ABSTRACT
The functional integrity of CD8+ T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8+ T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8+ T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8+ T cell activation and anti-tumor immune response in vitro and in vivo. Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8+ T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8+ T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.
Subject(s)
CD8-Positive T-Lymphocytes , Death-Associated Protein Kinases , Fumarates , Lymphocyte Activation , Mice, Inbred C57BL , Animals , CD8-Positive T-Lymphocytes/immunology , Death-Associated Protein Kinases/genetics , Death-Associated Protein Kinases/metabolism , Fumarates/metabolism , Fumarates/pharmacology , Mice, Knockout , Cell Line, Tumor , Adenosine Triphosphate/metabolism , Signal Transduction , Humans , Mice , Energy MetabolismABSTRACT
The tumor suppressor p53 is critical for tumor suppression, but the regulatory role of p53 in alcohol-induced fatty liver remains unclear. Here, we show a role for p53 in regulating ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for the oxidization of alcohol. By repressing ethanol oxidization, p53 suppresses intracellular levels of acetyl-CoA and histone acetylation, leading to the inhibition of the stearoyl-CoA desaturase-1 (SCD1) gene expression. Mechanistically, p53 directly binds to ALDH2 and prevents the formation of its active tetramer and indirectly limits the production of pyruvate that promotes the activity of ALDH2. Notably, p53-deficient mice exhibit increased lipid accumulation, which can be reversed by ALDH2 depletion. Moreover, liver-specific knockdown of SCD1 alleviates ethanol-induced hepatic steatosis caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol-induced fatty liver development in wild-type mice, while it has a mild effect on p53-/- or ALDH2-/- mice. Overall, our findings reveal a previously unrecognized function of p53 in alcohol-induced fatty liver and uncover pyruvate as a natural regulator of ALDH2.
Subject(s)
Aldehyde Dehydrogenase, Mitochondrial , Fatty Liver, Alcoholic , Fatty Liver , Tumor Suppressor Protein p53 , Animals , Mice , Aldehyde Dehydrogenase, Mitochondrial/genetics , Aldehyde Dehydrogenase, Mitochondrial/metabolism , Ethanol/toxicity , Ethanol/metabolism , Fatty Liver/genetics , Fatty Liver/metabolism , Fatty Liver, Alcoholic/genetics , Fatty Liver, Alcoholic/metabolism , Liver/metabolism , Pyruvates/metabolism , Pyruvates/pharmacology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
T cell lymphomas (TCLs) are a group of rare and heterogeneous tumors. Although proto-oncogene MYC has an important role in driving T cell lymphomagenesis, whether MYC carries out this function remains poorly understood. Here, we show that malic enzyme 2 (ME2), one of the NADPH-producing enzymes associated with glutamine metabolism, is essential for MYC-driven T cell lymphomagenesis. We establish a CD4-Cre; Mycâflox/+transgenic mouse mode, and approximately 90% of these mice develop TCL. Interestingly, knockout of Me2 in Myc transgenic mice almost completely suppresses T cell lymphomagenesis. Mechanistically, by transcriptionally up-regulating ME2, MYC maintains redox homeostasis, thereby increasing its tumorigenicity. Reciprocally, ME2 promotes MYC translation by stimulating mTORC1 activity through adjusting glutamine metabolism. Treatment with rapamycin, an inhibitor of mTORC1, blocks the development of TCL both in vitro and in vivo. Therefore, our findings identify an important role for ME2 in MYC-driven T cell lymphomagenesis and reveal that MYC-ME2 circuit may be an effective target for TCL therapy.
