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The importance of supraclavicular lymph node (SCLN) metastasis in cervical and upper thoracic esophageal squamous cell carcinoma (ESCC) has not been determined. The aim of the present study was to provide a detailed definition of the range of SCLN regions and to explore whether SCLNs should be considered as a regional lymph nodes for patients with cervical and upper thoracic ESCC. A retrospective analysis was performed on 230 patients with locally advanced cervical or upper thoracic ESCC who underwent radical radiotherapy and chemotherapy. The range of SCLN regions was defined in detail on contrast enhanced computed tomography images of the neck. According to whether the patient had lymph node metastasis in the supraclavicular region, the included patients were divided into two groups, and the survival differences and reasons for treatment failure between the two groups were analyzed. Of the 230 patients with ESCC, 71 (30.87%) exhibited lymph node metastases in the supraclavicular region. The median overall survival time of ESCC patients with and without SCLN metastasis was 17 and 30 months, respectively (P<0.001). After propensity score matching (PSM), the median overall survival time of ESCC patients with and without SCLN metastasis was 17 and 28 months, respectively (P<0.001). During the follow-up period, there were a total of 101 cases of failure of treatment in the irradiation field, 6 cases had esophageal metastasis in the non-irradiated field and 27 cases had regional lymph node metastasis in the non-irradiated field. In addition, there were 33 cases of metastasis to the distant lymph nodes or organs. There was no significant difference in the local treatment failure rate between the groups with or without SCLN metastasis in both the irradiation field and the non-irradiation field, but the probability of distant metastasis in the SCLN metastasis group was significantly higher than that in the group without SCLN metastasis (P=0.025). In conclusion, patients with cervical and upper thoracic ESCC with SCLN metastasis have a poor prognosis and the median overall survival time is closer to that of metastatic ESCC than ESCC with regional lymph node metastasis; therefore, SCLNs should not be defined as regional lymph nodes in patients with cervical and upper thoracic ESCC.
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Background: To investigate the efficacy and safety of rituximab (RTX) with or without glucocorticoid (GC) in inducing remission of minimal change disease (MCD) in adults. Methods: Twenty-one adult MCD patients were included in the study. The patients were assigned to the following three groups according to their background before RTX treatment: an RTX single drug direct induction treatment group (Group A; n = 9), a short-term, low-dose GC combined with RTX induction treatment group (Group B; n = 4), and a short-term, adequate-dose GC-induced remission and RTX maintenance treatment group (Group C; n = 8). The primary endpoints were the time to induction of remission and the rate of clinical remission at 12 months. Results: All patients achieved clinical remission, with 19 (90.48%) achieving complete remission (CR), and the median remission time was 4 (2.5, 12) weeks. Eight (88.89%) patients in Group A achieved CR, and the median remission time was 3 (2.25, 14) weeks. In Group B, three (75.00%) patients achieved CR, with a median remission time of 4 (4, 10) weeks. In Group C, eight (100.00%) patients achieved CR, and the median remission time was 3.5 (2, 4) weeks. Conclusions: In MCD patients without acute kidney injury, adequate RTX alone or short-term combined treatment with low-dose GCs can effectively induce and maintain MCD remission. Adequate short-term GCs combined with RTX maintenance may be an effective alternative for MCD patients in context of acute kidney injury. There is a need to investigate different induction therapy regimens for the remission of MCD patients with different backgrounds.
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The oral delivery of doxorubicin (DOX), an anti-cancer drug, encounters multiple hurdles such as limited gastrointestinal permeability, P-glycoprotein-mediated efflux, brief intestinal residence, and rapid degradation. This study introduced a novel approach utilizing hyaluronic acid (HA)-grafted fatty acid monoglycerides (HGD) to encapsulate DOX, forming HGD-DOX nanoparticles, aimed at enhancing its oral bioavailability. Drug encapsulated by HGD provided several advantages, including extended drug retention in the gastrointestinal tract, controlled release kinetics, and promotion of lymphatic absorption in the intestine. Additionally, HGD-DOX nanoparticles could specifically target CD44 receptors, potentially increasing therapeutic efficacy. The uptake mechanism of HGD-DOX nanoparticles primarily involved clathrin-mediated, caveolin-mediated and macropinocytosis endocytosis. Pharmacokinetic analysis further revealed that HGD significantly prolonged the in vivo residence time of DOX. In vivo imaging and pharmacodynamic studies indicated that HGD possessed tumor-targeting capabilities and exhibited a significant inhibitory effect on tumor growth, while maintaining an acceptable safety profile. Collectively, these findings position HGD-DOX nanoparticles as a promising strategy to boost the oral bioavailability of DOX, offering a potential avenue for improved cancer treatment.
