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The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune-checkpoint blockade (ICB) in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to anti-tumor responses may facilitate development of improved treatment strategies. Lymphotoxin beta receptor (LTßR) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and ICB treatment to augment tumor-associated HEV formation. Here, we demonstrated that LTßR signaling modulates the tumor microenvironment via multiple mechanisms to promote anti-tumor T cell responses. Systemic activation of the LTßR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTßR agonism on DC activation and maturation and associated DC-mediated T cell activation. Single agent LTßR agonist treatment inhibited syngeneic tumor growth in a CD8+ T cell- and HEV-dependent manner, and the LTßR agonist enhanced anti-tumor effects of anti-PD-1 and CAR T cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTßR agonism and lymphotoxin alpha (LTâº) expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA-4 treatment. Collectively, this study highlights crucial functions of LTßR signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments.
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Introduction: This study investigates the role of Fibroblast Activation Protein (FAP)-positive cancer-associated fibroblasts (FAP+CAF) in shaping the tumor immune microenvironment, focusing on its association with immune cell functionality and cytokine expression patterns. Methods: Utilizing immunohistochemistry, we observed elevated FAP+CAF density in metastatic versus primary renal cell carcinoma (RCC) tumors, with higher FAP+CAF correlating with increased T cell infiltration in RCC, a unique phenomenon illustrating the complex interplay between tumor progression, FAP+CAF density, and immune response. Results: Analysis of immune cell subsets in FAP+CAF-rich stromal areas further revealed significant correlations between FAP+ stroma and various T cell types, particularly in RCC and non-small cell lung cancer (NSCLC). This was complemented by transcriptomic analyses, expanding the range of stromal and immune cell subsets interrogated, as well as to additional tumor types. This enabled evaluating the association of these subsets with tumor infiltration, tumor vascularization and other components of the tumor microenvironment. Our comprehensive study also encompassed cytokine, angiogenesis, and inflammation gene signatures across different cancer types, revealing heterogeneous cellular composition, cytokine expressions and angiogenic profiles. Through cytokine pathway profiling, we explored the relationship between FAP+CAF density and immune cell states, uncovering potential immunosuppressive circuits that limit anti-tumor activity in tumor-resident immune cells. Conclusions: These findings underscore the complexity of tumor biology and the necessity for personalized therapeutic and patient enrichment approaches. The insights gathered from FAP+CAF prevalence, immune infiltration, and gene signatures provide valuable perspectives on tumor microenvironments, aiding in future research and clinical strategy development.
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Fibroblastos Asociados al Cáncer , Inmunoterapia , Serina Endopeptidasas , Microambiente Tumoral , Microambiente Tumoral/inmunología , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/inmunología , Inmunoterapia/métodos , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Citocinas/metabolismo , Endopeptidasas , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Gelatinasas/metabolismo , Gelatinasas/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Neoplasias Renales/terapia , Neoplasias Renales/metabolismo , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismoRESUMEN
AIM OF THE STUDY: Chronic cholestasis leads to liver fibrosis, which lacks effective treatment. In this study, we investigated the role and mechanisms of action of loureirin B (LB) in cholestatic liver fibrosis. MATERIALS AND METHODS: Bile duct ligation (BDL)-induced hepatic fibrosis mice were used as in vivo models. Transforming growth factor-ß1 (TGF-ß1)-pretreated HSC-T6 cells were used to explore the mechanism by which LB attenuates liver fibrosis in vitro. RNA sequencing, quantitative PCR (qPCR), western blotting, immunohistochemistry and immunofluorescence were performed to detect the fibrosis markers and measure autophagy levels. Flow cytometry, cell counting kit-8 (CCK-8) assay, and 5'-ethynyl-2'-deoxyuridine (EdU) assay were conducted to detect cell proliferation and viability. GFP-RFP-LC3 adenovirus, autophagy-related protein 7 (ATG7) siRNA, and bafilomycin A1 (BafA1) were used to verify autophagic flux. RESULTS: Our results showed that LB ameliorates liver injury, inhibits collagen deposition, and decreases the expressions of fibrosis-related markers in BDL-induced mouse livers. In vitro, we found that LB inhibited proliferation and migration, promoted apoptosis, and inhibited the activation of HSC-T6 cells pretreated with TGF-ß1. RNA sequencing analysis of HSC-T6 cells showed that LB treatment predominantly targeted autophagy-related pathways. Further protein analysis indicated that LB downregulated the expression of phosphorylated AKT (p-AKT) and phosphorylated mTOR (p-mTOR), and upregulated LC3-II, p62, and ATG7 both in vivo and in vitro. Intriguingly, ATG7 inactivation reversed the antifibrotic effects of LB on HSC-T6 cells. CONCLUSIONS: LB can improve BDL-induced liver fibrosis by inhibiting the activation and proliferation of HSCs and is expected to be a promising antifibrotic drug.
