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BACKGROUND: Pretreatment stratification tools can help in clinical decision making in prostate cancer. To date, none incorporates well-established routinely reported adverse prognostic pathologic features such as intraductal carcinoma of prostate (IDC) or cribriform pattern 4 (CC). OBJECTIVE: To assess the impact of addition of CC and/or IDC on the Cancer of Prostate Risk Assessment (CAPRA) and National Cancer Comprehensive Network (NCCN) tools for predicting biochemical recurrence free survival (BCR-FS) and event-free survival (EFS) across multiple patient cohorts. DESIGN, SETTING, AND PARTICIPANTS: Matched prostate biopsies and radical prostatectomies from institutions in Toronto, Wisconsin and Rotterdam. The presence/absence of CC/IDC was recorded on all biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationship to outcome was assessed using Cox proportional hazard models, ANOVA and Harrell's concordance index. RESULTS AND LIMITATIONS: We included 1326 patients (Toronto- 612, Wisconsin- 542, Rotterdam- 172) with median follow up of 4.2 years (IQR 2.9-6.4 years); 306 (23.1%) had CC/IDC on biopsy with 207 (20.9%) BCR and 154 (11.6%) events (metastases/death). Addition of CC/IDC improved stratification in CAPRA scores 3 to 5 for BCR-FS (c-index increase 0.633-0.658, P < .001) and scores 6-10 for EFS (c-index increase 0.653-0.697, P < .001). For NCCN, all risk groups apart from score 1 to 2 showed improvement in BCR-FS (c-index increase 0.599-0.636, P < 0.001) and EFS prediction (c-index increase 0.648-0.697, P < .001). Sub-analysis of grade group (GG) 2 biopsies showed similar findings. The retrospective nature and inclusion of cases only reported by genitourinary pathologists are study limitations. CONCLUSIONS: The clinical benefit of the addition of CC/IDC to both CAPRA and NCCN pretreatment tools was validated in 3 cohorts, including the subset of biopsy GG2 prostate cancer patients. PATIENT SUMMARY: Including additional pathologic features to existing pretreatment, clinical decision making tools improves the ability to predict prostate cancer recurrence, cancer spread and death of disease.
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Carcinoma Intraductal não Infiltrante , Neoplasias da Próstata , Masculino , Humanos , Próstata/cirurgia , Próstata/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Carcinoma Intraductal não Infiltrante/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Biópsia , Medição de Risco/métodos , Gradação de Tumores , ProstatectomiaRESUMO
Objective: Drug-resistant tuberculosis (DR-TB) in children seriously threatens TB control. Information on the epidemiology and characteristics of DR-TB in children in China is limited. We studied data in Shenyang Tenth People's Hospital to understand the DR-TB epidemiology in children in Shenyang. Design or Methods: We retrospectively analyzed drug resistance testing data of pediatric TB patients between 2017 and 2021, and included 2976 clinically-diagnosed pediatric TB patients. We described the epidemiology of DR-TB and analyzed the trends of DR-TB incidence. The Kappa value was calculated to assess the agreement between MGIT 960 DST and Xpert MTB/RIF for detecting rifampicin resistance. Multivariate logistic regression was used to identify the risk factors for DR-TB in pediatric patients. Results: Of the 2976 TB patients, 1076 were confirmed by MGIT 960 culture and/or Xpert MTB/RIF. Among the 806 patients identified by MGIT 960 culture, 232 cases (28.78%) were DR-TB. Resistance to the six drugs was in the following order: streptomycin (21.09%), isoniazid (9.35%), rifampin (15.01%), levofloxacin (6.20%), ethambutol (4.22%), and amikacin (3.23%). Alarmingly, 12.90% were MDR-TB (104/806), including 28 (3.47%) pre-XDR-TB. Of the 1076 pediatric TB patients, 295 (27.4%) developed DR-TB to any one drug (including 69 rifampicin-resistant cases identified by Xpert MTB/RIF only). No difference was found in the incidence of pediatric DR-TB between 2017 and 2021. Among 376 patients who were positive for both methods, using the MGIT 960 DST results as the gold standard, Xpert MTB/RIF's sensitivity for detecting rifampicin resistance was 91.38% and its specificity was 94.65%. Conclusion: Between 2017 and 2021, the DR-TB incidence in children remained unchanged in Shenyang. RR-TB, MDR-TB, and even Pre-XDR-TB require attention in children with drug-resistant TB. Xpert MTB/RIF helped to detect more rifampicin-resistant pediatric patients; thus Xpert MTB/RIF should be widely used as an important complementary tool to detect rifampicin-resistant TB in children.
