RESUMEN
BACKGROUND: Perioperative management to maintain intraoperative haemodynamic stability is crucial during surgical treatment of pheochromocytomas and paragangliomas (PPGLs). Although approximately 70% of PPGLs carry pathogenic variants (PVs) in susceptibility genes, whether intraoperative haemodynamic instability (IHI) is associated with genetic background remains unclear. This study aimed to analyse IHI in patients with PPGL due to PVs in different genes. MATERIALS AND METHODS: This retrospective study recruited 756 patients with abdominal PPGL from two tertiary care centres. Clinical information including sex, age, catecholamine-associated signs and symptoms (CAS), tumour location and size, biochemistry, and perioperative characteristics were collected. Genetic mutations were investigated using next-generation sequencing. RESULTS: Among the 671 patients included in the analysis, 61.8% (415/671) had IHI. IHI was significantly associated with genetic background in patients with PPGL. Most (80.9%, 89/110) patients with PPGL due to PVs in HRAS suffered IHI. In contrast, only half (31/62) of patients with PPGL due to PVs in VHL had IHI. In the multivariate regression analysis, compared to those with negative genetic testing results, patients with PPGL due to PVs in HRAS (OR 3.82, 95% CI 2.187-6.679, P<0.001), the other cluster 2 genes (OR 1.95, 95% CI 1.287-2. 569, P< 0.05), and cluster 1 genes other than VHL (OR 2.35, 95% CI 1.338-4.111, P<0.05) were independent risk factors for IHI, while PVs in VHL was not independent risk factor (OR 1.09, 95% CI 0.605-1.953, P>=0.05). In addition, age at diagnosis of primary tumour, presenting of CAS, and tumour size were identified as independent factors for IHI. The nomogram illustrated that genetic background as sharing the largest contribution to IHI, followed by tumour size, age, and presenting of CAS. CONCLUSION: IHI is associated with the genetic background in patients with PPGL. The perioperative management of patients with PPGL can be personalized according to their genetic backgrounds, tumour size, age, and presenting of CAS.
RESUMEN
BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields. METHODS: This trial compared two aspects of radiation treatment, total dose and field, using a two-by-two factorial design. The high-dose (HD) group received 59.4 Gy radiation, and the standard-dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field. RESULTS: The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80-1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82-1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72-1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons. CONCLUSIONS: IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.
RESUMEN
Cancer, caused by uncontrolled proliferation of abnormal cells, has long been a global public health issue. For decades, natural products have been proven to be an essential source for novel anticancer drug discovery. But their instability, low solubility and bioavailability, poor targeting impede therapeutic efficacy. With the development of nanotechnology, nanomedicine delivery systems have emerged as promising strategies to improve bioavailability and enhance the therapeutic efficacy of drugs. However, constructing suitable nanocarrier is still a major challenge. Polysaccharides are extensively employed as carrier materials in nanomedicine delivery systems, owing to their unique physicochemical properties, biocompatibility and low immunogenicity. Polysaccharide-based nanomedicine delivery systems show high drug delivery efficiency, controlled drug release, and precise tumor targeting. This paper reviews influencing factors in the construction of polysaccharide-based nanocarriers and the application of polysaccharide-based nanocarriers for the delivery of natural products in treating various cancers. It focuses on their in vitro and in vivo anticancer efficacy and mechanisms. Furthermore, the review contrasts the capabilities and limitations of polysaccharide-based nanocarriers with traditional delivery methods, underlining their potential to enable targeted, reduced toxicity and excellent cancer treatment modalities. Finally, we discuss the current research limitations and future prospects in this emerging field.
