RÉSUMÉ
Pyroptosis has been regarded as caspase-1-mediated monocyte death that induces inflammation, showing a critical and detrimental role in the development of cerebral ischemia-reperfusion injury (IRI). MARCH1 is an E3 ubiquitin ligase that exerts potential anti-inflammatory functions. Therefore, the study probed into the significance of MARCH1 in inflammation and pyroptosis elicited by cerebral IRI. Middle cerebral artery occlusion/reperfusion (MCAO/R)-treated mice and oxygen glucose deprivation/reoxygenation (OGD/R)-treated hippocampal neurons were established to simulate cerebral IRI in vivo and in vitro. MARCH1 and PCSK9 expression was tested in MCAO/R-operated mice, and their interaction was identified by means of the cycloheximide assay and co-immunoprecipitation. The functional roles of MARCH1 and PCSK9 in cerebral IRI were subsequently determined by examining the neurological function, brain tissue changes, neuronal viability, inflammation, and pyroptosis through ectopic expression and knockdown experiments. PCSK9 expression was increased in the brain tissues of MCAO/R mice, while PCSK9 knockdown reduced brain damage and neurological deficits. Additionally, inflammation and pyroptosis were inhibited in OGD/R-exposed hippocampal neurons upon PCSK9 knockdown, accompanied by LDLR upregulation and NLRP3 inflammasome inactivation. Mechanistic experiments revealed that MARCH1 mediated ubiquitination and degradation of PCSK9, lowering PCSK9 protein expression. Furthermore, it was demonstrated that MARCH1 suppressed inflammation and pyroptosis after cerebral IRI by downregulating PCSK9 both in vivo and in vitro. Taken together, the present study demonstrate the protective effect of MARCH1 against cerebral IRI through PCSK9 downregulation, which might contribute to the discovery of new therapies for improving cerebral IRI.
RÉSUMÉ
Thioamides are widely used structures in pharmaceuticals and agrochemicals, as well as important synthons for the construction of sulfur-containing heterocycles. This report presents a series of visible-light-driven multicomponent reactions of amines, carbon disulfide, and olefins for the mild and versatile synthesis of linear thioamides and cyclic thiolactams. The use of inexpensive and readily available carbon disulfide as the thiocarbonyl source in a radical pathway enables the facile assembly of structurally diverse amine moieties with non-nucleophilic carbon-based reaction partners. Radical thiocarbamoylative cyclization provides a practical protocol that complements traditional approaches to thiolactams relying on deoxythionation. Mechanistic studies reveal that direct photoexcitation of in situ formed dithiocarbamate anions as well as versatile photoinduced electron transfer with diverse electron acceptors are key to the reactions.
RÉSUMÉ
Background: Identification is the first step for treatment of hypertension. However, the awareness rate of hypertension was not high globally. This study aimed to examine the potential role of health insurance for early-identifying hypertension among urban older residents in China. Methods: In this cross-sectional study, urban residents aged 60+ years were chosen from Nanjing municipality of China in 2018. The outcome measure was hypertension status ("no hypertension," "diagnosed hypertension" or "un-diagnosed hypertension"). Independent variable was health insurance ("Urban Employee Basic Medical Insurance scheme, UEBMI" or "Urban Resident Basic Medical Insurance scheme, URBMI"). Logistic regression models were introduced to estimate odds ratio (OR) and 95% confidence interval (CI) to examine the association between health insurance and hypertension. Results: Totally, 19,742 participants completed the study. Among overall, URBMI and UEBMI participants, 47.2% (95%CI = 46.5, 47.9%), 38.4% (95%CI = 37.3, 39.6%) and 52.1% (95%CI = 51.2, 53.0%), separately, were diagnosed with hypertension, while the prevalence of un-diagnosed hypertension was 12.7% (95%CI = 12.2, 13.2%), 18.5% (95%CI = 17.6, 19.4%) and 9.6% (95%CI = 9.1, 10.1%), respectively. For overall participants, those with UEBMI were more likely to have hypertension identified (OR = 1.20; 95%CI = 1.11, 1.29) and at lower odds to experience un-diagnosed hypertension (OR = 0.68; 95%CI = 0.61, 0.76) compared to their counterparts with URBMI after control for potential confounders. Moreover, such associations of health insurance with diagnosed and un-diagnosed hypertension were also observed among participants stratified by age and gender. Conclusion: Favorable health insurance may be a pathway for identifying hypertension among urban older residents in China. This study has important public health implications that hypertension may be identified early through favorable health insurance policies for older residents in China.
