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AIMS: To investigate the expression of polo-like kinase 1 protein (PLK1) and its phosphorylation level (p-PLK1) in extranodal NK/T cell lymphoma (NKTCL) and their correlation with clinical characteristics and prognosis. METHODS: We collected 40 cases of NKTCL (referred to as the experimental group), which received diagnoses at the First Affiliated Hospital of Zhengzhou University between January 2018 and October 2022. Concurrently, we assembled a control group, including 20 cases afflicted with nasopharyngeal mucosal lymphoid hyperplasia diseases during the same timeframe. We utilized immunohistochemical techniques to evaluate the levels of PLK1 and p-PLK1 expression in both the experimental and control groups. Subsequently, we conducted an analysis to identify disparities in their expression and explore their relationships with clinical characteristics and patient prognosis. RESULTS: Among the 40 NKTCL patients, there were 27 males and 11 females, with a median age of 51 years (range 12-80 years). Compared to the control group, the tissue samples of NKTCL patients exhibited significantly elevated expression levels and active phosphorylation levels of PLK1 (P < 0.05). Correlation analysis of the immunohistochemical H score and Ki-67 positive rate of PLK1 and p-PLK1, revealed a significant positive correlation for both (P < 0.0001, each). No statistically significant differences were observed in the distribution of PLK1 and p-PLK1 expression in NKTCL patients with respect to gender, age, Ann Arbor stage, PINK-E score, B-symptoms, lactate dehydrogenase, ß2-microglobulin, blood EBV-DNA, bone marrow invasion, and lymph node metastasis (p > 0.05). Grouping based on PLK1 and p-PLK1 immunohistochemical H-scores revealed that the high expression of PLK1 and p-PLK1 was associated with poor prognosis. CONCLUSIONS: The expression levels and active phosphorylation levels of PLK1 were significantly increased in NK/T cell lymphoma, and patients with overexpression of PLK1 and p-PLK1 had a poorer prognosis.
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Linfoma Extranodal de Células T-NK , Linfoma de Células T , Masculino , Feminino , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Relevância Clínica , Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinases , Prognóstico , Linfoma de Células T/diagnóstico , Linfoma Extranodal de Células T-NK/patologia , Quinase 1 Polo-LikeRESUMO
Neuronal synchronization at gamma frequency (30-100 Hz: γ) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric Aß1-42 caused a concentration-dependent reduction of γ-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the Aß1-42-induced suppression of γ-oscillations, whereas the mTOR activator leucine mimicked the Aß1-42-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the Aß1-42-induced suppression. The involvement of the mTOR/S6K1 signaling in the Aß1-42-induced suppression was confirmed in Aß-overexpressing APP/PS1 mice, where inhibiting mTOR or S6K1 restored degraded γ-oscillations. To assess the network changes that may underlie the mTOR/S6K1 mediated γ-oscillation impairment in AD, we tested the effect of Aß1-42 on IPSCs and EPSCs recorded in pyramidal neurons. Aß1-42 reduced EPSC amplitude and frequency and IPSC frequency, which could be prevented by inhibiting mTOR or S6K1. These experiments indicate that in early AD, oligomer Aß1-42 impairs γ-oscillations by reducing inhibitory interneuron activity by activating the mTOR/S6K1 signaling pathway, which may contribute to early cognitive decline and provides new therapeutic targets.
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Esophageal squamous cell carcinoma (ESCC) is an invasive malignant tumor with a high incidence rate and mortality. It is imperative to study its tumorigenesis and development for better treatment. CircRNA has been proven to play an important role in various cancers. Our previous studies found that the circ8199 gene is associated with tumor prognosis. To further clarify the role of circ8199 in ESCC, we performed functional experiments and found that overexpression of circ8199 significantly inhibited the proliferation of ESCC cells and the activity of O-linked N-acetylglucosamine transferase (OGT) simultaneously. Further experiments demonstrated that circ8199 could interact with OGT, leading to a decrease in OGT's activity. The reduction of circ8199 expression stimulated the binding activity between OGT and its downstream gene JAK2, promoting the O-GlcNAc glycosylation modification of JAK2 and activating the JAK2-STAT3 pathway. Our study indicated that circ8199 regulates the JAK2-STAT3 pathway through OGT, providing a candidate mechanism for drug discovery and development.
