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Introduction: Primary Sjögren's syndrome (PSS) is a systemic autoimmune disease that mainly affects exocrine glands. Little is known about PSS associated cervical and intracranial cerebral large-vessel vasculitis outside of individual case reports. Methods: We present 5 cases of ischemic stroke or transient ischemic stroke (TIA) caused by PSS associated cervical and intracranial large-vessel vasculitis. Literature review was performed to summarize and identify the demographic, clinical features, treatment, and prognosis of this condition. Results: The review resulted in 8 included articles with 8 patients, plus our 5 new patients, leading to a total of 13 subjects included in the analysis. The median age was 43 (range, 17-69) years old, among which 69.2 % (9/13) were female, and 92.3 % (12/13) came from Asia. Among them, 84.6 % (11/13) presented with cerebral infarction and 70.0 % (7/10) with watershed infarction. Middle cerebral artery (MCA) (6/13, 46.2 %) and internal carotid artery (ICA) (6/13, 46.2 %) were the most frequently involved arteries. Remarkable vessel wall concentric thickening and enhancement was observed in 57.1 % (4/7) patients and intravascular thrombi was identified in 28.6 % (2/7) patients. Glucocorticoid combined with non-glucocorticoid immunosuppressants (8/12, 66.7 %) were the most often chosen medication therapy and 4 patients received surgical intervention. Conclusion: Asian females are the most vulnerable population to ischemic stroke or TIA due to PSS associated cervical and intracranial large-vessel vasculitis. Cerebral infarctions were characterized by recurrence and watershed pattern. Magnetic resonance vessel wall imaging (MR-VWI) helps to identify the inflammatory pathology of large vessel lesion in PSS.
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BACKGROUND AND AIMS: The brain age gap (BAG), calculated as the difference between a machine learning model-based predicted brain age and chronological age, has been increasingly investigated in psychiatric disorders. Tobacco and alcohol use are associated with increased BAG; however, no studies have compared global and regional BAG across substances other than alcohol and tobacco. This study aimed to compare global and regional estimates of brain age in individuals with substance use disorders and healthy controls. DESIGN: This was a cross-sectional study. SETTING: This is an Enhancing Neuro Imaging through Meta-Analysis Consortium (ENIGMA) Addiction Working Group study including data from 38 global sites. PARTICIPANTS: This study included 2606 participants, of whom 1725 were cases with a substance use disorder and 881 healthy controls. MEASUREMENTS: This study used the Kaufmann brain age prediction algorithms to generate global and regional brain age estimates using T1 weighted magnetic resonance imaging (MRI) scans. We used linear mixed effects models to compare global and regional (FreeSurfer lobestrict output) BAG (i.e. predicted minus chronological age) between individuals with one of five primary substance use disorders as well as healthy controls. FINDINGS: Alcohol use disorder (ß = -5.49, t = -5.51, p < 0.001) was associated with higher global BAG, whereas amphetamine-type stimulant use disorder (ß = 3.44, t = 2.42, p = 0.02) was associated with lower global BAG in the separate substance-specific models. CONCLUSIONS: People with alcohol use disorder appear to have a higher brain-age gap than people without alcohol use disorder, which is consistent with other evidence of the negative impact of alcohol on the brain.
