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The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Animais , Camundongos , Resistencia a Medicamentos Antineoplásicos/genética , Modelos Animais de Doenças , Conhecimento , Células-Tronco Neoplásicas , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genéticaRESUMO
Tumor acidity-driven nanomotors may offer robust propulsion for tumor-specific penetrating drug delivery. Herein, an acidity-actuated poly(amino acid) calcium phosphate (CaP) hybrid nanomotor (PCaPmotor) was designed, using a mPEG-PAsp-PPhe@THZ531 micelle (Poly@THZ) for CaP mineralization accompanied by αPD-L1 antibody encapsulation. Dissolution of the CaP layer in an acidic tumor environment gave off heat energy to propel the nanomotor to augment the cellular uptake and penetration into deeply seated cancer cells while facilitating αPD-L1 release. THZ531 delivered by the PCaPmotor inhibited CDK12 and its down-streamed phosphorylation of RNAP-II to increase the cancer immunogenicity events such as the DNA damage, cell apoptosis, immunogenic cell death, lysosomal function disturbance, and MHC-I upregulation. THZ531 and αPD-L1 cosupplied by PCaPmotor significantly increased the frequency of DCs maturation and intratumoral infiltration of CTLs, but the two free drugs did not. Consequently, the PCaP@THZ/αPD-L1 nanomotor resulted in synergistic anticancer immunotherapy in mice. This acid-actuated PCaPmotor represented a new paradigm for penetrating drug delivery.
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INTRODUCTION: This retrospective study aimed to investigate treatment patterns and outcomes in patients with NSCLC harboring EGFR20ins in China. EGFR20ins mutations are associated with poor responses to EGFR-TKIs, and limited real-world data exist regarding the efficacy of various treatment modalities. METHODS: In this retrospective, single-center study, treatment outcomes, including PFS and ORR, were evaluated for different treatment regimens based on imaging assessments. The impact of mutation heterogeneity on treatment efficacy was also explored. RESULTS: Data from 302 patients diagnosed with NSCLC with EGFR20ins were analyzed. EGFR-TKI monotherapy demonstrated suboptimal PFS compared to platinum-based chemotherapy in the first-line setting (3.00 m vs. 6.83 m, HR = 3.674, 95%CI = 2.48-5.44, p < 0.001). Platinum plus pemetrexed plus bevacizumab combination therapy showed improved PFS and ORR compared to platinum plus pemetrexed (7.50m vs. 5.43 m, HR = 0.593, 95%CI = 0.383-0.918, p = 0.019). In later-line treatments, monotherapy with EGFR-TKIs or ICIs exhibited suboptimal efficacy. The specific EGFR20ins subtype, A763_Y764insFQEA, showed favorable responses to EGFR-TKIs in real-world settings. CONCLUSIONS: This large-scale real-world study provides valuable insights into the treatment patterns and outcomes of NSCLC patients with EGFR20ins mutations in China. These findings contribute to the understanding of EGFR20ins treatment and provide real-world benchmark for future clinical trials and drug development.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Éxons , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Feminino , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , China , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Adulto , Pemetrexede/uso terapêutico , Pemetrexede/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Mutagênese Insercional , Mutação , Idoso de 80 Anos ou mais , População do Leste AsiáticoRESUMO
Pyroptosis is a proinflammatory form of programmed cell death that results in the release of cellular contents and activation of immune responses. However, GSDME (a pyroptosis-executed protein) is suppressed in many cancers. Herein, we constructed a nanoliposome (GM@LR) for codelivering the GSDME-expressing plasmid and manganese carbonyl (MnCO) into TNBC cells. MnCO generated Mn2+ and carbon monoxide (CO) in the presence of H2O2. The CO-activated caspase-3, which cleaved the expressed GSDME, converting apoptosis to pyroptosis in 4T1 cells. In addition, Mn2+ promoted maturation of dendritic cells (DCs) by the activation of STING signaling pathway. The increased proportion of intratumoral mature DCs brought about massive infiltration of cytotoxic lymphocytes, leading to a robust immune response. Besides, Mn2+ could be applied for magnetic resonance imaging (MRI)-guided metastasis detection. Taken together, our study showed that GM@LR nanodrug could effectively inhibit tumor growth via pyroptosis and STING activation combined immunotherapy.
