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BACKGROUND: Circular RNAs (circRNAs) are known to play a crucial role in a variety of malignancies. However, the precise role of circRNAs in cervical squamous cell carcinoma (CSCC) remains largely unknown. METHODS: The expression of circ0001955 was determined by real-time quantitative PCR and fluorescence in situ hybridization. To examine the effects of circ0001955 on CSCC metastasis and growth, functional experiments were conducted in vitro and in vivo. Mechanistically, nucleocytoplasmic separation, dual luciferase reporter assay, RNA antisense purification experiments, and rescue experiments were performed to confirm the interaction between circ0001955, miR-188-3p, and NCAPG2 in CSCC. RESULTS: Here, we demonstrated that a circRNA derived from the CSNK1G1 gene (circ0001955) is significantly upregulated in CSCC. The overexpression of circ0001955 promotes tumor proliferation and metastasis, whereas the knockdown of circ0001955 exerts the opposite effects. Mechanistically, circ0001955 competitively binds miR-188-3p and prevents miR-188-3p from reducing the levels of NCAPG2, activating the AKT/mTOR signaling pathway to induce epithelial mesenchymal transformation. Notably, the application of an inhibitor of mTOR significantly antagonized circ0001955-mediated CSCC tumorigenesis. CONCLUSION: circ0001955 promotes CSCC tumorigenesis and metastasis via the miR-188-3p/NCAPG2 axis which would provide an opportunity to search new therapeutic targets for CSCC.
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MicroARNs , Neoplasias del Cuello Uterino , Femenino , Humanos , ARN Circular/genética , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias del Cuello Uterino/genética , Hibridación Fluorescente in Situ , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Serina-Treonina Quinasas TOR/metabolismo , Proliferación Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas Cromosómicas no Histona/metabolismoRESUMEN
BACKGROUND: In the absence of practical and reliable predictors for whether the endocervical curettage (ECC) procedure should be performed, decisions regarding patient selection are usually based on the colposcopists' clinical judgment instead of evidence. We aimed to develop and validate a practical prediction model that uses available information to reliably estimate the need to perform ECC in patients suspected of having cervical lesions. METHODS: In this retrospective study, 2088 patients who underwent colposcopy, colposcopically directed biopsy (CDB) and ECC procedures between September 2019 and September 2020 at the Second Hospital of Shanxi Medical University were included. The data were analyzed with univariate and multivariable logistic regression. Least absolute shrinkage and selection operator (LASSO) was used to select predictors for ECC positivity. The ECC prediction model was presented as a nomogram and evaluated in terms of discrimination and calibration. Furthermore, this model was validated internally with cross-validation and bootstrapping. RESULTS: Significant trends were found for ECC positivity with increasing age (P = 0.001), menopause (P = 0.003), Human papillomavirus (HPV) status (P < 0.001), severity of ThinPrep Cytological Test (TCT) (P < 0.001), original squamous epithelium ectopia (P = 0.037) and colposcopy impression (P < 0.001) by multivariable logistic regression analysis. The ECC prediction model was developed based on the following predictors: age, menopause, symptom of contact bleeding, severity of TCT, HPV status, cervix visibility, original squamous epithelium ectopia, acetowhite changes and colposcopic impression. This model had satisfactory calibration and good discrimination, with an area under the receiver operator characteristic curve (AUC) of 0.869 (95% confidence interval 0.849 to 0.889). CONCLUSIONS: A readily applicable clinical prediction model was constructed to reliably estimate the probability of ECC positivity in patients suspicious of having cervical lesions, which may help clinicians make decisions regarding the ECC procedure and possibly prevent adverse effects.