Sujet(s)
Hypertension artérielle , Assurance maladie , Population urbaine , Humains , Hypertension artérielle/épidémiologie , Hypertension artérielle/diagnostic , Femelle , Chine/épidémiologie , Mâle , Études transversales , Sujet âgé , Adulte d'âge moyen , Assurance maladie/statistiques et données numériques , Population urbaine/statistiques et données numériques , Sujet âgé de 80 ans ou plusRÉSUMÉ
BACKGROUND: To further clarify the predictive value of pretreatment Naples prognostic score (NPS), calculating based on the serum albumin concentration, total cholesterol level, neutrophil to lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR), among esophageal cancer patients based on available evidence. METHODS: The PubMed, EMBASE, Web of Science and CNKI databases were searched up to December 1, 2023 for relevant studies. Overall survival (OS), progression-free survival (PFS) and cancer-specific survival (CSS) were endpoints and the hazard ratio (HR) with 95% confidence interval (CI) was combined to evaluate the predictive role of NPS for survival. Subgroup analysis based on pathological type and treatment were further conducted. RESULTS: Ten retrospective studies with 2250 cases were included in our analysis. Pooled results demonstrated that higher pretreatment NPS predicted poorer OS (HRâ =â 2.24, 95% CI: 1.57-3.20, Pâ <â .001), PFS (HRâ =â 3.03, 95% CI: 1.84-4.98, Pâ <â .001) and CSS (HRâ =â 2.90, 95% CI: 1.80-4.68, Pâ <â .001). Then subgroup analysis for the OS and PFS stratified by the pathological type (squamous cell carcinoma vs esophageal cancer) and treatment (surgery vs non-surgery) were further conducted, which showed similar results. CONCLUSION: Pretreatment NPS is significantly associated with prognosis in esophageal cancer and higher NPS predicts worse survival among patients with esophageal cancer.
Sujet(s)
Tumeurs de l'oesophage , Humains , Tumeurs de l'oesophage/mortalité , Tumeurs de l'oesophage/anatomopathologie , Tumeurs de l'oesophage/sang , Pronostic , Sérumalbumine/analyse , Granulocytes neutrophiles , Cholestérol/sang , Valeur prédictive des tests , Lymphocytes , Monocytes , Études rétrospectivesRÉSUMÉ
BACKGROUND AND OBJECTIVE: Progranulin (PGRN), a multifunctional growth factor, plays indispensable roles in the regulation of cancer, inflammation, metabolic diseases, and neurodegenerative diseases. Nevertheless, its immune regulatory role in periodontitis is insufficiently understood. This study attempts to explore the regulatory effects of PGRN on macrophage polarization in periodontitis microenvironment. METHODS: Immunohistochemical (IHC) and multiplex immunohistochemical (mIHC) stainings were performed to evaluate the expression of macrophage-related markers and PGRN in gingival samples from periodontally healthy subjects and periodontitis subjects. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were polarized towards M1 or M2 macrophages by the addition of LPS or IL-4, respectively, and were treated with or without PGRN. Real-time fluorescence quantitative PCR (qRT-PCR), immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), and flow cytometry were used to determine the expressions of M1 and M2 macrophage-related markers. Co-immunoprecipitation was performed to detect the interaction between PGRN and tumor necrosis factor receptor 