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Nanopartículas , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Peróxido de Hidrogênio/farmacologia , Nanopartículas/uso terapêutico , Nucleotidiltransferases/farmacologia , Piroptose , Feminino , Animais , CamundongosRESUMO
Although extensive research has been carried out on the epigenetic regulation of single RNA modifications in gastric cancer, little is known regarding the crosstalk of four major RNA adenosine modifications, namely, m6A, m1A, alternative polyadenylation and adenosine-to-inosine RNA editing. By analyzing 26 RNA modification "writers" in 1750 gastric cancer samples, we creatively constructed a scoring model called the "Writers" of the RNA Modification Score (WRM_Score), which was able to quantify the RNA modification subtypes of individual patients. In addition, we explored the relationship between WRM_Score and transcriptional and posttranscriptional regulation, tumor microenvironment, clinical features and molecular subtypes. We constructed an RNA modification scoring model including two different subgroups: WRM_Score_low and WRM_Score_high. The former was associated with survival benefit and good efficacy of immune checkpoint inhibitors (ICIs) due to gene repair and immune activation, while the latter was related to poor prognosis and bad efficacy of ICIs because of stromal activation and immunosuppression. The WRM score based on immune and molecular characteristics of the RNA modification pattern is a reliable predictor of the prognosis of gastric cancer and the therapeutic efficacy of immune checkpoint inhibitors in gastric cancer.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Epigênese Genética , Inibidores de Checkpoint Imunológico , Imunoterapia , Adenosina/genética , RNA/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: To date, the optimal recommended specific neoadjuvant regimens for resectable or borderline resectable pancreatic cancer (RPC or BRPC) remain an unanswered issue. METHODS: We systematically searched the electronic databases to identify randomized controlled trials (RCTs) comparing different neoadjuvant therapy strategies for RPC or BRPC. The primary outcome was overall survival (OS). Comprehensive analyses and evaluations were performed using the single-arm, paired, and network meta-analyses. RESULTS: Twelve RCTs involving 1279 patients with RPC or BRPC were enrolled. The paired meta-analysis showed that neoadjuvant therapy improved OS for both RPC (hazard ratio (HR) 0.69, 95% c.i. 0.54 to 0.87) and BRPC (HR 0.60, 0.42 to 0.86) compared with upfront surgery (UP-S). Neoadjuvant chemotherapy (NAC) also improved OS for both RPC (HR 0.63, 0.47 to 0.85) and BRPC (HR 0.44, 0.27 to 0.71), while neoadjuvant chemoradiotherapy (NACR) improved OS only for BRPC (HR 0.68, 0.52 to 0.89) and not for RPC (HR 0.79, 0.54 to 1.16). Network meta-analysis found that NAC was superior to NACR in OS for RPC/BRPC (HR 0.58, 0.37 to 0.90). Neoadjuvant chemotherapy based on modified fluorouracil/folinic acid/irinotecan/oxaliplatin (NAC-mFFX) and neoadjuvant chemotherapy based on abraxane/gemcitabine (NAC-AG) ranked first and second in OS for RPC/BRPC. CONCLUSIONS: Both RPC and BRPC could obtain OS benefits from neoadjuvant therapy compared with UP-S, and NAC improved OS both in RPC and BRPC while NACR only improved OS in BRPC. Furthermore, NAC was superior to NACR, and NAC-mFFX and NAC-AG might be recommended sequentially as the best neoadjuvant therapy strategies.