RESUMEN
To develop machine learning models based on preoperative dynamic enhanced magnetic resonance imaging (DCE-MRI) radiomics and to explore their potential prognostic value in the differential diagnosis of human epidermal growth factor receptor 2 (HER2)-low from HER2-positive breast cancer (BC). A total of 233 patients with pathologically confirmed invasive breast cancer admitted to our hospital between January 2018 and December 2022 were included in this retrospective analysis. Of these, 103 cases were diagnosed as HER2-positive and 130 cases were HER2 low-expression BC. The Synthetic Minority Oversampling Technique is employed to address the class imbalance problem. Patients were randomly split into a training set (163 cases) and a validation set (70 cases) in a 7:3 ratio. Radiomics features from DCE-MRI second-phase imaging were extracted. Z-score normalization was used to standardize the radiomics features, and Pearson's correlation coefficient and recursive feature elimination were used to explore the significant features. Prediction models were constructed using 6 machine learning algorithms: logistic regression, random forest, support vector machine, AdaBoost, decision tree, and auto-encoder. Receiver operating characteristic curves were constructed, and predictive models were evaluated according to the area under the curve (AUC), accuracy, sensitivity, and specificity. In the training set, the AUC, accuracy, sensitivity, and specificity of all models were 1.000. However, in the validation set, the auto-encoder model's AUC, accuracy, sensitivity, and specificity were 0.994, 0.976, 0.972, and 0.978, respectively. The remaining models' AUC, accuracy, sensitivity, and specificity were 1.000. The DeLong test showed no statistically significant differences between the machine learning models in the training and validation sets (Zâ =â 0, Pâ =â 1). Our study investigated the feasibility of using DCE-MRI-based radiomics features to predict HER2-low BC. Certain radiomics features showed associations with HER2-low BC and may have predictive value. Machine learning prediction models developed using these radiomics features could be beneficial for distinguishing between HER2-low and HER2-positive BC. These noninvasive preoperative models have the potential to assist in clinical decision-making for HER2-low breast cancer, thereby advancing personalized clinical precision.
Asunto(s)
Neoplasias de la Mama , Aprendizaje Automático , Radiómica , Receptor ErbB-2 , Femenino , Humanos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Diagnóstico Diferencial , Imagen por Resonancia Magnética/métodos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análisis , Estudios Retrospectivos , Curva ROC , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Small artery occlusion (SAO) is a common ischemic stroke subtype. However, its clinical outcome can be more severe than commonly understood. The severity of SAO can vary, ranging from mild to moderate. Iron deposition has been associated with the development and progression of stroke. However, its specific distribution and relationship with stroke severity in SAO remain unclear. The study's purpose is to investigate the differences in iron deposition between mild stroke with SAO (SAO-MiS) and moderate stroke with SAO (SAO-MoS) through quantitative susceptibility mapping (QSM) and its association with neurological deficits. METHODS: Sixty-eight SAO participants within 24 hours of first onset were enrolled and separated into SAO-MiS and SAO-MoS according to the National Institutes of Health Stroke Scale (NIHSS) scores. QSM helped calculate the susceptibility maps, reflecting the iron content within the brain. The susceptibility maps were analyzed using voxel-wise statistical analysis to compare the iron deposition between SAO-MiS and SAO-MoS. Then, differentially distributed iron deposition helped differentiate between mild and moderate stroke using support vector machine (SVM) methods. RESULTS: Compared with SAO-MiS, SAO-MoS depicted elevated iron deposition in the left pallidum, parahippocampal gyrus, and superior frontal gyrus medial region, and is lower in the right superior/middle frontal gyrus and bilateral supplementary motor area. Based on iron deposition, the SVM classifier's analysis revealed a high power to discriminate SAO-MoS from SAO-MiS. In addition, fibrinogen, triglyceride (TG), and total cholesterol (TC) were linked with QSM values in specific brain regions. CONCLUSIONS: Our study first revealed the brain iron distribution after SAO and differently distributed iron deposition in SAO-MiS and SAO-MoS. The results indicate that iron deposition could play a role in the pathophysiology of SAO and its correlation with stroke severity.