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Biopsia/métodos , Colposcopía/métodos , Legrado/métodos , Neoplasias del Cuello Uterino/cirugía , Adulto , Toma de Decisiones , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Currently, no study has focused on the postoperative erectile function in patients with benign prostatic hyperplasia (BPH) by comparing Hiraoka's transurethral detachment of prostate (TUDP) and transurethral resection of prostate (TURP). AIM: To compare the effects of Hiraoka's TUDP and TURP on postoperative erectile function in patients with BPH after long-term follow-up. METHODS: A total of 104 consecutive patients with BPH treated in our hospital between September 2018 and February 2019 were included in the study. All patients who met the inclusion criteria were randomly divided into the Hiraoka's TUDP (n = 52) and TURP (n = 52) groups. Patient baseline data were collected. The international index of erectile function (IIEF-5), minimal clinically important difference (MCID), and quality of life scale (QOLS) were used to evaluate erectile function and quality of life 3, 6, and 12 months after surgery. Primary study endpoints were IIEF-5 and MCID. Secondary study endpoints were QOLS and independent prognostic factors for MCID. OUTCOMES: Hiraoka's TUDP experienced greater improvement in postoperative IIEF5 scores than patients who underwent TURP. RESULTS: Patients in the Hiraoka's TUDP group had significantly higher mean IIEF-5 scores than those in the TURP group 6 and 12 months after surgery (6 months: 18.9 vs 14.8, P < .001; 12 months: 18.1 vs 15.7, P < .001). The percentages of patients in the TUDP group who achieved an MCID were 88.5% and 80.8%, compared to 30.8% and 46.2% in the TURP group (P < .001 for both), 6 and 12 months after the operation, respectively. Patients in the TUDP group had lower QOLS scores than those in the TURP group after the surgery. The surgical method was an independent prognostic factor for MCID (odds ratio = 0.218). CLINICAL IMPLICATIONS: Until now, no study has focused on the postoperative erectile function in patients with BPH by comparing Hiraoka's TUDP and TURP. Our study addressed this issue, which can add a new paradigm in the management to BPH. STRENGTH & LIMITATIONS: The comparison between Hiraoka's TUDP and TURP using a statistically appropriate, adequately powered methodology is the strength of the study. The single center and less participants are the limitations of the study. We believe that multicenter and large-sample studies are needed to further verify these study conclusions. CONCLUSIONS: Among similar cohorts of patients with BPH who underwent TUDP and TURP, patients who underwent Hiraoka's TUDP experienced greater improvement in postoperative IIEF5 scores than patients who underwent TURP, while improvement in IPSS was similar among both groups. Pan C, Zhan Y, Zhao Y, et al. Comparison of Hiraoka's Transurethral Detachment Prostatectomy and Transurethral Resection of the Prostate Effects on Postoperative Erectile Function in Patients With Benign Prostatic Hyperplasia: A Prospective Randomized Controlled Study. J Sex Med 2020;17:2181-2190.
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Disfunción Eréctil , Hiperplasia Prostática , Resección Transuretral de la Próstata , Disfunción Eréctil/etiología , Humanos , Masculino , Estudios Prospectivos , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/cirugía , Calidad de Vida , Resección Transuretral de la Próstata/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Surgical resection of pheochromocytoma may lead to high risk factors for intraoperative hemodynamic instability (IHD), which can be life-threatening. This study aimed to investigate the risk factors that could predict IHD during pheochromocytoma surgery by data mining. METHOD: Relief-F was used to select the most important features. The accuracies of seven data mining models (CART, C4.5, C5.0, and C5.0 boosted), random forest algorithm, Naive Bayes and logistic regression were compared, the cross-validation, hold-out, and bootstrap methods were used in the validation phase. The accuracy of these models was calculated independently by dividing the training and the test sets. Receiver-Operating Characteristic curves were used to obtain the area under curve (AUC). RESULT: Random forest had the highest AUC and accuracy values of 0.8636 and 0.8509, respectively. Then, we improved the random forest algorithm according to the classification of imbalanced data. Improved random forest model had the highest specificity and precision among all algorithms, including relatively higher sensitivity (recall) and the highest f1-score integrating recall and precision. The important attributes were body mass index, mean age, 24 h urine vanillylmandelic acid/upper normal limit value, tumor size and enhanced computed tomography difference. CONCLUSIONS: The improved random forest algorithm may be useful in predicting IHD risk factors in pheochromocytoma surgery. Data mining technologies are being increasingly applied in clinical and medical decision-making, and provide continually expanding support for the diagnosis, treatment, and prevention of various diseases.