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Terapia Neoadjuvante , Neoplasias Pancreáticas , Humanos , Metanálise em Rede , Neoplasias Pancreáticas/tratamento farmacológico , Gencitabina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias PancreáticasRESUMO
OBJECTIVES: This study aimed to assess the efficacy of Aidi combined with standard treatment, including radiotherapy (R), chemotherapy (C), or chemoradiotherapy (CR), for unresectable esophageal cancer (EC). METHODS: Eight online databases were queried to collect randomized controlled trials (RCTs) published from database construction to August 2022. Patients in the control group underwent standard treatment with R, C, or CR, whereas those in the experimental group underwent Aidi combined with standard treatment. RESULTS: In this meta-analysis, 29 reports with 2079 patients were included. The results showed that the Aidi-based combination therapy groups had higher objective response rates (ORRs), disease control rates (DCRs), one-year overall survival (OS) and improvement and stability of Karnofsky performance status (KPS) than the control group (risk ratio (RR) = 1.24 (95% CI = 1.17-1.33), 1.09 (95% CI = 1.05-1.14), 1.50 (95% CI = 1.31-1.72), and 1.28 (95% CI = 1.16-1.41)). The Aidi-based combination therapy groups also had lower total incidence rates of bone marrow suppression (BMS), chemotherapy-induced nausea and vomiting (CINV) and radiation esophagitis (RE) than the control group (RR = 0.48 (95% CI = 0.41-0.56), 0.46 (95% CI = 0.36-0.58), and 0.49 (95% CI = 0.38-0.62)). In addition, subgroup analysis suggested that the optimal dose and cycle of Aidi injection combined therapy was 80-100 ml/time and 30 days/2 cycles. The efficacy of Aidi combined with DP (docetaxel + cisplatin) was better than the Aidi combined with PF (cisplatin plus fluorouracil). CONCLUSION: Aidi-based combination therapy showed high efficacy for unresectable EC treatment and reduced the incidence rates of adverse events. However, further studies including higher-quality RCTs are needed to validate these findings. TRIAL REGISTRATION NUMBER: INPLASY 202290020.
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Carcinoma Pulmonar de Células não Pequenas , Medicamentos de Ervas Chinesas , Neoplasias Esofágicas , Neoplasias Pulmonares , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiorradioterapia , Cisplatino , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Schwann cells (SCs) respond to nerve injury by transforming into the repair-related cell phenotype, which can provide the essential signals and spatial cues to promote axonal regeneration and induce target reinnervation. Endothelial cells (ECs) contribute to intraneural angiogenesis contributing to creating a permissive microenvironment. The coordination between ECs and SCs within injury sites is crucial in the regeneration process, however, it still unclear. As the intercellular vital information mediators in the nervous system, exosomes have been proposed to take a significant role in regulating regeneration. Thus, the main purpose of this study is to determine the facilitative effect of ECs-derived exosomes on SCs and to seek the underlying mechanism. RESULTS: In the present study, we collected exosomes from media of ECs. We demonstrated that exosomes derived from ECs possessed the favorable neuronal affinity both in vitro and in vivo. Further research indicated that EC-exosomes (EC-EXO) could boost and maintain repair-related phenotypes of SCs, thereby enhancing axonal regeneration, myelination of regenerated axons and neurologically functional recovery of the injured nerve. MiRNA sequencing in EXO-treated SCs and control SCs indicated that EC-EXO significantly up-regulated expression of miR199-5p. Furthermore, this study demonstrated that EC-EXO drove the conversion of SC phenotypes in a PI3K/AKT/PTEN-dependent manner. CONCLUSION: In conclusion, our research indicates that the internalization of EC-EXO in SCs can promote nerve regeneration by boosting and maintaining the repair-related phenotypes of SCs. And the mechanism may be relevant to the up-regulated expression of miR199-5p and activation of PI3K/AKT/PTEN signaling pathway.
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Células Endoteliais , Exossomos , MicroRNAs , Regeneração Nervosa , Células de Schwann , Exossomos/metabolismo , Regeneração Nervosa/fisiologia , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células de Schwann/metabolismoRESUMO
Woodchip bioreactor (WBR) is commonly used to remove nitrate from drainage and runoff. However, the efficiency of nitrate removal in WBR is highly variable due to the properties of filling materials. In this study, we investigated the potential of recycling two waste materials, biochar (B) and silage leachate (SL), to enhance nitrate removal by providing a better living habitat and extra available carbon for denitrification. We constructed twelve lab-scale bioreactors with different filling materials (WBR, WBR + B, WBR + SL, WBR + B + SL), hydraulic retention times (HRT: 0.5-24 h), and nitrate concentrations (5.4-33 mg L-1) to test nitrate removal efficiency (NRE) and nitrate removal rate (NRR). Our results showed that the combination of biochar and silage leachate led to the highest NRE and NRR, with improvements of 23% and 48%, respectively, compared to WBR alone. However, the benefits of adding biochar and silage leachate were less apparent at longer HRTs. According to the results of our structural equation modeling (SEM), we have attributed the improved denitrification to several factors. These factors include the decrease in dissolved oxygen, saturated hydraulic conductivity, and pH value, as well as an increase in dissolved organic carbon after the addition of silage leachate. Therefore, our study provides evidence that recycling biochar and silage leachate as an additive to WBR could be a beneficial strategy for enhancing nitrate removal. Overall, this study highlights the potential of a win-win solution to improve the efficiency of nitrate removal in water treatment processes.
