ABSTRACT
Fluid shear stress (FSS) from blood flow, sensed by the vascular endothelial cells (ECs) that line all blood vessels, regulates vascular development during embryogenesis, controls adult vascular physiology and determines the location of atherosclerotic plaque formation. While a number of papers that reported a critical role for cell-cell adhesions or adhesion receptors in these processes, a recent publication challenged this paradigm, presenting evidence that ECs can very rapidly align in fluid flow as single cells without cell-cell contacts. To address this controversy, four independent laboratories assessed EC alignment in fluid flow across a range of EC cell types. These studies demonstrate a strict requirement for cell-cell contact in shear stress sensing over timescales consistent with previous literature and inconsistent with the newly published data.
ABSTRACT
BACKGROUND: Major depressive disorder (MDD) is a serious and disabling condition characterized by abnormal mood changes. Clinical guidelines for depression treatment recommend antidepressant medications, with benzodiazepines acting as short-term synergists. However, little is currently known about the prevalence and associated clinical risk factors of benzodiazepine use among Chinese patients with MDD. This study aimed to explore the prevalence and clinical risk factors associated with benzodiazepine use in this population. METHODS: A total of 2742 patients with MDD (males/females = 816/1926, aged 14-60 years) participated in this cross-sectional observational study. General information and psychosis assessments were collected online. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), anxiety symptoms using the Generalized Anxiety Disorder-7 (GAD-7), and sleep problems and suicidal tendencies using the third and ninth items of the PHQ-9. Multivariable logistic regression analysis models were employed to identify factors associated with benzodiazepine use. RESULTS: The prevalence of benzodiazepine use among patients with MDD was 42.9 %. Among these patients, 99.6 % used a single benzodiazepine, with oxazepam being the most frequently prescribed. Age, severity of sleep problems, depressive symptoms, and anxiety symptoms were significantly correlated with benzodiazepine use (all P < 0.001). LIMITATIONS: The cross-sectional design of this study precludes establishing causal relationships. CONCLUSION: Our findings indicate a high prevalence of benzodiazepine use among Chinese patients with MDD. Factors such as severe depressive symptoms, anxiety symptoms, age, and sleep problems appear to be associated with benzodiazepine use. These results underscore the importance of vigilance regarding benzodiazepine use in patients with MDD.
ABSTRACT
The suppression of soil carbon mineralization has been demonstrated to be effectively facilitated by carboniron interactions, yet the specific mechanisms by which artificial humic substances (A-HS) coupled with ferrihydrite influence this process remain insufficiently explored. This study is to investigate how the A-HS, specifically artificial fulvic acid (A-FA) and artificial humic acid (A-HA), coupled with ferrihydrite, affect carbon mineralization under anaerobic system that simulates paddy flooding conditions. The object is to investigate trends in carbon emissions and to delineate microbial community structure and functional pathways. The findings indicate that A-HA and A-FA substantially reduce CO2 and CH4 emissions, with A-FA having a particularly pronounced effect on carbon fixation, halving CO2 concentrations. The low concentration of Fe(II) observed suggest that A-FA and A-HA impede the dissimilatory iron reduction (DIR) process. Detailed 16S rDNA sequencing and gene prediction analyses reveal changes in microbial community structures and functions, highlighting Methanobacterium as the dominant hydrogenotrophic methanogens. The reductive citric acid cycle, predominantly utilized by Clostridium carboxidivorans, was identified as the principal carbon fixation pathway. This work provides a novel insight into the microbial mechanisms of carbon sequestration and highlights the potential of A-HS in improving soil fertility and contributing to climate change mitigation through enhancing soil carbon storage.