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Neoplasias de las Glándulas Suprarrenales , Minería de Datos , Feocromocitoma , Adulto , Anciano , Teorema de Bayes , Femenino , Hemodinámica , Humanos , Masculino , Persona de Mediana EdadRESUMEN
In order to ensure the safety of spacecrafts in orbit, impact location is an important part of structural health monitoring systems. In this paper, an impact location algorithm based on posterior probability correlation is proposed to solve the problem, that is, the impact point in the stiffened structure of a spacecraft is difficult to locate. The algorithm combines the Gaussian cross-correlation possibility weight method and the Bayesian posterior probability method. The cross-correlation possibility weight superposition based on grids was used to reduce the dependence of the accuracy of time difference extraction. Gaussian and normalized fitting were used to compensate the reflection, modal transformation, and amplitude attenuation of a stiffened plate. The location result was further optimized by the posterior probability. The proposed algorithm can be applied to the impact source localization of complex stiffened plate structures. The experiment results showed that the average location error can be 2.57 cm with proper sensor network schemes.
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AIMS: The optimal time for mesenchymal stem cell (MSCs) transplantation remains an unresolved issue. We compared the effects of MSCs on a rat remnant kidney model. METHODS: Male Sprague-Dawley rats were randomly divided and treated with a corresponding reagent at 4, 8, 12 and 16 weeks, respectively. A remnant kidney model was established and MSCs were injected into rats. The migration of MSCs was then assessed by using cell-tracking experiments. Renal function and histological analyses were performed 4 weeks after MSC transplantation. Immunohistochemistry, Western blotting and real-time polymerase chain reaction were used to detect the TGF-ß1 and α-SMA levels. RESULTS: Four weeks after MSC injection, MSCs were found to migrate to the injured kidney. Significant histological damage improvement was observed after the treatment of MSCs at 4 and 8 weeks. The functional benefits of MSC treatment were observed in the 5/6 nephrectomy (Nx) + MSC group and the benefits were significantly higher at 4 and 8 weeks than at other time points (p < 0.05). Meanwhile, serum creatinine and urea levels as well as glomerular sclerosis and tubulointerstitial injury indexes were decreased at 4 and 8 weeks. Compared with the 5/6 Nx + PBS group, TGF-ß1 and α-SMA levels were decreased in the 5/6 Nx + MSC group. CONCLUSION: These data can be used to optimize the MSC transplantation time point as a therapeutic modality.
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Trasplante de Riñón/métodos , Células Madre Mesenquimatosas/citología , Actinas/metabolismo , Animales , Movimiento Celular , Creatinina/sangre , Fibrosis/terapia , Tasa de Filtración Glomerular , Glomeruloesclerosis Focal y Segmentaria/sangre , Túbulos Renales/lesiones , Masculino , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Factor de Crecimiento Transformador beta/metabolismo , Urea/sangreRESUMEN
ABSTRACT: Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-ß in neurons, which is a key step in senile plaque formation. Therefore, restoring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease. Microtubule acetylation/deacetylation plays a central role in lysosomal acidification. Here, we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease. Furthermore, we found that treatment with valproic acid markedly enhanced autophagy, promoted clearance of amyloid-ß aggregates, and ameliorated cognitive deficits in a mouse model of Alzheimer's disease. Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease, in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
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BACKGROUND: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. METHODS: Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. RESULTS: During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55-7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41-8.05, p = 0.006) and 4.72 (95%CI: 1.47-15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). CONCLUSION: Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Metilaminas , Humanos , Diabetes Mellitus Tipo 2/prevención & control , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Metilaminas/sangre , Femenino , Masculino , Persona de Mediana Edad , Estudios Longitudinales , China/epidemiología , Adulto , Factores de Riesgo , Dieta , Estudios Prospectivos , Incidencia , Anciano , Colina/sangreRESUMEN
Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr-/- mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr-/- SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr-/- mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr-/- mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory.