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The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with 225Ac and evaluated its in vitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer. Methods: 225Ac-ch806 was prepared using different chelators, yielding [225Ac]Ac-macropa-tzPEG3Sq-ch806 and [225Ac]Ac-DOTA-dhPzPEG4-ch806. Radiochemical yield, purity, apparent specific activity, and serum stability of 225Ac-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy of 225Ac-ch806 were investigated in mice with U87MG.de2-7 and DiFi tumors. Pharmacodynamic analysis of tumors after therapy was performed, including DNA double-strand break immunofluorescence of γH2AX, as well as immunohistochemistry for proliferation, cell cycle arrest, and apoptosis. Results: [225Ac]Ac-macropa-tzPEG3Sq-ch806 surpassed [225Ac]Ac-DOTA-dhPzPEG4-ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [225Ac]Ac-macropa-tzPEG3Sq-ch806 was therefore used for both in vitro and in vivo studies. It displayed a significant, specific, and dose-dependent in vitro cell-killing effect in U87MG.de2-7 cells. 225Ac-ch806 also displayed high tumor uptake and minimal uptake in normal tissues. 225Ac-ch806 significantly inhibited tumor growth and prolonged survival in both U87MG.de2-7 and DiFi models. Enhanced γH2AX staining was observed in 225Ac-ch806-treated tumors compared with controls. Reduced Ki-67 expression was evident in all 225Ac-ch806-treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated with 225Ac-ch806. Conclusion: In glioblastoma and colorectal tumor models, 225Ac-ch806 significantly inhibited tumor growth via induction of double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. These findings underscore the potential clinical applicability of 225Ac-ch806 as a potential therapy for EGFR-expressing solid tumors.
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PURPOSE: Cachexia is a complex syndrome characterized by unintentional weight loss, progressive muscle wasting and loss of appetite. Anti-Fn14 antibody (mAb 002) targets the TWEAK receptor (Fn14) in murine models of cancer cachexia and can extend the lifespan of mice by restoring the body weight of mice. Here, we investigated glucose metabolic changes in murine models of cachexia via [18F]FDG PET imaging, to explore whether Fn14 plays a role in the metabolic changes that occur during cancer cachexia. METHODS: [18F]FDG PET/MRI imaging was performed in cachexia-inducing tumour models versus models that do not induce cachexia. SUVaverage was calculated for all tumours via volume of interest (VOI) analysis of PET/MRI overlay images using PMOD software. RESULTS: [18F]FDG PET imaging demonstrated increased tumour and brain uptake in cachectic versus non-cachectic tumour-bearing mice. Therapy with mAb 002 was able to reduce [18F]FDG uptake in tumours (P < 0.05, n = 3). Fn14 KO tumours did not induce body weight loss and did not show an increase in [18F]FDG tumour and brain uptake over time. In non-cachectic mice bearing Fn14 KO tumours, [18F]FDG tumour uptake was significantly lower (P < 0.01) than in cachectic mice bearing Fn14 WT counterparts. As a by-product of glucose metabolism, l-lactate production was also increased in cachexia-inducing tumours expressing Fn14. CONCLUSION: Our results demonstrate that Fn14 receptor activation is linked to glucose metabolism of cachexia-inducing tumours.
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The serine protease CORIN catalyzes pro-atrial natriuretic peptide (pro-ANP) into an active ANP and maintains homeostasis of the internal environment. However, it is unclear whether CORIN participates in the regulation of tumor progression. We analyzed the expression profile of CORIN in gastric cancer tissues (GCs) and adjacent nontumoral tissues (NTs). We investigated the prognostic value of CORIN in GC patients. We characterized the in vitro and in vivo activity of CORIN in cultured GC cells with gain-of-function and loss-of-function experiments. The underlying mechanism was explored by using bioinformatics, a signaling antibody array, and confirmative western blot analyses, as well as rescue experiments with highly selective small-molecule inhibitors targeting the ERK1/2 MAPK signaling pathway. CORIN was upregulated in GCs than in NTs. Overexpression of CORIN was correlated with unfavorable prognoses in patients with GC. Ectopic expression of CORIN was promoted, whereas silencing of CORIN suppressed proliferation, colony formation, migration and invasion of GC cells, and tumor growth in vivo. Overexpression of CORIN-induced epithelial-mesenchymal transition (EMT) and activation of the ERK1/2 MAPK signaling pathway, while silencing of CORIN yielded opposite results. The in vitro tumor-promoting potency of CORIN could be antagonized by selective inhibitors targeting the ERK1/2 MAPK pathway. In conclusion, CORIN is a potential prognostic marker and therapeutic target for GC patients, which may promote tumor progression by mediating the ERK1/2 MAPK signaling pathway and EMT in GC cells.