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BACKGROUND: Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer's disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. METHODS: To investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory. RESULTS: In the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner. CONCLUSIONS: Our study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions.
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Doença de Alzheimer , Consolidação da Memória , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Colinérgicos/metabolismo , Colinérgicos/farmacologia , Neurônios Colinérgicos , Hipocampo/metabolismo , Transtornos da Memória/metabolismo , Proteínas tau/metabolismoRESUMO
AIMS: To investigate the clinicopathological features, immunophenotypes and differential diagnosis of CD5-positive splenic marginal zone lymphoma (SMZL). METHODS: We retrospectively analysed 16 CD5-positive cases of SMZL. Assess their clinicopathological features and survival outcomes to evaluate their similarities and differences with a control group of 25 CD5-negative cases of SMZL. RESULTS: Compared with CD5-negative patients, CD5-positive SMZL tends to be more prone to B symptoms, peripheral lymphadenopathy and extranodal infiltration, high Ann Arbor stage, high International Prognostic Index scores, high serum lactic dehydrogenase and high rates of bone marrow involvement. The 5-year survival rate was significantly shorter than that of the CD5-negative group (52.1% and 81.8%, respectively). CONCLUSIONS: There are many similarities between CD5-positive SMZL and classical CD5-negative SMZL in clinical presentations, morphology and immunohistochemistry, but the former may have a more aggressive clinical course with a poorer prognosis.
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BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer's disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H+-ATPase (v-ATPase) activity, respectively, which were analysed by One-way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One-way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC). RESULTS: We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P = 0.0038; Glutamic acid, P = 0.0348; Alanine, P = 0.0037; Glycine, P = 0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P = 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P = 0.0015] and inhibition of autophagosome formation [microtubule-associated protein light chain 3 II (LC3 II), P = 0.0073; LC3 puncta, P < 0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment. CONCLUSIONS: Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.
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Autofagossomos , Alvo Mecanístico do Complexo 1 de Rapamicina , Antígeno-1 Intracelular de Células T , Proteínas tau , Aminoácidos/metabolismo , Autofagossomos/metabolismo , Células HEK293 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Antígeno-1 Intracelular de Células T/metabolismo , Proteínas tau/metabolismo , Proteínas tau/farmacologiaRESUMO
In medical domain, risk factors are often used to model disease predictions. In order to make the most use of the predictive models, linking the model with real patient data generates personalized disease progression and predictions. However, the risk factors are fragmented all over medical literature, certain risks can be accumulated for a disease and the aggregated probability may increase or decrease the occurrence of a disease. In this paper, a risk predictive framework which forms a base for a complete risk prediction model that can be used for various health applications is proposed.
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BACKGROUND: Glycogen synthase kinase-3ß (GSK-3ß) is one of the most effective kinases in promoting tau hyperphosphorylation and accumulation in Alzheimer's disease (AD). However, it is not clear how GSK-3ß activity is regulated during AD progression. METHODS: We firstly used mass spectrometry to identify the acetylation site of GSK-3ß, and then established the cell and animal models of GSK-3ß acetylation. Next, we conducted molecular, cell biological and behavioral tests. Finally, we designed a peptide to test whether blocking tau-mediated GSK-3ß acetylation could be beneficial to AD. FINDINGS: We found that GSK-3ß protein levels increased in the brains of AD patients and the transgenic mice. Overexpressing tau increased GSK-3ß protein level with increased acetylation and decreased ubiquitination-related proteolysis. Tau could directly acetylate GSK-3ß at K15 both in vitro and in vivo. K15-acetylation inhibited ubiquitination-associated proteolysis of GSK-3ß and changed its activity-dependent phosphorylation, leading to over-activation of the kinase. GSK-3ß activation by K15-acetylation in turn exacerbated the AD-like pathologies. Importantly, competitively inhibiting GSK-3ß K15-acetylation by a novel-designed peptide remarkably improved cognitive impairment and the AD-like pathologies in 3xTg-AD mice. INTERPRETATION: Tau can directly acetylate GSK-3ß at K15 which reveals a vicious cycle between tau hyperphosphorylation and GSK-3ß activation. FUNDING: This study was supported in parts by grants from Science and Technology Committee of China (2016YFC1305800), Hubei Province (2018ACA142), Natural Science Foundation of China (91949205, 82001134, 31730035, 81721005), Guangdong Provincial Key S&T Program (018B030336001).
