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The effects of RNF213, which leads to moyamoya disease susceptibility, on radiation-induced moyamoya syndrome (MMS) remain unknown. We report a case of MMS after proton beam therapy (PBT) was deployed to treat a brain tumor in a patient with an RNF213 polymorphism. An 8-year-old boy underwent whole ventricular and local PBT for a pineal germ cell tumor and was diagnosed with radiation-induced MMS 9 months later. He underwent right and left revascularization surgeries for cerebral hemodynamic compromise at 17- and 18-years of age, respectively. Genetic analysis revealed a heterozygous germline polymorphism RNF213 p.R4810K. This is the first report to suggest an association between RNF213 polymorphism and radiation-induced MMS.
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We derive an entropy formula satisfied by the ground states of 1+1D conformal field theories. The formula implies that the ground state is the critical point of an entropy function. We conjecture that this formula may serve as an information-theoretic criterion for conformal field theories, which differs from the conventional algebraic definition. In addition to these findings, we use the same proof method to extract the six global conformal generators of the conformal field theory from its ground state. We validate our results by testing them on different critical lattice models, with excellent agreement.
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Entanglement entropies of two-dimensional gapped ground states are expected to satisfy an area law, with a constant correction term known as the topological entanglement entropy (TEE). In many models, the TEE takes a universal value that characterizes the underlying topological phase. However, the TEE is not truly universal: it can differ even for two states related by constant-depth circuits, which are necessarily in the same phase. The difference between the TEE and the value predicted by the anyon theory is often called the "spurious" topological entanglement entropy. We show that this spurious contribution is always non-negative, thus the value predicted by the anyon theory provides a universal lower bound. This observation also leads to a definition of TEE that is invariant under constant-depth quantum circuits.
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We investigated the effects of antibiotics, drugs, and metals on lung and intestinal microbiomes after sub-chronic exposure of low-level air pollution in ageing rats. Male 1.5-year-old Fischer 344 ageing rats were exposed to low-level traffic-related air pollution via whole-body exposure system for 3 months with/without high-efficiency particulate air (HEPA) filtration (gaseous vs. particulate matter with aerodynamic diameter of ≤2.5 µm (PM2.5) pollution). Lung functions, antibiotics, drugs, and metals in lungs were examined and linked to lung and fecal microbiome analyses by high-throughput sequencing analysis of 16 s ribosomal (r)DNA. Rats were exposed to 8.7 µg/m3 PM2.5, 10.1 ppb NO2, 1.6 ppb SO2, and 23.9 ppb O3 in average during the study period. Air pollution exposure decreased forced vital capacity (FVC), peak expiratory flow (PEF), forced expiratory volume in 20 ms (FEV20), and FEF at 25â¼75% of FVC (FEF25-75). Air pollution exposure increased antibiotics and drugs (benzotriazole, methamphetamine, methyl-1 H-benzotriazole, ketamine, ampicillin, ciprofloxacin, pentoxifylline, erythromycin, clarithromycin, ceftriaxone, penicillin G, and penicillin V) and altered metals (V, Cr, Cu, Zn, and Ba) levels in lungs. Fusobacteria and Verrucomicrobia at phylum level were increased in lung microbiome by air pollution, whereas increased alpha diversity, Bacteroidetes and Proteobacteria and decreased Firmicutes at phylum level were occurred in intestinal microbiome. Lung function decline was correlated with increasing antibiotics, drugs, and metals in lungs as well as lung and intestinal microbiome dysbiosis. The antibiotics, drugs, and Cr, Co, Ca, and Cu levels in lung were correlated with lung and intestinal microbiome dysbiosis. The lung microbiome was correlated with intestinal microbiome at several phylum and family levels after air pollution exposure. Our results revealed that antibiotics, drugs, and metals in the lung caused lung and intestinal microbiome dysbiosis in ageing rats exposed to air pollution, which may lead to lung function decline.