ABSTRACT
Constructing frustrated Lewis pairs (FLPs) on catalysts will provide catalytic sites to activate CO2 and boost photocatalytic CO2 reduction. Herein, a Ce-doped bismuth oxide (CeBiOX) with FLPs was designed by loading [(α-SbW9O33)2Cu3(H2O)3]12- (Cu3) via strong electrostatic interactions to create oxygen vacancies (OVs). Detailed experiments and measurements showed that Cu3 could regulate the FLPs and optimize the band structure of CeBiOX to boost photocatalytic CO2 reduction. In particular, the Cu3/CeBiOX composite exhibited the highest yields of CO (42.85 µmoL g-1) and CH4 (13.23 µmoL g-1), being 6.6 and 3.3 times, and 4.9 and 6.3 times higher than those of pristine Bi2O3 and CeBiOX, respectively. This work provides a significant and mild approach to obtaining advanced catalysts with tuneable FLPs for more fields.
ABSTRACT
Dental caries is a chronic and destructive disease and matrix metalloproteinase-2 (MMP-2) plays a major role in caries. The inhibitory mechanisms of theaflavins [theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3'-gallate (TF2B), and theaflavin-3,3'-digallate (TF3)] on MMP-2 were investigated using techniques such as enzyme inhibition kinetics, multi-spectral methods, molecular docking, and molecular dynamics simulations. The results showed that TF1, TF2A, TF2B, and TF3 all competitively and reversibly inhibited MMP-2 activity. Fluorescence spectra and molecular docking indicated that four theaflavins spontaneously bind to MMP-2 through noncovalent interactions, driven by hydrogen bonds and hydrophobic interactions, constituting a static quenching mechanism and resulting in an altered tryptophan residue environment around MMP-2. Molecular dynamic simulations demonstrated that four theaflavins can form stable, compact complexes with MMP-2. In addition, the order of theaflavins' ability to inhibit MMP-2 was found to be TF1 > TF2B > TF2A > TF3. Interestingly, the order of binding capacity between MMP-2 and TF1, TF2A, TF2B, and TF3 was consistent with the order of inhibitory capacity, and was opposite to the order of steric hindrance of theaflavins. This may be due to the narrow space of the active pocket of MMP-2, and the smaller the steric hindrance of theaflavins, the easier it is to enter the active pocket and bind to MMP-2. This study provided novel insights into theaflavins as functional components in the exploration of natural MMP-2 inhibitors.
Subject(s)
Biflavonoids , Catechin , Matrix Metalloproteinase 2 , Matrix Metalloproteinase Inhibitors , Molecular Docking Simulation , Molecular Dynamics Simulation , Biflavonoids/chemistry , Biflavonoids/pharmacology , Catechin/chemistry , Catechin/pharmacology , Catechin/analogs & derivatives , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 2/metabolism , Kinetics , Matrix Metalloproteinase Inhibitors/pharmacology , Matrix Metalloproteinase Inhibitors/chemistry , Humans , Hydrogen Bonding , Spectrometry, Fluorescence , Gallic Acid/analogs & derivativesABSTRACT
Transcranial ultrasound stimulation (TUS) has been clinically applied as a neuromodulation tool. Particularly, the phase array ultrasound can be applied in TUS to non-invasively focus on the cortex or deep brain. However, the vital phase distortion of the ultrasound induced by the skull limits its clinical application. In the current study, we aimed to develop a hybrid method that combines the ultrashort echo time (UTE) magnetic resonance imaging (MRI) sequences with the prDeep technique to achieve focusing ventral intermediate thalamic nucleus (VIM). The time-reversal (TR) approach of the UTE numerical acoustic model of the skull combined with the prDeep algorithm was used to reduce the number of iterations. The skull acoustic model simulation therapy process was establish to valid this method's prediction and focus performance, and the classical TR method were considered as the gold standard (GS). Our approach could restore 75% of the GS intensity in 25 iteration steps, with a superior the noise immunity. Our findings demonstrate that the phase aberration caused by the skull can be estimated using phase retrieval techniques to achieve a fast and accurate transcranial focus. The method has excellent adaptability and anti-noise capacity for satisfying complex and changeable scenarios.
Subject(s)
Acoustics , Magnetic Resonance Imaging , Skull , Skull/diagnostic imaging , Magnetic Resonance Imaging/methods , Humans , AlgorithmsABSTRACT
Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.
