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Receptor-interacting protein kinase 3 (RIP3) is the core regulator that switches cell death from apoptosis to necrosis. However, its role in tumor immunity is unknown. In this study, decreased RIP3 expression was observed in patients with hepatocellular carcinoma (HCC), which correlates with myeloid-derived suppressor cell (MDSC) accumulation. Moreover, RIP3 is a prognosis factor for patients with HCC. We further found that RIP3 knockdown results in an increase of MDSCs and a decrease of interferon gamma-positive (IFN-γ+ ) cluster of differentiation 8-positive (CD8+ ) tumor-infiltrating lymphocytes (IFN-γ+ CD8+ T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65Ser536 and promoting phosphorylated P65Ser536 nuclear translocation, RIP3 knockdown increases the expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in HCC cells. RIP3 knockdown induces MDSC recruitment through the CXCL1-chemokine (C-X-C motif) receptor 2 (CXCR2) axis. Furthermore, a CXCR2 antagonist substantially suppresses MDSC chemotaxis and HCC growth in RIP3 knockout mice. Conclusion: RIP3 deficiency is an essential factor directing MDSC homing to HCC and promoting CXCL1/CXCR2-induced MDSC chemotaxis to facilitate HCC immune escape and HCC progression; blocking the CXCL1-CXCR2 chemokine axis may provide an immunological therapeutic approach to suppress progression of RIP3 deficiency HCC.
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Carcinoma Hepatocelular/patologia , Quimiocina CXCL1/fisiologia , Neoplasias Hepáticas/patologia , Células Supressoras Mieloides/fisiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Receptores de Interleucina-8B/fisiologia , Animais , Quimiotaxia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
Blockade of the immunosuppressive checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed death 1 (PD-1) and its cognate ligand, programmed death 1 ligand (PD-L1), has altered the landscape of anti-tumor immunotherapy. B7 family and tumor necrosis factor receptor (TNFR) superfamily play a crucial role in T cell activation, tolerance, and anergy through co-stimulatory and inhibitory signal transduction. Investigating the immune molecular landscapes of the B7 and TNFR families is critical in defining the promising responsive candidates. Herein, we performed comprehensive alteration analysis of the B7 and TNFR family genes across six hepatocellular carcinoma (HCC) datasets with over 1000 patients using cBioPortal TCGA data. About 16% of patients had both B7 and TNFR gene alterations. TNFR gene amplifications were relatively more common (1.73â»8.82%) than B7 gene amplifications (1.61â»2.94%). Analysis of 371 sequenced samples revealed that all genes were upregulated: B7 and TNFR mRNA were upregulated in 23% of cases (86/371) and 28% of cases (105/371), respectively. Promoter methylation analysis indicated an epigenetic basis for B7 and TNFR gene regulation. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. B7-H6 expression was significantly associated with worse overall survival, and B7-H6 mRNA was increased gradually in cases with gene copy number alterations. B7-H6 overexpression was associated with aggressive clinicopathologic features and poor prognosis in HCC. Downregulation of B7-H6 in HCC cells significantly inhibited cell adhesion, proliferation, migration, and invasion. Knockdown of B7-H6 in HCC cells inhibited tumor growth and metastasis in vivo. B7-H6 promoted HCC metastasis via induction of MMP-9 expression and STAT3 activation. B7-H6 and STAT3 performed functional overlapping roles on enhancing the MMP-9 promoter activity in HCC cells. These results suggest that alterations of the immunologic co-stimulator B7 and TNFR families correlate with HCC metastasis and prognosis, and especially B7-H6 plays a critical role in promoting metastasis of HCC.