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Acetilcolina , Neuronas Colinérgicas , Corteza Prefrontal , Animales , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/fisiología , Acetilcolina/metabolismo , Ratones , Masculino , Ratones Noqueados , Reconocimiento en Psicología/fisiología , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/fisiología , Ratones Endogámicos C57BL , Células Piramidales/metabolismo , Células Piramidales/fisiología , Hipocampo/metabolismo , Receptores de Factor de Crecimiento NerviosoRESUMEN
Background: Periodontitis is one of the most common oral diseases and has been shown to be a risk factor for systemic diseases. Our aim was to investigate the relationship between periodontitis and cognitive impairment and to explore the role of the P38 MAPK signaling pathway in this process. Methods: We established a periodontitis model by ligating the first molars of SD rats with silk thread and injecting Porphyromonas gingivalis (P. gingivalis) or P. gingivalis plus the P38 MAPK inhibitor SB203580 at the same time for ten weeks. We assessed alveolar bone resorption and spatial learning and memory using microcomputed tomography and the Morris water maze test, respectively. We used transcriptome sequencing to explore the genetic differences between the groups. The gingival tissue, peripheral blood and hippocampal tissue were assessed for the cytokines TNF-α, IL-1ß, IL-6, IL-8 and C reactive protein (CRP) with enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). We observed the presence of P. gingivalis in the hippocampus of rats by paraffin-fluorescence in situ hybridization (FISH). We determined the activation of microglia by immunofluorescence. Finally, Western blot analysis was employed to determine the expression of amyloid precursor protein (APP), ß-site APP-cleaving enzyme 1 (BACE1) and P38MAPK pathway activation. Results: We demonstrated that silk ligature-induced periodontitis plus injection of P. gingivalis into subgingival tissue could lead to memory and cognitive impairment. Transcriptome sequencing results suggested that there were neurodegenerative diseases in the P. gingivalis group, and the MWM test showed that periodontitis reduced the spatial learning and memory ability of mild cognitive impairment (MCI) model rats. We found high levels of inflammatory factors (TNF-α, IL-1ß, IL-6, and IL-8) and CRP in the gingiva, peripheral blood and hippocampus, and the expression of APP and BACE1 was upregulated, as was the P38 MAPK pathway activation. Activated microglia and the presence of P. gingivalis were also found in the hippocampus. P38 MAPK inhibitors mitigated all of these changes. Conclusion: Our findings strongly suggest that topical application of P. gingivalis increases the inflammatory burden in the peripheral and central nervous systems (CNS) and that neuroinflammation induced by activation of P38 MAPK leads to impaired learning and memory in SD rats. It can also modulate APP processing. Therefore, P38 MAPK may serve as a linking pathway between periodontitis and cognitive impairment.
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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloidß (Aß) in the brain. The gut/brain axis may serve a role in AD pathogenesis. The present study investigated deposition of Aß in the intestinal epithelium and its potential effects on intestinal barrier function in a transgenic mouse model of AD. To investigate alterations in the structure and functionality of the intestinal mucosal barrier in AD model mice, hematoxylin and eosin staining for Paneth cell count, Alcian blueperiodic acid Schiff staining for goblet cells, immunohistochemistry and immunofluorescence for mucin (MUC)2 and wheat germ agglutin expression, transmission electron microscopy for mucosal ultrastructure, FITClabeled dextran assay for intestinal permeability, quantitative PCR for goblet cell precursor expression and western blot analysis for tight junction proteins, MUC2 and inflammatory cytokine detection were performed. The results showed that AD model mice exhibited excessive Aß deposition in the intestinal epithelium, which was accompanied by increased intestinal permeability, inflammatory changes and decreased expression of tight junction proteins. These alterations in the intestinal barrier led to an increased proliferation of goblet and Paneth cells and increased mucus synthesis. Dysfunction of gut barrier occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve early manipulation of gut physiology and its microbiota.