Subject(s)
Doxorubicin , Hyaluronan Receptors , Hyaluronic Acid , Nanoparticles , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Doxorubicin/pharmacology , Hyaluronic Acid/chemistry , Animals , Nanoparticles/chemistry , Hyaluronan Receptors/metabolism , Humans , Administration, Oral , Mice , Drug Carriers/chemistry , Cell Line, Tumor , Drug Delivery Systems , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Previous researches examining the impact of dietary nutrition on mortality risk have mainly focused on individual nutrients, however the interaction of these nutrients has not been considered. The purpose of this study was to identify of nutrient deficiencies patterns and analyze their potential impact on mortality risk in older adults with hypertension. METHODS: We included participants from the National Health and Nutrition Examination Survey (NHANES) study. The latent class analysis (LCA) was applied to uncover specific malnutrition profiles within the sample. Risk of the end points across the phenogroups was compared using Kaplan-Meier analysis and Cox proportional hazard regression model. Multinomial logistic regression was used to determine the influencing factors of specific malnutrition profiles. RESULTS: A total of 6924 participants aged 60 years or older with hypertension from NHANES 2003-2014 was followed until December 31, 2019 with a median follow-up of 8.7 years. Various nutrients included vitamin A, vitamin B1, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, fiber, folate, calcium, magnesium, zinc, copper, iron, and selenium, and LCA revealed 4 classes of malnutrition. Regarding all-cause mortality, "Nutrient Deprived" group showed the strongest hazard ratio (1.42 from 1.19 to 1.70) compared with "Adequate Nutrient" group, followed by "Inadequate Nutrient" group (1.29 from 1.10 to 1.50), and "Low Fiber, Magnesium, and Vit E" group (1.17 from 1.02 to 1.35). For cardiovascular mortality, "Nutrient Deprived" group showed the strongest hazard ratio (1.61 from 1.19 to 2.16) compared with "Adequate Nutrient" group, followed by "Low Fiber, Magnesium, and Vit E" group (1.51 from 1.04 to 2.20), and "Inadequate Nutrient" group (1.37 from 1.03 to 1.83). CONCLUSIONS: The study revealed a significant association between nutrients deficiency patterns and the risk of all-cause and cardiovascular mortality in older adults with hypertension. The findings suggested that nutrients deficiency pattern may be an important risk factor for mortality in older adults with hypertension.
Subject(s)
Cardiovascular Diseases , Hypertension , Latent Class Analysis , Nutrition Surveys , Humans , Female , Male , Aged , Hypertension/mortality , Cardiovascular Diseases/mortality , Middle Aged , Malnutrition/mortality , Malnutrition/epidemiology , Risk Factors , Cause of Death , Aged, 80 and over , Proportional Hazards ModelsABSTRACT
INTRODUCTION: The purpose of this study was to investigate the effects and potential mechanisms of ferroptosis-related gene heat shock protein beta-1 (HSPB1) on acute myeloid leukemia (AML). METHODS: The RNA-seq and clinical data of AML samples were obtained from the Genomic Data Commons database, and the FerrDb database was used to screen the marker, drive and suppressor of ferroptosis. Besides, DESeq2 was applied for differential expression analysis on AML samples and screening for differentially expressed genes (DEGs). The screened DEGs were subjected to the intersection analysis with ferroptosis-related genes to identify the ferroptosis-related DEGs. Next, the functional pathways of ferroptosis-related DEGs were further be discussed by Gene Ontology as well as Kyoto Encyclopedia of Genes and Genomes enrichment analysis of DEGs. Additionally, lasso regression analysis was employed to determine the differential genes related to prognosis in patients with AML and the survival analysis was performed. Subsequently, quantitative real-time polymerase chain reaction and western blot assay were applied to detect the mRNA and protein expression levels of HSPB1 in normal/AML bone marrow tissues and human normal (HS-5)/AML (HL-60) bone marrow cells, respectively. Furthermore, HSPB1 was knocked down to assess the expression changes of glutathione peroxidase 4 and acyl-CoA synthetase long-chain family member 4. Ultimately, the viability and oxidative stress levels of HL-60 were analyzed by Cell Counting Kit-8 and biochemical detection. RESULTS: A total of 4986 DEGs were identified in AML samples, with 3324 up-regulated and 1662 down-regulated. The enrichment analysis illustrated that ferroptosis-related DEGs were significantly enriched in response to metal irons, oxidative stress, and other pathways. After lasso regression analysis, 17 feature genes related to the prognosis of patients with AML were obtained, with HSPB1 exhibiting a significant correlation. The reliability of our models was verified by Cox regression analysis and survival analysis of the hazard model. Furthermore, the outcomes of quantitative real-time polymerase chain reaction and western blot showed that mRNA and protein expression levels of HSPB1 were significantly increased in the AML Group and HL-60 cells. The knockdown of HSPB1 in HL-60 cells reduced the protein level of glutathione peroxidase 4, increased the protein level of acyl-CoA synthetase long-chain family member 4, decreased the cell viability, and aggravated oxidative stress. CONCLUSION: Ferroptosis-related gene HSPB1 is highly expressed in patients with AML. In addition, HSPB1 may be involved in the occurrence and development of AML by regulating oxidative stress and ferroptosis-related pathways. This study provides new clues for further understanding of AML molecular mechanisms. Also, HSPB1 is expected to be a potential therapeutic target for AML in the future.