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Antígenos B7/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antígenos B7/antagonistas & inibidores , Antígenos B7/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores do Fator de Necrose Tumoral/genéticaRESUMO
Four new monoterpenoid glycosides 1-4, named magnoliaterpenoid A-D, were isolated from a 50% aqueous acetone extract of flower buds of Magnolia biondii, along with one known compound, (1'R,3'S,5'R,8'S,2Z,4E)-dihydrophaseic acid 3-O-ß-d-glucopyranoside (5). Their structures and relative configuration were identified by extensive spectroscopic analysis (IR, UV, MS, 1D and 2D NMR). The aglycones of these four new compounds possess seven-membered rings systems, which are very rare. A plausible biosynthetic route for the four new compounds was proposed via the biogenetic isoprene rule. Compounds 1, 2, 3, and 4 showed no antimicrobial activity at the concentration range of 1.95-250 µg/mL.
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Glicosídeos/isolamento & purificação , Magnolia/química , Monoterpenos/isolamento & purificação , Anti-Infecciosos/química , Flores/química , Glicosídeos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Monoterpenos/química , Extratos Vegetais/químicaRESUMO
PURPOSE: This study examined the contribution of the central and peripheral retina to the development of form deprivation myopia in chicks. METHODS: Chicks were treated for 7 days either with centrally form-deprived (CFD) lenses of 2/4/6/8 mm diameter central diffuse zone, or a full size diffuser lens on their right eyes. The left eyes wore a full field plano lens. Axial dimensions and refractions were measured before and after 4 and 7 days of lens wear. RESULTS: All eyes that had worn CFD lenses of 2/4/6/8 mm had significant changes in refractive errors (from -2.69 ± 0.40 D to -6.13 ± 0.76 D, p < 0.05), vitreous chamber depth (from 0.19 ± 0.04 mm to 0.56 ± 0.04 mm, p < 0.05) and axial length (from 0.42 ± 0.03 mm to 0.96 ± 0.04 mm, p < 0.05) during the experiment, except for the changes in refractive error (-2.81 ± 0.33 D, p = 0.053) and axial length (0.77 ± 0.04 mm, p = 0.050) in the 2 mm lens group after 7 days of lens wear. The myopic shift in the CFD lens wearing eyes was due primarily to an increase in vitreous chamber depth. Linear regression analysis showed that the changes of refractive error, vitreous chamber depth and axial length were positively correlated with the size of central form-deprived retina. Form depriving the central retina produced axial myopia even in the presence of clear peripheral vision. CONCLUSIONS: The current study showed that both the central and peripheral retina contributes to myopia development in chicks. The amount of myopia induced increased linearly with the area of retina being form-deprived. It suggests that in terms of decoding optical input for growth, the area of retina being exposed to optical signals may be critical in determining eye growth.
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Miopia/fisiopatologia , Refração Ocular/fisiologia , Campos Visuais/fisiologia , Animais , Comprimento Axial do Olho , Galinhas , Modelos Animais de Doenças , Erros de Refração/fisiopatologia , Privação Sensorial/fisiologia , Corpo Vítreo/patologiaRESUMO
BACKGROUND: Esophageal variceal diameter (EVD) is one of the most important predictors of variceal bleeding, as well as an important predictor of the effectiveness of endoscopic esophageal varices (EV) treatments. EVD is currently determined using visual inspection by endoscopic operators, meaning that results can vary widely between operators. This approach also means that cases unsuitable for endoscopic variceal ligation (EVL) can be complicated by postoperative hemorrhage. Thus, the purpose of this study was to explore the value of a virtual ruler (VR) in predicting rebleeding after the endoscopic treatment of EV in patients with cirrhosis. METHODS: We enrolled 588 patients with cirrhosis and EV (with and without gastric varices), who were treated with EVL or endoscopic injection sclerotherapy across 3 hospitals. We categorized participants into 2 groups, a nonbleeding group and a rebleeding group, according to whether they bled again after surgery. We compared basic demographic and clinical data, laboratory tests, EVD, and treatment modalities between the 2 groups. Potential risk factors for rebleeding after EV operations were analyzed using univariate and multivariable regression analyses. Correlations between esophageal variceal rebleeding and EVD were also analyzed, as was the consistency between visual EVD estimates and EVD measured using a VR. RESULTS: Child-Pugh class, albumin (ALB) levels, prothrombin time (PT), EVD (visual value), EVD (VR value), red sign, and the number of laps used for EVL showed statistically significant differences between the rebleeding and nonbleeding groups. Univariate regression analysis showed that Child-Pugh classification, ALB levels, PT, EVD (VR value), and red sign were strongly associated with rebleeding after endoscopic treatment of EV, whereas multivariable regression analysis showed that Child-Pugh classification, ALB levels, and EVD (VR value) were predictive factors for rebleeding after endoscopic treatment of EV. Differences between visual EVD estimates and VR EVD measurements were large. (Kappa value: 0.391, P < .001). However, the 2 methods showed high agreement for EVD >1 cm (87/95) CONCLUSION: EVD (VR value) can more accurately predict rebleeding rates. It can also provide a basis for selecting appropriate endoscopic treatment modalities for EV and effectively circumvent postoperative EV rebleeding.