Subject(s)
Proto-Oncogene Proteins c-akt , Signal Transduction , TOR Serine-Threonine Kinases , Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Female , Phosphatidylinositol 3-Kinases/metabolism , Molecular Targeted Therapy/methods , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , MTOR Inhibitors/therapeutic use , MTOR Inhibitors/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacologyABSTRACT
BACKGROUND: CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells. METHODS: To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells. RESULTS: We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a decrease in cell proliferation, tube formation, and NO production. CONCLUSIONS: Overall, our results demonstrate the existence of an endothelial-specific HSF (heat shock factor)-regulated transcriptional enhancer that mediates CALCRL expression. A better understanding of CALCRL gene regulation and the role of single-nucleotide polymorphisms in the modulation of CALCRL expression could provide important steps toward understanding the genetic regulation of shear stress signaling responses.
Subject(s)
Calcitonin Receptor-Like Protein , Coronary Artery Disease , Endothelial Cells , Enhancer Elements, Genetic , Polymorphism, Single Nucleotide , Stress, Mechanical , Humans , Endothelial Cells/metabolism , Coronary Artery Disease/genetics , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Calcitonin Receptor-Like Protein/genetics , Calcitonin Receptor-Like Protein/metabolism , Heat Shock Transcription Factors/genetics , Heat Shock Transcription Factors/metabolism , Mechanotransduction, Cellular , Cells, Cultured , Gene Expression Regulation , Protein Binding , Genetic Predisposition to Disease , Binding SitesABSTRACT
Purpose: Despite the implementation of various insulation measures, the incidence of hypothermia during thyroid surgery remains high. This randomized controlled study aimed to evaluate the effects of aggressive thermal management combined with resistive heating mattresses to prevent perioperative hypothermia in patients undergoing thyroid surgery. Patients and Methods: 142 consecutive patients scheduled for elective thyroid surgery were enrolled in the study. They were randomly and equally allocated to the aggressive warming or routine care groups (n = 71). The patients' body temperature was monitored before the induction of anesthesia until they returned to the ward. The primary outcome was the incidence of perioperative hypothermia. Secondary outcomes included postoperative complications, such as mortality, cardiovascular complications, wound infection, shivering, postoperative nausea and vomiting (PONV), visual analog scale (VAS) pain scores, fever, headache and hospital length of stay (LOS). Results: In our study, the results showed that a significantly higher rate of hypothermia was observed in the routine care group compared with the aggressive warming group. The incidence of perioperative hypothermia was 19.72% (14/71) in the aggressive warming group and 35.21% (25/71) in the routine care group (P < 0.05). The incidence of shivering in the aggressive warming group (1.41%) was significantly lower than that in the routine care group (11.27%) (P < 0.05), and a one-day reduction in hospital length of stay was observed in the aggressive warming group (P < 0.05). There was no significant difference in mortality or other postoperative complications, such as cardiovascular complications, wound infection, PONV, pain, fever or headache, between the two groups (P > 0.05). Conclusion: Our results suggest that aggressive thermal management combined with resistive heating mattresses provided improved perioperative body temperature and reduced the incidence of perioperative hypothermia and shivering compared to routine thermal management.
âThe incidence of perioperative hypothermia during thyroid surgery was high. âThe use of resistive heating mattresses during thyroid surgery can effectively reduce the occurrence of perioperative hypothermia. âIt is recommended to take aggressive thermal protection during the operation of minor and medium surgeries, and to continuously monitor the temperature.