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Desnitrificação , Nitratos , Silagem , Reatores Biológicos , NitrogênioRESUMO
Phosphorus (P) as an essential nutrient for life sustains the productivity of food systems; yet misdirected P often accumulates in wastewater and triggers water eutrophication if not properly treated. Although technologies have been developed to remove P, little attention has been paid to the recovery of P from wastewater. This work provides a comprehensive review of the state-of-the-art P removal technologies in the science of wastewater treatment. Our analyses focus on the mechanisms, removal efficiencies, and recovery potential of four typical water and wastewater treatment processes including precipitation, biological treatment, membrane separation, and adsorption. The design principles, feasibility, operation parameters, and pros & cons of these technologies are analyzed and compared. Perspectives and future research of P removal and recovery are also proposed in the context of paradigm shift to sustainable water treatment technology.
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In this paper, bismuth oxybromide (BiOBr)/biochar composites were synthesized by a facile ball milling method for synergistic adsorption and photodegradation of Reactive red 120 (RR120). The characterizations show that ball milling changed the degree of crystallization, increased the surface area, and promoted the charge transfer ability of biochar. The 70% BiOBr/BC composite showed the best removal efficiency for RR120 removal with or without light illumination, which proves its enhanced removal ability by adsorption and photodegradation. The biochar is served as a support of BiOBr for preventing its aggregation and a transporter of charges for promoting the separation of photo-induced carriers in composites. BiOBr can release the adsorption sites on the surface of composites by degradation, which facilitated the RR120 removal and regenerated the photocatalyst for reusing. The strong interactions between BiOBr and biochar in composites resulted from ball milling were beneficial for the charge transfer and synergistic removal of adsorption and degradation. Findings of this work indicate that ball milling method is an effective method to prepare highly efficient biochar-based composites for RR120 removal through synergistic adsorption and photodegradation.
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Bismuto , Carvão Vegetal , Adsorção , Carvão Vegetal/química , FotóliseRESUMO
A more common and noninvasive predicting biomarker for programmed cell death 1 (PD-1) antibody remains to be explored. We assessed 46 patients with advanced gastric cancer who received PD-1 antibody immunotherapy and 425-genes next-generation sequencing (NGS) testing. Patients who had a > 25% decline in maximal somatic variant allelic frequency (maxVAF) had a longer progression free survival (PFS) and higher response rate than those who did not (7.3 months vs 3.6 months, p = 0.0011; 53.3% vs 13.3%, p = 0.06). The median PFS of patients with undetectable and detectable post-treatment circulating tumor DNA (ctDNA) was 7.4 months vs. 4.9 months (p = 0.025). Mutation status of TGFBR2, RHOA, and PREX2 in baseline ctDNA influenced the PFS of immunotherapy (p < 0.05). Patients with alterations in CEBPA, FGFR4, MET or KMT2B (p = 0.09) gene had greater likelihood of immune-related adverse events (irAEs). ctDNA can serve as a potential biomarker of the response to immunotherapy in advanced gastric cancers, and its potential role in predicting irAEs worth further exploration.
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Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Gástricas/patologia , DNA Tumoral Circulante/sangue , Feminino , Humanos , Masculino , Prognóstico , Neoplasias Gástricas/sangue , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Taxa de SobrevidaRESUMO
Immune checkpoint blockade (ICB) is demonstrating great potential in cancer immunotherapy nowadays. Yet, the low response rate to ICB remains an urgent challenge for tumor immunotherapy. A pH and matrix metalloproteinase dual-sensitive micellar nanocarrier showing spatio-temporally controlled release of anti-PD-1 antibody (aPD-1) and paclitaxel (PTX) in solid tumors is prepared to realize synergistic cancer chemoimmunotherapy. Antitumor immunity can be activated by PTX-induced immunogenic cell death (ICD), while aPD-1 blocks the PD-1/PD-L1 axis to suppress the immune escape due to PTX-induced PD-L1 up-regulation, thus resulting in a synergistic antitumor chemoimmunotherapy. Through decoration with a sheddable polyethylene glycol (PEG) shell, the nanodrug may better accumulate in tumors to boost the synergistic antitumor treatment in a mouse melanoma model. The present study demonstrates a potent antitumor chemoimmunotherapy utilizing tumor microenvironment-sensitive micelles bearing a sheddable PEG layer to mediate site-specific sequential release of aPD-1 and PTX.