Subject(s)
Glutamine , Malate Dehydrogenase , T-Lymphocytes , Animals , Mice , Glutamine/metabolism , Homeostasis , Mechanistic Target of Rapamycin Complex 1/genetics , Mice, Transgenic , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , T-Lymphocytes/metabolism , Malate Dehydrogenase/genetics , Malate Dehydrogenase/metabolismABSTRACT
Granulocytes are indispensable for various immune responses. Unlike other cell types in the body, the nuclei of granulocytes, particularly neutrophils, are heavily segmented into multiple lobes. Although this distinct morphological feature has long been observed, the underlying mechanism remains incompletely characterized. In this study, we utilize cryo-electron tomography to examine the nuclei of mouse neutrophils, revealing the cytoplasmic enrichment of intermediate filaments on the concave regions of the nuclear envelope. Aided by expression profiling and immuno-electron microscopy, we then elucidate that the intermediate-filament protein vimentin is responsible for such perinuclear structures. Of importance, exogenously expressed vimentin in nonimmune cells is sufficient to form cytoplasmic filaments wrapping on the concave nuclear surface. Moreover, genetic deletion of the protein causes a significant reduction of the number of nuclear lobes in neutrophils and eosinophils, mimicking the hematological condition of the Pelger-Huët anomaly. These results have uncovered a new component establishing the nuclear segmentation of granulocytes.
Subject(s)
Intermediate Filaments , Neutrophils , Animals , Mice , Neutrophils/metabolism , Vimentin/metabolism , Cell Nucleus , EosinophilsABSTRACT
BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)-induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic studies revealed that ME1 inhibition promoted downstream adenosine production and activated A2AR-mediated adenosine signaling, which leads to an increase in nitric oxide generation and a decrease in proinflammatory molecule expression in endothelial cells. ME1 inhibition activated adenosine production in an ATP-dependent manner through regulating malate-aspartate NADH (nicotinamide adenine dinucleotide plus hydrogen) shuttle and thereby balancing oxidative phosphorylation and glycolysis. Pharmacological inactivation of ME1 attenuated the progression of PH in both preventive and therapeutic settings by promoting adenosine production in vivo. CONCLUSIONS: Our findings indicate that ME1 upregulation in endothelial cells plays a causative role in PH development by negatively regulating adenosine production and subsequently dysregulating endothelial functions. Our findings also suggest that ME1 may represent as a novel pharmacological target for upregulating protective adenosine signaling in PH therapy.
ABSTRACT
Cancer cells exhibit altered and usually increased metabolic processes to meet their high biogenetic demands1,2. Under these conditions, ammonia is concomitantly produced by the increased metabolic processing. However, it is unclear how tumour cells dispose of excess ammonia and what outcomes might be caused by the accumulation of ammonia. Here we report that the tumour suppressor p53, the most frequently mutated gene in human tumours, regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1, OTC and ARG1, p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumour growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC, thereby inhibiting the biosynthesis of polyamine and cell proliferation. Together, these findings link p53 to ureagenesis and ammonia metabolism, and further reveal a role for ammonia in controlling polyamine biosynthesis and cell proliferation.
Subject(s)
Ammonia/metabolism , Gene Expression Regulation/genetics , Polyamines/metabolism , Tumor Suppressor Protein p53/metabolism , Urea/metabolism , Arginase/genetics , Carbamoyl-Phosphate Synthase (Ammonia)/genetics , Cell Proliferation , Humans , Neoplasms/genetics , Neoplasms/pathology , Ornithine Carbamoyltransferase/genetics , Ornithine Decarboxylase/biosynthesis , Ornithine Decarboxylase/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription, Genetic/geneticsABSTRACT
In Fig. 1c of this Letter, the labels p53+/+ and p53-/- were inadvertently swapped. The original figure has been corrected online.