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Enfermedad de Alzheimer , Mucinas , Ratones , Animales , Mucinas/metabolismo , Enfermedad de Alzheimer/patología , Uniones Estrechas/metabolismo , Mucosa Intestinal/metabolismo , Ratones Transgénicos , Permeabilidad , Proteínas de Uniones Estrechas/metabolismoRESUMEN
Osteoporosis (OP) is a debilitating skeletal abnormality involving bone remodeling and bone cell homeostasis characterized by decreased bone strength and high fracture risk. A novel therapeutic intervention for OP by manipulating cellular autophagy-apoptosis processes to promote skeletal homeostasis is presented. Protective effects of the naturally occurring plant extract Liquiritigenin (LG) were demonstrated in an ovariectomy (OVX)-OP mouse model and preosteoblast MC3T3-E1 cells. Micro-CT and histological staining assessments of skeletal phenotype were applied alongside detection of autophagy activity in osteocytes and MC3T3-E1 cells by transmission electron microscopy (TEM). The effects of LG on chloroquine (CQ)- and the apoptosis-inducing TS-treated osteogenic differentiations and status of lysosomes within MC3T3-E1 cells were analyzed by Neutral red, Alizarin red S and alkaline phosphatase (ALP) staining and Western blot assays. Treatment with LG prevented bone loss, increased osteogenic differentiation in vivo and in vitro, and inhibited osteoclast formation to some extent. TEM analyses revealed that LG can improve auto-lysosomal degradation within osteocytes from OVX mice and MC3T3-E1 cells. The abnormal status of lysosomes associated with CQ and TS treatments was notably alleviated by LG which also reduced levels of apoptosis-induced inhibition of osteogenic differentiation and averted abnormal osteogenic differentiation as a consequence of a blockage in autolysosome degradation. Overall, LG stimulates bone growth in OVX mice through increased osteogenic differentiation and regulation of autophagy-apoptosis mechanisms, presenting an auspicious natural therapy for OP.
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Clear cell carcinoma (CCC), endometrioid carcinoma (EC), and serous carcinoma (SC) are the major histological subtypes of epithelial ovarian cancer (EOC), whose differences in carcinogenesis are still unclear. Here, we undertake comprehensive proteomic profiling of 80 CCC, 79 EC, 80 SC, and 30 control samples. Our analysis reveals the prognostic or diagnostic value of dysregulated proteins and phosphorylation sites in important pathways. Moreover, protein co-expression network not only provides comprehensive view of biological features of each histological subtype, but also indicates potential prognostic biomarkers and progression landmarks. Notably, EOC have strong inter-tumor heterogeneity, with significantly different clinical characteristics, proteomic patterns and signaling pathway disorders in CCC, EC, and SC. Finally, we infer MPP7 protein as potential therapeutic target for SC, whose biological functions are confirmed in SC cells. Our proteomic cohort provides valuable resources for understanding molecular mechanisms and developing treatment strategies of distinct histological subtypes.
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Carcinoma Endometrioide , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/genética , Neoplasias Ováricas/metabolismo , Proteómica , Carcinoma Endometrioide/metabolismo , Transducción de Señal , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas de la MembranaRESUMEN
Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERß-mediated IGF-1/IGF-1R/GSK-3ß signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.
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BACKGROUND: Data on kidney cancer burden are valuable for health-related policy making. OBJECTIVE: To report the results of the Global Burden of Disease 2017 study on global kidney cancer burden estimates grouped by gender, age, region, country or territory, and sociodemographic index (SDI) from 1990 to 2017. DESIGN, SETTING, AND PARTICIPANTS: This study is based on the Global Burden of Disease database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We report here detailed estimates and temporal trends of the burden estimates of kidney cancer from 1990 to 2017, stratified by gender and age, in 195 countries and territories. We further evaluated the relationship between these estimates and the SDI, a composite indicator of income per person, years of education, and fertility as a measurement of the socioeconomic level of a country/region. The percentage change and estimated annual percentage change of incidence, mortality, and disability-adjusted life years (DALYs) were calculated to quantify temporal trends. RESULTS AND LIMITATIONS: Globally, age-standardized incidence rates, age-standardized death rates, and DALYs of kidney cancer in males exhibited an increase of 0.387%/yr, 0.345%/yr, and 0.046%/yr, respectively, from 1990 to 2017. This trend was mainly due to the increase in middle and low-middle SDI quintile countries. However, in females, decreasing trends of -0.324%/yr, -0.330%/yr, and -0.669%/yr, respectively, were observed. These trends were mainly due to the decrease in high, high-middle, and middle SDI quintile countries. Study limitations included differences in data collection practices, coding systems, and quality of data sources. CONCLUSIONS: The burden estimate pattern of kidney cancer trends varies widely between genders and throughout the world. Low-middle and middle SDI quintile countries face the highest burden estimates, especially for males. Efforts to increase health care investment are needed in these countries. PATIENT SUMMARY: The global burden estimate of kidney cancer trends increased in males; however, it decreased in females.