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Doença de Alzheimer , Proteínas tau , Acetilação , Doença de Alzheimer/metabolismo , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Camundongos , Fosforilação , Proteínas tau/metabolismoRESUMO
Abnormal tau accumulation and spatial memory loss constitute characteristic pathology and symptoms of Alzheimer disease (AD). Yet, the intrinsic connections and the mechanism between them are not fully understood. In the current study, we observed a prominent accumulation of the AD-like hyperphosphorylated and truncated tau (hTau N368) proteins in hippocampal dentate gyrus (DG) mossy cells of 3xTg-AD mice. Further investigation demonstrated that the ventral DG (vDG) mossy cell-specific overexpressing hTau for 3 months induced spatial cognitive deficits, while expressing hTau N368 for only 1 month caused remarkable spatial cognitive impairment with more prominent tau pathologies. By in vivo electrophysiological and optic fiber recording, we observed that the vDG mossy cell-specific overexpression of hTau N368 disrupted theta oscillations with local neural network inactivation in the dorsal DG subset, suggesting impairment of the ventral to dorsal neural circuit. The mossy cell-specific transcriptomic data revealed that multiple AD-associated signaling pathways were disrupted by hTau N368, including reduction of synapse-associated proteins, inhibition of AKT and activation of glycogen synthase kinase-3ß. Importantly, chemogenetic activating mossy cells efficiently attenuated the hTau N368-induced spatial cognitive deficits. Together, our findings indicate that the mossy cell pathological tau accumulation could induce the AD-like spatial memory deficit by inhibiting the local neural network activity, which not only reveals new pathogenesis underlying the mossy cell-related spatial memory loss but also provides a mouse model of Mossy cell-specific hTau accumulation for drug development in AD and the related tauopathies.
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Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/patologia , Animais , Cognição , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Fibras Musgosas Hipocampais/metabolismo , Fibras Musgosas Hipocampais/patologia , Proteínas tau/metabolismoRESUMO
Our previous study identified annexin A2 (ANXA2) as a Gaq-interacting partner in natural killer/T cell lymphoma (NKTCL) cells transfected with the GNAQ T96S mutation vector by immunoprecipitation and mass spectrometry; however, the detailed molecular mechanisms by which GNAQ T96S might regulate ANXA2 remain to be defined in NKTCL. Herein, we found that the GNAQ T96S mutation significantly promotes the phosphorylation of ANXA2 at the Y24 site, whereas phosphorylation of ANXA2 abolishes the ability of WT GNAQ to trigger cell apoptosis. Further investigation revealed that a GNAQ T96S peptide inhibitor induced apoptosis by competing with ANXA2 binding to GNAQ T96S in NKTCL cells. In vivo animal experiments showed that a GNAQ T96S peptide inhibitor suppresses the growth of NKTCL cells carrying the GNAQ T96S mutation. Our current data suggest a role for GNAQ T96S/Src/ANXA2 in mediating the apoptosis of NKTCL cells, and the GNAQ T96S peptide could be a promising agent for therapy in NKTCL patients.