ABSTRACT
BACKGROUND: Postoperative pulmonary complications (PPCs) extend the length of stay of patients and increase the perioperative mortality rate after video-assisted thoracoscopic (VATS) pulmonary surgery. Thoracic paravertebral block (TPVB) provides effective analgesia after VATS surgery; however, little is known about the effect of TPVB on the incidence of PPCs. The aim of this study is to determine whether TPVB combined with GA causes fewer PPCs and provides better perioperative lung protection in patients undergoing VATS pulmonary surgery than simple general anaesthesia. METHODS: A total of 302 patients undergoing VATS pulmonary surgery will be randomly divided into two groups: the paravertebral block group (PV group) and the control group (C group). Patients in the PV group will receive TPVB: 15 ml of 0.5% ropivacaine will be administered to the T4 and T7 thoracic paravertebral spaces before general anaesthesia induction. Patients in the C group will not undergo the intervention. Both groups of patients will be subjected to a protective ventilation strategy during the operation. Perioperative protective mechanical ventilation and standard fluid management will be applied in both groups. Patient-controlled intravenous analgesia is used for postoperative analgesia. The primary endpoint is a composite outcome of PPCs within 7 days after surgery. Secondary endpoints include blood gas analysis, postoperative lung ultrasound score, NRS score, QoR-15 score, hospitalization-related indicators and long-term prognosis indicators. DISCUSSION: This study will better evaluate the impact of TPVB on the incidence of PPCs and the long-term prognosis in patients undergoing VATS lobectomy/segmentectomy. The results may provide clinical evidence for optimizing perioperative lung protection strategies. TRIAL REGISTRATION: ClinicalTrials.gov NCT05922449 . Registered on June 25, 2023.
Subject(s)
Nerve Block , Thoracic Surgery, Video-Assisted , Humans , Thoracic Surgery, Video-Assisted/adverse effects , Nerve Block/adverse effects , Respiration , Analgesia, Patient-Controlled , Lung/surgery , Randomized Controlled Trials as TopicABSTRACT
Vascular homeostasis and pathophysiology are tightly regulated by mechanical forces generated by hemodynamics. Vascular disorders such as atherosclerotic diseases largely occur at curvatures and bifurcations where disturbed blood flow activates endothelial cells while unidirectional flow at the straight part of vessels promotes endothelial health. Integrated analysis of the endothelial transcriptome, the 3D epigenome, and human genetics systematically identified the SNP-enriched cistrome in vascular endothelium subjected to well-defined atherosclerosis-prone disturbed flow or atherosclerosis-protective unidirectional flow. Our results characterized the endothelial typical- and super-enhancers and underscored the critical regulatory role of flow-sensitive endothelial super-enhancers. CRISPR interference and activation validated the function of a previously unrecognized unidirectional flow-induced super-enhancer that upregulates antioxidant genes NQO1, CYB5B, and WWP2, and a disturbed flow-induced super-enhancer in endothelium which drives prothrombotic genes EDN1 and HIVEP in vascular endothelium. Our results employing multiomics identify the cis-regulatory architecture of the flow-sensitive endothelial epigenome related to atherosclerosis and highlight the regulatory role of super-enhancers in mechanotransduction mechanisms.
Subject(s)
Atherosclerosis , Endothelial Cells , Mechanotransduction, Cellular , Humans , Atherosclerosis/genetics , Endothelium, VascularABSTRACT
Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm of solid tumors. To date, many ongoing studies of ADC combinations with a variety of anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical studies and clinical trial settings. Nevertheless, combination therapy does not always guarantee a synergistic or additive effect and may entail overlapping toxicity risks. Therefore, understanding the current status and underlying mechanisms of ADC combination therapy is urgently required. This comprehensive review analyzes existing evidence concerning the additive or synergistic effect of ADCs with other classes of oncology medicines. Here, we discuss the biological mechanisms of different ADC combination therapy strategies, provide prominent examples, and assess their benefits and challenges. Finally, we discuss future opportunities for ADC combination therapy in clinical practice.