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Contaminantes Atmosféricos , Contaminación del Aire , Microbioma Gastrointestinal , Masculino , Ratas , Animales , Disbiosis/inducido químicamente , Antibacterianos/análisis , Exposición a Riesgos Ambientales/análisis , Contaminación del Aire/análisis , Material Particulado/análisis , Pulmón , Metales/análisis , Envejecimiento , Contaminantes Atmosféricos/análisisRESUMEN
The clinical spectrum of novel coronavirus infection appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia, with respiratory failure and even death. Autoantibodies, especially antiphospholipid antibodies, can occur in severe infections. Other autoantibodies are seldom reported. Here, a 60-year-old female patient without dry-mouth symptoms detected positive for anti-60 kDa SSA/Ro antibodies on day 43 after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To investigate this unique clinical case of SARS-CoV-2 infection, immunological characteristics of this case were detected by using flow cytometry and were compared to the other three groups of patients-health subjects, 2019 novel coronavirus disease (COVID-19) recovery patients, and Sjögren's syndrome (SS) patients. Monitoring the autoantibody level and the development of subsequently related autoimmune diseases are warranted after SARS-CoV-2 infection.
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Anticuerpos Antinucleares/inmunología , Anticuerpos Antivirales/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Inmunofenotipificación , Neumonía Viral/inmunología , COVID-19 , Femenino , Citometría de Flujo , Humanos , Persona de Mediana Edad , Pandemias , SARS-CoV-2 , Síndrome de SjögrenRESUMEN
We observed the small-size-induced hardening and plasticity of brittle ionic MgO as a result of abnormally triggered dislocation gliding on a non-charge-balanced slip system. The indentation tests of ⟨111⟩ MgO pillars revealed an increased hardness with decreasing pillar size, and the tips of the pillars that were ≤200 nm were plastically deformed. The in situ compression tests of ⟨111⟩ MgO nanopillars in transmission electron microscopy verified aligned dislocation-mediated plasticity on the {111}⟨110⟩ and {100}⟨110⟩ systems rather than the charge-balanced {110}⟨110⟩ slip system.
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BACKGROUND: Asthma is a chronic airway inflammatory disease that has a high prevalence nowadays, and seeking the means of relieving asthmatic symptoms is now an issue with increased importance. While mesenchymal stem cells have been demonstrated to display immunomodulatory effects, the effect of fetus-type mesenchymal stem cells (MSCs) on asthmatic symptoms in vivo have not been reported to date. METHODS: Female BALB/c mice at 8 weeks of age were sensitized by ovalbumin, and MSCs derived from Wharton's jelly of human umbilical cord mesenchymal stem cells (hUCMSCs) were injected into the asthmatic mice. Airway hyper-responsiveness, lung eosinophil infiltration, cytokine level in splenocyte cultures and serum immunoglobulin level were measured. Enzyme-linked immunosorbent assay was used to determine cytokine and immunoglobulin levels. RESULTS: This current study demonstrated that hUCMSCs attenuated both lung lymphocyte and eosinophil infiltration, and significantly decreased the concentration of Th2 cytokines interleukin-5 in splenocyte cultures. CONCLUSIONS: Human umbilical cord mesenchymal stem cells have the advantage of being easily harvested non-invasively and are capable of rapid proliferation, therefore an ideal material for stem cell-based immune therapies. The current study showed that fetal-type MSCs were able to suppress asthmatic symptoms efficiently, and its immunomodulatory effect resulted primarily from suppressing the Th2 pathway in the animal model. This study suggested that hUCMSCs could be an ideal candidate for cell-based therapies of asthma.
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Asma/terapia , Trasplante de Células Madre Mesenquimatosas , Alérgenos , Animales , Asma/inmunología , Líquido del Lavado Bronquioalveolar/citología , Citocinas/inmunología , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Femenino , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Recuento de Leucocitos , Ratones Endogámicos BALB C , Ovalbúmina , Bazo/citología , Células Th2/inmunología , Cordón Umbilical/citologíaRESUMEN
PURPOSE: Occlusion of the artery of Percheron (AOP), a rare vascular variant of basilar artery branch, is presumed to cause bilateral paramedian thalamic infarction. We present a case of acute AOP infarction with status epilepticus. CASE REPORT: A 65-year-old woman had past history of hypertension, type 2 diabetes mellitus, and major depressive disorder. She was found to have altered mental status on awakening. She developed tonic convulsion and progressed to status epilepticus later. The brain magnetic resonance imaging (MRI) showed acute bilateral paramedian thalamic and interpeduncular mesencephalic infarction. The electroencephalography (EEG) showed continuous epileptiform discharges. After receiving antiplatelet and anticonvulsant agents, she regained her level of consciousness and has completely recovered to previous baseline. CONCLUSIONS: To our knowledge, this is the first case of AOP infarction presenting status epilepticus. Early recognition and treatment of seizure may reverse altered mental status in those patients.