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Anexina A2 , Linfoma de Células T , Linfoma , Animais , Anexina A2/genética , Anexina A2/metabolismo , Apoptose/genética , Células Matadoras Naturais/metabolismo , Linfoma de Células T/genética , MutaçãoRESUMO
Polydimethylsiloxane (PDMS) has been widely used in many fields. However, the polymerization process of the siloxane chain is highly complex, and it is challenging to enhance the mechanical properties of PDMS elastomers significantly. We found that adding a small amount of polyoxyethylene lauryl ether (Brij-35) into siloxane polymers can result in B-PDMS elastomers with high tensile properties and strong adhesion. It is worth noting that this is the first study to improve the mechanical properties of PDMS using Brij-35. Here, we intensely studied a variety of process conditions that influence the cross-linking of PDMS, emphasizing the modification mechanism of the polymer chain. The hydroxyl groups in Brij-35 and the platinum catalyst in PDMS form a complex, which inhibits the cross-linking process of PDMS, not only forming a heterogeneous cross-linking network in the B-PDMS but also disentangling the strongly wound siloxane polymer chain, thereby rearranging the PDMS polymer chains. Furthermore, in order to prepare a strain sensor based on the B-PDMS elastomer under safe and convenient conditions, we prepared laser-scribed graphene powder (LSGP) by laser-scribing of graphene oxide (GO) films, and the LSGP and carbon nanotubes (CNTs) endowed the B-PDMS elastomers with excellent electrical properties. The sensor could firmly adhere to the skin and generate a high-quality response to a variety of human motions, and it could drive the robotic hand to grasp and lift objects accurately. The high-performance strain sensors based on B-PDMS have broad applications in medical sensing and biopotential measurement.
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BACKGROUND: Camrelizumab, an anti-PD-1 antibody, has shown moderate efficacy in oesophageal squamous cell carcinoma. Apatinib, a selective inhibitor of VEGFR2, has a synergistic effect with immunotherapy. We aimed to assess the combination of camrelizumab and apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma. METHODS: This single-arm, open-label, phase 2 study was conducted at eight centres in China. Eligible patients were aged 18-75 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had unresectable locally advanced, locally recurrent, or metastatic oesophageal squamous cell carcinoma, and had progressed after or were intolerant to first-line chemotherapy. Patients received intravenous camrelizumab 200 mg once every 2 weeks plus oral apatinib 250 mg once daily for a 28-day cycle until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was investigator-assessed confirmed objective response rate. Efficacy was analysed in patients who had received at least one dose of study drug, and safety was analysed in patients who received the study drug and had at least one post-baseline safety assessment. The study of this cohort is complete and this trial is registered with ClinicalTrials.gov, number NCT03736863. FINDINGS: Between Dec 5, 2019, and Feb 10, 2021, 52 patients were enrolled and included in analyses. At data cutoff (June 20, 2021), median follow-up was 7·5 months (IQR 4·0-11·2). 18 (34·6%, [95% CI 22·0-49·1]) of 52 patients had a confirmed objective response. 23 (44%) of 52 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or worse treatment-related adverse events were increased aspartate aminotransferase (10 [19%]), increased gamma-glutamyltransferase (10 [19%]), and increased alanine aminotransferase (five [10%]). No treatment-related deaths occurred. INTERPRETATION: Camrelizumab combined with apatinib showed promising activity and manageable toxicity, and might be a potential second-line treatment option for patients with advanced oesophageal squamous cell carcinoma. Another cohort of this study, enrolling patients previously treated with first-line immunotherapy, is ongoing. FUNDING: Jiangsu Hengrui Pharmaceuticals.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Piridinas/administração & dosagem , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Masculino , Intervalo Livre de Progressão , gama-Glutamiltransferase/sangueRESUMO
Background: Sarcomatoid hepatocellular carcinoma (SHC) is a rare epithelial malignancy with high invasiveness and poor prognosis. However, the molecular characteristics and main driver genes for SHC have not been determined. The aim of this study is to explore the potentially actionable mutations of driver genes, which may provide more therapeutic options for SHC. Methods: In this study, DNA extraction and library preparation were performed using tumor tissues from 28 SHC patients. Then we used Miseq platform (Illumina) to sequence the target-enriched library, and we aligned and processed the sequencing data. The gene groups were tested for SNVs/Indels/CNVs. Tumor mutation burden (TMB) was assessed by the 425-cancer-relevant gene panel. Multivariate analysis of COX's model was used for survival analysis (OS) of patients' clinical characteristics. Result: The median overall survival (OS) of the patients was only 4.4 months. TP53, TERT, and KRAS were the top three frequently mutated genes, with frequencies of 89.3%, 64.3%, and 21.4%, respectively. A considerable number of patients carried mutations in genes involved in the TP53 pathway (96%) and DNA Damage Repair (DDR) pathway (21%). Multiple potentially actionable mutations, such as NTRK1 fusions and BRCA1/2 mutations, were identified in SHCs. Conclusions: This study shows a landscape of gene mutations in SHC. SHC has high mutation rates in TP53 pathway and DDR pathway. The potentially actionable mutations of driver genes may provide more therapeutic options for SHC. Survival analysis found that age, smoking, drinking, and tumor diameter may be independent prognostic predictors of SHC.