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Anticorpos , Antineoplásicos , Tratamento Farmacológico , Imunoterapia , Metaloproteinases da Matriz , Micelas , Paclitaxel , Animais , Anticorpos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Concentração de Íons de Hidrogênio , Imunoterapia/métodos , Metaloproteinases da Matriz/administração & dosagem , Camundongos , Paclitaxel/administração & dosagem , Polietilenoglicóis/químicaRESUMO
Microplastics (MPs) are small plastic pieces with size less than 5â¯mm that have entered and polluted the environment. While many investigations including several critical reviews on MPs in the environment have been conducted, most of them are focused on their occurrences in marine environment. Current understanding on the occurrences, behaviors, and impacts of MPs in the terrestrial environment is far from complete. A systematic review of the literature was thus conducted to promote the research on MPs in the environment. This work is designed to provide a comprehensive overview that summarizes current knowledge and research findings on environmental occurrences, fate and transport, and impacts of MPs. In addition to discussing the occurrences, characteristics, and sources of MPs in the ocean, freshwater, sediments, soils, and atmosphere, the review also summarizes both the experimental and modeling data of the environmental fate and transport of MPs. Research findings on the toxic effects, bioaccumulation, and bioavailability of MPs in the environment are also covered in this critical review. Future perspectives are discussed as well.
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Monitoramento Ambiental , Poluentes Ambientais/análise , Poluição Ambiental/análise , Microplásticos/análise , Disponibilidade Biológica , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Poluição Ambiental/efeitos adversos , Microplásticos/metabolismo , Microplásticos/toxicidade , Modelos TeóricosRESUMO
BACKGROUND: Intracranial involvement is an uncommon manifestation of Rosai-Dorfman disease (RDD) and had been rarely reported. In this study, we explore clinical characteristics, imageology manifestations and pathological features of primary intracranial RDD so as to improve the understanding for this disease. METHODS: One case (16-years-old boy) with primary intracranial RDD was analyzed and studied retrospectively by MRI features, histopathological observation and immunohistochemical staining, and the related literatures were reviewed. RESULTS: The case was single lesion and involved the dura of the left middle cranial fossa base, which was iso-hypo signal intensity on T1WI and hypointense on T2WI and FLAIR image. The lesion was a homogeneous contrast enhancement mass with dural tail sign and had peritumoral brain edema. Pathological analysis showed the lesion consisted of variable numbers of mature lymphocytes, plasma cells and neutrophils. The characteristic histiocytes were emperipolesis and positively expressed for S-100 and CD-68 and negatively expressed for CD-1a by immunohistochemical analysis. Based on clinical presentations and histological findings after surgical excision, a final diagnosis of primary intracranial RDD was made. CONCLUSION: Primary intracranial RDD, especially located in the cranial base, is exceptionally rare, which hard to be distinguished with meningoma by imageology and clinical manifestations, but could be diagnosed by pathological and immunohistochemical examinations. Surgery is of the most importance treatment and prognosis is optimistic for this disease.