Asunto(s)
Hierro , Imagen por Resonancia Magnética , Índice de Severidad de la Enfermedad , Humanos , Masculino , Femenino , Hierro/metabolismo , Persona de Mediana Edad , Anciano , Proyectos Piloto , Máquina de Vectores de Soporte , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/diagnóstico por imagenRESUMEN
The reduction of carbon dioxide to methane using hydrogen is an important process in biogas production. However, designing gas anaerobic digesters (GADs) based on this reaction presents several challenges. In this study, we developed an innovative spiral-pipe gas anaerobic digester (SGAD) to increase the displacement distance between the bubbles, thus prolonging the gas retention time and facilitating the reduction of CO2 to CH4 via H2. The process was successfully demonstrated by using a CO2/H2 ratio of 1:3 and a gas-feeding rate of 3.9 L Lr -1 d-1. During the experiment, more than 98% of the CO2 and 96% of the H2 were consumed, resulting in biogas containing ca. 86-96% CH4. Additionally, we applied our proposed evaluation methodology for assessing GAD performance to evaluate the performance of the SGAD. This methodology serves as a reference for evaluating and designing GAD systems. The innovative design of the SGAD and the corresponding evaluation methodology offer new insights into the design of reactors.
RESUMEN
To explore the value of machine learning (ML) models based on contrast-enhanced cone-beam breast computed tomography (CE-CBBCT) radiomics features for the preoperative prediction of human epidermal growth factor receptor 2 (HER2)-low expression breast cancer (BC). Fifty-six patients with HER2-negative invasive BC who underwent preoperative CE-CBBCT were prospectively analyzed. Patients were randomly divided into training and validation cohorts at approximately 7:3. A total of 1046 quantitative radiomic features were extracted from CE-CBBCT images and normalized using z-scores. The Pearson correlation coefficient and recursive feature elimination were used to identify the optimal features. Six ML models were constructed based on the selected features: linear discriminant analysis (LDA), random forest (RF), support vector machine (SVM), logistic regression (LR), AdaBoost (AB), and decision tree (DT). To evaluate the performance of these models, receiver operating characteristic curves and area under the curve (AUC) were used. Seven features were selected as the optimal features for constructing the ML models. In the training cohort, the AUC values for SVM, LDA, RF, LR, AB, and DT were 0.984, 0.981, 1.000, 0.970, 1.000, and 1.000, respectively. In the validation cohort, the AUC values for the SVM, LDA, RF, LR, AB, and DT were 0.859, 0.880, 0.781, 0.880, 0.750, and 0.713, respectively. Among all ML models, the LDA and LR models demonstrated the best performance. The DeLong test showed that there were no significant differences among the receiver operating characteristic curves in all ML models in the training cohort (Pâ >â .05); however, in the validation cohort, the DeLong test showed that the differences between the AUCs of LDA and RF, AB, and DT were statistically significant (Pâ =â .037, .003, .046). The AUCs of LR and RF, AB, and DT were statistically significant (Pâ =â .023, .005, .030). Nevertheless, no statistically significant differences were observed when compared to the other ML models. ML models based on CE-CBBCT radiomics features achieved excellent performance in the preoperative prediction of HER2-low BC and could potentially serve as an effective tool to assist in precise and personalized targeted therapy.
Asunto(s)
Neoplasias de la Mama , Aprendizaje Automático , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/diagnóstico por imagen , Estudios Prospectivos , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Adulto , Tomografía Computarizada de Haz Cónico/métodos , Medios de Contraste , Curva ROC , Anciano , Máquina de Vectores de Soporte , Área Bajo la Curva , RadiómicaRESUMEN
OBJECTIVE: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. DESIGN, PATIENTS AND MEASUREMENTS: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. RESULTS: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p < .001), had larger tumours (2.9 vs. 1.8 cm, p < .001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p < .001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p = .003), hypertension (50.0% vs. 31.7%, p = .041) and catecholamine-related symptoms (37.9% vs. 17.5%, p = .012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p = .013), micturition spells (OR = 6.79, p = .007), hypertension (OR = 3.98, p = .011), and sweating (OR = 41.72, p = .013) increased the probability of initiating presurgical biochemical testing. CONCLUSIONS: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis.