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Infarto Cerebral/complicaciones , Estado Epiléptico/etiología , Tálamo/patología , Anciano , Electroencefalografía , Femenino , HumanosRESUMEN
Near-infrared supercontinnum (SC) generation, accompanied with several emission bands at visible and ultraviolet, is experimentally investigated in an all-fiber single-mode Yb(3+)-doped silica fiber MOPA. The seed is an all-normal-dispersion mode-locked Yb(3+)-doped single-mode fiber laser using a nonlinear polarization evolution mechanism. With the pump power of several hundreds of milliwatts, SC spanning of 1010 nm to 1600 nm was generated in a 20-m single-mode germano-zirconia-silica Yb(3+)-doped fiber amplifier. The intensive nonlinear effects, namely stimulated Raman scattering, four wave mixing, and self-phase modulation, enable the SC generation in the small-core fiber amplifier without the use of photonic crystal fibers or tapered fibers. Such a compact and cost-effective SC generation system enables applications in optical coherent tomography, optical metrology, and nonlinear microscopy.
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Neuropathic pain is characterized by spontaneous pain, hyperalgesia, and allodynia. The aim of this study was to investigate whether KMUP-1 (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) could improve pain hypersensitivity and reduce inflammatory mediators, and also explore possible mechanisms in the rat sciatic nerve using bilateral chronic constriction injury (CCI) to induce neuropathic pain. Sprague-Dawley rats were randomly divided into four groups: Sham, Sham+KMUP-1, CCI, and CCI+KMUP-1. KMUP-1 (5 mg/kg/day) was injected intraperitoneally starting at day 1 after surgery. Mechanical and thermal responses were assessed before surgery and at days 3, 7, and 14 after CCI. Sciatic nerves around the injury site were isolated for Western blots and enzyme-linked immunosorbent assay to analyze protein and cytokine levels. The results show that thermal hyperalgesia and mechanical allodynia were reduced in the KMUP-1 treated group as compared to that in the CCI group. Inflammatory proteins (COX2, iNOS, and nNOS) and proinflammatory cytokines (TNF-α and IL-1ß) induced by CCI were decreased in the KMUP-1 treated group at day 7 after surgery. KMUP-1 also inhibited neuropathic pain-related mechanisms, including p38 and ERK activation, but not JNK. Furthermore, KMUP-1 blocked IκB phosphorylation (p-IκB) and phospho-nuclear factor κB (p-NF-κB) translocation to nuclei. Double immunofluorescent staining further demonstrated that p-IκB (an indicator of activated NFκB) and p-NFκB proteins were almost abolished by KMUP-1 in peripheral macrophages and spinal microglia cells at day 7 after surgery. On the basis of these findings, we concluded that KMUP-1 has antiinflammatory and antihyperalgesia properties in CCI-induced neuropathic pain via decreases in MAPKs and NF-κB activation.
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Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Piperidinas/química , Piperidinas/uso terapéutico , Xantina/química , Xantinas/química , Xantinas/uso terapéutico , Animales , Western Blotting , Hiperalgesia , Inmunohistoquímica , Masculino , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The influence of gut microbiota on gut health is well-documented, but it remains obscure for extraintestinal diseases such as breast cancer. Moreover, it is entirely unknown how gut dysbiosis during early life contributes to breast tumorigenesis later in life. In this study, we hypothesized that a high-fat diet during early life leads to alterations in the gut microbiome and is associated with disruptions in the mammary microenvironment. Female C57BL/6 mice were fed a low-fat diet (10% kcal fat) or a high-fat diet (HF, 60% kcal fat) for 8 weeks from the age of 4 to 12 weeks, which is equivalent to human childhood and adolescence. Twelve mice were sacrificed immediately after the 8-week feeding, the remainder were euthanized after switching to a normal lifecycle-supporting diet for an additional 12 weeks; the gut microbiome was then sequenced. The 8-week HF diet feeding altered the beta-diversity (Bray & Jaccard P < .01), and the difference remained significant after switching the diet (Bray & Jaccard P < .05). Immediately after HF feeding, a greater number of microbial taxa (>50) were altered, and about half of the taxa (25) remained significantly changed after switching the diet. The abundance of Alistipes, Bilophila, and Rikenellaceae stood out as significantly associated with multiple metabolic and inflammatory biomarkers in mammary tissue, including aromatase, Ccl2, and Cox2. In conclusion, an 8-week early-life HF feeding reshaped the gut microbiome, which connected with disrupted mammary microenvironments.