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Objectives: We conducted an assessment to explore potential associations of the dietary oxidative balance score (DOBS), cardiovascular disease (CVD), with all-cause mortality among older adults, while also exploring the potential moderating effect of DOBS on the relationship between CVD and mortality. Methods: This study included 9059 older adults (≥60 years) from NHANES 2003-2014. Determination of DOBS involves scoring the combination of 16 nutrients, comprising 2 pro-oxidants and 14 anti-oxidants. Cox regression analysis was used to assess the individual associations of CVD and DOBS status with all-cause mortality. Additional evaluations were conducted to assess the combined impact of CVD and DOBS status on mortality, and the interaction were estimated. Sensitivity analyses were performed by excluding participants who died within two years. Results: The findings demonstrated a significant association between pro-oxidant diet (lower DOBS) or CVD and elevated mortality risk among older adults. It is also suggested that older adults with CVD and pro-oxidant diet exhibit the highest risk of all-cause mortality (HR = 1.96, 95% CI: 1.64-2.34), compared to individuals without CVD who follow an antioxidant-rich diet. Further stratified analysis based on CVD status revealed a different pattern in the correlation between pro-oxidant diet and all-cause mortality risk (P for interaction = 0.015). The results of sensitivity analysis were consistent. Conclusions: The lower levels of DOBS and/or CVD were significantly associated with an increased risk of all-cause mortality in older adults. Notably, we also identified a significant interaction between DOBS and CVD affecting all-cause mortality.
Subject(s)
Cardiovascular Diseases , Diet , Nutrition Surveys , Humans , Cardiovascular Diseases/mortality , Aged , Male , Female , Middle Aged , Antioxidants/metabolism , Aged, 80 and over , Oxidative Stress , Risk FactorsABSTRACT
Breast cancer, the most prevalent malignant tumor among women globally, is significantly influenced by the Wnt/ß-catenin signaling pathway, which plays a crucial role in its initiation and progression. While conventional chemotherapy, the standard clinical treatment, suffers from significant drawbacks like severe side effects, high toxicity, and limited prognostic efficacy, Traditional Chinese Medicine (TCM) provides a promising alternative. TCM employs a multi-targeted therapeutic approach, which results in fewer side effects and offers a high potential for effective treatment. This paper presents a detailed analysis of the therapeutic impacts of TCM on various subtypes of breast cancer, focusing on its interaction with the Wnt/ß-catenin signaling pathway. Additionally, it explores the effectiveness of both monomeric and compound forms of TCM in the management of breast cancer. We also discuss the potential of establishing biomarkers for breast cancer treatment based on key proteins within the Wnt/ß-catenin signaling pathway. Our aim is to offer new insights into the prevention and treatment of breast cancer and to contribute to the standardization of TCM.
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Electrical stimulation provides a clinically viable approach for treating neurological disorders. Here, we present a protocol for recording neural activity evoked by electrical stimulation in mice using two-photon calcium imaging. We detail steps for chronically implanting a head fixation bar, a stimulating electrode, and a glass imaging window. We additionally describe the procedures for viral injections and awake head-fixed recordings. For complete details on the use and execution of this protocol, please refer to Dadarlat et al.1.