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BACKGROUND: Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next-generation sequencing (NGS). We investigated the characteristics of complex ALK rearrangements in non-small cell lung cancers using multiple molecular tests. METHODS: Samples of non-small cell lung cancer patients were analyzed by targeted-capture DNA-based NGS with probes tilling the selected intronic regions of fusion partner genes, RNA-based NGS, RT-PCR, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS: In a large cohort of 6576 non-small cell lung cancer patients, 343 (5.2%) cases harboring ALK rearrangements were identified. Fourteen cases with complex ALK rearrangements were identified by DNA-based NGS and classified into three types by integrating various genomic features, including intergenic (n = 3), intragenic (n = 5) and "bridge joint" rearrangements (n = 6). All thirteen cases with sufficient samples actually expressed canonical EML4-ALK fusion transcripts confirmed by RNA-based NGS. Besides, positive ALK IHC was detected in 13 of 13 cases, and 9 of 11 cases were positive in FISH testing. Patients with complex ALK rearrangements who received ALK inhibitors treatment (n = 6), showed no difference in progression-free survival (PFS) compared with patients with canonical ALK fusions n = 36, P = 0.9291). CONCLUSIONS: This study firstly reveals the molecular characteristics and clinical outcomes of complex ALK rearrangements in NSCLC, sensitive to ALK inhibitors treatment, and highlights the importance of utilizing probes tilling the selected intronic regions of fusion partner genes in DNA-based NGS for accurate fusion detection. RNA and protein level assay may be critical in validating the function of complex ALK rearrangements in clinical practice for optimal treatment decision.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genéticaRESUMO
Tau accumulation and cholinergic impairment are characteristic pathologies in Alzheimer's disease (AD). However, the causal role of tau accumulation in cholinergic lesion is elusive. Here, we observed an aberrant tau accumulation in the medial septum (MS) of 3xTg and 5xFAD mice, especially in their cholinergic neurons. Overexpressing hTau in mouse MS (MShTau ) for 6 months but not 3 months induced spatial memory impairment without changing object recognition and anxiety-like behavior, indicating a specific and time-dependent effect of MS-hTau accumulation on spatial cognitive functions. With increasing hTau accumulation, the MShTau mice showed a time-dependent cholinergic neuron loss with reduced cholinergic projections to the hippocampus. Intraperitoneal administration of donepezil, a cholinesterase inhibitor, for 1 month ameliorated the MS-hTau-induced spatial memory deficits with preservation of MS-hippocampal cholinergic pathway and removal of tau load; and the beneficial effects of donepezil was more prominent at low dose. Proteomics revealed that MS-hTau accumulation deregulated multiple signaling pathways with numerous differentially expressed proteins (DEPs). Among them, the vacuolar protein sorting-associated protein 37D (VP37D), an autophagy-related protein, was significantly reduced in MShTau mice; the reduction of VP37D was restored by donepezil, and the effect was more significant at low dose than high dose. These novel evidences reveal a causal role of tau accumulation in linking MS cholinergic lesion to hippocampus-dependent spatial cognitive damages as seen in the AD patients, and the new tau-removal and autophagy-promoting effects of donepezil may extend its application beyond simple symptom amelioration to potential disease modification.
