence of immunemediated liver diseases such as autoimmune liver disease or viral hepatitis has increased in recent years, and the side effects of preexisting treatments are a worldwide problem. Regulatory T cells (Tregs) and T helper 17 (Th17) cells play important roles in the development of immunemediated hepatitis and may serve as potential therapeutic targets. Tofacitinib, a new Janus kinase (JAK) inhibitor, is under investigation for the treatment of rheumatoid arthritis; it is also helpful in treating ulcerative colitis and psoriasis. The roles of tofacitinib were investigated in conferring protection against immunemediated liver injury in mice. T cellmediated hepatitis was induced by concanavalin A (ConA). The mice in the treatment groups were administered with tofacitinib intragastrically before the ConA injection. Histopathological examination was performed by hematoxylin and eosin (H&E) staining, and the serum transaminase and inflammatory cytokine levels were determined using an automatic biochemistry analysis apparatus or cytometric bead array (CBA) kits. Flow cytometric analysis was used to detect Tregs and Th17 cells. Tofacitinib significantly decreased the hepatic injury induced by ConA and prominently decreased the liver transaminase level. The secretion of several antiinflammatory cytokines such as interleukin (IL)10 was upregulated in mice from the treatment group, compared to that in mice treated with ConA alone, while the expression of interferonγ (IFNγ) and tumor necrosis factorα (TNFα) decreased. Tofacitinib treatment increased the number of Tregs and reduced the number of Th17 cells. Furthermore, tofacitinib could relieve liver fibrosis under conditions of autoimmune hepatitis (AIH). The present results indicated that tofacitinib improved immunemediated hepatitis and restored the impaired Treg/Th17 cell ratio, which suggests that it may serve as a novel treatment approach for immunemediated liver diseases.