ABSTRACT
BACKGROUND: Accurate clinical structural variant (SV) calling is essential for cancer target identification and diagnosis but has been historically challenging due to the lack of ground truth for clinical specimens. Meanwhile, reduced clinical-testing cost is the key to the widespread clinical utility. METHODS: We analyzed massive data from tumor samples of 476 patients and developed a computational framework for accurate and cost-effective detection of clinically-relevant SVs. In addition, standard materials and classical experiments including immunohistochemistry and/or fluorescence in situ hybridization were used to validate the developed computational framework. RESULTS: We systematically evaluated the common algorithms for SV detection and established an expert-reviewed SV call set of 1,303 tumor-specific SVs with high-evidence levels. Moreover, we developed a random-forest-based decision model to improve the true positive of SVs. To independently validate the tailored 'two-step' strategy, we utilized standard materials and classical experiments. The accuracy of the model was over 90% (92-99.78%) for all types of data. CONCLUSION: Our study provides a valuable resource and an actionable guide to improve cancer-specific SV detection accuracy and clinical applicability.
Subject(s)
Genomics , Neoplasms , Humans , Benchmarking , Cost-Benefit Analysis , In Situ Hybridization, Fluorescence , Neoplasms/diagnosis , Neoplasms/genetics , Genome, Human , High-Throughput Nucleotide SequencingABSTRACT
Bladder cancer (BLCA) is a common type of urogenital malignancy worldwide. The recurrence and metastasis of bladder cancer are closely related to angiogenesis, but the underlying mechanisms are unclear. In this study, we developed a method to predict survival outcomes among BLCA patients, which could be used to guide immunotherapy and chemotherapy. We obtained patient data from The Cancer Genome Atlas (TCGA) and identified angiogenesis-related genes from the GeneCards database. First, we used differential expression analysis and univariate Cox analysis to identify angiogenesis-related genes and used correlation analysis to generate molecular subtypes based on M2 macrophages. Next, we constructed a prognostic signature consisting of four genes (ECM1, EFEMP1, SLIT2, and PDGFRΑ), which was found to be an independent prognostic factor. Higher risk scores were associated with worse overall survival and higher expression of immune checkpoints. We also evaluated immune cell infiltration using the CIBERSORT and ssGSEA algorithms. Additionally, we performed stratification analyses, constructed a nomogram, and predicted chemotherapeutic responses based on the risk signature. Finally, we validated our findings by using qRT-PCR as well as IHC data to detect the expression levels of the four genes at mRNA and protein levels in BLCA patients and obtained results that were consistent with our predictions. Our study demonstrates the utility of a four-gene prognostic signature for prognostication in bladder cancer patients and designing personalized treatments, which could provide new avenues for personalized management of these patients.
Subject(s)
Tumor Microenvironment , Urinary Bladder Neoplasms , Humans , Algorithms , Angiogenesis , Databases, Factual , Extracellular Matrix Proteins , Prognosis , Urinary Bladder Neoplasms/geneticsABSTRACT
In colloid quantum dot light-emitting diodes (QLEDs), the control of interface states between ZnO and quantum dots (QDs) plays a vital role. We present a straightforward and efficient method using a negative corona discharge to modify the QD film, creating a dipole moment at the interface of QDs and magnesium-doped ZnO (ZnMgO) for balanced charge carrier distribution within the QDs. This process boosts external quantum efficiencies in red, green, and blue QLEDs to 17.71%, 14.53%, and 9.04% respectively. Notably, optimized devices exhibit significant enhancements, especially at lower brightness levels (1000 to 10,000â cd·m-2), vital for applications in mobile displays, TV screens, and indoor lighting.
ABSTRACT
Macrophage polarization determines the production of pro- or anti-inflammatory cytokines in response to various bacterial and virus infections. Here, we report that pro-inflammatory macrophage polarization induced by lipopolysaccharide (LPS) skews the TRIM21-SIRT5 interplay toward TRIM21 activation and SIRT5 degradation, resulting in an enhancement of interleukin (IL)-1ß production in vitro and in vivo. Mechanistically, LPS challenge enhances the interaction between TRIM21 and SIRT5 to promote SIRT5 ubiquitination and degradation, while reducing the binding of SIRT5 to HAUSP, a deubiquitinating enzyme that stabilizes SIRT5. In a feedback loop, SIRT5 degradation sustains the acetylation of TRIM21 at Lys351, thereby increasing its E3 ligase activity in LPS-activated macrophages. Thus, we identify a functional balance between TRIM21 and SIRT5 that is tilted toward SIRT5 suppression in response to LPS stimulation, thereby enhancing IL-1ß production during inflammation.