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Colinérgicos/metabolismo , Hipocampo/patologia , Transtornos da Memória/patologia , Proteoma/metabolismo , Núcleos Septais/patologia , Memória Espacial/fisiologia , Proteínas tau/metabolismo , Animais , Hipocampo/metabolismo , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteoma/análise , Núcleos Septais/metabolismo , Proteínas tau/genéticaRESUMO
CRC is a heterogeneous disease due to global molecular alterations, including mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H). Immunotherapy has achieved durable responses in a subset of patients with dMMR-MSI-H metastatic CRC. It has been showed that Loss of ZG16 is highly associated with colorectal cancer. However, whether ZG16 modulates tumor immunity in colorectal cancer is unclear. In this study, we demonstrated that the expression of ZG16 is associated with distant metastasis and lymphatic invasive in colorectal cancer. Besides, ZG16 is negatively correlated to PD-L1 expression in patient with CRC and overexpression of ZG16 blocks PD-L1 expression in colorectal cancer cells. In addition, overexpression of ZG16 promotes NK cells survival and proliferation, which is dependent on NKG2D expression. Our data demonstrate that ZG16 plays a role in modulation of immune response in colorectal cancer. The strong correlation between ZG16 and PD-L1 suggests that ZG16 may serve a biomarker to stratify patient who will benefit from immunotherapy.
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Joint optimal subcarrier and transmit power allocation with QoS guarantee for enhanced packet transmission over Cognitive Radio (CR)-Internet of Vehicles (IoVs) is a challenge. This open issue is considered in this paper. A novel SNBS-based wireless radio resource scheduling scheme in OFDMA CR-IoV network systems is proposed. This novel scheduler is termed the SNBS OFDMA-based overlay CR-Assisted Vehicular NETwork (SNO-CRAVNET) scheduling scheme. It is proposed for efficient joint transmit power and subcarrier allocation for dynamic spectral resource access in cellular OFDMA-based overlay CRAVNs in clusters. The objectives of the optimization model applied in this study include (1) maximization of the overall system throughput of the CR-IoV system, (2) avoiding harmful interference of transmissions of the shared channels' licensed owners (or primary users (PUs)), (3) guaranteeing the proportional fairness and minimum data-rate requirement of each CR vehicular secondary user (CRV-SU), and (4) ensuring efficient transmit power allocation amongst CRV-SUs. Furthermore, a novel approach which uses Lambert-W function characteristics is introduced. Closed-form analytical solutions were obtained by applying time-sharing variable transformation. Finally, a low-complexity algorithm was developed. This algorithm overcame the iterative processes associated with searching for the optimal solution numerically through iterative programming methods. Theoretical analysis and simulation results demonstrated that, under similar conditions, the proposed solutions outperformed the reference scheduler schemes. In comparison to other scheduling schemes that are fairness-considerate, the SNO-CRAVNET scheme achieved a significantly higher overall average throughput gain. Similarly, the proposed time-sharing SNO-CRAVNET allocation based on the reformulated convex optimization problem is shown to be capable of achieving up to 99.987% for the average of the total theoretical capacity.
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BACKGROUND: Microsatellite instability (MSI) has been a hot topic in cancer research. Determining MSI status greatly aids tumor prognosis and treatment plans. However, MSI data for Asian cancer patients with prognostic information are scarce. Here, our aim was to clarify MSI status and its prognostic value in a large Chinese cohort with different tumors. PATIENTS AND METHODS: Tissue samples from 600 Chinese cases, including 150 endometrial cancers, 150 colorectal cancers, 150 liver cancers and 150 gastric cancers, were used for IHC and MSI examinations. Two mononucleotide and three dinucleotide markers were used to analyze MSI status. RESULTS: In total,17.3% (26/150) of endometrial cancer patients showed positive MSI,10.0% (15/150) in colorectal cancer, 2.7% (4/150) in liver cancer, and 2.7% (4/150) in gastric cancer. Tumor location (P < 0.001 for colorectal cancer) and clinical stage (P =0.038 for gastric cancer) showed significant correlations with MSI status in gastrointestinal carcinogenesis. The mismatch repair (MMR) deficiency was observed in 20 colorectal cases (13.3%) and was significantly more frequent in the MSI-positive group (P < 0.001). Interestingly, the prevalence of MSI-H was mostly occurred in early-stage tumors, and none was in late stage (stage IV). Meanwhile, low clinicopathological stage had significant correlation with longer survival in multiple cancers here. CONCLUSION: The incidence of microsatellite instability varies among different cancer types. And the prevalence of MSI-H mostly occurred early clinicopathological stage. In addition, our study provided a large Asian cohort screened by five loci PCR method and significantly increased knowledge on the prognostic significance of MSI in Asia.