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Dieta Alta en Grasa , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Ratones , Glándulas Mamarias Animales/microbiología , Disbiosis/microbiología , Ciclooxigenasa 2/metabolismo , Dieta con Restricción de GrasasRESUMEN
OBJECTIVE: This study aims to overcome challenges in lumbar spine imaging, particularly lumbar spinal stenosis, by developing an automated segmentation model using advanced techniques. Traditional manual measurement and lesion detection methods are limited by subjectivity and inefficiency. The objective is to create an accurate and automated segmentation model that identifies anatomical structures in lumbar spine magnetic resonance imaging scans. METHODS: Leveraging a dataset of 539 lumbar spinal stenosis patients, the study utilizes the residual U-Net for semantic segmentation in sagittal and axial lumbar spine magnetic resonance images. The model, trained to recognize specific tissue categories, employs a geometry algorithm for anatomical structure quantification. Validation metrics, like Intersection over Union (IOU) and Dice coefficients, validate the residual U-Net's segmentation accuracy. A novel rotation matrix approach is introduced for detecting bulging discs, assessing dural sac compression, and measuring yellow ligament thickness. RESULTS: The residual U-Net achieves high precision in segmenting lumbar spine structures, with mean IOU values ranging from 0.82 to 0.93 across various tissue categories and views. The automated quantification system provides measurements for intervertebral disc dimensions, dural sac diameter, yellow ligament thickness, and disc hydration. Consistency between training and testing datasets assures the robustness of automated measurements. CONCLUSION: Automated lumbar spine segmentation with residual U-Net and deep learning exhibits high precision in identifying anatomical structures, facilitating efficient quantification in lumbar spinal stenosis cases. The introduction of a rotation matrix enhances lesion detection, promising improved diagnostic accuracy, and supporting treatment decisions for lumbar spinal stenosis patients.
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BACKGROUND: Recessive GJB2 variants, the most common genetic cause of hearing loss, may contribute to progressive sensorineural hearing loss (SNHL). The aim of this study is to build a realistic predictive model for GJB2-related SNHL using machine learning to enable personalized medical planning for timely intervention. METHOD: Patients with SNHL with confirmed biallelic GJB2 variants in a nationwide cohort between 2005 and 2022 were included. Different data preprocessing protocols and computational algorithms were combined to construct a prediction model. We randomly divided the dataset into training, validation, and test sets at a ratio of 72:8:20, and repeated this process ten times to obtain an average result. The performance of the models was evaluated using the mean absolute error (MAE), which refers to the discrepancy between the predicted and actual hearing thresholds. RESULTS: We enrolled 449 patients with 2184 audiograms available for deep learning analysis. SNHL progression was identified in all models and was independent of age, sex, and genotype. The average hearing progression rate was 0.61 dB HL per year. The best MAE for linear regression, multilayer perceptron, long short-term memory, and attention model were 4.42, 4.38, 4.34, and 4.76 dB HL, respectively. The long short-term memory model performed best with an average MAE of 4.34 dB HL and acceptable accuracy for up to 4 years. CONCLUSIONS: We have developed a prognostic model that uses machine learning to approximate realistic hearing progression in GJB2-related SNHL, allowing for the design of individualized medical plans, such as recommending the optimal follow-up interval for this population.