Subject(s)
Colitis , Interleukin-1beta , Ribonucleoproteins , Sirtuins , Animals , Colitis/chemically induced , Colitis/genetics , Colitis/metabolism , Cytokines/metabolism , Interleukin-1beta/metabolism , Lipopolysaccharides , Macrophages/metabolism , Ribonucleoproteins/genetics , Ribonucleoproteins/metabolism , Sirtuins/genetics , Sirtuins/metabolism , UbiquitinationABSTRACT
Improvements in cryo-electron tomography sample preparation, electron-microscopy instrumentations, and image processing algorithms have advanced the structural analysis of macromolecules in situ. Beyond such analyses of individual macromolecules, the study of their interactions with functionally related neighbors in crowded cellular habitats, i.e. 'molecular sociology', is of fundamental importance in biology. Here we present a NEighboring Molecule TOpology Clustering (NEMO-TOC) algorithm. We optimized this algorithm for the detection and profiling of polyribosomes, which play both constitutive and regulatory roles in gene expression. Our results suggest a model where polysomes are formed by connecting multiple nonstochastic blocks, in which translation is likely synchronized.
Improvements in cryo-electron tomography sample preparation, electron-microscopy instrumentations, and image processing algorithms have advanced the structural analysis of macromolecules in situ. Beyond such analyses of individual macromolecules, the study of their interactions with functionally related neighbors in crowded cellular habitats, i.e. "molecular sociology", is of fundamental importance in biology. Here we present a NEighboring Molecule TOpology Clustering (NEMO-TOC) algorithm. We optimized this algorithm for the detection and profiling of polyribosomes, which play both constitutive and regulatory roles in gene expression. Our results suggest a model where polysomes are formed by connecting multiple nonstochastic blocks, in which translation is likely synchronized.
Subject(s)
Algorithms , Electron Microscope Tomography , Polyribosomes/ultrastructure , Cluster Analysis , Cryoelectron Microscopy , Electron Microscope Tomography/methods , Macromolecular Substances/chemistryABSTRACT
Chronic noise exposure is correlated with gut microbiota dysbiosis and glucose and lipid metabolism disorders. However, evidence on the mechanisms underlying of gut microbiota alterations in chronic noise induced glucose and lipid metabolism disorders is limited, and the potential aftereffects of chronic noise exposure on metabolic disorders remain unclear. In present study, we established chronic daytime and nighttime noise exposure mice models to explore the effects and underlying mechanism of gut microbiota on chronic noise-induced glucose and lipid metabolism disorders. The results showed that exposure to chronic daytime or nighttime noise significantly increased the fasting blood glucose, serum and liver TG levels, impaired glucose tolerance, and decreased serum HDL-C levels and liver TC levels in mice. However, after 4 weeks of recovery, only serum TG of mice in nighttime noise recovery group remained elevated. Besides, exposure to chronic noise reduced the intestinal tight junction protein levels and increased intestinal permeability, while this effect did not completely dissipate even after the recovery period. Moreover, chronic noise exposure changed the gut microbiota and significantly regulated metabolites and metabolic pathways, and further activate hepatic gluconeogenesis CRTC2/CREB-PCK1 signaling pathway and lipid synthesis SREBP1/SCD signaling pathway through intestinal hepatic axis. Together, our findings demonstrated that chronic daytime and nighttime noise exposure could cause the glucose and lipid metabolism disorder by modulating the gut microbiota and serum metabolites, and activating hepatic gluconeogenic CREB/CRTC2-PCK1 signaling and lipid synthesis SREBP1/SCD signaling pathway. The potential aftereffects of noise exposure during wakefulness on metabolic disorders are more significant than that of noise exposure during sleep.