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Colestasis , Proteínas Proto-Oncogénicas c-akt , Resinas de Plantas , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Células Estrelladas Hepáticas , Cirrosis Hepática/inducido químicamente , Serina-Treonina Quinasas TOR/metabolismo , Hígado/metabolismo , Autofagia , Colestasis/patologíaRESUMEN
Introduction: Fibroblast activation protein (FAP) is predominantly upregulated in various tumor microenvironments and scarcely expressed in normal tissues. Methods: We analyzed FAP across 1216 tissue samples covering 23 tumor types and 70 subtypes. Results: Elevated FAP levels were notable in breast, pancreatic, esophageal, and lung cancers. Using immunohistochemistry and RNAseq, a correlation between FAP gene and protein expression was found. Evaluating FAP's clinical significance, we assessed 29 cohorts from 12 clinical trials, including both mono and combination therapies with the PD-L1 inhibitor atezolizumab and chemotherapy. A trend links higher FAP expression to poorer prognosis, particularly in RCC, across both treatment arms. However, four cohorts showed improved survival with high FAP, while in four others, FAP had no apparent survival impact. Conclusions: Our results emphasize FAP's multifaceted role in therapy response, suggesting its potential as a cancer immunotherapy biomarker.
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Neoplasias Pulmonares , Serina Endopeptidasas , Humanos , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Inmunoterapia , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Fibroblastos/metabolismo , Microambiente Tumoral/genéticaRESUMEN
Epigenetics underpins the regulation of genes known to play a key role in the adaptive and innate immune system (AIIS). We developed a method, EpiNN, that leverages epigenetic data to detect AIIS-relevant genomic regions and used it to detect 2,765 putative AIIS loci. Experimental validation of one of these loci, DNMT1, provided evidence for a novel AIIS-specific transcription start site. We built a genome-wide AIIS annotation and used linkage disequilibrium (LD) score regression to test whether it predicts regional heritability using association statistics for 176 traits. We detected significant heritability effects (average |τ∗|=1.65) for 20 out of 26 immune-relevant traits. In a meta-analysis, immune-relevant traits and diseases were 4.45× more enriched for heritability than other traits. The EpiNN annotation was also depleted of trans-ancestry genetic correlation, indicating ancestry-specific effects. These results underscore the effectiveness of leveraging supervised learning algorithms and epigenetic data to detect loci implicated in specific classes of traits and diseases.