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Proliferación Celular , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Sistema de Señalización de MAP Quinasas , Serina Endopeptidasas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Animales , Ratones , Femenino , Masculino , Pronóstico , Línea Celular Tumoral , Movimiento Celular , Persona de Mediana Edad , Ratones Desnudos , Ratones Endogámicos BALB C , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genéticaRESUMEN
PURPOSE: ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with 89Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo. METHODS: ATG-101, anti-PD-L1, and an isotype control were conjugated with p-SCN-Deferoxamine (Df). The Df-conjugated antibodies were radiolabelled with 89Zr, and their radiochemical purity, immunoreactivity, and serum stability were assessed. We conducted PET/MRI and biodistribution studies on [89Zr]Zr-Df-ATG-101 in BALB/c nude mice bearing PD-L1-expressing MDA-MB-231 breast cancer xenografts for up to 10 days after intravenous administration of [89Zr]Zr-labelled antibodies. The specificity of [89Zr]Zr-Df-ATG-101 was evaluated through a competition study with unlabelled ATG-101 and anti-PD-L1 antibodies. RESULTS: The Df-conjugation and [89Zr]Zr -radiolabelling did not affect the target binding of ATG-101. Biodistribution and imaging studies demonstrated biological similarity of [89Zr]Zr-Df-ATG-101 and [89Zr]Zr-Df-anti-PD-L1. Tumour uptake of [89Zr]Zr-Df-ATG-101 was clearly visualised using small-animal PET imaging up to 7 days post-injection. Competition studies confirmed the specificity of PD-L1 targeting in vivo. CONCLUSION: [89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101.
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Correlating transcriptional profiles with imaging-derived phenotypes has the potential to reveal possible molecular architectures associated with cognitive functions, brain development and disorders. Competitive null models built by resampling genes and self-contained null models built by spinning brain regions, along with varying test statistics, have been used to determine the significance of transcriptional associations. However, there has been no systematic evaluation of their performance in imaging transcriptomics analyses. Here, we evaluated the performance of eight different test statistics (mean, mean absolute value, mean squared value, max mean, median, Kolmogorov-Smirnov (KS), Weighted KS and the number of significant correlations) in both competitive null models and self-contained null models. Simulated brain maps (n = 1,000) and gene sets (n = 500) were used to calculate the probability of significance (Psig) for each statistical test. Our results suggested that competitive null models may result in false positive results driven by co-expression within gene sets. Furthermore, we demonstrated that the self-contained null models may fail to account for distribution characteristics (e.g., bimodality) of correlations between all available genes and brain phenotypes, leading to false positives. These two confounding factors interacted differently with test statistics, resulting in varying outcomes. Specifically, the sign-sensitive test statistics (i.e., mean, median, KS, Weighted KS) were influenced by co-expression bias in the competitive null models, while median and sign-insensitive test statistics were sensitive to the bimodality bias in the self-contained null models. Additionally, KS-based statistics produced conservative results in the self-contained null models, which increased the risk of false negatives. Comprehensive supplementary analyses with various configurations, including realistic scenarios, supported the results. These findings suggest utilizing sign-insensitive test statistics such as mean absolute value, max mean in the competitive null models and the mean as the test statistic for the self-contained null models. Additionally, adopting the confounder-matched (e.g., coexpression-matched) null models as an alternative to standard null models can be a viable strategy. Overall, the present study offers insights into the selection of statistical tests for imaging transcriptomics studies, highlighting areas for further investigation and refinement in the evaluation of novel and commonly used tests.
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Encéfalo , Fenotipo , Encéfalo/diagnóstico por imagen , Encéfalo/anatomía & histología , Humanos , Transcriptoma , Modelos Estadísticos , Perfilación de la Expresión Génica/métodosRESUMEN
Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H2MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H2MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H2MacropaSq-hG250 was radiolabeled quantitatively with [225Ac]AcIII within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.