Subject(s)
Calcium , Electric Stimulation , Animals , Mice , Calcium/metabolism , Electric Stimulation/methods , Neurons/physiology , Neurons/metabolismABSTRACT
Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1+ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.
Subject(s)
Prostatic Neoplasms , Zinc Finger E-box-Binding Homeobox 1 , Male , Zinc Finger E-box-Binding Homeobox 1/metabolism , Zinc Finger E-box-Binding Homeobox 1/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Humans , Animals , Chromatin/metabolism , Epithelial-Mesenchymal Transition , Cell Line, Tumor , Mice , Gene Expression Regulation, Neoplastic , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/genetics , Cell Plasticity , Glycolysis , Chromatin Assembly and DisassemblyABSTRACT
Although there are many microorganisms in nature, the limitations of isolation and cultivation conditions have restricted the development of artificial enhanced remediation technology using functional microbial communities. In this study, an integrated technology of Magnetic Nanoparticle-mediated Enrichment (MME) and Microfluidic Single Cell separation (MSC) that breaks through the bottleneck of traditional separation and cultivation techniques and can efficiently obtain more in situ functional microorganisms from the environment was developed. MME technology was first used to enrich rapidly growing active bacteria in the environment. Subsequently, MSC technology was applied to isolate and incubate functional bacterial communities in situ and validate the degradation ability of individual bacteria. As a result, this study has changed the order of traditional pure culture methods, which are first selected and then cultured, and provided a new method for obtaining non-culturable functional microorganisms.
Subject(s)
Bacteria , Magnetite Nanoparticles , Magnetite Nanoparticles/chemistry , Cell Separation/methods , Microfluidic Analytical Techniques/methods , Single-Cell Analysis/methods , Biodegradation, Environmental , Microfluidics/methodsABSTRACT
Gas sensors play a crucial role in various industries and applications. In recent years, there has been an increasing demand for gas sensors in society. However, the current method for screening gas-sensitive materials is time-, energy-, and cost-consuming. Consequently, an imperative exists to enhance the screening efficiency. In this study, we proposed a collaborative screening strategy through integration of density functional theory and machine learning. Taking zinc oxide (ZnO) as an example, the responsiveness of ZnO to the target gas was determined quickly on the basis of the changes in the electronic state and structure before and after gas adsorption. In this work, the adsorption energy and electronic and structural characteristics of ZnO after adsorbing 24 kinds of gases were calculated. These computed features served as the basis for training a machine learning model. Subsequently, various machine learning and evaluation algorithms were utilized to train the fast screening model. The importance of feature values was evaluated by the AdaBoost, Random Forest, and Extra Trees models. Specifically, charge transfer was assigned importance values of 0.160, 0.127, and 0.122, respectively, ranking as the highest among the 11 features. Following closely was the d-band center, which was presumed to exert influence on electrical conductivity and, consequently, adsorption properties. With 5-fold cross-validation using the Extra Tree accuracy, the 24-sample data set achieved an accuracy of 88%. The 72-sample data set achieved an accuracy of 78% using multilayer perceptron after 5-fold cross-validation, with both data sets exhibiting low standard deviations. This verified the accuracy and reliability of the strategy, showcasing its potential for rapidly screening a material's responsiveness to the target gas.
Subject(s)
Gases , Machine Learning , Zinc Oxide , Gases/chemistry , Gases/analysis , Zinc Oxide/chemistry , Adsorption , Density Functional TheoryABSTRACT
Theaflavins are beneficial to human health due to various bioactivities. Biosynthesis of theaflavins using polyphenol oxidase (PPO) is advantageous due to cost effectiveness and environmental friendliness. In this review, studies on the mechanism of theaflavins formation, the procedures to screen and prepare PPOs, optimization of reaction systems and immobilization of PPOs were described. The challenges associated with the mass biosynthesis of theaflavins, such as poor enzyme activity, undesirable subproducts and inclusion bodies of recombinant PPOs were presented. Further strategies to solve these challenges and improve theaflavins production, including enzyme engineering, immobilization enzyme technology, water-immiscible solvent-water biphasic systems and recombinant enzyme technology, were proposed.
