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Adjuvant treatment after surgical resection usually plays an important role in delaying disease recurrence. Immunotherapy displays encouraging results in increasing patients' chances of staying cancer-free after surgery, as reported by recent clinical trials. However, the clinical outcomes of current immunotherapy need to be improved due to the limited responses, patient heterogeneity, nontargeted distribution, and immune-related adverse effects. This work describes a programmable hydrogel adjuvant for personalized immunotherapy after surgical resection. By filling the hydrogel in the cavity, this system aims to address the limited secretion of granzyme B (GrB) during immunotherapy and improve the low immunotherapy responses typically observed, while minimizing immune-related side effects. The TLR7/8 agonist imidazoquinoline (IMDQ) is linked to the self-assembling peptide backbone through a GrB-responsive linkage. Its release could enhance the activation and function of immune cells, which will lead to increased secretion of GrB and enhance the effectiveness of immunotherapy together. The hydrogel adjuvant recruits immune cells, initiates dendritic cell maturation, and induces M1 polarized macrophages to reverse the immunosuppressive tumor microenvironment in situ. In multiple murine tumor models, the hydrogel adjuvant suppresses tumor growth, increases animal survival and long-term immunological memory, and protects mice against tumor rechallenge, leading to effective prophylactic and therapeutic responses. This work provides a potential chemical strategy to overcome the limitations associated with immunotherapy.
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Hidrogéis , Neoplasias , Humanos , Animais , Camundongos , Imunoterapia/métodos , Neoplasias/terapia , Adjuvantes Imunológicos , Peptídeos , Microambiente TumoralRESUMO
Glaucoma, an insidious ophthalmic pathology, is typified by an aberrant surge in intraocular pressure (IOP) which culminates in the degeneration of retinal ganglion cells and optical neuropathy. The mitigation of IOP stands as the principal therapeutic strategy to forestall vision loss. The trabecular meshwork's (TM) integrity and functionality are pivotal in modulating aqueous humor egress. Despite their potential significance in glaucomatous pathophysiology, the implications of microRNAs (miRNAs) on TM functionality remain largely enigmatic. Transcriptomic sequencing was employed to delineate the miRNA expression paradigm within the limbal region of rodent glaucoma models, aiming to elucidate miRNA-mediated mechanisms within the glaucomatous milieu. Analytical scrutiny of the sequencing data disclosed 174 miRNAs with altered expression profiles, partitioned into 86 miRNAs with augmented expression and 88 with diminished expression. Notably, miRNAs such as hsa-miR-196b-5p were identified as having substantial expression discrepancies with concomitant statistical robustness, suggesting a potential contributory role in glaucomatous progression. Subsequent in vitro assays affirmed that miR-196b-5p augments the inflammatory cascade within immortalized human TM (iHTM) and glaucoma-induced human TM (GTM3) cells, concurrently attenuating cellular proliferation, motility, and cytoskeletal architecture. Additionally, miR-196b-5p implicates itself in the regulation of IOP and inflammatory processes in rodent models. At a mechanistic level, miR-196b-5p modulates its effects via the targeted repression of Nras (neuroblastoma RAS viral oncogene homolog). Collectively, these transcriptomic investigations furnish a comprehensive vista into the regulatory roles of miRNAs within the glaucomatous framework, and the identification of differentially expressed miRNAs alongside their targets could potentially illuminate novel molecular pathways implicated in glaucoma, thereby aiding in the development of innovative therapeutic avenues.