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Carga Global de Enfermedades , Neoplasias Renales , Años de Vida Ajustados por Discapacidad , Femenino , Humanos , Incidencia , Neoplasias Renales/epidemiología , Masculino , Años de Vida Ajustados por Calidad de VidaRESUMEN
The cellulose nanocrystals (CNC) has attracted widespread attention in reinforced materials. However, the application of CNC in electrospinning has been limited due to its self-polymerization. Herein, a cobweb-like nanofibrous membrane was fabricated by electrospinning the polyacrylonitrile (PAN) and sulfydryl-functionalized CNC (SC). The SC content could reach to 48 wt% after the thiolation modification. The membrane with ultrafine fibers and interlaced nets possessed outstanding porosity (91.7%) and underwater superoleophobicity. An ultrahigh permeation flux of 1244 L·m-2·h-1 with a separation efficiency of >99.9% was achieved driven by gravity. The mechanical properties also enhanced significantly with the increase of SC. When the addition amount of SC was 48 wt%, the maximum tensile stress was 2.9 MPa, which was 3.4 times than that of the PAN membrane. The antifouling performance and chemical stability endowed the SC(48)/PAN membrane with intriguing reusability, thus making it exhibit enormous potential in oil/water separation.
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Background: Fuzheng Kang'ai decoction (FZKA) has been widely used to treat Non-Small Cell Lung Cancer (NSCLC) patients in China for decades, showing definitively curative effects in clinic. Recently, we found that FZKA could induce NSCLC cell ferroptosis, another type of programmed cell death (PCD), which is totally different from cell apoptosis. Therefore, in the present study, we aim to discover the exact mechanism by which FZKA induces NSCLC cell ferroptosis, which is rarely studied in Traditional Chinese Medicine (TCM). Methods: Cell proliferation assay were performed to detect the cell viability. Cell ferroptosis triggered by FZKA was observed by performing lipid peroxidation assay, Fe2+ Ions assay, and mitochondrial ultrastructure by transmission electron microscopy. Ferroptosis inhibitors including liproxstatin-1 and UAMC 3203 were used to block ferroptosis. The ratio of GSH/GSSG was done to measure the alteration of oxidative stress. Western blot and qRT-PCR were carried out to detect the expression of solute carrier family 7 member 11 (SLC7A11), solute carrier family 3 member 2 (SLC3A2) and glutathione peroxidase 4 (GPX4) at protein and mRNA levels, respectively. Lentivirus transfection was performed to overexpress GPX4 stably. Animal model was done to verify the effect of FZKA-induced ferroptosis in NSCLC in vivo and immunohistochemistry was done to detect the expression of SLC7A11, SLC3A2 and GPX4 at protein level. Results: First of all, in vitro experiments confirmed the inhibition effect of FZKA on NSCLC cell growth. We then, for the first time, found that FZKA induced NSCLC cell ferroptosis by increasing lipid peroxidation and cellular Fe2+ Ions. Moreover, characteristic morphological changes of NSCLC cell ferroptosis was observed under transmission electron microscopy. Mechanistically, GPX4, as a key inhibitor of lipid peroxidation, was greatly suppressed by FZKA treatment both at protein and mRNA levels. Furthermore, system xc- (SLC7A11 and SLC3A2) were found to be suppressed and a decreased GSH/GSSG ratio was observed at the same time when treated with FZKA. Notably, overexpressing GPX4 reversed the effect of FZKA-induced NSCLC cell ferroptosis significantly. Finally, the above effect was validated using animal model in vivo. Conclusion: Our findings conclude that GPX4 plays a crucial role in FZKA-induced NSCLC cell ferroptosis, providing a novel molecular mechanism by which FZKA treats NSCLC.