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Intervertebral disc degeneration (IVDD) is invariably accompanied by excessive accumulation of reactive oxygen species (ROS), resulting in progressive deterioration of mitochondrial function and senescence in nucleus pulposus cells (NPCs). Significantly, the main ROS production site in non-immune cells is mitochondria, suggesting mitochondria is a feasible therapeutic target to reverse IVDD. Triphenylphosphine (TPP), which is known as mitochondrial-tropic ligands, is utilized to modify carbon dot-supported Prussian blue (CD-PB) to scavenge superfluous intro-cellular ROS and maintain NPCs at normal redox levels. CD-PB-TPP can effectively escape from lysosomal phagocytosis, permitting efficient mitochondrial targeting. After strikingly lessening the ROS in mitochondria via exerting antioxidant enzyme-like activities, such as superoxide dismutase, and catalase, CD-PB-TPP rescues damaged mitochondrial function and NPCs from senescence, catabolism, and inflammatory reaction in vitro. Imaging evaluation and tissue morphology assessment in vivo suggest that disc height index, mean grey values of nucleus pulposus tissue, and histological morphology are significantly improved in the IVDD model after CD-PB-TPP is locally performed. In conclusion, this study demonstrates that ROS-induced mitochondrial dysfunction and senescence of NPCs leads to IVDD and the CD-PB-TPP possesses enormous potential to rescue this pathological process through efficient removal of ROS via targeting mitochondria, supplying a neoteric strategy for IVDD treatment.
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Ferrocianuros , Degeneración del Disco Intervertebral , Núcleo Pulposo , Humanos , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patología , Degeneración del Disco Intervertebral/metabolismo , Especies Reactivas de Oxígeno/metabolismo , MitocondriasRESUMEN
BACKGROUND AND AIMS: Recently, we demonstrated that a distinct pattern of structural covariance networks (SCN) from magnetic resonance imaging (MRI)-derived measurements of brain cortical thickness characterized young adults with alcohol use disorder (AUD) and predicted current and future problematic drinking in adolescents relative to controls. Here, we establish the robustness and value of SCN for identifying heavy alcohol users in three additional independent studies. DESIGN AND SETTING: Cross-sectional and longitudinal studies using data from the Pediatric Imaging, Neurocognition and Genetics (PING) study (n = 400, age range = 14-22 years), the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) (n = 272, age range = 17-22 years) and the Human Connectome Project (HCP) (n = 375, age range = 22-37 years). CASES: Cases were defined based on heavy alcohol use patterns or former alcohol use disorder (AUD) diagnoses: 50, 68 and 61 cases were identified. Controls had none or low alcohol use or absence of AUD: 350, 204 and 314 controls were selected. MEASUREMENTS: Graph theory metrics of segregation and integration were used to summarize SCN. FINDINGS: Mirroring our prior findings, and across the three data sets, cases had a lower clustering coefficient [area under the curve (AUC) = -0.029, P = 0.002], lower modularity (AUC = -0.14, P = 0.004), lower average shortest path length (AUC = -0.078, P = 0.017) and higher global efficiency (AUC = 0.007, P = 0.010). Local efficiency differences were marginal (AUC = -0.017, P = 0.052). That is, cases exhibited lower network segregation and higher integration, suggesting that adjacent nodes (i.e. brain regions) were less similar in thickness whereas spatially distant nodes were more similar. CONCLUSION: Structural covariance network (SCN) differences in the brain appear to constitute an early marker of heavy alcohol use in three new data sets and, more generally, demonstrate the utility of SCN-derived metrics to detect brain-related psychopathology.