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Genómica , Sitios de Carácter Cuantitativo , Fenotipo , Desequilibrio de Ligamiento/genética , Epigénesis Genética/genéticaRESUMEN
Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Inflamación/genética , Neoplasias Pulmonares/genética , Pulmón , Progresión de la EnfermedadRESUMEN
Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness and paralysis. Motor function is monitored in the clinical setting using assessments including the 32-item Motor Function Measure (MFM-32), but changes in disease severity between clinical visits may be missed. Digital health technologies may assist evaluation of disease severity by bridging gaps between clinical visits. We developed a smartphone sensor-based assessment suite, comprising nine tasks, to assess motor and muscle function in people with SMA. We used data from the risdiplam phase 2 JEWELFISH trial to assess the test-retest reliability and convergent validity of each task. In the first 6 weeks, 116 eligible participants completed assessments on a median of 6.3 days per week. Eight of the nine tasks demonstrated good or excellent test-retest reliability (intraclass correlation coefficients >0.75 and >0.9, respectively). Seven tasks showed a significant association (P < 0.05) with related clinical measures of motor function (individual items from the MFM-32 or Revised Upper Limb Module scales) and seven showed significant association (P < 0.05) with disease severity measured using the MFM-32 total score. This cross-sectional study supports the feasibility, reliability, and validity of using smartphone-based digital assessments to measure function in people living with SMA.
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Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Humanos , Reproducibilidad de los Resultados , Teléfono Inteligente , Estudios de Factibilidad , Estudios Transversales , Extremidad Superior , Atrofias Musculares Espinales de la Infancia/complicacionesRESUMEN
Challenges in social communication is one of the core symptom domains in autism spectrum disorder (ASD). Novel therapies are under development to help individuals with these challenges, however the ability to show a benefit is dependent on a sensitive and reliable measure of treatment effect. Currently, measuring these deficits requires the use of time-consuming and subjective techniques. Objective measures extracted from natural conversations could be more ecologically relevant, and administered more frequently-perhaps giving them added sensitivity to change. While several studies have used automated analysis methods to study autistic speech, they require manual transcriptions. In order to bypass this time-consuming process, an automated speaker diarization algorithm must first be applied. In this paper, we are testing whether a speaker diarization algorithm can be applied to natural conversations between autistic individuals and their conversational partner in a natural setting at home over the course of a clinical trial. We calculated the average duration that a participant would speak for within their turn. We found a significant correlation between this feature and the Vineland Adaptive Behaviour Scales (VABS) expressive communication score (r = 0.51, p = 7 × 10-5). Our results show that natural conversations can be used to obtain measures of talkativeness, and that this measure can be derived automatically, thus showing the promise of objectively evaluating communication challenges in ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Trastorno Autístico/terapia , Trastorno del Espectro Autista/terapia , Trastorno del Espectro Autista/diagnóstico , Comunicación , HablaRESUMEN
Digital health technologies enable remote and therefore frequent measurement of motor signs, potentially providing reliable and valid estimates of motor sign severity and progression in Parkinson's disease (PD). The Roche PD Mobile Application v2 was developed to measure bradykinesia, bradyphrenia and speech, tremor, gait and balance. It comprises 10 smartphone active tests (with ½ tests administered daily), as well as daily passive monitoring via a smartphone and smartwatch. It was studied in 316 early-stage PD participants who performed daily active tests at home then carried a smartphone and wore a smartwatch throughout the day for passive monitoring (study NCT03100149). Here, we report baseline data. Adherence was excellent (96.29%). All pre-specified sensor features exhibited good-to-excellent test-retest reliability (median intraclass correlation coefficient = 0.9), and correlated with corresponding Movement Disorder Society-Unified Parkinson's Disease Rating Scale items (rho: 0.12-0.71). These findings demonstrate the preliminary reliability and validity of remote at-home quantification of motor sign severity with the Roche PD Mobile Application v2 in individuals with early PD.