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Conexina 26 , Pérdida Auditiva Sensorineural , Aprendizaje Automático , Humanos , Conexina 26/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/fisiopatología , Femenino , Masculino , Adulto , Niño , Adolescente , Persona de Mediana Edad , PreescolarRESUMEN
PURPOSE: One complication of thrombolysis is intracranial hemorrhage (ICH). We investigated whether treatment with tissue plasminogen activator (t-PA) for ischemic infarction results in a higher risk of ICH in patients with kidney dysfunction, who are predisposed to treatment complications due to their bleeding tendency. METHODS: A total of 297 patients given thrombolytic therapy for ischemic stroke were classified into 2 groups on the basis of their estimated renal glomerular filtration rate (eGFR). The outcome measures included the incidence of ICH and modified Rankin scale scores at 1 month and 1 year. RESULTS: ICH was more common in the renal dysfunction group (23 vs. 12.5%). Nevertheless, multivariate logistic regression showed that the odds of ICH were not high in the group with low eGFR. Also, eGFR values <60 ml/min/1.73 m(2) did not predict the odds for functional dependence or death at 1 month and 1 year. CONCLUSION: After adjusting for confounding factors, the odds ratio for ICH was not higher in intravenous t-PA-treated stroke patients with renal dysfunction. A trend to the occurrence of ICH among these patients, however, was noted. Renal dysfunction does not predict the odds for functional dependence or death at 1 month and 1 year.
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Isquemia Encefálica/tratamiento farmacológico , Hemorragia Cerebral/etiología , Enfermedades Renales/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Activador de Tejido Plasminógeno/efectos adversos , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/complicaciones , Femenino , Fibrinolíticos/efectos adversos , Fibrinolíticos/uso terapéutico , Tasa de Filtración Glomerular/fisiología , Humanos , Enfermedades Renales/complicaciones , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/complicaciones , Terapia Trombolítica/efectos adversos , Activador de Tejido Plasminógeno/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: We aimed to assess whether intracranial carotid artery calcification (ICAC) evident on head computed tomography is a risk factor for symptomatic intracerebral hemorrhage (sICH) following tissue plasminogen activator (tPA) treatment for acute stroke. METHODS: We classified 297 consecutive patients into 2 groups (no to mild ICAC and moderate to severe ICAC) according to ICAC severity. Outcome measures included detection of intracerebral hemorrhage and assessment using a modified Rankin scale (mRS) at 1 month and 1 year after stroke. RESULTS: ICH (any type) was significantly more common in patients with moderate to severe ICAC than in patients with no to mild ICAC (22.5% versus 12%; relative risk [RR], 1.67; 95% confidence interval [CI], 1.1-2.5; P<.05). The moderate to severe ICAC group tended to have a higher percentage of sICH, but this association was not statistically significant (RR, 1.57; 95% CI, .75-3.3, P>.05). Multivariate adjusted regression analysis revealed that moderate to severe ICAC was an independent risk factor for ICH following tPA treatment (odds ratio, 2.52; 95% CI, 1.07-5.94; P=.04). Dependent functional outcome (mRS score 3-6) at 1-month and 1-year follow-up was significantly associated with moderate to severe ICAC (RR, 1.56; 95% CI, 1.06-2.27; and RR, 1.56; 95% CI, 1.06-2.33; P<.05). However, ICAC was not an independent factor of functional dependency at 1-month and 1-year follow-up in the final multivariate regression model. CONCLUSION: A significantly higher percentage of patients with moderate to severe ICAC developed ICH following tPA administration for stroke. ICAC severity is an independent risk factor for ICH events. ICAC severity can help predict short-term and long-term functional dependency in tPA-treated patients, although this can be confounded by other cardiovascular risk factors and stroke severity.
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Enfermedades de las Arterias Carótidas/complicaciones , Hemorragia Cerebral/inducido químicamente , Fibrinolíticos/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica/efectos adversos , Activador de Tejido Plasminógeno/efectos adversos , Calcificación Vascular/complicaciones , Anciano , Enfermedades de las Arterias Carótidas/diagnóstico , Angiografía Cerebral/métodos , Hemorragia Cerebral/diagnóstico , Distribución de Chi-Cuadrado , Evaluación de la Discapacidad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Taiwán , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Calcificación Vascular/diagnósticoRESUMEN
Emerging evidence highlights the important impact of early-life exposures on cancer development later in life. The present study aimed to investigate the impacts of a high-fat diet in early life on the mammary microenvironment in relation to breast tumorigenesis. Forty-four female C57BL/6 mice were fed a low-fat diet (LF, 10 kcal% fat) or a high-fat diet (HF, 60 kcal% fat) for 8 weeks starting at ~4 weeks of age. Twenty-two mice were sacrificed immediately after an 8 week feeding, and the rest of mice were switched to a normal diet for maintenance (Lab Diet, #5P76) for additional 12 weeks. A panel of metabolic parameters, inflammatory cytokines, as well as tumorigenic Wnt-signaling target genes were analyzed. The HF diet increased body weight and exacerbated mammary metabolic and inflammatory status. The disrupted microenvironment remains significant to the later life equivalent to young adulthood (p < 0.05). Mammary Wnt-signaling was elevated right after the HF diet as indicated by the upregulated expression of its downstream genes, whereas it was surprisingly suppressed after switching diets (p < 0.05). In summary, HF-induced overweight/obesity in early life altered the mammary metabolic and inflammatory microenvironments in favor of breast tumorigenesis, although its overall impact to breast cancer later in life warrants further investigation.