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Glaucoma , MicroRNAs , Humanos , Humor Aquoso/metabolismo , Linhagem Celular Tumoral , Glaucoma/genética , MicroRNAs/metabolismo , Malha TrabecularRESUMO
BACKGROUND: There are big differences in treatments and prognosis between diabetic kidney disease (DKD) and non-diabetic renal disease (NDRD). However, DKD patients couldn't be diagnosed early due to lack of special biomarkers. Urine is an ideal non-invasive sample for screening DKD biomarkers. This study aims to explore DKD special biomarkers by urinary proteomics. MATERIALS AND METHODS: According to the result of renal biopsy, 142 type 2 diabetes mellitus (T2DM) patients were divided into 2 groups: DKD (n = 83) and NDRD (n = 59). Ten patients were selected from each group to define urinary protein profiles by label-free quantitative proteomics. The candidate proteins were further verifyied by parallel reaction monitoring (PRM) methods (n = 40). Proteins which perform the same trend both in PRM and proteomics were verified by enzyme-linked immunosorbent assays (ELISA) with expanding the sample size (n = 82). The area under the receiver operating characteristic curve (AUC) was used to evaluate the accuracy of diagnostic biomarkers. RESULTS: We identified 417 peptides in urinary proteins showing significant difference between DKD and NDRD. PRM verification identified C7, SERPINA4, IGHG1, SEMG2, PGLS, GGT1, CDH2, CDH1 was consistent with the proteomic results and p < 0.05. Three potential biomarkers for DKD, C7, SERPINA4, and gGT1, were verified by ELISA. The combinatied SERPINA4/Ucr and gGT1/Ucr (AUC = 0.758, p = 0.001) displayed higher diagnostic efficiency than C7/Ucr (AUC = 0.632, p = 0.048), SERPINA4/Ucr (AUC = 0.661, p = 0.032), and gGT1/Ucr (AUC = 0.661, p = 0.029) respectively. CONCLUSIONS: The combined index SERPINA4/Ucr and gGT1/Ucr can be considered as candidate biomarkers for diabetic nephropathy after adjusting by urine creatinine.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/urina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/urina , Proteômica , Biomarcadores/urina , Prognóstico , RimRESUMO
Bisphenol A (BPA) and its analogues are still one of the most important substances that pollute aquatic systems and pose a threat to aquatic organisms. Tannic acid (TAN) is a kind of glycosyl compound, which has the functions of anti-oxidation, anti-inflammation and anti-apoptosis. However, it is unknown if BPA can regulate PTEN/PI3K/AKT pathway to induce pyroptosis of grass carp hepatocytes (L8824) and the antagonistic effect of tannic acid (TAN) through oxidative stress. Therefore, we established the grass carp hepatocytes (L8824) cell model treated with BPA. The oxidative stress indexes (SOD, CAT, GSH, H2O2 and T-AOC) were detected by oxidative stress kit, mRNA and protein expression of associated genes were examined using qRT-PCR and western blotting. The results showed that BPA treatment increased the content of hydrogen peroxide and decreased the activities of antioxidant enzymes and antioxidants (SOD, CAT, GSH, and T-AOC) in L8824 cells. We also found that PTEN/PI3K/AKT pathway was activated dramatically and the expression of pyroptosis-related genes (GSDMD, NLRP3, Caspase1, ASC and IL-1ß) was increased significantly. In addition, TAN could significantly reduce the toxicity of BPA on L8824 cells. After the addition of PTEN specific inhibitor SF1670, the activation of PTEN/PI3K/AKT pathway decreased by BPA was inhibited and the expression of scorch related genes was decreased. On the whole, TAN inhibits BPA-induced pyroptosis of L8824 by modulating the PTEN/PI3K/AKT pathway. The present study provides a novel perspective for toxicological mechanism of BPA, and new insights into the detoxification mechanism of TAN.
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Compostos Benzidrílicos , Carpas , Fenóis , Polifenóis , Proteínas Proto-Oncogênicas c-akt , Animais , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fosfatidilinositol 3-Quinases/metabolismo , Carpas/genética , Carpas/metabolismo , Piroptose , Peróxido de Hidrogênio/farmacologia , Antioxidantes/farmacologia , Hepatócitos/metabolismo , Superóxido Dismutase/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The molecular chaperones are essential and play significant roles in controlling the protein phase transition and maintaining physiological homeostasis. However, manipulating phase transformation in biomimetic peptide self-assembly is still challenging. This work shows that an artificial chaperone modulates the energy landscape of supramolecular polymerization, thus controlling the phase transition of amyloid-like assemblies from crystals to hydrogels to solution. The absence of a chaperone allows the NapP to form crystals, while the presence of the chaperone biases the pathway to form nanofibrous hydrogels to soluble oligomers by adjusting the chaperone ratios. Mechanistic studies reveal that the aromatic-aromatic interaction is the key to trapping the molecules in a higher energy fold. Adding the chaperone relieves this restriction, lowers the energy barrier, and transforms the crystal into a hydrogel. This phase transformation can also be achieved in the macromolecular crowding environment, thus providing new insights into understanding molecular self-assembly in multiple component systems.