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Aplicaciones Móviles , Enfermedad de Parkinson , Tecnología de Sensores Remotos , Humanos , Enfermedad de Parkinson/fisiopatología , Reproducibilidad de los Resultados , Teléfono Inteligente , Temblor/fisiopatologíaRESUMEN
Obesity is a major public health concern worldwide with a rising prevalence. Diets containing whole grains have been demonstrated to benefit body composition and inflammatory conditions in individuals at a high risk of metabolic disorders. This study investigated the effects of dehulled adlay on blood lipids and inflammation in overweight and obese adults. We recruited 21 individuals with abdominal obesity to participate in a 6-week experiment, providing them 60 g of dehulled adlay powder per day as a substitute for their daily staple. Before and after the 6-week intervention, we performed anthropometric analyses and measured blood lipid profiles, adipokines, and markers of inflammation. At the end of the study, the percentage of body fat mass, blood total cholesterol, and triglyceride levels were significantly decreased compared with the baseline. Plasma tumor necrosis factor alpha, interleukin-6, leptin, and malondialdehyde levels were also reduced. In addition, participants with higher basal blood lipid levels exhibited enhanced lipid lowering effects after the dehulled adlay intervention. These results suggest that a dietary pattern containing 60 g of dehulled adlay per day may have a beneficial effect on lipid profiles and inflammatory markers in individuals that are overweight and obese.
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Metabolismo de los Lípidos , Sobrepeso , Adulto , Humanos , Inflamación , Lípidos , Obesidad/complicaciones , Sobrepeso/complicaciones , Proyectos PilotoRESUMEN
PURPOSES: To investigate the relationships and interactions between temporal and radiological features of gangrene and perforation of inflamed appendices. METHODS: A total of 402 patients were included who underwent laparoscopic appendectomies between January 1, 2016 and March 30, 2020 and had pathologically proved acute appendicitis and preoperative non-enhanced CT examinations. The radiological features (appendix diameter, appendicolith, appendiceal intraluminal gas, periappendiceal gas, periappendiceal fat stranding/fluid, and short axial diameter of the mesenteric lymph nodes) were obtained from the preoperative CT images of 382 patients with visible appendices. Clinical parameters and temporal variables (pre-CT delay, preoperative delay, estimated complication delay, symptom delay, and system delay) were recorded. RESULTS: Among simple/suppurative, gangrenous, and perforated appendicitis, the radiological characteristics except for short axial diameters of lymph nodes, and the temporal variables other than system delay were significantly different. The Cox regression analysis identified the appendicolith as the independent risk factor for both gangrene and perforation of inflamed appendices by using the preoperative delay or estimated complication delay. By the preoperative delay, the median time for gangrene and perforation was 76.23 (95%CI 73.89-78.58) h and 77.55 (95%CI 74.12-80.98) h, respectively, if appendicolith was present. If estimated complication delay was used as the elapsed time and the appendicolith was perceptible, the median time for gangrene and perforation and was 72.33 (95%CI 62.93-81.74) h and 75.07 (95%CI 69.48-80.65) h, respectively. CONCLUSION: There were interactions between the time evolution and radiological features of acute appendicitis. The evaluation of gangrene and perforation rate of acute appendicitis could be benefitted from combining the preoperative delay/estimated complication delay with CT characteristics in the preoperative urgent radiological analysis.
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Apendicitis , Gangrena , Enfermedad Aguda , Apendicectomía , Apendicitis/diagnóstico por imagen , Apendicitis/cirugía , Gangrena/diagnóstico por imagen , Gangrena/patología , Humanos , Factores de Tiempo , Tomografía Computarizada por Rayos X/métodosRESUMEN
Dietary modification plays a vital role in the treatment of non-alcoholic liver diseases. We investigated the effects of the consumption of a different amount of dehulled adlay, which has hypolipidaemic and anti-inflammatory properties, on non-alcoholic fatty liver disease (NAFLD). We fed rats a high-fat-high-fructose liquid diet for 16 weeks to induce NAFLD. The rats were divided into three groups fed the NAFLD diet only (NN) or a diet containing 44·9 or 89·8 g/l of dehulled adlay (NA and NB groups, respectively). After 8 weeks, the NA and NB groups had lower C-reactive protein levels and improvement in insulin resistance. In addition, the NB group had lower liver weight and hepatic TAG and cholesterol concentrations than did the NN group. Compared with the NN group, the high-dose NB group had improved steatosis, lower hepatic TNF-α, IL-1ß and IL-6 levels and lower adipose leptin levels. Our results suggest that a diet containing dehulled adlay can ameliorate NAFLD progression by decreasing of insulin resistance, steatosis and inflammation.