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Hydrogen sulfide (H2 S) is a crucial endogenous signaling component in organisms that is involved in redox homeostasis and numerous biological processes. Modern medical research has confirmed that hydrogen sulfide plays an important role in the pathogenesis of many diseases. Herein, a fluorescent probe Eu(ttbd)3 abt based on europium(III) complex was designed and synthesized for the detection of H2 S. Eu(ttbd)3 abt exhibited significant quenching for H2 S at long emission wavelength (625 nm), with rapid detection ability (less than 2 min), high sensitivity [limit of detection (LOD) = 0.41 µM], and massive Stokes shift (300 nm). Additionally, this probe showed superior selectivity for H2 S despite the presence of other possible interference species such as biothiols. Furthermore, the probe Eu(ttbd)3 abt was successfully applied to detect H2 S in water samples.
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Objective: This retrospective study aimed to determine the prevalence and risk factors of combined pulmonary embolism (PE) among patients with pulmonary tuberculosis (TB), as well as evaluate the clinical efficacy of anticoagulation in combination with anti-tuberculosis therapy. Methods: A total of 96 TB patients were included in the study. Among them, 31 patients had combined PE (PE group) and 65 patients did not have PE (no-PE group). Various indicators including lung images, clinical symptoms, blood tests, coagulation function, and others were analyzed to identify risk factors for combined PE in TB patients. Within the PE group, patients were divided into a combined treatment group (received anticoagulation therapy alongside anti-tuberculosis treatment) and a control group (received only anti-tuberculosis treatment). The effectiveness of anticoagulation, serological indexes, and incidence of adverse reactions were compared between the two groups. Results: The prevalence of combined PE in TB patients was 32.29%. Encapsulated effusion or upper lobe predominance, dyspnea, and high creatinine levels were identified as risk factors for combined PE in TB patients. The combined treatment group showed a significantly higher anticoagulation efficiency rate (95.00%) compared to the control group (72.73%). After treatment, serum D-dimer levels were significantly lower in the rivaroxaban group compared to the warfarin group. The incidence of adverse reactions did not differ significantly between the two groups. Conclusion: Combined PE was found in 32.29% of TB patients. Encapsulated effusion or upper lobe predominance, dyspnea, and high creatinine levels were identified as risk factors for combined PE in TB patients. Anticoagulation combined with anti-tuberculosis therapy was effective and safe for managing TB patients with combined PE.
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Aim: To investigate the clinical characteristics and health resource costs among children hospitalised for injuries in southern Sichuan, China, and to provide guidance for prevention and treatment. Methods: We collected clinical data concerning children aged from 29 days to 18 years hospitalised for injuries from January 1, 2017, to December 31, 2021, retrospectively analysing the basic characteristics, evolution of injury characteristics over time, risk factors for events with adverse outcomes, and health resource costs. Results: Among 5,826 hospitalised children with injuries, males (63.6%), those in rural areas (40.3%), and adolescents (33.5%) were most commonly injured. Most injuries occurred at home (52.6%), and during summer. The most common injury types were falls, burns, road traffic injuries, poisoning, and foreign body injuries (32.0%, 17.9%, 13.6%, 8.8%, and 7.9%, respectively). After 2019, the proportion of intentional injuries among adolescent girls was significantly higher. Road traffic injuries most commonly led to poor clinical outcomes (95%CI: 5.39-31.51), followed by falls (95%CI: 2.20-10.67). Adolescents were at higher risk of poor prognosis. Injuries occurring in rural areas, adolescents, road traffic injuries, and falls cost high health resource. Conclusion: Injuries among children remain serious, with males and adolescents from villages predominantly affected. Attention should be paid to intentional injuries among adolescent females also. Targeted prevention and control measures for road traffic injuries and falls should be strengthened.