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Dieta Alta en Grasa , Obesidad , Ratones , Femenino , Humanos , Animales , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Peso Corporal , Carcinogénesis/metabolismo , Microambiente TumoralRESUMEN
Strong evidence from observational studies shows that having body fatness is associated with an individual's risk of developing colorectal cancer (CRC), but the causality between obesity and CRC remains inadequately elucidated. Our previous studies have shown diet-induced obesity is associated with elevated TNF-α and enhanced activation of Wnt-signaling, yet the causal role of TNF-α on intestinal tumorigenesis has not been precisely studied. The present study aims to examine the functionality of TNF-α in the development of CRC associated with obesity. We first examined the extent to which diet-induced obesity elevates intestinal tumorigenesis by comparing Apc1638N mice fed a low fat diet (LFD, 10 kcal% fat) with those fed a high fat diet (HFD, 60 kcal% fat), and then investigated the degree that the genetic ablation of TNF-α attenuates the effect by crossing the TNF-α-/- mice with Apc1638N mice and feeding them with the same HFD (TNF-α KO HFD). After 16-weeks of feeding, the HFD significantly increased intestinal tumorigenesis, whereas the deletion of TNF-α attenuated the effect (P < .05). Accompanying the changes in macroscopic tumorigenesis, HFD significantly elevated intestinal inflammation and procarcinogenic Wnt-signaling, whereas abolishment of TNF-α mitigated the magnitude of these elevations (P < .05). In summary, our findings demonstrate that the knockout of TNF-α attenuates obesity-associated intestinal tumorigenesis by decreasing intestinal inflammation and thereby the Wnt-signaling, indicating that TNF-α signaling is a potential target that can be utilized to reduce the risk of CRC associated with obesity.
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Obesidad , Factor de Necrosis Tumoral alfa , Ratones , Animales , Factor de Necrosis Tumoral alfa/genética , Obesidad/genética , Carcinogénesis , Dieta Alta en Grasa/efectos adversos , Transformación Celular Neoplásica , Vía de Señalización Wnt , Inflamación/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones ObesosRESUMEN
Introduction: Diet-induced obesity has been shown to decrease the abundance of Turicibacter, a genus known to play a role in the serotonin signaling system, which is associated with colorectal tumorigenesis, making the presence of Turicibacter potentially influential in the protection of intestinal tumorigenesis. Recently, Antrodia camphorata (AC), a medicinal fungus native to Taiwan, has emerged as a promising candidate for complementary and alternative cancer therapy. Small molecules and polysaccharides derived from AC have been reported to possess health-promoting effects, including anti-cancer properties. Methods: Bacterial culture followed with cell culture were used in this study to determine the role of Turicibacter in colorectal tumorigenesis and to explore the anti-cancer mechanism of AC with Turicibacter fermentation. Results: Turicibacter fermentation and the addition of AC polysaccharide led to a significant increase in the production of nutrients and metabolites, including α-ketoglutaric acid and lactic acid (p < 0.05). Treatment of Turicibacter fermented AC polysaccharide was more effective in inhibiting serotonin signaling-related genes, including Tph1, Htr1d, Htr2a, Htr2b, and Htr2c (p < 0.05), and Wnt-signaling related protein and downstream gene expressions, such as phospho-GSK-3ß, active ß-catenin, c-Myc, Ccnd1, and Axin2 (p < 0.05). Additionally, it triggered the highest generation of reactive oxygen species (ROS), which activated PI3K/Akt and MAPK/Erk signaling and resulted in cleaved caspase-3 expression. In comparison, the treatment of AC polysaccharide without Turicibacter fermentation displayed a lesser effect. Discussion: Our findings suggest that AC polysaccharide effectively suppresses the tumorigenic serotonin and Wnt-signaling pathways, and promotes ROS-mediated apoptosis in Caco-2 cells. These processes are further enhanced by Turicibacter fermentation.