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BACKGROUND: Increased tau acetylation at K174, K274, K280, and K281 has been observed in the brains of Alzheimer's disease (AD) patients or in transgenic mice, but the role of acetylation in tau propagation is elusive. OBJECTIVE: To study the effect of tau acetylation in entorhinal cortex on tau transmission and learning and memory. METHODS: Stereotactic brain injection, behavioral test, electrophysiological recording, immunohistochemistry, and immunofluorescence were used. RESULTS: We constructed the hyperacetylation mimics of tau (AAV-Tau-4Q), the non-acetylation tau mutant (AAV-Tau-4R), and the wild-type tau (AAV-Tau-WT). By overexpressing these different tau proteins in the entorhinal cortex (EC) of 2-month-old mice, we found that overexpressing Tau-4Q in EC for 3 or 6 months (to 5 or 8 months of age) neither induces tau propagation to dentate gyrus (DG) nor glial activation in DG, nor spatial memory deficit. However, overexpressing Tau-WT and Tau-4Q in EC for 13.5 months (15.5 months of age) at 2 months promoted tau propagation respectively to granulosa and hilus of DG with glial activation, synaptic dysfunction, and memory deficit, while overexpressing Tau-4R abolished tau propagation with improved cellular pathologies and cognitive functions. Furthermore, overexpressing Tau-4Q in unilateral DG of 2-month-old mice for 8 weeks also promoted its contralateral transmission with glial activation, and mice with tau (Tau-WT, Tau-4Q, and Tau-4R) overexpression in DG showed cognitive deficits compared with the empty vector controls. CONCLUSION: Tau acetylation induces a time-dependent propagation from EC to DG, and only hippocampus but not EC tau accumulation induces cognitive deficits.
Assuntos
Disfunção Cognitiva/metabolismo , Córtex Entorrinal/metabolismo , Hipocampo/metabolismo , Proteínas tau/metabolismo , Acetilação , Animais , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Córtex Entorrinal/patologia , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas tau/genéticaRESUMO
BACKGROUND: The aim of this study was to identify prognostic long non-coding RNAs (lncRNAs) and develop a multi-lncRNA signature for suvival prediction in esophageal squamous cell carcinoma (ESCC). METHODS: The clinical and gene expression data from Gene Expression Omnibus database (GSE53624, n = 119) were obtianed as training set. A total of 98 paired ESCC tumor and normal tissues were detected by RNA sequencing and used as test set. Another 84 ESCC tissues were used for real-time quantitative PCR(qRT-PCR) and as an independent validation cohort. Survival analysis, Cox regression and Kaplan-Meier analysis were performed. RESULTS: We screened a prognostic marker of ESCC from the GSE53624 dataset and named it as the five-lncRNA signature including AC007179.1, MORF4L2-AS1, RP11-488I20.9, RP13-30A9.2, RP4-735C1.6, which could classify patients into high- and low-risk groups with significantly different survival(median survival: 1.75 years vs. 4.01 years, log rank P < 0.05). Then test dataset and validation dataset confirmed that the five-lncRNA signature can determine the prognosis of ESCC patients. Predictive independence of the prognostic marker was proved by multivariable Cox regression analyses in the three datasets (P < 0.05). In addition, the signature was found to be better than TNM stage in terms of prognosis. CONCLUSION: The five-lncRNA signature could be a good prognostic biomarker for ESCC patients and has important clinical value.