2 (TNFR2). Neutralizing antibody was used to block TNFR2 to confirm the role of TNFR2 in PGRN-mediated macrophage polarization. RESULTS: The IHC and mIHC staining of human gingival slices showed a significant accumulation of macrophages in the microenvironment of periodontitis, with increased expressions of both M1 and M2 macrophage markers. Meanwhile, PGRN was widely expressed in the gingival tissue of periodontitis and co-expressed mainly with M2 macrophages. In vitro experiments showed that in RAW264.7 cells and BMDMs, M1 markers (CD86, TNF-α, iNOS, and IL-6) substantially decreased and M2 markers (CD206, IL-10, and Arg-1) significantly increased when PGRN was applied to LPS-stimulated macrophages relatively to LPS stimulation alone. Besides, PGRN synergistically promoted IL-4-induced M2 markers expression, such as CD206, IL-10, and Arg1. In addition, the co-immunoprecipitation result showed the direct interaction of PGRN with TNFR2. mIHC staining further revealed the co-localization of PGRN and TNFR2 on M2 macrophages (CD206+). Blocking TNFR2 inhibited the regulation role of PGRN on macrophage M2 polarization. CONCLUSIONS: In summary, PGRN promotes macrophage M2 polarization through binding to TNFR2 in both pro- and anti-inflammatory periodontal microenvironments.
Sujet(s)
Polarité de la cellule , Macrophages , Parodontite , Progranulines , Récepteur au facteur de nécrose tumorale de type II , Parodontite/métabolisme , Parodontite/anatomopathologie , Macrophages/métabolisme , Humains , Animaux , Récepteur au facteur de nécrose tumorale de type II/métabolisme , Progranulines/métabolisme , Souris , Cellules RAW 264.7 , Gencive/métabolisme , Gencive/anatomopathologie , Mâle , Femelle , Adulte , Activation des macrophages , Lipopolysaccharides/pharmacologie , Souris de lignée C57BLRÉSUMÉ
AIM: To evaluate the effect of subgingival delivery of progranulin (PGRN)/gelatin methacryloyl (GelMA) complex as an adjunct to scaling and root planing (SRP) on an experimental periodontitis dog model with Class II furcation involvement (FI). MATERIALS AND METHODS: A Class II FI model was established, and the defects were divided into four treatment groups: (a) no treatment (control); (b) SRP; (c) SRP + GelMA; (d) SRP + PGRN/GelMA. Eight weeks after treatment, periodontal parameters were recorded, gingival crevicular fluid and gingival tissue were collected for ELISA and RT-qPCR, respectively, and mandibular tissue blocks were collected for micro computed tomography (micro-CT) scanning and hematoxylin and eosin (H&E) staining. RESULTS: The SRP + PGRN/GelMA group showed significant improvement in all periodontal parameters compared with those in the other groups. The expression of markers related to M1 macrophage and Th17 cell significantly decreased, and the expression of markers related to M2 macrophage and Treg cell significantly increased in the SRP + PGRN/GelMA group compared with those in the other groups. The volume, quality and area of new bone and the length of new cementum in the root furcation defects of the PGRN/GelMA group were significantly increased compared to those in the other groups. CONCLUSIONS: Subgingival delivery of the PGRN/GelMA complex could be a promising non-surgical adjunctive therapy for anti-inflammation, immunomodulation and periodontal regeneration.