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Alcoholismo , Conectoma , Adulto Joven , Adolescente , Niño , Humanos , Adulto , Alcoholismo/patología , Estudios Transversales , Imagen por Resonancia Magnética/métodos , Encéfalo/patología , Conectoma/métodosRESUMEN
Endometritis is a significant contributor to reduced productivity in yaks in Tibet, China. The Cyt-c/Caspase-3 signaling axis plays a crucial role in the mitochondrial pathway that triggers cell apoptosis due to endogenous factors. In this study, we examined the endometrial epithelial tissue of yaks with endometritis using pathological examination, immunohistochemical analysis, TUNEL staining, qRT-PCR, and Western blot. The results indicated significant changes in the apoptotic factors of the Cyt-c/Caspase-3 signaling axis. The expression levels of Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 were significantly increased (P < 0.05), while the expression level of Bcl-2 was significantly decreased. Immunohistochemistry results revealed significant increase in Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 expression in the cytoplasm compared to the healthy group, except for Bcl-2, which showed a significant decrease. Pathological section analysis demonstrated that clinical endometritis in yaks led to structural damage, bleeding, congestion, and inflammatory cell infiltration in the endometrial epithelium. Our study findings indicated that clinical endometritis in yaks can modulate apoptosis of endometrial epithelial cells via the Cyt-c/Caspase-3 signaling pathway, resulting in different levels of damage. This research is pioneering in exploring cell apoptosis induced by clinical endometritis in yaks, offering novel insights and potential strategies for the future prevention and treatment of endometritis in yaks.
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Endometritis , Animales , Femenino , Bovinos , Humanos , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Endometritis/veterinaria , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal , Células Epiteliales/metabolismoRESUMEN
Persistent hypoglossal artery (PHA) is a rare carotid-vertebrobasilar anastomosis in adults. Here, we report a case of mechanical thrombectomy for acute basilar artery occlusion via the PHA. A 44-year-old man was admitted to our stroke unit with an unstable gait and aphasia for 2 h. The baseline National Institutes of Health Stroke Scale (NIHSS) score was 4, but the clinical symptoms continued to worsen. Computed tomography angiography showed the absence of the basilar artery and an abnormal anastomosis between the anterior and posterior circulation. Clinical symptoms continued to worsen, and endovascular treatment was scheduled. PHA was demonstrated and basilar artery occlusion was confirmed using digital subtraction angiography. Mechanical thrombectomy with a stent retriever and aspiration was performed via the PHA, and modified thrombolysis in cerebral infarction level 3 was achieved. The patient underwent intravenous antiplatelet therapy after the operation, and follow-up neuroimaging revealed multiple small infarcts in the cerebellum and medulla oblongata. The patient was discharged after 10 days for further rehabilitation, with an NIHSS score of 25. At 10 months follow-up, the NIHSS score decreased to 18. Recognition of this rare variation is particularly important for interventional strategy determination and rapid recanalization of basilar artery occlusion.
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Soluble growth stimulation expressed gene 2 protein (sST2) is a myocardial protein induced by biomechanical stress. sST2 is widely present in the serum of patients with heart failure and is recommended as an important indicator to predict adverse outcomes in these patients. However, no postmortem biochemical analysis of sST2 in forensic practice has been reported. The present pilot study aimed to investigate the expression of sST2 in the pericardial fluid of patients with sudden cardiac death (SCD) caused by ischemic heart disease (IHD). In addition, to explore the relationship of sST2 with CK-MB, cTnT, and NT-proBNP, which have been proven to be auxiliary biomarkers for the diagnosis of SCD, we analyzed CK-MB, cTnT, NT-proBNP, and sST2 levels in twenty-one pericardial fluid samples from the Center of Forensic Investigation, China Medical University, with a Roche cobas e 411 electrochemiluminescence automatic immunoassay system and ST2/IL-33R Valukine™ enzyme-linked immunosorbent assay kit. The levels of sST2 in the pericardial fluid of patients with SCD caused by IHD were significantly increased (P < 0.01) and positively correlated with CK-MB and NT-proBNP (P < 0.0001). Receiver operating characteristic curve analysis indicated that the combined measurement of sST2 and NT-proBNP has a higher diagnostic value for SCD caused by IHD than the measurement of either indicator alone. This study preliminarily demonstrated that sST2 in the pericardial fluid was significantly increased in patients with SCD caused by IHD and might be used as a novel auxiliary biomarker for postmortem diagnosis of SCD in forensic practice.