Subject(s)
Biflavonoids , Catechin , Catechol Oxidase , Biflavonoids/chemistry , Biflavonoids/metabolism , Biocatalysis , Catechin/chemistry , Catechin/metabolism , Catechol Oxidase/metabolism , Catechol Oxidase/chemistry , Enzymes, Immobilized/chemistry , Enzymes, Immobilized/metabolismABSTRACT
Definitive concurrent chemoradiotherapy has been the main standard treatment method for unresectable locally advanced esophageal squamous cell cancer (ESCC) since 1999. However, several disadvantages continue to be associated with this type of treatment, including a high local failure rate (reaching ~50% within 3 years) and a median overall survival (OS) time of 16.9 months. In addition, the 5year overall survival rate of patients remains relatively low, at only ~21% for patients with ESCC with TNM stage T13N01M0. Burgeoning clinical trials and continually updating treatment modalities are currently in the process of being developed for the treatment of unresectable locally advanced ESCC. Compared with definitive concurrent chemoradiotherapy alone, clinical trials that have examined the efficacy of induction therapy, consolidation therapy, immunotherapy and targeted therapy have observed a prolonged median progressionfree survival and OS. Salvage surgery can also bring benefits to some patients. Therefore, the present review aimed to provide a comprehensive overview on the latest progress that is being made in the development of treatment strategies for unresectable locally advanced ESCC, taking into account the several new challenges that need to be overcome.
Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Carcinoma, Squamous Cell/drug therapy , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Chemoradiotherapy/methods , Epithelial CellsABSTRACT
To reduce the damage to reinforced concrete shear walls in earthquakes and repair costs, a self-centering wall with sloped plane friction dampers (SPFDs) is proposed. In addition to the SPFDs, the proposed wall includes a precast composite wall, steel wall toes, and post-tensioned (PT) tendons. The steel wall toes embedded in the base of the precast wall were used to improve its strength, and the SPFDs installed in the steel toes were used to increase its energy dissipation capacity. To investigate the effect of the initial PT force and prestressing clamping force of the friction bolt on the seismic performance of the wall, quasistatic cyclic loading tests were carried out on three precast wall specimens. The damage to the self-centering walls was slight, the residual drift was small, and the energy dissipation met the specification requirements. The wall with the greater initial PT force showed higher self-centering and bearing capacity, and the wall with higher prestressing clamping forces showed greater energy dissipation capacity. Additionally, a calculation method for the bearing capacity of the precast wall, which was verified by comparison with the test results, is suggested.
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With the advancement of multi-photon microscopy and molecular technologies, fluorescence imaging is rapidly growing to become a powerful approach for studying the structure, function, and plasticity of living brain tissues. In comparison to conventional electrophysiology, fluorescence microscopy can capture the neural activity as well as the morphology of the cells, enabling long-term recordings of the identified neuron populations at single-cell or subcellular resolution. However, high-resolution imaging typically requires a stable, head-fixed setup that restricts the movement of the animal, and the preparation of a flat surface of transparent glass allows visualization of neurons at one or more horizontal planes but is limited in studying the vertical processes running across different depths. Here, we describe a procedure to combine a head plate fixation and a microprism that gives multilayer and multimodal imaging. This surgical preparation not only gives access to the entire column of the mouse visual cortex but allows two-photon imaging in a head-fixed position and one-photon imaging in a freely moving paradigm. Using this approach, one can sample identified cell populations across different cortical layers, register their responses under head-fixed and freely moving states, and track the long-term changes over months. Thus, this method provides a comprehensive assay of the microcircuits, enabling direct comparison of neural activities evoked by well-controlled stimuli and under a natural behavioral paradigm.
Subject(s)
Movement , Neurons , Mice , Animals , Neurons/physiology , Microscopy, Fluorescence , Optical ImagingABSTRACT
This study aimed to construct nomograms for predicting the likelihood of clinically significant prostate cancer (csPCa) in patients with lesions rated as Prostate Imaging Reporting and Data System (PI-RADS) 3 on biparametric magnetic resonance imaging (bpMRI). We retrospectively analyzed a cohort of 457 patients from the Peking Union Medical College Hospital (January 2017-July 2021) to develop the model and externally validated it with a cohort of 238 patients from the Second Hospital of Tianjin Medical University (September 2017-September 2021). Univariate and multivariate logistic regression analyses identified significant predictors of csPCa, defined by tumor volumes ≥ 0.5 cm3, Gleason score ≥ 7, or presence of extracapsular extension. Diagnostic performance for the peripheral zone (PZ) and transitional zone (TZ) was compared using the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Through univariate and multivariate logistic regression analyses, we identified age, prostate-specific antigen (PSA), and prostate volume (PV) as predictors of csPCa for the PZ, and age, serum-free to total PSA ratio (f/t PSA), and PSA density (PSAD) for the TZ. The nomograms demonstrated robust discriminative ability, with an area under the ROC curve (AUC) of 0.819 for PZ and 0.804 for TZ. The external validation corroborated the model's high predictive accuracy (AUC of 0.831 for PZ and 0.773 for TZ). Calibration curves indicated excellent agreement between predicted and observed outcomes, and DCA underscored the nomogram's clinical utility for both PZ and TZ. Overall, the nomograms offer high predictive accuracy for csPCa at initial biopsy, potentially reducing unnecessary biopsies in clinical settings.