Sujet(s)
Détartrage dentaire , Anomalies de furcation , Hydrogels , Progranulines , Animaux , Chiens , Anomalies de furcation/thérapie , Hydrogels/usage thérapeutique , Détartrage dentaire/méthodes , Immunomodulation , Surfaçage radiculaire/méthodes , Modèles animaux de maladie humaine , Parodontite/thérapie , Parodontite/immunologie , Gélatine , Mâle , Microtomographie aux rayons XRÉSUMÉ
BACKGROUND: Biallelic pathogenic variants in PIP5K1C (MIM #606,102) lead to lethal congenital contractural syndrome 3 (LCCS3, MIM #611,369), a rare autosomal recessive genetic disorder characterized by small gestational age, severe multiple joint contractures and muscle atrophy, early death due to respiratory failure. Currently, 5 individuals with LCCS3 were reported and 5 pathogenic variants in PIP5K1C were identified. Here, we reported the two fetuses in a Chinese pedigree who displayed multiple joint contractures and other congenital anomalies. METHODS: Trio-based whole-exome sequencing (WES) was performed for the parents and the recent fetus to detect the genetic cause for fetus phenotype. RESULTS: A novel variant, NM_012398.3: c.949_952dup, p.S318Ifs*28 and a previously reported variant, c.688_689del, p.G230Qfs*114 (ClinVar database) in PIP5K1C, were detected in the individuals, and these variants were inherited from the mother and father, respectively. We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers, which have not been delineated detailedly in previously reported LCCS3 individuals. Furthermore, novel phenotype, bilateral dilated lateral ventricles, was revealed in one fetus. CONCLUSIONS: These findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3, which will help with the prenatal diagnosis and genetic counseling for this family.
Sujet(s)
Contracture , Amyotrophie , Femelle , Humains , Grossesse , Chine , Contracture/génétique , PedigreeRÉSUMÉ
The contact and pull-off tests and finite element simulations were used to study the extraocular muscle-sclera adhesion and its variation with eye movement in this research. The effect of the adhesion on the eye movements was also determined using equilibrium equations of eye motion. The contact and pull-off tests were performed using quasi-static and non-quasi-static unloading velocities. Finite element models were developed to simulate these tests in cases with high unloading velocity which could not be achieved experimentally. These velocities range from the eye's fixation to saccade movement. The tests confirmed that the pull-off force is related to the unloading velocity. As the unloading velocity increases, the pull-off force increases, with an insignificant increase at the high ocular saccade velocities. The adhesion moment between the extraocular muscles and the sclera exhibited the same trend, increasing with higher eye movement velocities and higher separation angles between the two interfaces. The adhesion moment ratio to the total moment was calculated by the traditional model and the active pulley model of eye movements to assess the effect of adhesion behavior on eye movements. At the high ocular saccade velocities (about 461 deg/s), the adhesion moment was found to be 0.53% and 0.50% of the total moment based on the traditional and active pulley models, respectively. The results suggest that the adhesion behavior between the extraocular muscles and the sclera has a negligible effect on eye movements. At the same time, this adhesion behavior can be ignored in eye modeling, which simplifies the model reasonably well. STATEMENT OF SIGNIFICANCE: 1. Adhesion behavior between the extraocular muscles and the sclera at different indenter unloading velocities determined by contact and pull-off tests. 2. A finite element model was developed to simulate the adhesive contact between the extraocular muscles and the sclera at different indenter unloading velocities. The bilinear cohesive zone model was used for adhesive interactions. 3. The elastic modulus and viscoelastic parameters of the extraocular muscle along the thickness direction were obtained by using compressive stress-relaxation tests. 4. The influence of the adhesion moment between the extraocular muscles and the sclera on eye movement was obtained according to the equation of oculomotor balance. The adhesion moment between the extraocular muscles and the sclera was found to increase with increased eye movement velocity and increased separation angle between the two interfaces.
Sujet(s)
Mouvements oculaires , Muscles oculomoteurs , Muscles oculomoteurs/physiologie , Mouvement , Face , Phénomènes physiquesRÉSUMÉ
Alzheimer's disease (AD) is a type of neurodegenerative disease characterized by cognitive impairment that is aggravated with age. The pathological manifestations include extracellular amyloid deposition, intracellular neurofibrillary tangles and loss of neurons. As the world population ages, the incidence of AD continues to increase, not only posing a significant threat to the well-being and health of individuals but also bringing a heavy burden to the social economy. There is epidemiological evidence suggesting a link between AD and metabolic diseases, which share pathological similarities. This potential link would deserve further consideration; however, the pathogenesis and therapeutic efficacy of AD remain to be further explored. The complex pathogenesis and pathological changes of AD pose a great challenge to the choice of experimental animal models. To understand the role of metabolic diseases in the development of AD and the potential use of drugs for metabolic diseases, the present article reviews the research progress of the comorbidity of AD with diabetes, obesity and hypercholesterolemia, and summarizes the different roles of animal models in the study of AD to provide references for researchers.