Subject(s)
Antineoplastic Agents , Immunoconjugates , Neoplasms , Humans , Immunoconjugates/therapeutic use , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , ImmunotherapyABSTRACT
PURPOSE: Antibody-drug conjugate (ADC) has had a transformative effect on the treatment of many solid tumors, yet it remains unclear how ADCs exert bystander activity in the tumor microenvironment. EXPERIMENTAL DESIGN: Here, we directly visualized and spatiotemporally quantified the intratumor biodistribution and pharmacokinetics of different ADC components by developing dual-labeled fluorescent probes. RESULTS: Mechanistically, we found that tumor penetration of ADCs is distinctly affected by their ability to breach the binding site barrier (BSB) in perivascular regions of tumor vasculature, and bystander activity of ADC can only partially breach BSB. Furthermore, bystander activity of ADCs can work in synergy with coadministration of their parental antibodies, leading to fully bypassing BSBs and enhancing tumor penetration via a two-step process. CONCLUSIONS: These promising preclinical data allowed us to initiate a phase I/II clinical study of coadministration of RC48 and trastuzumab in patients with malignant stomach cancer to further evaluate this treatment strategy in humans.
Subject(s)
Cancer Vaccines , Immunoconjugates , Stomach Neoplasms , Humans , Antibodies , Binding Sites , Immunoconjugates/pharmacology , Stomach Neoplasms/drug therapy , Tissue Distribution , Tumor MicroenvironmentABSTRACT
Cerebrospinal fluid (CSF) flow patterns and their relationship with arterial pulsation can depict the function of glymphatic system (GS). We propose an improved multi-directional diffusion-sensitized driven-equilibrium (iMDDSDE) prepared heavily T2-weighted 3D FSE (iMDDSDE-HT2) magnetic resonance imaging (MRI) method to noninvasively assess the mobility (MO) of CSF distributed in the ventricles and perivascular spaces (PVS). This method could obtain 3D high resolution (1 mm isotropic) imaging of CSF MO with full brain coverage within five min and distinguish the CSF MO across different pulse phases using a peripheral pulse unit (PPU). The MO curves had the largest amplitude value in the PVS of middle cerebral artery (11.11 × 10-9 m2/s) and the largest amplitude growth rate in the posterior cerebral artery (189%). The average coefficient of variations (CVs) in non-pulse trigger and pulse phase 1 and 3 were 0.11, 0.10 and 0.09 respectively. The MO in older healthy participants was lower compared to the young participants, and the MO in cerebral major artery stenosis patients with acute ischemia stroke (AIS) were lower compared to those without AIS in several ventriclar ROIs (P < 0.05). This sequence is a clinically feasible method to effectively evaluate CSF flow patterns in human brain.
Subject(s)
Brain , Magnetic Resonance Imaging , Humans , Aged , Magnetic Resonance Imaging/methods , Head , Cerebrospinal Fluid/diagnostic imaging , Imaging, Three-Dimensional/methodsABSTRACT
BACKGROUND: Meningeal lymphatic vessels (mLVs) have proven to bear a relationship with tumor immunity and therapeutic efficacy of intracranial malignant tumors in pre-clinical animal studies. We aimed to explore the association between mLV function and intracranial malignant tumors in clinical participants. METHODS: The participants were allocated to a control group or a group of patients with intracranial tumors. Dynamic enhanced magnetic resonance was used to evaluate the wash-in and wash-out functions of mLVs around the superior sagittal sinus and the sigmoid sinus. FINDINGS: A total of 246 individuals were recruited for our study. The area under curve and wash-in rate of mLVs in the intracranial tumor group were higher than in the control group (2,749 vs. 2,110, p < 0.001 and 3.72 vs. 2.87, p < 0.001, respectively). The wash-out ratio of mLVs was lower in the intracranial tumor group than in the control group (0.65 vs. 0.73, p < 0.001). Decreased wash-out of mLVs was associated with tumor progression (ß = -0.118; p < 0.001). High-grade glioma and isocitrate dehydrogenase wild type were associated with a lower mLV wash-out function (ß = -0.057, p = 0.044 and ß = -0.069, p = 0.047, respectively). CONCLUSIONS: Intracranial malignant tumors were associated with elevated wash-in function and decreased wash-out function of mLVs. High-grade glioma and isocitrate dehydrogenase wild type were associated with low mLV wash-out function, and long-term decreased mLV wash-out function was a risk factor for tumor progression. FUNDING: There was no funding.