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Histiocitose Sinusal , Adolescente , Dura-Máter , Histiócitos , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos RetrospectivosRESUMO
Integrins function as bi-directional signaling transducers that regulate cell-cell and cell-matrix signals across the membrane. A key modulator of integrin activation is talin, a large cytoskeletal protein that exists in an autoinhibited state in quiescent cells. Talin is a large 235-kDa protein composed of an N-terminal 45-kDa FERM (4.1, ezrin-, radixin-, and moesin-related protein) domain, also known as the talin head domain, and a series of helical bundles known as the rod domain. The talin head domain consists of four distinct lobes designated as F0-F3. Integrin binding and activation are mediated through the F3 region, a critically regulated domain in talin. Regulation of the F3 lobe is accomplished through autoinhibition via anti-parallel dimerization. In the anti-parallel dimerization model, the rod domain region of one talin molecule binds to the F3 lobe on an adjacent talin molecule, thus achieving the state of autoinhibition. Platelet functionality requires integrin activation for adherence and thrombus formation, and thus regulation of talin presents a critical node where pharmacological intervention is possible. A major mechanism of integrin activation in platelets is through heterotrimeric G protein signaling regulating hemostasis and thrombosis. Here, we provide evidence that switch region 2 (SR2) of the ubiquitously expressed G protein (Gα13) directly interacts with talin, relieves its state of autoinhibition, and triggers integrin activation. Biochemical analysis of Gα13 shows SR2 binds directly to the F3 lobe of talin's head domain and competes with the rod domain for binding. Intramolecular FRET analysis shows Gα13 can relieve autoinhibition in a cellular milieu. Finally, a myristoylated SR2 peptide shows demonstrable decrease in thrombosis in vivo Altogether, we present a mechanistic basis for the regulation of talin through Gα13.
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Plaquetas/metabolismo , Proteínas do Citoesqueleto/metabolismo , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Proteínas de Membrana/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Talina/antagonistas & inibidores , Animais , Sítios de Ligação , Adesão Celular , Células Cultivadas , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Humanos , Camundongos , Modelos Moleculares , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Ligação Proteica , Talina/metabolismo , Trombose/metabolismo , Trombose/patologiaRESUMO
BACKGROUND: Gastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death. Identifying novel molecular signaling pathways participating in gastric tumorigenesis and progression is pivotal for rational design of targeted therapies to improve advanced GC outcome. Recently, the endoplasmic reticulum (ER) protein 29 (ERp29) has been shown to inversely associate with primary tumor development and function as a tumor suppressor in breast cancer. However, the role of ERp29 in GC patients' prognosis and its function in GC progression is unknown. METHODS: Clinical importance of ERp29 in the prognosis of GC patients was assessed by examining its expression in 148 GC tumor samples and correlation with clinicopathological characteristics and survival of the patients. The function and underlying mechanisms of ERp29 in GC growth, invasion and metastasis were explored both in vitro and in vivo. RESULTS: Downregulation of ERp29 was commonly found in GC tissues and highly correlated with more aggressive phenotypes and poorer prognosis. Functional assays demonstrated that knockdown of ERp29 increased GC cell migration and invasion and promoted metastasis. Conversely, ectopic overexpression of ERp29 produced opposite effects. Mechanistic studies revealed that loss of ERp29 induced an epithelial-to-mesenchymal transition (EMT) in the GC cells through activation of PI3K/Akt pathway signaling. CONCLUSION: These findings suggest that downregulation of ERp29 is probably one of the key molecular mechanisms responsible for the development and progression of GC.
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Transição Epitelial-Mesenquimal/genética , Proteínas de Choque Térmico/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Expressão Ectópica do Gene , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico/metabolismo , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias Gástricas/patologiaRESUMO
The objective of the present study was to reveal different tolerance of peanut plants to Ca deficiency by determining Ca uptake and Fourier transform infrared spectral (FTIR) differences of two peanut cultivars grown in nutrition solution. Peanut cultivars LH11 and YZ9102 were selected. Seedlings at the first leaf stage were cultivated for 28 days in nutrient solution with 0, 0.01 and 2.0 mmol x L(-1) Ca treatments, respectively. The results showed that under 0 and 0.01 mmol x L(-1) Ca supply, YZ9102 did not show Ca deficiency symptoms and the plant biomass did not change, whereas LH11 exhibited shoot-tip necrosis, smaller plant size, more lateral branches, and plant dry matter weights decreased significantly. YZ9102 had higher plant Ca concentration and Ca accumulation than LH11. Besides, for LH11, Ca was mainly accumulated in roots, while for YZ9102 mainly in leaves. As compared with plants cultivated in 2.0 mol x L(-1) Ca nutrition, root, stem and leaf of LH11 plants under Ca deficiency stress showed higher transmittance at peaks 1 060, 1 380, 1 655, 2 922, and 3 420 cm(-1) in FTIR spectra, indicating that the contents of protein, sugar and lipid decreased obviously in LH11 plants in condition that Ca supply was limited. However, the FTIR spectra of YZ9102 were less affected by Ca deficiency. It is suggested that YZ9102 might be more tolerant to Ca deficiency.