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Chaperonas Moleculares , Peptídeos , Peptídeos/química , Hidrogéis/químicaRESUMO
BACKGROUND: Immunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC. METHODS: We conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). RESULTS: Between January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3-8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5-7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83-1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62-1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group. CONCLUSIONS: Our research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Antígeno B7-H1 , Etoposídeo , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Platina/farmacologia , Platina/uso terapêutico , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
OBJECTIVE: Oncogenic alternation in RET is one of the important targets of non-small cell lung cancer (NSCLC). Pralsetinib has shown great efficacy in RET fusion-positive NSCLC, but a series of adverse reactions will inevitably occur in the meantime. We aimed to explore the clinical characteristics of patients with pneumonia and recognition it in early stage, so patients could longer benefit from pralsetinib. METHODS: This is a multicenter, retrospective study. RET fusion-positive advanced NSCLC patients who developed pneumonia during pralsetinib treatment from January 2020 to December 2022 were included. Clinical data, time to onset of pneumonia, methods of pneumonia diagnosis, treatment with pneumonia, prognosis of pneumonia, and the effect of pneumonia on the efficacy of pralsetinib. RESULTS: A total of 8 patients with pneumonia were included in the study, most of which were non-smoking female patients and the main fusion gene was KIF5B (87.5%), which was consistent with the general characteristics of RET fusion population. The median occurrence time of pralsetinib-associated pneumonia was 2.15 (range 1.1-6.63) months. All patients were infected by opportunistic pathogens, and the most common pathogen was human herpesviruses and pneumospora yerbii. Fever was always the first symptom, and timely anti-infective treatment including antibiotics, antiviral drugs, and antifungal drugs was effective. Until February 28, 2023, the median follow-up time was 18.7 months, the mean PFS of patients was 17.4 months, and the median PFS was not reached. Fortunately, patients who restarted pralsetinib after infection control continued to benefit. CONCLUSIONS: Opportunistic infection may be a unique adverse effect of pralsetinib. During the treatment of pralsetinib, we should be vigilant about the occurrence of pneumonia and achieve early recognition and timely treatment.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Feminino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Retrospectivos , Piridinas/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/uso terapêuticoRESUMO
Liposarcoma is a carcinomatous mesenchymal tumor with various histologic features and is the most common soft tissue sarcoma originating in adipose tissue. Liposarcoma commonly occurs in the lower extremities and retroperitoneum but rarely in the mediastinum, specially extending into the thoracic cavity. We report a giant primary liposarcoma of the posterior mediastinum in a 63-year-old female who complained of cough, sputum, and pain in the right chest wall. A computed tomography scan of the chest showed a giant mass of 24 × 15 × 24 cm in the posterior mediastinum of the right thoracic cavity. After a thorough examination, no suspected lipomatous lesions were found elsewhere in the patient's body. The patient underwent a thoracotomy to remove the mediastinal mass through a right thoracic approach. Subsequently, hematoxylin-eosin staining revealed dedifferentiated liposarcoma (DDL), immunohistochemistry showed positive expression of cyclin-dependent kinase 4, and murine double minute 2 (MDM2), in addition, fluorescence in situ hybridization for the MDM2 gene was also positive, which suggested DDL. The patient was discharged without any complications, and no metastasis or recurrence was observed after 19 months of follow-up. To provide a reference for clinical diagnosis and treatment, we reviewed and discussed the literature on primary liposarcoma of the mediastinum.