Asunto(s)
Paraganglioma , Neoplasias de la Vejiga Urinaria , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/diagnóstico , Femenino , Masculino , Adulto , Paraganglioma/diagnóstico , Paraganglioma/cirugía , Europa (Continente) , Estados Unidos , Anciano , ChinaRESUMEN
Xinnaotongluo liquid has been used to improve the clinical symptoms of patients with myocardial infarction. However, the molecular mechanism of Xinnaotongluo liquid is not completely understood. H9c2 cells exposed to hypoxia/reoxygenation (H/R) was used to simulate damage to cardiomyocytes in myocardial infarction in vitro. The biological indicators of H9c2 cells were measured by cell counting kit-8, enzyme linked immunoabsorbent assay, and western blot assay. In H/R-induced H9c2 cells, a markedly reduced murine double minute 2 (MDM2) was observed. However, the addition of Xinnaotongluo liquid increased MDM2 expression in H/R-induced H9c2 cells. And MDM2 overexpression strengthened the beneficial effects of Xinnaotongluo liquid on H9c2 cells from the perspective of alleviating oxidative damage, cellular inflammation, apoptosis and ferroptosis of H/R-induced H9c2 cells. Moreover, MDM2 overexpression reduced the protein expression of p53 and Six-Transmembrane Epithelial Antigen of Prostate 3 (STEAP3). Whereas, STEAP3 overexpression hindered the function of MDM2-overexpression in H/R-induced H9c2 cells. Our results insinuated that Xinnaotongluo liquid could protect H9c2 cells from H/R-induced damage by regulating MDM2/STEAP3, which provide a potential theoretical basis for further explaining the working mechanism of Xinnaotongluo liquid.
Asunto(s)
Medicamentos Herbarios Chinos , Hipoxia , Infarto del Miocardio , Animales , Masculino , Apoptosis/efectos de los fármacos , Hipoxia de la Célula , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Ratas , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
PURPOSE: Adrenal and extra-adrenal paragangliomas (PGLs) are a group of neuroendocrine tumors (NETs) with strong heterogeneity, which often express somatostatin receptor subtype 2 A (SSTR2A). However, the association between SSTR2A expression and genetic status of PGLs remains unclear. The purpose of the study was to identify whether various pathogenic variants (PVs) had an impact on SSTR2A expression in PGLs. METHODS: This retrospective study included 184 patients with pathologically confirmed PGLs. The immunohistochemical expression of SSTR2A were studied in 184 tumors and PVs were tested in 159 tumor samples. Clinical and genetic data were compared in SSTR2A positive and negative PGLs. RESULTS: SSTR2A was positive in 63.6% (117/184) of all tumors. PGLs with negative SSTR2A were more likely to be extra-adrenal (37.0% vs 18.0%; P = 0.005) and exhibited a considerably greater proportion of PVs (75.4% vs. 49.0%; P = 0.001) than those with positive SSTR2A. Compared to those without PVs, a higher proportion of PGLs with PVs in cluster 1B (P = 0.004) and cluster 2 (P = 0.004) genes, especially VHL (P = 0.009), FGFR1 (P = 0.010) and HRAS (P = 0.007), were SSTR2A negative. SSTR2A was positive in all tumors (4/4) with SDHx PVs and in 87.5% (7/8) of metastatic PGLs. CONCLUSIONS: SSTR2A negativity was correlated with extra-adrenal tumor location and PVs in cluster 1B and cluster 2 genes such as VHL, FGFR1 and HRAS. Immunohistochemistry of SSTR2A should be taken into consideration in the personalized management of PGLs.