RÉSUMÉ
BACKGROUND AND AIMS: Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first month of life. METHODS: We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis, and re-analyzed phenotype and whole-exome sequencing (WES) data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. RESULTS: Overall, we identified disease-causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) had metabolic liver diseases, 9 (17%) had syndromic cholestasis, 9 (17%) had progressive familial intrahepatic cholestasis, 3 (6%) had bile acid synthesis defects, 3(6%) had infantile liver failure and 10 (19%) had a phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G > A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By re-analyzing WES data, two patients were newly solved, who had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved WES families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice models. CONCLUSIONS: In a single-center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Our findings suggest that re-evaluating existing WES data from well-phenotyped patients on a regular basis can increase the diagnostic yield for cholestatic liver disease in children.
Sujet(s)
Cholestase intrahépatique , Cholestase , Protéines de transport membranaire , Enfant , Humains , Animaux , Souris , Études rétrospectives , Séquençage nucléotidique à haut débit , Cholestase intrahépatique/génétique , Cholestase intrahépatique/diagnostic , Mutation , Kinésine/génétique , Ubiquitin thiolesterase/génétique , Ubiquitin-specific proteases/génétique , Protéines du cycle cellulaire/génétique , Adenosine triphosphatases/génétiqueSujet(s)
Aquaporine-1 , Tumeurs , Humains , Aquaporine-1/génétique , Tumeurs/génétique , Gènes suppresseurs de tumeur , OncogènesRÉSUMÉ
In this study, we propose a pioneering spatially frequency-shifted super-resolution microscopy technique that utilizes the synergy of quasiperiodic gratings and deep learning. First, a quasiperiodic grating capable of converting evanescent waves into propagating waves is designed. The grating is positioned between the object under investigation and the objective lens, and the high-frequency information carried by the evanescent waves in the near-field region of the object is shifted into the detection window and becomes accessible in the far field for imaging. Subsequently, we provide two deep learning models for image and video reconstructions to achieve the reconstruction of static and dynamic samples respectively. Simulation results demonstrate the high feasibility of the proposed method, and both static and dynamic objects with sub-wavelength features can be resolved. The developed method paves the way to the realization of super-resolution imaging by using a traditional bright-field microscope without the need for an extensive optical system design.
RÉSUMÉ
BACKGROUND: Gastro-intestinal (GI) tract inflammation is as a result of inflammatory hypoxia which is also induced by long-standing group of disorders like inflammatory-bowel disease (IBD). Regulation of GI immune homeostasis by macrophage involves hypoxia-inducible factor (HIF). As inhibitor of HIF prolyl hydroxylase, roxadustat (ROX) increases the levels of HIF. METHODS: We induced experimental colitis (EC) model in mice via dextran-sulfate sodium (DSS) to evaluate ROX role in above-mentioned disease. RESULTS: ROX ameliorated EC in mice by blocking colonic length shorten and loss of body weight, thereby reducing scores of disease-activity index (DAI) and histopathology. ROX significantly reduced inflammatory cytokines levels, suppressed M1 and increased M2 macrophage polarization in colonic tissues. Besides, ROX blocked declining hematocrit (HCT) level in blood and increased HIF-1-α and HIF-2-α level in colonic tissues. The inhibitor of HIF-1- α, KC7F2 decreased body weight and colonic length in ROX-treated DSS mice. Meanwhile, DAI scores and histopathology in KC7F2 treated DSS mice were markedly higher than that of treatment with ROX alone. KC7F2 treatments also significantly increased inflammatory cytokines levels, respectively promoted and reduced polarization of M1 and M2 macrophages in colonic tissue from ROX treated mice. Further, KC7F2 treatments inhibited ROX induced HCT level increasing in blood and decreased HIF-1-α and HIF-2-α level in colonic tissue. CONCLUSION: Collectively, we discovered that ROX ameliorated EC in mice by regulating macrophage polarization through promotion of HIF expression. GENERAL SIGNIFICANCE: Taken together, we developed a new application of ROX, which provides new ideas and a scientific basis for IBD treatment.