Subject(s)
Gastrointestinal Microbiome , Lipid Metabolism Disorders , Metabolic Diseases , Animals , Mice , Lipid Metabolism , Glucose/metabolism , Liver/metabolism , Metabolic Diseases/metabolism , Lipids , Mice, Inbred C57BLABSTRACT
The structural studies of macromolecules in their physiological context, particularly in tissue, is constrained by the bottleneck of sample preparation. In this study, we present a practical pipeline for preparing multicellular samples for cryo-electron tomography. The pipeline comprises sample isolation, vitrification, and lift-out-based lamella preparation using commercially available instruments. We demonstrate the efficacy of our pipeline by visualizing pancreatic ß cells from mouse islets at the molecular level. This pipeline enables the determination of the properties of insulin crystals in situ for the first time, using unperturbed samples.
Subject(s)
Electron Microscope Tomography , Specimen Handling , Animals , Mice , Electron Microscope Tomography/methods , Cryoelectron Microscopy/methods , Macromolecular Substances , Specimen Handling/methods , VitrificationABSTRACT
Cholesterol is essential for membrane biogenesis, cell proliferation, and differentiation. The role of cholesterol in cancer development and the regulation of cholesterol synthesis are still under active investigation. Here we show that under normal-sterol conditions, p53 directly represses the expression of SQLE, a rate-limiting and the first oxygenation enzyme in cholesterol synthesis, in a SREBP2-independent manner. Through transcriptional downregulation of SQLE, p53 represses cholesterol production in vivo and in vitro, leading to tumor growth suppression. Inhibition of SQLE using small interfering RNA (siRNA) or terbinafine (a SQLE inhibitor) reverses the increased cell proliferation caused by p53 deficiency. Conversely, SQLE overexpression or cholesterol addition promotes cell proliferation, particularly in p53 wild-type cells. More importantly, pharmacological inhibition or shRNA-mediated silencing of SQLE restricts nonalcoholic fatty liver disease (NAFLD)-induced liver tumorigenesis in p53 knockout mice. Therefore, our findings reveal a role for p53 in regulating SQLE and cholesterol biosynthesis, and further demonstrate that downregulation of SQLE is critical for p53-mediated tumor suppression.
Subject(s)
Neoplasms , Squalene Monooxygenase , Animals , Cell Proliferation/genetics , Cholesterol , Mice , Neoplasms/genetics , Squalene Monooxygenase/metabolism , Tumor Suppressor Protein p53/geneticsABSTRACT
The incorporation of chirality endows Pt(II)-based metal-organic complexes (MOCs) with unique potentials in several fields such as nonlinear optics and chiral catalysis. However, the exploration of chiral Pt(II) metallacycles in biological responses remains underdeveloped. Herein, we designed and synthesized two chiral Pt(II) metallacycles 1 and 2 via the coordination-driven self-assembly of chiral 1,1'-spirobiindane-7,7'-diol (SPINOL)-derived ligands and cis-Pt(PEt3)2(OTf)2 (90°Pt). Their structures were well characterized by 1H NMR, 31P{1H} NMR, ESI-TOF-MS, and X-ray crystallography, and their photophysical properties were investigated by UV-vis absorption, fluorescence, and circular dichroism (CD) spectroscopies. Then, the antitumor activity of the two chiral metallacycles in vitro was further tested. Complexes 1 and 2 exhibited strong cytotoxicity, especially toward the A549 cells. The destruction of the mitochondrial function, the inhibition of the glutathione (GSH)/glutathione disulfide (GSSG) level, and the inactivation of superoxide dismutase (SOD) induced by complexes 1 and 2 led to the massive accumulation of reactive oxygen species (ROS). The overloaded ROS then triggered apoptotic cell death, and the release of damage-associated molecular patterns (DAMPs) further induced immunogenic cell death (ICD). To the best of our knowledge, this is the first example of Pt(II)-based metallacycles that can induce immunogenic cell death, providing a new strategy for the future design and construction of immune-modulating platinum agents in cancer therapy.