Asunto(s)
Paraganglioma , Receptores de Somatostatina , Humanos , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Paraganglioma/genética , Paraganglioma/patología , Paraganglioma/metabolismo , Anciano , Adulto Joven , Adolescente , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/metabolismoRESUMEN
Disulfidoptosis, a novel form of cell death, is distinct from other well-known cell death mechanisms. Consequently, a profound investigation into disulfidoptosis elucidates the fundamental mechanisms underlying tumorigenesis, presenting promising avenues for therapeutic intervention. Comprehensive analysis of disulfidoptosis-associated gene (DRG) expression in pan cancer utilized TCGA, GEO, and ICGC datasets, including survival and Cox-regression analyses for prognostic evaluation. We analyzed the association between DRG expression and both immune cell infiltration and immune-related gene expression using the ESTIMATE and TISDIB datasets. We obtained our single-cell RNA sequencing (scRNA-seq) data from the GEO repository. Subsequently, we assessed disulfidoptosis activity in various cell types. Evaluation of immune cell infiltration and biological functions was analyzed via single-sample gene set enrichment (ssGSEA) and gene set variation analysis (GSVA). For in vitro validation experiments, the results from real-time PCR (RT-qPCR) and Western blot were used to explore the expression of SLC7A11 in hepatocellular carcinoma (HCC) tissues and different cancer cell lines, while siRNA-mediated SLC7A11 knockdown effects on HCC cell proliferation and migration were examined. Expression levels of DRGs, especially SLC7A11, were significantly elevated in tumor samples compared to normal samples, which was associated with poorer outcomes. Except for SLC7A11, DRGs consistently exhibited high CNV and SNV rates, particularly in HCC. In various tumors, DRGs were negatively associated with DNA promoter methylation. TME analyses further illustrated a negative correlation of DRG expression with ImmuneScore and StromalScore and a positive correlation with tumor purity. Our analysis unveiled diverse cellular subgroups within HCC, particularly focusing on Treg cell populations, providing insights into the intricate interplay of immune activation and suppression within the tumor microenvironment (TME). These findings were further validated through RT-qPCR, Western blot analyses, and immunohistochemical analyses. Additionally, the knockdown of SLC7A11 induced a suppression of proliferation and migration in HCC cell lines. In conclusion, our comprehensive pan-cancer analysis research has demonstrated the significant prognostic and immunological role of disulfidoptosis across a spectrum of tumors, notably HCC, and identified SLC7A11 as a promising therapeutic target.
RESUMEN
PURPOSE: Neoadjuvant chemoradiotherapy is the recommended treatment for patients with resectable esophageal cancer but is associated with a higher incidence of adverse effects. Given the efficacy of immunotherapy, we propose a chemotherapy-free regimen of neoadjuvant radio-immunotherapy (NRIT) to balance therapeutic efficacy and potential side effects or overtreatment. METHODS AND MATERIALS: In this phase 1b clinical trial, we assessed the safety and efficacy of NRIT in esophageal squamous cell cancer. The enrolled patients received 41.4 Gy of radiation and 4 cycles of 240 mg of toripalimab injection before surgery. The primary endpoint was treatment-related adverse events and the secondary endpoints were pathologic complete response and major pathologic response. Immunohistochemistry and multiplex immunofluorescence staining were used to evaluate the tumor microenvironment before and after neoadjuvant treatment. RESULTS: Of the 22 patients enrolled, 19 underwent R0 surgery. One patient discontinued neoadjuvant immune therapy due to experiencing a grade 3 treatment-related adverse event. Three patients did not undergo surgery due to tumor progression or side effects. Among the patients who underwent surgery, 3 patients experienced serious complications shortly after surgery. Upon pathologic evaluation, the pathologic complete response and major pathologic response rates were 47.4% and 68.4%, respectively. CONCLUSIONS: The NRIT regimen is safe and feasible for patients with esophageal squamous cell cancer.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Terapia Neoadyuvante , Humanos , Terapia Neoadyuvante/efectos adversos , Masculino , Persona de Mediana Edad , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Femenino , Anciano , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/patología , Inmunoterapia/efectos adversos , Microambiente Tumoral , Adulto , Resultado del Tratamiento , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
Social isolation has emerged as a significant issue during the COVID-19 pandemic that can adversely impact human mental health and potentially lead to pathological aggression. Given the lack of effective therapeutic interventions for aggressive behavior, alternative approaches are necessary. In this study, we utilized a genetic method combined with a pharmacological approach to identify and demonstrate the crucial role of Cdk5 in escalated intermale attack behavior induced by 2-week social isolation. Moreover, we developed a small peptide that effectively disrupts the interaction between Cdk5 and GluN2B, given the known involvement of this complex in various neuropsychiatric disorders. Administration of the peptide, either systemically or via intrahippocampal injection, significantly reduced oxidative stress in the hippocampus and attenuated intermale attack behavior induced by 2-week social isolation. These findings highlight the previously unknown role of the hippocampal Cdk5-GluN2B complex in social isolation-induced aggressive behavior in mice and propose the peptide as a promising therapeutic strategy for regulating attack behavior and oxidative stress.