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Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Ratas , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Hígado/metabolismo , Inflamación/metabolismo , Dieta Alta en GrasaRESUMEN
High blood pressure is a crucial risk factor for many cardiovascular diseases, and a diet rich in whole-grain foods may modulate blood pressure. This study investigated the effects of dehulled adlay consumption on blood pressure in vivo. We initially fed spontaneous hypertensive rats diets without (SHR group) or with 12 or 24% dehulled adlay (SHR + LA and SHR + HA groups), and discovered that it could limit blood pressure increases over a 12-week experimental period. Although we found no significant changes in plasma, heart, and kidney angiotensin-converting enzyme activities, both adlay-consuming groups had lower endothelin-1 and creatinine concentrations than the SHR group; the SHR + HA group also had lower aspartate aminotransferase and uric acid levels than the SHR group did. We later recruited 23 participants with overweight and obesity, and they consumed 60 g of dehulled adlay daily for a six-week experimental period. At the end of the study, we observed a significant decrease in the group's systolic blood pressure (SBP), and the change in SBP was even more evident in participants with high baseline SBP. In conclusion, our results suggested that daily intake of dehulled adlay had beneficial effects in blood-pressure management. Future studies may further clarify the possible underlying mechanisms for the consuming of dehulled adlay as a beneficial dietary approach for people at risk of hypertension.
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Presión Sanguínea/fisiología , Coix , Dieta/métodos , Hipertensión/dietoterapia , Granos Enteros , Adulto , Animales , Modelos Animales de Enfermedad , Ingestión de Alimentos/fisiología , Femenino , Humanos , Hipertensión/etiología , Masculino , Fenómenos Fisiológicos de la Nutrición , Obesidad/complicaciones , Obesidad/dietoterapia , Obesidad/fisiopatología , Sobrepeso/complicaciones , Sobrepeso/dietoterapia , Sobrepeso/fisiopatología , Ratas , Ratas Endogámicas SHRRESUMEN
BACKGROUND: People living with multiple sclerosis (MS) experience impairments in gait and mobility, that are not fully captured with manually timed walking tests or rating scales administered during periodic clinical visits. We have developed a smartphone-based assessment of ambulation performance, the 5 U-Turn Test (5UTT), a quantitative self-administered test of U-turn ability while walking, for people with MS (PwMS). RESEARCH QUESTION: What is the test-retest reliability and concurrent validity of U-turn speed, an unsupervised self-assessment of gait and balance impairment, measured using a body-worn smartphone during the 5UTT? METHODS: 76 PwMS and 25 healthy controls (HCs) participated in a cross-sectional non-randomised interventional feasibility study. The 5UTT was self-administered daily and the median U-turn speed, measured during a 14-day session, was compared against existing validated in-clinic measures of MS-related disability. RESULTS: U-turn speed, measured during a 14-day session from the 5UTT, demonstrated good-to-excellent test-retest reliability in PwMS alone and combined with HCs (intraclass correlation coefficient [ICC]â¯=â¯0.87 [95 % CI: 0.80-0.92]) and moderate-to-excellent reliability in HCs alone (ICCâ¯=â¯0.88 [95 % CI: 0.69-0.96]). U-turn speed was significantly correlated with in-clinic measures of walking speed, physical fatigue, ambulation impairment, overall MS-related disability and patients' self-perception of quality of life, at baseline, Week 12 and Week 24. The minimal detectable change of the U-turn speed from the 5UTT was low (19.42 %) in PwMS and indicates a good precision of this measurement tool when compared with conventional in-clinic measures of walking performance. SIGNIFICANCE: The frequent self-assessment of turn speed, as an outcome measure from a smartphone-based U-turn test, may represent an ecologically valid digital solution to remotely and reliably monitor gait and balance impairment in a home environment during MS clinical trials and practice.