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BACKGROUND: DNA methyltransferase 3A (DNMT3A) is frequently mutated in acute myeloid leukemia (AML) with Arg882His (R882H) as the hotspot mutation. It has been reported that DNMT3A mutation plays a key role in leukemogenesis through hypomethylation of some target genes associated with cell growth and differentiation. In this study, we investigated the function of DNMT3A R882H in the malignant progression of AML by regulating metabolic reprogramming. METHODS: Ultra-High Performance Liquid Chromatography-High Resolution Tandem Mass Spectrometry (UHPLC-HRMS/MS) was used to detect metabolites in the serum of mice harboring Dnmt3a R878H mutation and the wild-type Dnmt3a. Methylated DNA Immunoprecipitation Sequencing (MeDIP-seq) and RNA sequencing (RNA-seq) were used to analyze the levels of DNA methylation and mRNA expression of genes in mouse Gr1+ bone marrow cells respectively. The TCGA and GO databases were used to analyze the differential genes between human samples carrying the DNMT3A R882 mutation and the wild-type DNMT3A. Co-immunoprecipitation and immunoblotting were used to illustrate the binding levels of Cyclins-CDKs and CDK inhibitors including CDKN1A and CDKN1B. Flow cytometry was used to analyze the cell differentiation, division, apoptosis and cell cycle. The effect of NAMPT inhibition on leukemia was evaluated by using in vivo fluorescence imaging in NOG mouse model bearing OCI-AML3 cells. RESULTS: DNMT3A mutation caused high expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the nicotinamide adenine dinucleotide (NAD) salvage synthetic pathway, through DNA hypomethylation, and finally led to abnormal nicotinamide (NAM) metabolism and NAD synthesis. The NAM-NAD metabolic abnormalities caused accelerated cell cycle progression. Inhibition of NAMPT can reduce the binding degree between Cyclins-CDKs, and increase the binding interaction of the CDK inhibitors with Cyclins-CDKs complexes. Moreover, cells with high expression of NAMPT were more sensitive to the NAMPT inhibitor FK866 with a lower IC50. The inhibition of NAMPT can remarkably extend the survival time of tumor-bearing mice and reduce the infiltration of tumor cells. CONCLUSIONS: Taken together, our data showed that DNMT3A mutation caused NAMPT overexpression to induce the reprogramming of NAM-NAD metabolism and contribute to abnormal proliferation, which provided a potential direction for targeted therapy at the metabolic level in AML with DNMT3A mutation.
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DNA Metiltransferase 3A , Leucemia Mieloide Aguda , Animais , Humanos , Camundongos , Ciclinas/genética , Citocinas/metabolismo , DNA , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Leucemia Mieloide Aguda/patologia , Mutação/genética , NAD/genética , NAD/metabolismoRESUMO
NCAPG2 has been reported to be associated with tumorigenesis in various types of cancer. However, data on the pathological mechanisms of NCAPG2 in pan-cancers remain lacking. Therefore, the study aimed to comprehensively elucidate the immune characteristics and prognostic of NCAPG2 in tumor microenvironments (TMEs). NCAPG2 was overexpressed in many tumor types, and this overexpression is related to poor clinical stages and prognosis. Furthermore, elevated NCAPG2 expression was strongly associated with TMEs. Moreover, gene set enrichment analysis was performed to investigate the pathways associated with NCAPG2, revealing its involvement in several immune-related pathways. Finally, we predicted the immunotherapeutic value and sensitivity to drugs based on NCAPG2 expression. Our study revealed that NCAPG2 could be utilized as an immune-related biomarker for both diagnosing and predicting the prognosis of multiple cancer types. Therefore, our findings suggest that targeting NCAPG2 in TMEs could be a promising therapeutic strategy.
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Abnormal upregulation of telomerase RNA (TR) is a hallmark event at various stages of tumor progression, providing a universal marker for early diagnosis of cancer. Here, we have developed a triple signal amplification strategy for in situ visualization of TR in living cells, which sequentially incorporated the target-initiated strand displacement circuit, multidirectional rolling circle amplification (RCA), and Mg2+ DNAzyme-mediated amplification. All oligonucleotide probes and cofactors were transfected into cells in one go, and then escaped from lysosomes successfully. Owing to the specific base pairing, the amplification cascades could only be triggered by TR and performed as programmed, resulting in a satisfactory signal-to-background ratio. Especially, the netlike DNA structure generated by RCA encapsulated high concentrations of DNAzyme and substrates (FQS) in a local region, thereby improving the reaction efficiency and kinetics of the third amplification cycle. Under optimal conditions, the proposed method exhibited ultrasensitive detection of TR mimic with a detection limit at pM level. Most importantly, after transfection with the proposed sensing platform, tumor cells can be easily distinguished from normal cells based on TR abundance-related fluorescence signal, providing a new insight into initial cancer screening.