Subject(s)
Coordination Complexes , Immunogenic Cell Death , Humans , Reactive Oxygen Species , Glutathione , A549 Cells , Apoptosis , Coordination Complexes/pharmacologyABSTRACT
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease of the lung. How to build a typical human mimicking animal model has been a challenge. Thus, to reveal the mechanism and to make it useful for IPF clinical treatment, a different type of mice model and inspection methods are used to evaluate which one is applicable for the study of IPF. METHOD: 69 Twelve-weeks-old C57BL/6 mice were divided into 3 type groups (n = 7 for each control group, n = 8 for each BLM-induced pulmonary fibrosis groups), as intraperitoneal injection, intratracheal administration, and intravenous administration of bleomycin (BLM) to initiate lung fibrosis. Changes of the lung function measured through mice Pulmonary function test (PFT). Morphological changes in mice were observed by PET/CT, Masson and Picro-Sirius staining, Transmission electron microscopy (TEM). Biochemical changes were tested by Enzyme-linked immunosorbent assay (Elisa). RESULTS: PET/CT of BLM-receiving mice showed an increase in fibrotic consolidations and an increase in non-aerated lung area in BLM-treated mice compared with that in controls. TGF-b1, TNF-a, IL-6, GM-CSF in BALF and serum. PAI-1, HYP in the lung tissue of mice were significantly different in each BLM groups than those in the controls. The results of Masson staining in mice indicate that the lung tissues of all BLM received groups, the intratracheal groups, the intravenous groups, and the intraperitoneal groups have a higher degree of pulmonary septal thickening and collagen fiber consolidation compare to saline control. Picro-Sirius staining results are consistent with the results of Masson staining. Compared with the saline control group, the ratio of Col 1/Col 3 was significantly increased in each BLM group. TEM results found that in BLM group, type I alveolar epithelial cells were degenerated. Exfoliated endothelial cells were swelling, and type II alveolar epithelial cells were proliferated, the shape of the nucleus was irregular, and some tooth-like protrusions were seen. CONCLUSIONS: With three different methods of animal model construction, high dose of each show more compliable, and BLM can successfully induce animal models of pulmonary fibrosis, however, certain differences in the fibrosis formation sites of them three, and tail vein injection of BLM induced PF model is closer to the idiopathic pulmonary interstitial fibrosis.
Subject(s)
Bleomycin , Idiopathic Pulmonary Fibrosis , Mice , Humans , Animals , Bleomycin/toxicity , Endothelial Cells , Positron Emission Tomography Computed Tomography , Bronchoalveolar Lavage Fluid , Mice, Inbred C57BL , Lung , Idiopathic Pulmonary Fibrosis/chemically induced , Disease Models, AnimalABSTRACT
PURPOSE: To examine the distribution of causes of death (CODs) in patients with small cell lung cancer (SCLC). METHODS: Patients diagnosed with SCLC were identified from the Surveillance, Epidemiology, and End Results Program database during 2004-2015. Standardized mortality rates (SMRs) were performed for each COD to present changes in risk for a particular COD following SCLC diagnosis. RESULTS: A total of 44,506 patients diagnosed with SCLC were identified in this study, and 42,476 patients died during the follow-up. Of total deaths, 69.5% occurred within the first years after diagnosis, 26% occurred from 1 to 3 years, and 4.5% individuals survived longer than 3 years. In addition, 88.7% of deaths were caused by SCLC, followed by non-cancer causes (7.1%) and other cancers (4.2%). Moreover, non-cancer CODs increased from 6.3 to 30% over time after 3 years of diagnosis. As for non-cancer CODs, cardiovascular diseases, COPD, and septicemia were the most common in SCLC. CONCLUSION: Non-cancer CODs, such as cardiovascular events, COPD and septicemia, contribute to a considerable proportion of deaths among long-term SCLC survivors, supporting the involvement of multidisciplinary care for the follow-up strategy in SCLC.