Subject(s)
Brain Neoplasms , Glioma , Lymphatic Vessels , Animals , Humans , Isocitrate Dehydrogenase , Brain Neoplasms/diagnostic imaging , Magnetic Resonance ImagingABSTRACT
Proanthocyanidins (PAs) are predominantly regulated at the transcriptional level by sophisticated regulatory networks. In cotton, the role of miRNAs as key regulatory factors at the post-transcriptional level is still unclear. Here, we demonstrated that GhmiR858 negatively regulates PA accumulation in cotton leaves and calli by targeting GhTT2L. Excessive expression of GhmiR858 restrained the expression of GhTT2L, resulting in a significant decrease in PA abundance. Conversely, a reduction in GhmiR858 activity upregulated GhTT2L, which increased PA accumulation. Additionally, GhTT2L was found to positively regulate PA accumulation in both cotton and Arabidopsis. Further analyses showed that GhTT2L interacted with transcription factor GhTTG1, which directly binds to the GhANR promoter, to facilitate its transcription. This study provides new information to guide future studies of the PA regulatory mechanisms affected by miRNAs as well as the breeding of novel varieties of colored cotton with rich PAs.
Subject(s)
Arabidopsis , MicroRNAs , Proanthocyanidins , Gossypium/genetics , Gossypium/metabolism , Proanthocyanidins/metabolism , Cotton Fiber , Plant Proteins/genetics , Plant Proteins/metabolism , Plant Breeding , Arabidopsis/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Gene Expression Regulation, PlantABSTRACT
In 2021, breast cancer accounted for a substantial proportion of cancer cases and represented the second leading cause of cancer deaths among women worldwide. Although tumor cells originate from normal cells in the human body, they possess distinct biological characteristics resulting from changes in gene structure and function of cancer cells in contrast with normal cells. These distinguishing features, known as hallmarks of cancer cells, differ from those of normal cells. The hallmarks primarily include high metabolic activity, mitochondrial dysfunction, and resistance to cell death. Current evidence suggests that the fundamental hallmarks of tumor cells affect the tissue structure, function, and metabolism of tumor cells and their internal and external environment. Therefore, these fundamental hallmarks of tumor cells enable tumor cells to proliferate, invade and avoid apoptosis. Modifying these hallmarks of tumor cells represents a new and potentially promising approach to tumor treatment. The key to breast cancer treatment lies in identifying the optimal therapeutic agent with minimal toxicity to normal cells, considering the specific types of tumor cells in patients. Some herbal medicines contain active ingredients which can precisely achieve this purpose. In this review, we introduce Ginsenoside's mechanism and research significance in achieving the therapeutic effect of breast cancer by changing the functional hallmarks of tumor cells, providing a new perspective for the potential application of Ginsenoside as a therapeutic drug for breast cancer.
ABSTRACT
OBJECTIVE: The present study, CLUS version 2.0, was conducted to evaluate the performance of new techniques in improving the implementation of lung cancer screening and to validate the efficacy of LDCT in reducing lung cancer-specific mortality in a high-risk Chinese population. METHODS: From July 2018 to February 2019, high-risk participants from six screening centers in Shanghai were enrolled in our study. Artificial intelligence, circulating molecular biomarkers and autofluorescencebronchoscopy were applied during screening. RESULTS: A total of 5087 eligible high-risk participants were enrolled in the study; 4490 individuals were invited, and 4395 participants (97.9%) finally underwent LDCT detection. Positive screening results were observed in 857 (19.5%) participants. Solid nodules represented 53.6% of all positive results, while multiple nodules were the most common location type (26.8%). Up to December 2020, 77 participants received lung resection or biopsy, including 70 lung cancers, 2 mediastinal tumors, 1 tracheobronchial tumor, 1 malignant pleural mesothelioma and 3 benign nodules. Lung cancer patients accounted for 1.6% of all the screened participants, and 91.4% were in the early stage (stage 0-1). CONCLUSIONS: LDCT screening can detect a high proportion of early-stage lung cancer patients in a Chinese high-risk population. The utilization of new techniques would be conducive to improving the implementation of LDCT screening.