Asunto(s)
Hipocampo , Pandemias , Ratones , Animales , Humanos , Aislamiento Social , Agresión/fisiología , Péptidos/farmacologíaRESUMEN
The safety of an open kitchen is a controversial topic in China. In this study, natural gas leakage and ventilation processes under an open kitchen layout and closed kitchen layout are simulated by CFD. The evolution of a hazardous gas cloud and the triggering behaviors of alarms are analyzed and discussed. For closing all windows in the leakage process, the state of the partition door is a major factor. A closed kitchen layout with a closing partition door performs best in confining a hazardous gas cloud. At this point, it is difficult for a hazardous gas cloud to appear in the living area. With the partition door open, the gas cloud develops rapidly. For opening windows in the leakage process, a large scale hazardous gas cloud is not able to form under all layouts. For alarm-triggering behaviors, a closed kitchen layout when closing the partition door also performs best. When opening the partition door, alarms cannot trigger stably under all layouts. For the ventilation process, hazardous gas cloud dissipation under an open kitchen layout is slightly faster than the closed kitchen layout. Under a weak convection effect, there is a transition stage which delays the time point for exhausting leaked gas. Based on the analysis, some recommendations for accident prevention are proposed. Residents should try to use closed kitchens and close partition doors when not cooking. If open kitchens are used, multiple alarms with lower trigger values should be installed. It is better to choose a ceiling type for gas alarms. The windows of the house are recommended to select two layers type. Higher layers can open during the ventilation process to accelerate the exhaust of leaked gas. These recommendations provide a reference for preventing fires and explosions.
RESUMEN
Circular RNAs (circRNAs) have been found to be abnormally expressed in many cancers, including colorectal cancer (CRC). Circ_0053277 has been found to mediate CRC malignant processes and may be a key regulator for CRC progression. Therefore, its role and potential molecular mechanism in CRC process deserve further investigation. Quantitative real-time PCR was used to detect the expression levels of circ_0053277, microRNA-520 h (miR-520 h) and hexokinase 1 (HK1). Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, wound healing assay, transwell assay, and tube formation assay were used to detect CRC cell proliferation, apoptosis, migration, invasion, and angiogenesis. The protein levels of apoptosis-related markers and HK1 were detected by western blot. The relationship between circ_0053277 and miR-520 h or miR-520 h and HK1 in CRC cells was verified by dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. Cell glycolysis was assessed by detecting glucose uptake and lactate production. The effect of silenced circ_0053277 on CRC tumor growth was evaluated by xenograft model in vivo. Our study found that circ_0053277 expression was elevated in CRC tissues and cells. Moreover, circ_0053277 knockdown suppressed CRC cell proliferation, angiogenesis, migration and invasion, while promoting apoptosis. In terms of mechanism, circ_0053277 sponged miR-520 h, and HK1 was the target of miR-520 h. Meanwhile, miR-520 h inhibitor reversed the inhibitory effect of circ_0053277 silencing on CRC cell progression, and HK1 overexpression also overturned the suppressive effect of miR-520 h on CRC cell growth, angiogenesis and metastasis. Moreover, circ_0053277 knockdown inhibited the glycolysis of CRC cells by regulating miR-520 h/HK1 pathway. In addition, knockdown of circ_0053277 reduced CRC tumor growth in vivo. Circ_0053277 promoted CRC cell growth, angiogenesis, metastasis and glycolysis by miR-520 h/HK1 pathway, confirming that circ_0053277 might be a potential clinical target for CRC treatment.