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Leveraging ~10 years of prospective longitudinal data on 704 participants, we examined the effects of adolescent versus young adult cannabis initiation on MRI-assessed cortical thickness development and behavior. Data were obtained from the IMAGEN study conducted across eight European sites. We identified IMAGEN participants who reported being cannabis-naïve at baseline and had data available at baseline, 5-year, and 9-year follow-up visits. Cannabis use was assessed with the European School Survey Project on Alcohol and Drugs. T1-weighted MR images were processed through the CIVET pipeline. Cannabis initiation occurring during adolescence (14-19 years) and young adulthood (19-22 years) was associated with differing patterns of longitudinal cortical thickness change. Associations between adolescent cannabis initiation and cortical thickness change were observed primarily in dorso- and ventrolateral portions of the prefrontal cortex. In contrast, cannabis initiation occurring between 19 and 22 years of age was associated with thickness change in temporal and cortical midline areas. Follow-up analysis revealed that longitudinal brain change related to adolescent initiation persisted into young adulthood and partially mediated the association between adolescent cannabis use and past-month cocaine, ecstasy, and cannabis use at age 22. Extent of cannabis initiation during young adulthood (from 19 to 22 years) had an indirect effect on psychotic symptoms at age 22 through thickness change in temporal areas. Results suggest that developmental timing of cannabis exposure may have a marked effect on neuroanatomical correlates of cannabis use as well as associated behavioral sequelae. Critically, this work provides a foundation for neurodevelopmentally informed models of cannabis exposure in humans.
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This work examined the physical and chemical properties and biocompatibility in vivo and in vitro of a unique triple composite scaffold incorporating silk fibroin, chitosan, and extracellular matrix. The materials were blended, cross-linked, and freeze-dried to create a composite scaffold of silk fibroin/chitosan/colon extracellular matrix (SF/CTS/CEM) with varying CEM contents. The SF/CTS/CEM (1:1:1) scaffold demonstrated the preferable shape, outstanding porosity, favorable connectivity, good moisture absorption, and acceptable and controlled swelling and degradation properties. Additionally, HCT-116 cells cultivated with SF/CTS/CEM (1:1:1) showed excellent proliferation capacity, cell malignancy, and delayed apoptosis, according to the in vitro cytocompatibility examination. We also examined the PI3K/PDK1/Akt/FoxO signaling pathway and discovered that cell culture using a SF/CTS/CEM (1:1:1) scaffold may prevent cell death by phosphorylating Akt and suppressing FoxO expression. Our findings demonstrate the potential of the SF/CTS/CEM (1:1:1) scaffold as an experimental model for colonic cancer cell culture and for replicating the three-dimensional in vivo cell growth environment.
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Magnetic topological materials have drawn markedly attention recently due to the strong coupling of their novel topological properties and magnetic configurations. In particular, the MnBi2Te4/(Bi2Te3)n family highlights the researches of multiple magnetic topological materials. Via first-principles calculations, we predict that Mn(Bi, Sb)4Se7, the close relatives of MnBi2Te4/(Bi2Te3)n family, are topological nontrivival in both antiferromagnetic and ferromagnetic configurations. In the antiferromagnetic ground state, Mn(Bi, Sb)4Se7 are simultaneously topological insulators and axion insulators. Massless Dirac surface states emerge on the surfaces parallel to the z axis. In ferromagnetic phases, they are axion insulators. Particularly, when the magnetization direction is along the x axis, they are also topological crystalline insulators. Mirror-symmetry-protected gapless surface states exist on the mirror-invariant surfaces. Hence, the behaviors of surface states are strongly dependent on the magnetization directions and surface orientations. Our work provides more opportunities for the study of magnetic topological physics.