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Marcha/fisiología , Esclerosis Múltiple/complicaciones , Calidad de Vida/psicología , Teléfono Inteligente/instrumentación , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Masculino , Esclerosis Múltiple/terapia , Evaluación de Resultado en la Atención de Salud , Equilibrio Postural , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: We aimed to develop a Human Activity Recognition (HAR) model using a wrist-worn device to assess patient activity in relation to negative symptoms of schizophrenia. METHODS: Data were analyzed in a randomized, three-way cross-over, proof-of-mechanism study (ClinicalTrials.gov: NCT02824055) comparing two doses of RG7203 with placebo, given as adjunct to stable antipsychotic treatment in patients with chronic schizophrenia and moderate levels of negative symptoms. Baseline negative symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS). Patients were given a GeneActiv™ wrist-worn actigraphy device to wear over a 15-week period. For this analysis, actigraphy data and behavioral and clinical assessments obtained during placebo treatment were used. Motivated behavior was evaluated with a computerized effort-choice task. A trained HAR model was used to classify activity and an activity-time ratio was derived. Gesture events and features were inferred from the HAR-detected activities and the acceleration signal. RESULTS: Thirty-three patients were enrolled: mean (±SD) age 36.6 ± 7 years; mean (±SD) baseline PANSS negative symptom factor score 23.0 ± 3.5; and mean (±SD) baseline BNSS total score 36.0 ± 11.5. Activity data were collected for 31 patients with a median monitoring time of 1,859 h per patient, equating to ~11 weeks or 74% monitoring ratio. The trained HAR model demonstrated >95% accuracy in separating ambulatory and stationary activities. A positive correlation was seen between the activity-time ratio and the percent of high-effort choices (Spearman r = 0.58; P = 0.002) in the effort-choice task. Median daily gesture counts correlated negatively with the BNSS total score (Spearman r = -0.44; P = 0.03), specifically with the diminished expression sub-score (Spearman r = -0.42; P = 0.03). Gesture features also correlated negatively with the BNSS total score and diminished expression sub-scores. Activity measures showed similar correlations with PANSS negative symptom factor but did not reach significance. CONCLUSION: Our findings support the use of wrist-worn devices to derive activity and gesture-based digital outcome measures for patients with schizophrenia with negative symptoms in a clinical trial setting.
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Consumption of a high-fat diet increases fat accumulation and may further lead to inflammation and hepatic injuries. The aim of the study was to investigate the effects of Camellia oleifera seed extract (CSE) on non-alcoholic fatty liver disease (NAFLD). After a 16-week NAFLD-inducing period, rats were assigned to experimental groups fed an NAFLD diet with or without CSE. At the end of the study, we found that consuming CSE decreased the abdominal fat weight and hepatic fat accumulation and modulated circulating adipokine levels. We also found that CSE groups had lower hepatic cytochrome P450 2E1 and transforming growth factor (TGF)-ß protein expressions. In addition, we found that CSE consumption may have affected the gut microbiota and reduced toll-like receptor (TLR)-4, myeloid differentiation primary response gene 88, toll/IL-1 receptor domain-containing adaptor-inducing interferon-ß (TRIF) expression and proinflammatory cytokine concentrations in the liver. Our results suggest that CSE may alleviate the progression of NAFLD in rats with diet-induced steatosis through reducing fat accumulation and improving lipid metabolism and hepatic inflammation.