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Aerobic glycolysis preferentially exists in many cancer cells. LMO2 is an adaptor protein ubiquitously expressed in many epithelia and their malignancies, and it mediates broad-spectrum protein interactions. In this study, results showed that LMO2 directly interacted with glycolytic enzymes PGK1, PGAM1 and LDHA/LDHB, attenuated the glycolytic metabolism flow characterized by decreased glucose intake, ATP production and lactic acid excretion in lung and breast cancer cells, and was positively associated with of CD8+ T-lymphocyte infiltration in the tumor microenvironment. These findings reveal a novel role of LMO2 on modulating glycolysis in tumor cells and cytotoxic T-lymphocyte infiltration in the tumor microenvironment, which expands our knowledge of LMO2 in the field of solid tumors.
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Neoplasias , Linfócitos T Citotóxicos , Humanos , Tórax , Glicólise , Pulmão , Microambiente Tumoral , Proteínas Proto-Oncogênicas , Proteínas Adaptadoras de Transdução de Sinal , Proteínas com Domínio LIMRESUMO
BACKGROUND: Saccadic eye movement (SEM) has been considered a non-invasive potential biomarker for the diagnosis of depression in recent years, but its application is not yet mature. In this study, we used eye-tracking technology to identify the eye movements of patients with depression to develop a new method for objectively identifying depression. METHODS: Thirty-six patients with depression as the depression group, while thirty-six matched healthy individuals as the control group were recruited and completed eye movement tests, including two tasks: the prosaccade task and the antisaccade task. iViewX RED 500 eye-tracking instruments from SMI were used to collect eye movement data for both groups. RESULTS: In the prosaccade task, there was no difference between the depression and control groups(t = 0.019ï¼ P > 0.05). In general, with increasing angle, both groups showed significantly higher peak velocity (F = 81.72ï¼ P < 0.0001), higher mean velocity (F = 32.83, P = 0.000), and greater SEM amplitude (F = 24.23, P < 0.0001). In the antisaccade task, there were significant differences in correct rate (t = 3.219, P = 0.002) and mean velocity (F = 3.253ï¼ P < 0.05) between the depression group and the control group. In the anti-effect analysis, there were significant differences in correct rate (F = 67.44, P < 0.0001) and accuracy (F = 79.02, P < 0.0001) between the depression group and the control group. Both groups showed longer latency and worse correct rate and precision in the antisaccade task compared with the prosaccade task. CONCLUSION: Patients with depression showed different eye movement features, which could be potential biomarkers for clinical identification. Further studies must validate these results with larger sample sizes and more clinical populations.
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Movimentos Oculares , Tecnologia de Rastreamento Ocular , Humanos , Depressão , Movimentos SacádicosRESUMO
There is limited evidence on the diagnostic accuracy of the FRAIL scale in community-dwelling older adults with diabetes. This study aimed to validate the diagnostic accuracy and determine the optimal cutoff point of the FRAIL scale in community-dwelling older adults with diabetes using the Fried Frailty Phenotype as the reference standard. A total of 489 community-dwelling older adults with diabetes aged 60 or above were recruited in this cross-sectional study. The FRAIL scale showed good diagnostic accuracy for frailty screening. The optimal cutoff point for frailty screening in older adults with diabetes was 2. The agreement between the FRAIL scale and the Fried Frailty Phenotype was substantial. The FRAIL scale classified more participants as frail (29.24%) than the Fried Frailty Phenotype (22.09%). These findings provide evidence that the FRAIL scale is a valid tool that can be applied to community-dwelling older adults with diabetes.