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Compared with postoperative adjuvant therapy, neoadjuvant therapy has more potential advantages, such as decreasing tumor stage, killing micrometastatic cells. Because of these advantages, neoadjuvant therapy is recommended for numerous types of tumor, such as breast, lung and rectal cancer. To determine the role of neoadjuvant therapy on overall survival and adverse for patients with resectable esophageal carcinoma. we summarized clinical studies on 7 types of neoadjuvant therapies in this review. Currently, patients with esophageal cancer (EC) in China mainly receive postoperative treatment with <30% of patients receiving neoadjuvant therapy. One reason for the limited use of neoadjuvant therapy in China is inaccurate staging based on imaging and neoadjuvant treatment may increase difficulties in surgery. After neoadjuvant therapy, there may be tissue edema, blurry surgical field of view and unclear tissue gaps, resulting in greater difficulty in surgical procedures. However, oncologists are interested in neoadjuvant treatment, especially neoadjuvant immunotherapy to treat EC. Concurrent chemoradiotherapy for esophageal squamous cell carcinoma (ESCC) is the most common neoadjuvant treatment regimen and increases the pathological complete response (pCR) and 5- and 10-year survival rates. Preoperative induction chemotherapy and sequential concurrent chemoradiotherapy are currently the most widely treatments used in clinical practice in China. However, this treatment strategy does not yield long-term survival. The pCR rate of neoadjuvant immunotherapy is greater than that of concurrent chemoradiotherapy but, to the best of our knowledge, no evidence of long-term survival benefit has been found in phase I and II clinical trials. Neoadjuvant treatment should be considered for patients with locally advanced ESCC.
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Caulerpa lentillifera polysaccharide (CLP) has been characterized as a sulfated polysaccharide which can effectively inhibit lipid digestion. However, little information was known regarding its inhibitory mechanisms. In the present study, desulfation and degradation were conducted to prepare the derivatives of CLP, and a series of chemical and spectroscopic methods were used to elucidate the structure-activity relationship of CLP on the inhibitory effect of lipid digestion. Results revealed that CLP possessed excellent binding capacities for sodium cholate, sodium glycocholate, and sodium taurocholate. In addition, CLP can effectively inhibit lipase activity by quenching the fluorescence intensity, changing the secondary structure, and decreasing the UV-Vis absorbance. Of note, sulfate groups in CLP took a vital role in inhibiting lipase activity, while the molecular weight of CLP showed a positive correlation with the binding activities of bile acids. Furthermore, adding CLP into the whey protein isolate (WPI) emulsion system also impeded lipid digestion, indicating that CLP can be a potential reduced-fat nutraceutical used in food emulsion systems.
Subject(s)
Caulerpa , Edible Seaweeds , Lipids , Polysaccharides , Emulsions , Polysaccharides/chemistry , Structure-Activity Relationship , Digestion , LipaseABSTRACT
Electrical stimulation is an effective tool for mapping and altering brain connectivity, with applications ranging from treating pharmacology-resistant neurological disorders to providing sensory feedback for neural prostheses. Paramount to the success of these applications is the ability to manipulate electrical currents to precisely control evoked neural activity patterns. However, little is known about stimulation-evoked responses in inhibitory neurons nor how stimulation-evoked activity patterns depend on ongoing neural activity. In this study, we used 2-photon imaging and cell-type specific labeling to measure single-cell responses of excitatory and inhibitory neurons to electrical stimuli in the visual cortex of awake mice. Our data revealed strong interactions between electrical stimulation and pre-stimulus activity of single neurons in awake animals and distinct recruitment and response patterns for excitatory and inhibitory neurons. This work demonstrates the importance of cell-type-specific labeling of neurons in future studies.
Subject(s)
Neurons , Wakefulness , Mice , Animals , Wakefulness/physiology , Neurons/physiology , Cerebral Cortex , Electric Stimulation , Mammals , Neural Inhibition/physiologyABSTRACT
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.