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Técnicas Biossensoriais , DNA Catalítico , Telomerase , DNA Catalítico/metabolismo , RNA , DNA/química , Telomerase/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Técnicas Biossensoriais/métodos , Limite de DetecçãoRESUMO
The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the model of antitumor therapy. With the continuous deepening of the research on the mechanism of immunotherapy, ICIs, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 inhibitors and cytotoxic T lymphocyte-associated protein 4 inhibitors, have been widely used in a variety of tumors. Nevertheless, the use of ICI can also lead to a series of immune-related adverse events. Common immune-related adverse events include gastrointestinal toxicity, pulmonary toxicity, endocrine system toxicity, and skin toxicity. Neurologic adverse events are relatively rare, but they seriously affect the quality of life and shorten the survival time of patients. This article reports cases of peripheral neuropathy mediated by PD-1 inhibitors and retrieves the relevant literatures at home and abroad to summarize the neurotoxicity caused by PD-1 inhibitors, so as to strengthen the awareness of clinicians and patients on neurologic adverse reactions and mitigate potential adverse effects of implemented therapies.
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Chimeric antigen receptor T (CAR-T) cell therapy has become a research hotspot in the field of hematological malignancies. However, CAR-T cell therapy can lead to immunotherapy-associated side effects including cytokine release syndrome and neurotoxicity. Gene depletion of GM-CSF in CAR-T cells was found preventive against adverse effects, but additional transfections were required to produce CAR-T cells. In this study, we interrupted GM-CSF expression in CAR-T cells by inserting the GM-CSF shRNA-expression cassette in the CAR vector. Reduction of GM-CSF in CAR-T cells could decrease the level of several proinflammatory cytokines without hampering the killing capacity. The manufacture of GM-CSF knockdown CAR-T cells does not require complicated transfections, which makes it more practical and feasible for clinical application.
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Fator Estimulador de Colônias de Granulócitos e Macrófagos , Receptores de Antígenos Quiméricos , Humanos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Citocinas/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Interferência de RNA , Linfócitos TRESUMO
Trabecular meshwork (TM) cell dysfunction is the leading cause of elevated intraocular pressure (IOP) and glaucoma. The long non-coding RNA (lncRNA) small nucleolar RNA host gene 11 (SNHG11) is associated with cell proliferation and apoptosis, but its biological functions and role in glaucoma pathogenesis remain unclear. In the present study, we investigated the role of SNHG11 in TM cells using immortalized human TM and glaucomatous human TM (GTM3 ) cells and an acute ocular hypertension mouse model. SNHG11 expression was depleted using siRNA targeting SNHG11. Transwell assays, quantitative real-time PCR analysis (qRT-PCR), western blotting, and CCK-8 assay were used to evaluate cell migration, apoptosis, autophagy, and proliferation. Wnt/ß-catenin pathway activity was inferred from qRT-PCR, western blotting, immunofluorescence, and luciferase reporter and TOPFlash reporter assays. The expression of Rho kinases (ROCKs) was detected using qRT-PCR and western blotting. SNHG11 was downregulated in GTM3 cells and mice with acute ocular hypertension. In TM cells, SNHG11 knockdown inhibited cell proliferation and migration, activated autophagy, and apoptosis, repressing the Wnt/ß-catenin signaling pathway, and activated Rho/ROCK. Wnt/ß-catenin signaling pathway activity increased in TM cells treated with ROCK inhibitor. SNHG11 regulated Wnt/ß-catenin signaling through Rho/ROCK by increasing GSK-3ß expression and ß-catenin phosphorylation at Ser33/37/Thr41 while decreasing ß-catenin phosphorylation at Ser675. We demonstrate that the lncRNA SNHG11 regulates Wnt/ß-catenin signaling through Rho/ROCK via ß-catenin phosphorylation at Ser675 or GSK-3ß-mediated phosphorylation at Ser33/37/Thr41, affecting cell proliferation, migration, apoptosis, and autophagy. Through its effects on Wnt/ß-catenin signaling, SNHG11 is implicated in glaucoma pathogenesis and is a potential therapeutic target.