RESUMEN
The biochemical phenotype of paragangliomas (PGLs) is highly dependent on the underlying genetic background and tumor location. PGLs at extra-adrenal locations usually do not express phenylethanolamine N-methyltransferase (PNMT), the enzyme required for epinephrine production, which was explained by the absence of glucocorticoids. PGLs with pathogenic variants (PVs) in Harvey rat sarcoma viral oncogene homolog (HRAS) can occur in or outside of the adrenal, but always synthesize epinephrine independently of the localization. Here, we characterize the signaling pathways through which PVs in HRAS influence PNMT expression. Catecholamines, cortisol, and transcriptional features of PGL tissues with known genetic background were analyzed. Genetically modified rat pheochromocytoma cells carrying PVs in Hras were generated and analyzed for regulation of Pnmt expression. Elevated epinephrine contents in PGLs with PVs in HRAS were accompanied by enrichment in mitogen-activated protein kinase (MAPK) signaling compared to PGLs with PVs in genes that activate hypoxia pathways. In vitro, Hras PVs increased Pnmt expression and epinephrine biosynthesis through increased phosphorylation of stimulatory protein 1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine production of PGLs.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/genética , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias de las Glándulas Suprarrenales/genética , Paraganglioma/genética , EpinefrinaRESUMEN
BACKGROUND: The hepatopancreas of crustaceans serves as a significant organ for both the synthesis and secretion of digestive enzymes, as well as energy storage. In the event of food shortage, the hepatopancreas can provide energy for survival. To investigate the potential regulatory mechanisms of the hepatopancreas in response to starvation in Eriocheir Sinensis, transcriptome analysis, histological study and qRT-PCR were performed. RESULTS: The results showed that starvation caused a decrease in the hepatopancreas index of E. sinensis, which had certain effects on the tissue structure, metabolism and angiogenesis in the hepatopancreas. In addition, WGCNA and linear regression analysis showed that the genes significantly related to the hepatopancreas index were mainly enriched in the angiogenesis pathway, in which AKT signaling played an important role. Starvation may inhibit AKT signaling pathway by reducing the expression of TGFBI, HSP27, HHEX, and EsPVF1, thereby hindering angiogenesis, promoting apoptosis, and leading to hepatopancreas atrophy. CONCLUSION: These results indicate that AKT plays an important role in the angiogenesis pathway and apoptosis of the starvation induced hepatopancreas index reduction, which is beneficial to further understand the effect of starvation stress on hepatopancreas of Chinese mitten crab.
Asunto(s)
Braquiuros , Hepatopáncreas , Animales , Hepatopáncreas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Perfilación de la Expresión Génica , Braquiuros/genéticaRESUMEN
The blending of hydrogen in natural gas may have effects on the safety of its usage in a domestic house. In this work, the leakage accident of hydrogen-blended natural gas (HBNG) in the kitchen of a domestic house is analyzed by CFD with a hydrogen blending ratio (HBR) ≤ 30%. The whole process is divided into the gas accumulation process and the ventilation process. In the initial leakage stage, the influence of heights and the HBR on the gas distribution is analyzed. HBNG concentration increases with increasing height. Based on the exit Froude number, the formation of a gas cloud in the kitchen is significantly influenced by the initial momentum and buoyancy, while it is more driven by the concentration gradient beyond the kitchen. In contrast to height, the variation of HBR on the HBNG distribution is not significant. In the ventilation process, the evolution of the hazardous gas cloud volume is analyzed. With windows and doors closed, the hazardous gas cloud fills the house in approximately 3600 s after the leakage occurs. When windows and doors are open for ventilation, the volume of the hazardous gas cloud first declines rapidly and then slowly. The reasons for the variation rate of hazardous gas cloud volume are analyzed according to ventilation conditions. The difference during the decline stage for different HBRs is analyzed according to the gas layering properties. Under a lack of convection condition, the ventilation process finally reaches a stagnant stage. In addition, another ventilation process has been investigated after extending the gas accumulation time. After extending the gas accumulation time, the effect of different HBRs on the ventilation process remains the same as before. However, it postpones the time point to enter the stagnation stage. As gas accumulation time extends from 3600 to 5400 and 7200 s, the ventilation time into the stagnation stage increases from about 4800 to 5400 and 6000 s, respectively. This study has implications for the establishment of a risk assessment system based on hazardous gas cloud volume.