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Tumour-selective theranostic agents have attracted considerable interest over the past decade in oncology owing to their extraordinary anticancer efficacy. However, it still remains a challenge to develop theranostic agents balancing biocompatibility, multidimensional theranostics, tumour-selectivity, and simple components. Inspired by the metabolic pathways of exogenous sodium selenite against selenium-deficient diseases, reported here is the first convertible bismuth-based agent for tumour-selective theranostic functionalities. The specifically overexpressed substances in tumour tissue enable it to act as a natural reactor for the conversion from bismuth selenite to bismuth selenide, activating the theranostic functionalities specifically in tumour tissues. The converted product exhibits excellent multidimensional imaging-guided therapy. This study not only demonstrates a simple agent with both biocompatibility and sophisticated tumour-selective theranostic functionalities, but also pioneers a new approach from emulating nature towards oncological theranostic applications.
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Nanomedicina , Neoplasias , Humanos , Medicina de Precisión , Nanomedicina Teranóstica/métodos , Bismuto/uso terapéutico , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológicoRESUMEN
In this study, we collected feces of Tibetan piglets from Nyingchi area for isolation, culture, identification, virulence gene analysis and drug resistance analysis of Escherichia Coli. The results demonstrated a 41.3% isolation rate of Diarrheagenic Escherichia Coli from Tibetan pigs with the main phylogenetic groups: group A (68.6%) and group B2 (15.7%). Typical E.coli accounted for 76.5%. The highest detection rates of porcine virulence genes were E.coli heat-resistant enterotoxin STb (58.82%) and F107 fimbrial subunit (23.53%). The highest detection rates of virulence genes from Tibetan pigs were fimC (80.39%) and ompA (76.47%). A drug sensitivity test showed that Diarrheagenic Escherichia Coli from Tibetan pigs had high drug resistance rates to mezlocillin, doxycycline and gentamicin. This study comprehensively analyzed the species composition, virulence and drug resistance of Diarrheagenic Escherichia Coli from Tibetan pigs, which provided a clearer and more targeted idea for the prevention and treatment of yellow and white dysentery in Tibetan pigs in the future.
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Infecciones por Escherichia coli , Animales , Porcinos , Infecciones por Escherichia coli/veterinaria , Infecciones por Escherichia coli/tratamiento farmacológico , Virulencia , Tibet , Filogenia , Diarrea/veterinaria , Escherichia coli , Resistencia a MedicamentosRESUMEN
The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.
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Trastornos Mentales , Canales de Potasio con Entrada de Voltaje , Adulto , Adolescente , Humanos , Niño , Encéfalo , Trastornos Mentales/genética , Trastornos Mentales/patología , Envejecimiento/genética , Imagen por Resonancia Magnética , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patologíaRESUMEN
B cells constitute a major component of infiltrating immune cells in colorectal cancer (CRC). However, the characteristics of B cells and their clinical significance remain unclear. In this study, using single-cell RNA sequencing and multicolour immunofluorescence staining experiments, we identified five distinct subtypes of B cells with their marker genes, distribution patterns and functional properties in the CRC tumour microenvironment. Meanwhile, we found a higher proportion of IgG plasma cells in tumour sites than that in adjacent normal mucosal tissues. In addition, the CXCL13-producing CD8+ T cells in the tumour tissues could promote the formation of tertiary lymphoid structure (TLS) B cells, and the CCL28-CCR10 axis is pivotal for IgG plasma cell migration from the periphery of TLSs to the tumour stroma. Finally, we identified four distinct colon immune classes (CICs: A-D) and found that CD20+ B cells within TLSs were enriched in one immune-inflamed or hot tumour group (CIC D). This B cell-rich group, which was characterized by strong antigen presentation, IgG plasma cells accumulation, microsatellite instability-high (MSI-H) and high tumour mutation burden (TMB-H), as well as immunosuppressive property in particular, might become a potential predictive biomarker for future immunotherapy. Additionally, in an immunotherapy cohort, patients with the enrichment of B cells and TLSs were demonstrated to obtain significant therapeutic advantages. Together, our findings provide the detailed landscape of infiltrating B cells and their potential clinical significance in CRC.