Sujet(s)
Colite , Maladies inflammatoires intestinales , Souris , Animaux , Colite/induit chimiquement , Colite/traitement médicamenteux , Cytokines/métabolisme , Macrophages/métabolisme , Facteurs de transcription à motif basique hélice-boucle-hélice , Poids , HypoxieRÉSUMÉ
OBJECTIVES: To assess the role of TNF-α/TNFR2 axis on promoting angiogenesis in oral squamous cell carcinoma (OSCC) cells and uncover the underlying mechanisms. MATERIALS AND METHODS: The expression of TNFR2 and CD31 in OSCC tissues was examined; gene expression relationship between TNF-α/TNFR2 and angiogenic markers or signaling molecules was analyzed; the expression of angiogenic markers, signaling molecules, TNFR1, and TNFR2 in TNF-α-stimulated OSCC cells treated with or without TNFR2 neutralizing antibody (TNFR2 Nab) were assessed; the concentration of angiogenic markers in the supernatant of OSCC cells was detected; conditioned mediums of OSCC cells treated with TNF-α or TNF-α + TNFR2 Nab were applied to human umbilical vein endothelial cells (HUVECs), followed by tube formation and cell migration assays. RESULTS: Significantly elevated expression of TNFR2 and CD31 in OSCC tissues was observed. A positive gene expression correlation was identified between TNF-α/TNFR2 and angiogenic markers or signaling molecules. TNFR2 Nab inhibited the effects of TNF-α on enhancing the expression of angiogenic factors and TNFR2, the phosphorylation of the Akt/mTOR signaling pathway, HUVECs migration, and tube formation. CONCLUSIONS: TNFR2 Nab counteracts the effect of TNF-α on OSCC cells through the TNFR2/Akt/mTOR axis, indicating that blocking TNFR2 might be a promising strategy against cancer.
RÉSUMÉ
BACKGROUND: Available literature has reported the association of Helicobacter pylori (H pylori) infection with inflammatory bowel disease (IBD) in adults. However, only a few studies have addressed the disease in children. AIM: To ascertain the correlation of H pylori infection with IBD among children. METHODS: The aim of this systematic review and meta-analysis is to assess the association between H pylori infection and IBD in children. We searched databases including Cochrane, EMBASE, Google Scholar, PubMed, Medline, and Web of Science to select relevant studies. Ultimately, based on predetermined inclusion criteria, we included 6 studies that met the requirements. Review Manager and Stata software were used to extract and analyze the data from the relevant studies. In the methods, we employed both qualitative and quantitative approaches for comprehensive analysis. Qualitative analysis involved describing study designs, sample characteristics, and results, while quantitative analysis involved statistical tests such as calculating pooled risk ratios and 95% confidence intervals to evaluate the association between H pylori infection and IBD in children. Lastly, by combining the results of the individual studies, our objective is to provide a comprehensive understanding of the relationship between H pylori infection and IBD in children. RESULTS: In totality, we involved 2236 participants that were recruited in 6 studies. We detected no significant difference in H pylori prevalence (9.8% vs 12.7%, P = .12) by comparing the children IBD group to controls. Among the IBD children, we estimated odds ratio (OR) of H pylori infection to 0.62 [(95% confidence interval (CI) of 0.34-1.12)]. In children suffering from ulcerative colitis (UC) and Crohn disease (CD), the H pylori infection rates were higher than in those with IBD-unclassified (IBDU).When analyzed stratified by disease of study design, In CD group [OR = 1.42, 95% CI: 0.72-2.80)] (I2 = 0%, P = .64). but no significant difference in CD group. CONCLUSIONS: No correlation was found between H pylori infection and the occurrence of IBD in children.