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The pathogenesis of Alzheimer's disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid ß peptide and aggregation of misfolded proteins. Autophagy is an important regulator of inflammatory bodies. However, autophagy shows dynamic changes in the development of AD, and its role in inflammation remains controversial. In this study, the key link between autophagic disorders and the NLRP3 inflammasome in AD was investigated. APP/PS1 double transgenic mice and C57 mice with Aß25-35 injected into the lateral ventricle were used as two animal models of AD. Immunofluorescence staining and Western blot analysis showed that NLRP3 inflammasome-related proteins and inflammatory cytokines, such as IL-1α, IL-1ß, IL-6, IL-12, and TNF-α, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of Aß25-35 increased the expression of NLRP3 inflammasome-related proteins, while exogenous Aß25-35 intervention more significantly activated inflammation. Furthermore, LC3 was increased in the AD animal and cell models, and the level of Lamp1 decreased. After overexpression of the primary regulator of lysosomal biogenesis, TFEB, the lysosome protein Lamp1 was increased, and LC3 and inflammatory protein expression were decreased. These results suggest that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, which may be related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells.
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Circular RNAs (circRNAs) are regulatory molecules that participate in the occurrence, development and progression of tumors. To obtain a complete blueprint of cervical carcinogenesis, we analyzed the temporal transcriptomic landscapes of mRNAs and circRNAs. Microarrays were performed to identify the circRNA and mRNA expression profiles of cervical squamous cell carcinoma (CSCC) and high-grade squamous intraepithelial lesion (HSIL) patients compared with normal controls (NC). Short time-series expression miner (STEM) was utilized to characterize the time-course expression patterns of circRNAs and mRNAs from NC to HSIL and CSCC. A total of 3 circRNA profiles and 3 mRNA profiles with continuous upregulated patterns were identified and selected for further analysis. Furthermore, functional annotation showed that the mRNAs were associated with DNA repair and cell division. The protein-protein interaction (PPI) network analysis revealed that the ten highest-degree genes were considered to be hub genes. Subsequently, a competing endogenous RNA (ceRNA) network analysis and real-time PCR validation indicated that hsa_circ_0001955/hsa-miR-6719-3p/CDK1, hsa_circ_0001955/hsa-miR-1277-5p/NEDD4L and hsa_circ_0003954/hsa-miR-15a-3p/SYCP2 were highly correlated with cervical carcinogenesis. Silencing of hsa_circ_0003954 inhibited SiHa cell proliferation and perturb the cell cycle in vitro. This study provides insight into the molecular events regulating cervical carcinogenesis, identifies functional circRNAs in CSCC, and improves the understanding of the pathogenesis and molecular biomarkers of CSCC and HSIL.
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BACKGROUND: BRCA2 mutation has a more substantial impact on the homologous recombination and superior therapeutic response to platinum-based chemotherapy than BRCA1 mutation. Whether BRCA2-mutated patients could benefit more from PARPi than BRCA1-mutated patients remains unclear. We performed a meta-analysis to assess the efficacy difference of PARPi between BRCA1 mutation carriers and BRCA2 mutation carriers. METHODS: Pubmed, Embase, and Cochrane Library were comprehensively searched for randomized controlled trials (RCTs) of PARPi that had available hazard ratios (HRs) of progression-free survival (PFS) in both BRCA1-mutated population and BRCA2-mutated population. We calculated the pooled PFS HRs and 95%CI using randomized-effect models, and the difference between the two estimates was compared by interaction test. RESULTS: A total of 11 eligible RCTs of high quality were identified through search. Overall, 1544 BRCA1 mutation carriers and 1191 BRCA2 mutation carriers were included in the final analysis. The pooled PFS HR was 0.42 (95% CI: 0.35-0.50) in BRCA1-mutated patients who were treated with PARPi compared with patients in the control group. In BRCA2-mutated patients treated with PARPi, the pooled PFS HR compared with the control groups was 0.35 (95% CI: 0.24-0.51). The difference in efficacy of PARPi was not significant between the two subgroups (P heterogeneity = 0.40, for interaction). CONCLUSION: BRCA1-mutated patients and BRCA2-mutated patients could benefit from PARPi, and the efficacy is comparable. Currently, there is no evidence that BRCA2-mutated patients would benefit more from PARPi than BRCA1-mutated patients. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42020214582.