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Glaucoma , Hipertensão Ocular , RNA Longo não Codificante , Humanos , Animais , Camundongos , Via de Sinalização Wnt/fisiologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Malha Trabecular/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Proliferação de Células/genética , Glaucoma/genética , Glaucoma/metabolismo , Hipertensão Ocular/metabolismo , Linhagem Celular TumoralRESUMO
The accurate and visual detection of circulating microRNA (miRNA) has attracted increasing interest due to its pivotal role in clinical disease diagnosis. Taking advantages of nucleic acid isothermal amplification and enzyme-catalyzed chromogenic reaction, here, a colorimetric sensing strategy was proposed for sensitive miRNA analysis. When the target miRNA was present, local catalytic hairpin assembly (CHA) would be triggered and proceed continuously to form dozens of double-stranded oligonucleotides with G-rich sticky ends on the gold nanoparticle, which could self-assemble into a spherical G-quadruplex (GQ)/hemin DNAzyme by binding with hemin and potassium ions. As a horseradish peroxidase-mimic, GQ/hemin DNAzyme could catalyze the redox reaction and color change of the substrates. Taking miRNA-21 as an example, the developed method exhibited satisfactory specificity as well as high sensitivity with a detection limit of 90.3 fM. Furthermore, the sensing platform has been successfully employed to detect miRNA-21 in spiked serum, providing a promising tool for early diagnosis of cancers.
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Técnicas Biossensoriais , DNA Catalítico , Quadruplex G , Nanopartículas Metálicas , MicroRNAs , Técnicas Biossensoriais/métodos , Catálise , Colorimetria/métodos , DNA Catalítico/metabolismo , Ouro , Hemina , Limite de Detecção , MicroRNAs/análise , HumanosRESUMO
PURPOSES: The purpose of this meta-analysis is to systematically compare the efficacy and safety between combined surgery (phacoemulsification combined with trabeculectomy) and phacoemulsification for primary angleclosure glaucoma (PACG) patients. METHODS: This work was done through the data searched from the PubMed, EMBASE and the Cochrane Library. The Cochrane Handbook was also used to evaluate the quality of the included studies. In addition, this meta-analysis was performed using Revman 5.4 software. RESULTS: A total of seven randomized controlled trials (RCTs) were included. Compared with phacoemulsification alone, combined surgery resulted in significant reduction in the IOP (MD = -1.45, 95%CI, -2.38 to -0.51, p = .002). And more reduction in number of glaucoma medications was shown in the combined surgery group (MD, -0.59; 95%CI, -1.01 to -0.17; p = .006). For the improvement of the best corrected visual acuity (BCVA), there was no statistical differences between two groups (MD, 0.05; 95%CI, -0.01 to 0.11; p = .08). In subgroup analysis, the BCVA improved more significantly for medically controlled PACG patients in the phacoemulsification alone group (MD, 0.09; 95%CI, 0.01 to 0.07; p = .02). Compared with the phacoemulsification alone group, more complications were shown in the combined surgery group (RR, 0.22; 95%CI, 0.09 to 0.56; p = .001). CONCLUSION: For lowering IOP, combined surgery was superior to phacoemulsification alone for PACG patients. Meanwhile, combined surgery generated more complications. For medically controlled PACG patients, phacoemulsification alone is more conducive to the improvement of BCVA.