Subject(s)
Lung Neoplasms , Pulmonary Disease, Chronic Obstructive , Sepsis , Small Cell Lung Carcinoma , Cause of Death , Humans , Small Cell Lung Carcinoma/diagnosisABSTRACT
BACKGROUND: NIHL is one of the most common occupational diseases induced by gene-environment interaction. The CDH23 gene is a candidate gene related to NIHL susceptibility. However, the relationship between CDH23 gene and NIHL is still inconclusive. AIM: To clarify the association between CDH23 gene and NIHL, a meta-analysis was performed. SUBJECTS AND METHODS: A search in MEDLINE, PubMed, Web of Science, EBSCO, China National Knowledge Infrastructure (CNKI), and Wanfang Data was implemented to collect data. RESULTS AND CONCLUSIONS: Six studies were eventually included and all the subjects were Chinese. The results showed that rs1227051, rs1227049, and rs3752752 were not associated with NIHL susceptibility under five genetic models. But rs3802711 reduced the risk of NIHL under the recessive model, and the BB genotype and B allele of rs3802711 were significantly linked to NIHL under recessive, super-dominant, homozygote, and allele genetic models when stratified by the HWE result. Moreover, when not conform to HWE, the BB + AB genotypes and B allele of Exon7 in dominant, super-dominant, homozygote, and allele genetic model increased the risk of NIHL. CDH23 may be a potential gene marker for the prevention and early screening of NIHL in Chinese. Further large and well-designed studies are needed to confirm this association.
Subject(s)
Hearing Loss, Noise-Induced , Asian People , Cadherin Related Proteins , Cadherins/genetics , Genetic Predisposition to Disease , Hearing Loss, Noise-Induced/genetics , Humans , Polymorphism, GeneticABSTRACT
Transcranial magneto-acoustic-electrical stimulation is a new non-invasive neuromodulation technology, in which the induced electric field generated by the coupling effect of ultrasound and static magnetic field are used to regulate the neural rhythm oscillation activity in the corresponding brain region. The purpose of this paper is to investigate the effects of transcranial magneto-acoustic-electrical stimulation on the information transfer and communication in neuronal clusters during memory. In the experiment, twenty healthy adult Wistar rats were randomly divided into a control group (five rats) and stimulation groups (fifteen rats). Transcranial magneto-acoustic-electrical stimulation of 0.05~0.15 T and 2.66~13.33 W/cm 2 was applied to the rats in stimulation groups, and no stimulation was applied to the rats in the control group. The local field potentials signals in the prefrontal cortex of rats during the T-maze working memory tasks were acquired. Then the coupling differences between delta rhythm phase, theta rhythm phase and gamma rhythm amplitude of rats in different parameter stimulation groups and control group were compared. The experimental results showed that the coupling intensity of delta and gamma rhythm in stimulation groups was significantly lower than that in the control group ( P<0.05), while the coupling intensity of theta and gamma rhythm was significantly higher than that in the control group ( P<0.05). With the increase of stimulation parameters, the degree of coupling between delta and gamma rhythm showed a decreasing trend, while the degree of coupling between theta and gamma rhythm tended to increase. The preliminary results of this paper indicated that transcranial magneto-acoustic-electrical stimulation inhibited delta rhythmic neuronal activity and enhanced the oscillation of theta and gamma rhythm in the prefrontal cortex, thus promoted the exchange and transmission of information between neuronal clusters in different spatial scales. This lays the foundation for further exploring the mechanism of transcranial magneto-acoustic-electrical stimulation in regulating brain memory function.