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Diabetes Mellitus , Fragilidade , Idoso , Humanos , Fragilidade/diagnóstico , Idoso Fragilizado , Vida Independente , Estudos Transversais , Avaliação Geriátrica , Diabetes Mellitus/diagnósticoRESUMO
The microbiomes of cesarean-born infants differ from vaginally delivered infants and are associated with increased disease risks. Vaginal microbiota transfer (VMT) to newborns may reverse C-section-related microbiome disturbances. Here, we evaluated the effect of VMT by exposing newborns to maternal vaginal fluids and assessing neurodevelopment, as well as the fecal microbiota and metabolome. Sixty-eight cesarean-delivered infants were randomly assigned a VMT or saline gauze intervention immediately after delivery in a triple-blind manner (ChiCTR2000031326). Adverse events were not significantly different between the two groups. Infant neurodevelopment, as measured by the Ages and Stages Questionnaire (ASQ-3) score at 6 months, was significantly higher with VMT than saline. VMT significantly accelerated gut microbiota maturation and regulated levels of certain fecal metabolites and metabolic functions, including carbohydrate, energy, and amino acid metabolisms, within 42 days after birth. Overall, VMT is likely safe and may partially normalize neurodevelopment and the fecal microbiome in cesarean-delivered infants.
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Microbioma Gastrointestinal , Microbiota , Feminino , Gravidez , Humanos , Lactente , Recém-Nascido , Parto Obstétrico , Cesárea/efeitos adversos , FezesRESUMO
Obesity has been reported to promote disordered folliculogenesis, but the exact molecular mechanisms are still not fully understood. In this study, we find that miR-133a is involved in obesity-induced follicular development disorder. After feeding with a high-fat diet (HFD) and fructose water for nine weeks, the mouse body weight is significantly increased, accompanied by an inflammatory state and increased expression of miR-133a in the adipose tissues and ovaries as well as accelerated follicle depletion. Although miR-133a is increased in the fat and ovaries of HFD mice, the increased miR-133a in the HFD ovaries is not derived from exosome transferred from obese adipose tissues but is synthesized by ovarian follicular cells in response to HFD-induced inflammation. In vivo experiments show that intrabursal injection of miR-133a agomir induces a decrease in primordial follicles and an increase in antral follicles and atretic follicles, which is similar to HFD-induced abnormal folliculogenesis. Overexpression of miR-133a modestly promotes granulosa cell apoptosis by balancing the expression of anti-apoptotic proteins such as C1QL1 and XIAP and pro-apoptotic proteins such as PTEN. Overall, this study reveals the function of miR-133a in obesity-induced ovarian folliculogenesis dysfunction and sheds light on the etiology of female reproductive disorders.
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Células da Granulosa , MicroRNAs , Feminino , Camundongos , Animais , Folículo Ovariano/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Apoptose , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Many clinical studies have shown that facial expression recognition and cognitive function are impaired in depressed patients. Different from spontaneous facial expression mimicry (SFEM), 164 subjects (82 in a case group and 82 in a control group) participated in our voluntary facial expression mimicry (VFEM) experiment using expressions of neutrality, anger, disgust, fear, happiness, sadness and surprise. Our research is as follows. First, we collected a large amount of subject data for VFEM. Second, we extracted the geometric features of subject facial expression images for VFEM and used Spearman correlation analysis, a random forest, and logistic regression-based recursive feature elimination (LR-RFE) to perform feature selection. The features selected revealed the difference between the case group and the control group. Third, we combined geometric features with the original images and improved the advanced deep learning facial expression recognition (FER) algorithms in different systems. We propose the E-ViT and E-ResNet based on VFEM. The accuracies and F1 scores were higher than those of the baseline models, respectively. Our research proved that it is effective to use feature selection to screen geometric features and combine them with a deep learning model for depression facial expression recognition.