Subject(s)
Lung Neoplasms , Humans , Lung Neoplasms/pathology , Early Detection of Cancer/methods , Bronchoscopy , Artificial Intelligence , Tomography, X-Ray Computed/methods , Neoplasm Staging , China , Biomarkers , Mass Screening/methodsABSTRACT
PURPOSE: Osteocytes in vivo exhibit different functional states, but no specific marker to distinguish these is currently available. MATERIALS AND METHODS: To simulate the differentiation process of pre-osteoblasts to osteocytes in vitro, MC3T3-E1 cells were cultured on type I collagen gel and a three-dimensional (3D) culture system was established. The Notch expression of osteocyte-like cells in 3D culture system was compared with that of in situ osteocytes in bone tissues. RESULTS: Immunohistochemistry demonstrated that Notch1 was not detected in "resting" in situ osteocytes, but was detected in normal cultured osteocyte-like cell line MLO-Y4. Osteocytes obtained from conventional osteogenic-induced osteoblasts and long-term cultured MLO-Y4 cells could not replicate the Notch1 expression pattern from in situ osteocytes. From day 14-35 of osteogenic induction, osteoblasts in 3D culture system gradually migrated into the gel to form canaliculus-like structures similar to bone canaliculus. On day 35, stellate-shaped osteocyte-like cells were observed, and expression of DMP1 and SOST, but not Runx2, was detected. Notch1 was not detected by immunohistochemistry, and Notch1 mRNA level was not significantly different from that of in situ osteocytes. In MC3T3-E1 cells, down-regulation of Notch2 increased Notch1, Notch downstream genes (ß-catenin and Nfatc1), and Dmp1. In MLO-Y4 cells, Notch2 decreased after Notch1 siRNA transfection. Downregulation of Notch1 or Notch2 decreased Nfatc1, ß-catenin, and Dmp1, and increased Sost. CONCLUSIONS: We established "resting state" osteocytes using an in vitro 3D model. Notch1 can be a useful marker to help differentiate the functional states of osteocytes (activated vs. resting state).
Subject(s)
Osteocytes , beta Catenin , Osteocytes/metabolism , beta Catenin/metabolism , Osteoblasts/metabolism , Cell Differentiation , Cell Line , Transcription Factors/metabolismABSTRACT
OBJECTIVE: To compare the complication rates, nutritional status, and physical state between esophageal cancer (EC) patients managed by nasogastric tube (NGT) feeding versus those managed by oral nutritional supplementation (ONS) during chemoradiotherapy. METHODS: EC patients undergoing chemoradiotherapy managed by nonintravenous nutritional support in our institute were retrospectively recruited and divided into an NGT group and an ONS group based on the nutritional support method. The main outcomes, including complications, nutritional status, and physical state, were compared between groups. RESULTS: The baseline characteristics of EC patients were comparable. There were no significant differences in the incidence of treatment interruption (13.04% vs. 14.71%, P = 0.82), death (2.17% vs. 0.00%, P = 0.84), or esophageal fistula (2.17% vs. 1.47%, P = 1.00) between the NGT group and ONS group. Body weight loss and decrease in albumin level were significantly lower in the NGT group than in the ONS group (both P < 0.05). EC patients in the NGT group had significantly lower Nutritional Risk Screening 2002 (NRS2002) and Patient-Generated Subjective Global Assessment (PG-SGA) scores and significantly higher Karnofsky Performance Status (KPS) scores than patients in the ONS group (all P < 0.05). The rates of grade > 2 esophagitis (10.00% vs. 27.59%, P = 0.03) and grade > 2 bone marrow suppression (10.00% vs. 32.76%, P = 0.01) were significantly lower in the NGT group than in the ONS group. There were no significant differences in the incidence of infection and upper gastrointestinal disorders or therapeutic efficacy between groups (all P > 0.05). CONCLUSIONS: EN through NGT feeding leads to significantly better nutritional status and physical state in EC patients during chemoradiotherapy than EN via ONS. NGT may also prevent myelosuppression and esophagitis..