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Camellia , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inflamación , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , RatasRESUMEN
Overweight and obesity are associated with many chronic diseases. This study aimed to clarify the possible effects of consuming golden kiwifruit as daily fruit intake on body composition, lipid metabolism and inflammatory responses. METHODS: We recruited twenty-two overweight and obese subjects and they were asked to consume two golden kiwifruit every day during the 6-wk experimental period. At the baseline and end of the study, fasting blood samples were collected and anthropometric and blood pressure measurement were conducted. RESULTS: During the experimental period, no adverse effect and dropout were reported. At the end of the study, a significant decrease in body fat and circulatory tumor necrosis factor (TNF)-α concentration were found. In addition, there was a reduction of angiotensin II (AgII) concentration and systolic blood pressure in subjects with baseline systolic blood pressure (SBP) ≥125 mmHg. CONCLUSION: Our results suggested that daily golden kiwifruit intake can reduce body fat mass, improve blood pressure and regulating inflammatory responses in overweight and obese young adults.
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Actinidia , Frutas , Composición Corporal , Humanos , Obesidad , Sobrepeso , Adulto JovenRESUMEN
Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis. Our analyses revealed that LSD1 bound to the NOTCH1 locus, thereby suppressing NOTCH1 expression and downstream signaling. Reactivation of NOTCH signaling with the LSD1 inhibitor reduced the expression of ASCL1 and neuroendocrine cell lineage genes. Knockdown studies confirmed the pharmacological inhibitor-based results. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlated with the extent of consequential NOTCH pathway activation and repression of a neuroendocrine phenotype. Complete and durable tumor regression occurred with ORY-1001-induced NOTCH activation in a chemoresistant PDX model. Our findings reveal how LSD1 inhibitors function in this tumor and support their potential as a new and targeted therapy for SCLC.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Histona Demetilasas/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Receptores Notch/genética , Transducción de Señal/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genéticaRESUMEN
OBJECTIVE: To compare the clinical results between the Wiltse approach and traditional approach in lumbar fusion. METHODS: The clinical data of 70 patients with lumbar disc herniation or lumbar spondylolisthesis within Meyerding II degree who underwent lumbar fusion surgery from May 2016 to May 2017 were retrospectively analyzed. According to the surgical approach, the patients were divided into Wiltse approach group and traditional approach group. A total of 35 patients in Wiltse approach group, included 18 males and 17 females, with an average age of (52±11) years old;other 35 patients in traditional approach group, included 19 males and 16 females, with an average age of (51±14) years old. Included 38 patients with lumbar disc herniation and 32 patients with spondylolisthesis of Meyerding II degree. The operation time, intraoperative blood loss and postoperative drainage, the VAS score of low back pain and leg pain, the level of creatine phosphokinase (CK) and the cross-sectional area of multifidus muscl on MRI were recorded. RESULTS: The operation time, intraoperative blood loss and postoperative drainage in Wiltse approach group were less than in traditional approach group(P<0.05). There were significant differences in VAS score of low back pain at 7 days and 3 months after operation between two groups(P<0.05). VAS of back pain at both 7 days and 3 months showed better results (P<0.05); VAS of leg pain showed better results in 3 months but had no significant difference in 7 days. There was no significant difference in VAS score of leg pain at 7 days after operation between two groups(P>0.05), but at 3 months had significant difference(P<0.05). The peripheral blood CK levels at 1 day and 3 days after operation respectively were(400±103)U/L and (176±58)U/L in Wiltse approach group, while in traditional approach group were (598±57) U/L and (222±50) U/L, with statistical significance between the two groups(P<0.05). Preoperative cross-sectional area of multifidus muscl on MRI was (424±66) mm² in Wiltse approach group and (428±82) mm² in traditional approach group, there was no significant difference between two groups(P=0.8); at 3 months after operation, in Wiltse approach group was (347±73) mm² and in traditional approach group was(239±78)mm², there was significant difference between two groups(P<0.05). CONCLUSIONS: For lumbar spinal fusion surgery, compared with the traditional approach, Wiltse approach has advantages of shorter operation time, smaller paravertebral muscles injury, and obviously releasing postoperative low back and leg pain. However, in determining the surgery program, the surgical operater also should fully recognize that the anatomical differences of Wiltse approach may influence on operation.