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Depressão , Emoções , Expressão Facial , Comportamento Imitativo , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Ira , Atenção , Correlação de Dados , Asco , Medo , Felicidade , Modelos Logísticos , Algoritmo Florestas Aleatórias , TristezaRESUMO
Brain glioma is one of the cancer types with worst prognosis, and LMO2 has been reported to play oncogenic functions in brain gliomas. Herein, analysis of datasets from The Cancer Genome Atlas (TCGA) indicated that higher LMO2 level in patient samples indicated worse prognosis in lower grade gliomas (LGG) but not glioblastoma multiforme (GBM). Further, in tumor tissues consisting of a variety of cell types, LMO2 level indicated intratumoral endothelium and pattern recognition receptor (PRR) response in both LGGs and GBMs, and additionally indicated cytotoxic T-lymphocyte, M2 macrophage infiltration and fibroblast specifically in LGGs. Moreover, only in LGGs these aspects were significantly associated with patient survival, in either risky or protective manner, and these dissected associations can give a better prediction on patient prognosis than LMO2 alone. This study not only provided more detailed understandings of LMO2 functional representatives in brain gliomas but also demonstrated that dealing with certain gene (LMO2 in this study) in transcriptome data with the Weighted Gene Co-Expression Network Analysis (WGCNA) method was a robust strategy for dissecting exact and reasonable gene functions/associations in a complicated tumor environment.
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BACKGROUND: Considerable evidence has shown that facial expression mimicry is impaired in patients with depression. We aimed to evaluate voluntary expression mimicry by facial expression recognition for diagnosing depression. METHODS: A total of 168 participants performed voluntary expression mimicry task, posing anger, disgust, fear, happiness, neutrality, sadness, and surprise. 9 healthy raters performed facial expression recognition task through the observer scoring method, and evaluated seven expressions imitated by participants. Emotional scores were calculated to measure any differences between two groups of participants and provided a basis for clinical diagnosis of depression. RESULTS: Compared with the control group, the depression group had lower accuracy in imitating happiness. Compared with the control group, the depression group imitated a higher neutrality bias for sadness, surprise, happiness and disgust, while sadness and surprise had a lower happiness bias; for imitating happiness, the depression group showed higher anger, disgust, fear, neutrality, and surprise bias; for imitating neutrality, the depression group showed higher sadness bias, and lower happiness bias. Compared with the control group, the raters had a higher reaction time to recognize the happiness imitated by depression group, and it was positively correlated with severity of depression. The severity of depression was also negatively correlated with accuracy in imitating happiness, and positively correlated with neutrality bias of imitating surprise. LIMITATIONS: The ecological effectiveness of static stimulus materials is lower than that of dynamic stimuli. Without synchronized functional imaging, there is no way to link brain activation patterns. CONCLUSION: The ability of patients with depression to voluntarily imitate facial expressions declines, which is mainly reflected in accuracy, bias and recognizability. Our experiment has discovered deficits in these aspects of patients with depression, which will be used as a method for diagnosising depression.
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Depressão , Emoções , Reconhecimento Facial , Humanos , Depressão/diagnóstico , Emoções/fisiologia , Expressão Facial , FelicidadeRESUMO
A nephrometry scoring system is a key standard to evaluate the feasibility of partial nephrectomy (PN). Whether based on two-dimensional or three-dimensional images, simplicity, effectiveness, and practicality are the keys to the nephrometric scoring system. Since the emergence of RENAL score in 2009, numerous scoring systems based on different anatomical parameters are established to seek accurately and few parameters to assess the risk of PN and complications. This study aimed to achieve a three-game winning streak in PN more easily and efficiently (negative resection margin, maximum preservation of normal nephron function, and avoiding short-term and long-term complications). Using PubMed, we counted 28 kinds of nephrometric scoring systems. We considered only English literatures published and excluded editorials, commentaries, and meeting abstracts. To the best of our knowledge, this is to date and most comprehensive summary as well as an outlook of the nephrometric scoring system.