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Rheumatoid arthritis (RA) is a common autoimmune disease. Janus kinase inhibitors (JAKi) have been approved for the treatment of RA; however, the impact of JAKi on immune cells remains inconclusive. This study investigated the response of immune cells to JAKi treatment to identify biomarkers by which to evaluate and predict clinical outcomes. Blood samples were collected from RA patients before and after JAKi treatment for the analysis of immunophenotypes. Our results revealed that JAKi mainly inhibited Fas+ T cell subsets. The percentage changes of Th Fas+ and Naive Th Fas+ cells were positively correlated with the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) values. Following treatment, moderate response (MR) RA patients presented a decrease in the number of Naive Th Fas+ cells (p = 0.0001). Initial percentages of 14 T cell and 20 B cell subsets were correlated with percentage changes in DAS28-ESR. Overall, 16 cell subsets presented significant differences between the non-response (NR) and MR groups. Excluding the multicollinearity of the immune cells, we constructed a JAKi treatment response prediction index (JRPI) using 5 subsets of T/B cells, the results of which were strongly correlated with percentage changes in DAS28-ESR (receiver operating characteristic curve of 1). Note that the NR group was clearly distinguished from the MR group (p = 0.0167). In conclusion, the efficacy of JAKi can be attributed mainly to the suppression of Fas+ T cell subsets. A positive correlation was shown between the therapeutic efficacy of JAKi and the percentage changes in both Th Fas+ cells and Naive Th Fas+ cells. Furthermore, the proposed JRPI could potentially be used as an indicator to predict the efficacy of JAKi prior to treatment in RA patients. These findings may contribute to the development of personalized treatment strategies for RA patients using JAKi.
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Antirreumáticos , Artritis Reumatoide , Inhibidores de las Cinasas Janus , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Subgrupos de Linfocitos T , Resultado del Tratamiento , Linfocitos T Colaboradores-Inductores , Antirreumáticos/uso terapéuticoRESUMEN
BACKGROUND/AIM: Regulatory T cells (Treg) play a crucial role in maintaining immune tolerance and preventing autoimmune diseases. Recent data also indicate that type 1 regulatory T (Tr1) and regulatory B (Breg) cells play an inhibitory (i.e., protective) role in autoimmune diseases. Conventional synthetic disease-modifying antirheumatic drugs (csDMARD) are a first-line therapy for rheumatoid arthritis (RA), and our aim was to predict clinical responses of this treatment using immunophenotyping. MATERIALS AND METHODS: We first detected the presence of immune cells in fresh blood from 16 healthy controls (HC) and 26 patients with RA (14 drug-naive and 12 csDMARD-experienced). Then, we recorded immunophenotypic changes in 14 drug-naive RA (naive RA) patients prior to csDMARD treatment (i.e., day 0) and after receiving treatment for 6 months. The observed changes were also compared with other clinical indicators, including the presence of anti-citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. RESULTS: Naive RA patients had significantly lower Tregs than HC and csDMARD-experienced patients (both p<0.0001) and the number of Tregs correlated with the diagnosis of RA and therapeutic efficacy of csDMARD treatment. Furthermore, lower baseline levels of Treg, memory Treg, Tr1, and higher PD-1+ Marginal B, Breg cells were significantly associated with decreased development of the 28-joint Disease Activity Score (DAS28) (all p<0.05), revealing better medical response. Multiple regression and principal component analysis identified Treg, Tr1, and Breg as potential predictors of csDMARD responses (Area under curve: 0.9; Accuracy: 92.86%). Furthermore, elevated Treg, Tr1, and Breg cells were associated with decreased DAS28, ESR, and CRP (all p<0.05); changes in Treg and Breg cell expression were also more pronounced among double negative anti-CCP and RF in RA patients with better outcomes (p<0.05). CONCLUSION: Immunophenotyping can be an adjunct clinical tool to identify patients who are poor candidates for csDMARD therapy. Alternative therapeutic interventions in the early stages of disease should be formulated for these patients.