Sujet(s)
Rectocolite hémorragique , Maladie de Crohn , Infections à Helicobacter , Helicobacter pylori , Maladies inflammatoires intestinales , Adulte , Enfant , Humains , Infections à Helicobacter/complications , Infections à Helicobacter/épidémiologie , Maladies inflammatoires intestinales/complications , Maladies inflammatoires intestinales/épidémiologieRÉSUMÉ
The poor prognosis of immunotherapy in patients with colorectal cancer (CRC) necessitates a comprehensive understanding of the immunosuppressive mechanisms within tumor microenvironment (TME). Undoubtedly, the anti-tumor immune cells play an indispensable role in immune tolerance. Therefore, it is imperative to investigate novel immune-related factors that have the capacity to enhance anti-tumor immunity. Here, we employed bioinformatic analysis using R and Cytoscape to identify the hub gene chemokine (C-X-C motif) ligand 8 (CXCL8), which is overexpressed in CRC, in the malignant progression of CRC. However, its specific role of CXCL8 in CRC immunity remains to be elucidated. For this purpose, we evaluated how tumor-derived CXCL8 promotes M2 macrophage infiltration by in vivo and in vitro, which can be triggered by IL-1ß within TME. Mechanistically, CXCL8-induced polarization of M2 macrophages depends on the activation of the STAT3 signaling. Finally, immunohistochemistry and multiplexed immunohistochemistry analysis identified that CXCL8 not only enhances PD-L1+ M2 macrophage infiltration but also attenuates the recruitment of PD-1+ CD8+ T cells in murine CRC models. Together, these findings emphasize the critical role for CXCL8 in promoting M2 macrophage polarization and inhibiting CD8+ T cell infiltration, thereby links CXCL8 to the emergency of immunosuppressive microenvironment facilitating tumor evasion. Overall, these findings may provide novel strategy for CRC immunotherapy.
Sujet(s)
Lymphocytes T CD8+ , Tumeurs colorectales , Interleukine-8 , Animaux , Humains , Souris , Biologie informatique , Immunosuppresseurs , Macrophages , Microenvironnement tumoral , Interleukine-8/génétiqueRÉSUMÉ
A reliable and stable method was developed to accurately analyze neptunium (237Np) and plutonium isotopes in environmental samples using 242Pu or 236Pu as a tracer. Key parameters, including the valence adjustment conditions and the stabilities of Pu and Np in the different resins, were investigated using TK200 and TEVA resin. It was found that Pu and Np could be efficiently extracted simultaneously using TK200 resin under the optimal loading conditions (6-12 M HNO3) with the addition of 0.01-0.12 M NaNO2 for valence adjustment. These isotopes were subsequently stripped out using a solution containing 0.1 M HCl, 0.05 M HF, and 0.01 M NH2OH·HCl. The separation efficiencies of Pu and Np were >93%, and the chemical yield ratio between Np and Pu was maintained steady at an average of 1.00 ± 0.03 (n > 50) under the optimal conditions. The analytical method was validated by analyzing environmental soil samples spiked with known amounts of 239Pu and 237Np standard solutions or certified reference materials. The measured values of 237Np, 239Pu, and 240Pu obtained by inductively coupled plasma tandem mass spectrometry were consistent with their International Atomic Energy Agency literature values within a 95% confidence interval. These results confirm the reliability and high analytical precision (<6%) of this developed method using Pu as a non-isotopic tracer for monitoring the chemical yield of 237Np. The developed method can also be used for environmental pollutant monitoring and for tracer studies of the 237Np and Pu isotopes.