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Neoplasias Renais , Humanos , Neoplasias Renais/cirurgia , Nefrectomia/métodos , Néfrons , Rim/cirurgia , Estudos RetrospectivosRESUMO
Background: The prognosis of bladder cancer (BC) is poor, and there is no effective personalized management method for BC patients at present. Developing an accurate model is helpful to make treatment plan and prognosis analysis for BC patients. Endogenous fatty acid metabolism causes cancer cells to become hypoxic, and the coexistence of hypoxia and inflammation is often characteristic of cancer. All three together influence the tumor immune microenvironment, treatment, and prognosis of BC. Methods: We used The Cancer Genome Atlas-Bladder Urothelial Carcinoma (TCGA-BLAC) cohorts as a train group to build a risk model based on fatty acid metabolism, hypoxia and inflammation-related gene signatures and performed external validation with GSE13507, GSE31684, and GSE39281 cohorts. We validated the model to correlate with the clinicopathological characteristics of patients, created an accuracy nomogram, and explored the differences in immune microenvironment and enrichment pathways. Results: We found significant differences in overall survival and progression-free survival between high- and low-risk groups, and patients in the low-risk group had a better prognosis than those in the high-risk group. In the train group, the AUCs for predicting overall survival at 1, 3, and 5 years were 0.745, 0.712, and 0.729, respectively. The 1-, 3-, and 5-year overall survival AUCs were 0.589, 0.672, and 0.666 in the external validation group, respectively. The risk score independently predicted the prognosis of BC patients with AUCs of 0.729. In addition, there was a significant correlation between risk scores and BC clinicopathological features and, in the GSE13507 cohort, we observed that BC progression and deeper invasion were associated with higher risk scores. Risk scores were highly correlated with coproptosis, pyroptosis, m7G, immune checkpoint-related genes, and immune microenvironment. In addition, we found that patients in the low-risk group responded better to immunotherapy, whereas patients in the high-risk group were more sensitive to commonly used chemotherapy drugs. Conclusion: Our findings provide new treatment decisions for BC, and can effectively predict the prognosis of BC patients, which is helpful for the management of BC patients.
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The role of endothelial injury and inflammation in atherosclerosis has been well established. miRNAs have been found to be key regulators in the development of atherosclerosis. Here we investigated whether miR-32-5p and its predicted target gene axin interactor, dorsalization associated (AIDA) are involved in endothelial injury and inflammation. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (oxLDL) to induce endothelial injury and inflammation. AIDA was predicted to be a target gene of miR-32-5p using TargetScan software. Cell viability, migration, and angiogenesis were evaluated using Cell Counting Kit-8, wound-healing, and tube formation assays, respectively. The expression of inflammatory factors was detected using quantitative PCR, enzyme-linked immunosorbent assay, and western blot. We found that miR-32-5p expression was significantly decreased, whereas AIDA expression was significantly increased in oxLDL-treated HUVECs and the increased AIDA expression was reversed by the up-regulation of miR-32-5p. Moreover, both miR-32-5p mimic and knockdown of AIDA enhanced cell viability, promoted cell migration and angiogenesis and suppressed the expression of inflammatory factors including IL-1ß, IL-6, TNF-α, ICAM-1, and VCAM-1 in oxLDL-induced HUVECs. Furthermore, miR-32-5p was verified to directly target AIDA using dual-luciferase reporter assay. Overall, these findings suggest that miR-32-5p/AIDA signal plays an important role in oxLDL-induced endothelial injury and inflammation. This study provides new insights into novel molecular mechanisms of endothelial dysfunction and atherosclerosis.