RESUMEN
BACKGROUND: The treatment of non-small cell lung cancer (NSCLC) is challenging due to immune tolerance and evasion. Salidroside (SAL) is an extract in traditional Chinese medicine and has a potential antitumor effect. However, the mechanism of SAL in regulating the immunological microenvironment of NSCLC is yet to be clarified. METHODS: The mouse model with Lewis lung cancer cell line (3LL) in C57BL/6 mice was established. And then, the percentage of tumor-infiltrating T cell subsets including Treg was detected in tumor-bearing mice with or without SAL treatment. In vitro, the effect of SAL on the expression of IL-10, Foxp3 and Stub1 and the function of Treg were detected by flow cytometry. Network pharmacology prediction and molecular docking software were used to predict the target of SAL and intermolecular interaction. Furthermore, the effect of SAL on the expression of Hsp70 and the co-localization of Stub1-Foxp3 in Treg was confirmed by flow cytometry and confocal laser microscopy. Finally, Hsp70 inhibitor was used to verify the above molecular expression. RESULTS: We discovered that SAL treatment inhibits the growth of tumor cells by decreasing the percentage of tumor-infiltrated CD4+Foxp3+T cells. SAL treatment downregulates the expression of Foxp3 in Tregs, but increases the expression of Stub1, an E3 ubiquitination ligase upstream of Foxp3, and the expression of Hsp70. Inhibiting the expression of Hsp70 reverses the inhibition of SAL on Foxp3 and disrupts the colocalization of Stub1 and Foxp3 in the nucleus of Tregs. CONCLUSIONS: SAL inhibits tumor growth by regulating the Hsp70/stub1/Foxp3 pathway in Treg to suppress the function of Treg. It is a new mechanism of SAL for antitumor therapy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Linfocitos T Reguladores , Microambiente Tumoral , Simulación del Acoplamiento Molecular , Neoplasias Pulmonares/metabolismo , Ratones Endogámicos C57BL , Ubiquitina-Proteína Ligasas/metabolismo , Factores de Transcripción Forkhead/metabolismoRESUMEN
Pheochromocytoma/paraganglioma (PPGL) is an endocrine-related tumor associated with excessive catecholamine release and has limited treatment options once metastasis occurs. Although recent phase 2 clinical trials of immune checkpoint inhibitors in the treatment of PPGL have preliminarily shown promising results, the fundamentals of immunotherapy for PPGL have not yet been established. In the early research, using bulk RNA sequencing of tumor samples from 7 PPGL patients, we found that PPGL tumor tissues exhibited high PD-L1 mRNA expression compared with adjacent normal adrenal medulla tissues, and this was related to T-cell exhaustion biomarkers. To further validate the association, in this study (n = 60), we first stratified all PPGL samples according to PD-L1 expression as determined by immunohistochemical staining, and then subjected 23 fresh PPGL tumor samples from the cohort to a quantitative polymerase chain reaction (n = 16), flow cytometry (n = 7), and multiplex-immunofluorescence staining. Subsequently, we evaluated the pathological manifestations of all 60 PPGL tumor samples and analyzed the correlation among PD-L1 expression, adverse pathological behavior, various clinicopathological data, and genotypes in PPGL. The results showed that PD-L1-positive expression correlated with the exhaustion of tumor-infiltrating T cells, preoperative abnormal elevation of plasma norepinephrine, high Ki67 index, and adverse pathological behavior in PPGL but not with genetic mutation or metastatic disease, possibly due to the limitation of the small number of patients with metastatic disease (n = 4) in the study cohort. In conclusion, our findings reveal that PD-L1 expression is associated with T-cell exhaustion and adverse pathological behavior in PPGL. These results are expected to provide a new theoretical basis and clinical guidance for the treatment of PPGL.