Sujet(s)
Polluants environnementaux , Neptunium , Plutonium , Contrôle des radiations , Contrôle des radiations/méthodes , Reproductibilité des résultats , Analyse spectrale , Plutonium/analyseRÉSUMÉ
Objective: Biallelic pathogenic variants in TOE1 cause pontocerebellar hypoplasia type 7 (PCH7), a rare neurological condition characterized by psychomotor retardation, spastic paraplegia, seizures, gonadal abnormalities and brain anomalies. Currently, only 14 postnatally diagnosed PCH7 patients have been described. However, the prenatal clinical profile of PCH7 has not yet been reported.Method: Whole-exome sequencing (WES) was performed to screen for causal variants.Results: We report the pedigree of a Chinese woman with two eventful pregnancies with fetuses that showed brain anomalies, including microcephaly, cerebral anomalies, enlarged ventricles, corpus callosum thinning, abnormal lateral fissure, underdeveloped insula and pons and brainstem hypoplasia. Interestingly, corpus callosum thinning was observed in fetus 1 but not in fetus 2. An abnormal lateral fissure and an underdeveloped insula were shown in fetus 2 but not fetus 1. Biallelic variants c.716T > C (p.Phe239Ser) and c.955C > T (p.His319Tyr) in TOE1 were identified in both fetuses.Conclusion: We first describe the prenatal features of a Chinese pedigree with PCH7 caused by biallelic pathogenic variants in TOE1, with phenotypic variability observed even within the same family. Novel phenotypes, an abnormal lateral fissure and an underdeveloped insula were observed in the fetus in our study. These findings will enrich our knowledge of the clinical characteristics, management and genetic counseling of PCH7.
Sujet(s)
Maladies du cervelet , Diagnostic prénatal , Femelle , Humains , Grossesse , Encéphalopathies , Maladies du cervelet/diagnostic , Maladies du cervelet/génétique , Peuples d'Asie de l'Est , Protéines nucléaires , PedigreeRÉSUMÉ
Ocular diseases and treatment related to rhegmatogenous retinal detachment (RRD) are highly correlated with retinal adhesion behavior. Therefore, this paper proposes to study the adhesion behavior of the intact retina. This can provide theoretical guidance for the treatment and research of retinal detachment (RD) related diseases. To systematically analyze this aspect, two experiments were performed on the porcine retina. The pull-off test combined with the modified JKR theory was used to study the adhesion behavior of the vitreoretinal interface, while the peeling test was used to study the adhesion behavior of the chorioretinal interface. In addition, the adhesion phase involved in the pull-off test was simulated and analyzed by building the corresponding finite element method (FEM). The experimental results of adhesion force on the vitreoretinal interface were obtained by pull-off test with five sizes of rigid punch. The experimental value of the pull-off force FPO tends to increase gradually with increasing punch radius in the range of 0.5-4 mm. A comparison of the experimental results with the simulation results shows that they are in a well agreement. And there is no statistical difference between the experimental and theoretical values of the pull-off force FPO. In addition, the values of retinal adhesion work were also obtained by pull-off test. Interestingly, there is a significant scale effect of the retinal work of adhesion. Finally, the peeling test gave a maximum peeling strength TMax of about 13 mN/mm and a stable peeling strength TD of about 11 mN/mm between the retina and the choroid. The pull-off test well shows the process of retinal traction by the diseased vitreous at the beginning of RRD. A comparison of the experimental results with the finite element results verifies the accuracy of the simulation. The peeling test well investigated the adhesion behavior between the retina and the choroid and obtained key biomechanical data (peeling strength, etc.). The combination of the two experiments allows a more systematic study of the whole retina. This research can provide more complete material parameters for finite element modeling of retina-related diseases, and it also can provide the theoretical guidance for individualized design of retinal repair surgery.