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Aterosclerose , MicroRNAs , Apoptose , Aterosclerose/genética , Aterosclerose/metabolismo , Proteína Axina/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Transferência de Fosfolipídeos , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula VascularRESUMO
Transcriptional profiling of muscle-invasive bladder cancer (MIBC) using RNA sequencing (RNA-seq) technology has demonstrated the existence of intrinsic basal and luminal molecular subtypes that vary in their prognosis and response to therapy. However, routine use of RNA-seq in a clinical setting is restricted by cost and technical difficulties. Herein, we provide a single-sample NanoString-based seven-gene (KRT5, KRT6C, SERPINB13, UPK1A, UPK2, UPK3A and KRT20) MIBC molecular classifier that assigns a luminal and basal molecular subtype. The classifier was developed in a series of 138 chemotherapy naïve MIBCs split into training (70%) and testing (30%) datasets. Further, we validated the previously published CK5/6 and GATA3 immunohistochemical classifier which showed high concordance of 96.9% with the NanoString-based gene expression classifier. Immunohistochemistry-based molecular subtypes significantly correlated with recurrence-free survival (RFS) and disease-specific survival (DSS) in univariable (p = 0.006 and p = 0.011, respectively) and multivariate cox regression analysis for DSS (p = 0.032). Used sequentially, the immunohistochemical- and NanoString-based classifiers provide faster turnaround time, lower cost per sample and simpler data analysis for ease of clinical implementation in routine diagnostics.
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BACKGROUND: To determine whether SIRPα can be a diagnostic marker of pulmonary tuberculosis (PTB) and the molecular mechanism of SIRPα regulating macrophages to kill Mycobacterium tuberculosis (MTB). METHODS: Meta-analysis combined with subsequent qRT-PCR, western-blotting and flow cytometry assay were used to detect SIRPα expression in PTB patients. Cell-based assays were used to explore the regulation of macrophage function by SIRPα. SIRPα-/- and wide type macrophages transplanted C57BL/6J mice were used to determine the function of SIRPα on MTB infection in vivo. FINDINGS: SIRPα levels are closely correlated with the treatment outcomes among PTB patients. Cell-based assay demonstrated that MTB significantly induces the expression of SIRPα on macrophages. SIRPα deficiency enhances the killing ability of macrophages against MTB through processes that involve enhanced autophagy and reduced necroptosis of macrophages. Mechanistically, SIRPα forms a direct interaction with PTK2B through its intracellular C-terminal domain, thus inhibiting PTK2B activation in macrophages. Necroptosis inhibition due to SIRPα deficiency requires PTK2B activity. The transfer of SIRPα-deficient bone marrow-derived macrophages (BMDMs) into wild type mice resulted in a drop of bacterial load in the lungs but an enhancement of inflammatory lung damage, and the combination of ulinastatin and SIRPα-/-âWT treatment could decrease the inflammation and maintain the bactericidal capacity. INTERPRETATION: Our data define SIRPα a novel biomarker for tuberculosis infection and underlying mechanisms for maintaining macrophage homeostasis. FUNDING: This work was financially supported by the Chinese National Natural Science Foundation project (No.81401635). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Mycobacterium tuberculosis , Tuberculose Pulmonar , Tuberculose , Animais , Camundongos , Autofagia/genética , Quinase 2 de Adesão Focal/metabolismo , Homeostase , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Necroptose , Tuberculose/microbiologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/metabolismo , HumanosRESUMO
Clear cell renal cell carcinoma (ccRCC) is one of the most common tumors in the urinary system. ccRCC has obvious immunological characteristics, and the infiltration of immune cells is related to the prognosis of ccRCC. The effect of immune checkpoint therapy is related to the dynamic changes of the tumor immune microenvironment (TIM). The 7-methylguanosine (m7G) is an additional mRNA modification ability besides m6A, which is closely related to the TIM and affects the occurrence and development of tumors. At present, the correlations between m7G and the immune microenvironment, treatment, and prognosis of ccRCC are not clear. As far as we know, there was no study on the relationship between m7G and the immune microenvironment and survival of clear cell renal cell carcinomas. A comprehensive analysis of the correlations between them and the construction of a prognosis model are helpful to improve the treatment strategy. Two different molecular subtypes were identified in 539 ccRCC samples by describing the differences of 29 m7G-related genes. It was found that the clinical features, TIM, and prognosis of ccRCC patients were correlated with the m7G-related genes. We found that there were significant differences in the expression of PD-1, CTLA4, and PD-L1 between high- and low-risk groups. To sum up, m7G-related genes play a potential role in the TIM, treatment, and prognosis of ccRCC. Our results provide new findings for ccRCC and help to improve the immunotherapy strategies and prognosis of patients.