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Extração de Catarata , Catarata , Glaucoma de Ângulo Fechado , Glaucoma , Facoemulsificação , Trabeculectomia , Humanos , Facoemulsificação/métodos , Glaucoma de Ângulo Fechado/cirurgia , Pressão Intraocular , Glaucoma/cirurgia , Trabeculectomia/métodos , Catarata/complicações , Resultado do TratamentoRESUMO
The self-assembly of peptides plays an important role in optics, catalysis, medicine, and disease treatment. In recent years, peptide-based materials have exhibited great potential for cancer therapy and disease imaging due to their excellent biocompatibility, structural tenability, and ease of functionality. Peptides could self-assemble into diverse nanostructures inâ vivo triggered by endogenous stimuli, which initiated chemical reactions and self-assembled to achieve desired biological functions in the tumor microenvironment. This concept introduces the utilization of endogenous triggers to construct functional nanostructures inâ vivo and their corresponding biological applications. After briefly discussing the representative example of chemical reactions induced self-assembly of peptides in the living system, we describe the several stimuli triggered self-assembly for constructing therapeutic assemblies and serving as an imaging probe. Finally, we give a brief outlook to discuss the future direction of this exciting new field.
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Nanoestruturas , Peptídeos , Peptídeos/química , Nanoestruturas/química , CatáliseRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide every year, and most HCC patients are diagnosed with advanced disease and can only receive systemic treatment. TKIs are the most important components of the systemic treatment of HCC and have both good efficacy and adverse events (AEs). METHODS: This analysis included 207 patients with locally advanced unresectable or metastatic HCC who received oral treatment with apatinib. We analyzed the overall survival (OS) and progression-free survival (PFS) of patients with or without corresponding AEs to evaluate which AEs can predict the efficacy of apatinib. RESULTS: Patients with hand-foot syndrome (HFS; p = 0.005), proteinuria (p = 0.006) and diarrhea (p < 0.001) had significantly better OS than those without corresponding AEs, and the appearance of HFS (p = 0.006) and proteinuria (p = 0.004) was associated with longer PFS. CONCLUSION: Among all the AEs induced by apatinib in the treatment of advanced HCC, proteinuria could potentially predict PFS, and diarrhea was a potential predictor of OS.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Antineoplásicos/efeitos adversos , Resultado do Tratamento , Diarreia/induzido quimicamente , Proteinúria/induzido quimicamenteRESUMO
Chimeric antigen receptor (CAR)-engineered T (CAR-T) cells have obtained prominent achievement in the clinical immunotherapy of hematological malignant tumors, leading to a rapid development of cellular immunotherapy in cancer treatment. Scientists are also aware of the prospective advantages of CAR engineering in cellular immunotherapy. Due to various limitations such as the serious side effects of CAR-T therapy, researchers began to investigate other immune cells for CAR modification. Natural killer (NK) cells are critical innate immune cells with the characteristic of non-specifically recognizing target cells and with the potential to become "off-the-shelf" products. In recent years, many preclinical studies on CAR-engineered NK (CAR-NK) cells have shown their remarkable efficacy in cancer therapy and their superiority over autologous CAR-T cells. In this review, we summarize the generation, mechanisms of anti-tumor activity and unique advantages of CAR-NK cells, and then analyze some challenges and recent clinical trials about CAR-NK cells therapy. We believe that CAR-NK therapy is a promising prospect for cancer immunotherapy in the future.
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Biological components (protein, DNA, lipid rafts, etc.) self-sort to form higher-order structures with elegant modulation by endogenous stimuli for maintaining cellular functions in living cells. However, the challenge of producing self-sorted higher-order assemblies of peptides in living systems (cells and tissues) spatiotemporally has yet to be achieved. This work reports the using of a biocompatible strategy to construct self-sorted assemblies of peptides in living cells and tumor-bearing mice. The results show that the designed peptides self-sort to form distinct nanostructures in living cancer cells using an endogenous trigger, as evidenced by confocal laser scanning microscopy and Bio-EM. Wound-healing experiments indicate that the in situ generation of self-sorted nanostructures exhibits a synergistic effect that significantly decreases the migration of cancer cells. In vivo experiments demonstrate that the designed peptides could self-sort in tumor-bearing mice and improve the tumor penetrating ability of the impenetrable component in tumor tissue. We can further program the formation of self-sorted materials through orthogonal triggers by introducing an exogenous trigger (light) and an endogenous trigger independently. Thus, this work provides a strategy to control multiple self-assembling processes in the context of the living system and provides a general strategy to construct self-sorted structures for the emergent properties of materials science.