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BACKGROUND: High-flow nasal cannula (HFNC) and conventional oxygen therapy (COT) are important respiratory support strategies for acute hypoxemic respiratory failure (AHRF) in coronavirus disease 2019 (COVID-19) patients. However, the results are conflicting for the risk of intubation with HFNC as compared to COT. OBJECTIVES: We systematically synthesized the outcomes of HFNC relative to COT in COVID-19 patients with AHRF and evaluated these outcomes in relevant subpopulations. DESIGN: This study was designed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES AND METHODS: We searched PubMed, EMBASE, Web of Science, Scopus, ClinicalTrials.gov, medRxiv, BioRxiv, and the Cochrane Central Register of Controlled Trials for randomized controlled trials and observational studies that compared the efficacy of HFNC with COT in patients with COVID-19-related AHRF. Primary outcomes were intubation rate and mortality rate. Secondary outcomes were the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), respiratory rate, hospital length of stay, intensive care unit (ICU) length of stay, and days free from invasive mechanical ventilation. RESULTS: In total, 20 studies with 5732 patients were included. We found a decreased risk of requiring intubation in HFNC compared to COT [odds ratio (OR) = 0.61, 95% confidence interval (CI): 0.46-0.82, p = 0.0009, I2 = 75%]. Similarly, we found HFNC was associated with lower risk of intubation rate compared to COT in the subgroup of patients with baseline PaO2/FiO2 < 200 mmHg (OR = 0.69, 95% CI: 0.55-0.86, p = 0.0007, I2 = 45%), and who were in ICU settings at enrollment (OR = 0.57, 95% CI: 0.38-0.85, p = 0.005, I2 = 80%). HFNC was associated with an improvement of PaO2/FiO2 and respiratory rate compared to COT. The use of HFNC compared to COT did not reduce the mortality rate, days free from invasive mechanical ventilation, hospital length of stay, or ICU length of stay. CONCLUSION: Compared to COT, HFNC may decrease the need for tracheal intubation in patients with COVID-19-related AHRF, particularly among patients with baseline PaO2/FiO2 < 200 mmHg and those in ICU settings. TRIAL REGISTRATION: This systematic review and meta-analysis protocol was prospectively registered with PROSPERO (no. CRD42022339072).
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COVID-19 , Ventilação não Invasiva , Insuficiência Respiratória , Humanos , Cânula , COVID-19/terapia , Ventilação não Invasiva/efeitos adversos , Ventilação não Invasiva/métodos , Oxigênio , Oxigenoterapia/efeitos adversos , Insuficiência Respiratória/terapia , Insuficiência Respiratória/etiologiaRESUMO
Systemic anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a group of heterogenous CD30 + T-cell non-Hodgkin lymphomas. Previous studies have highlighted the importance of JAK/STAT3 signaling activation in the molecular pathogenesis of ALK - ALCLs. In the present study, we aimed to establish a potential relationship between JAK/STAT3 signaling activation and clinicopathologic features in ALK - ALCLs, and further recognize the heterogenous nature of these neoplasms. Immunohistochemistry staining of the phosphorylated-STAT3 (p-STAT3) and dual-specificity protein phosphatase 22 ( DUSP22 ) gene rearrangement analysis were performed. Forty-five cases of ALK - ALCL were divided into 3 groups, including 9 DUSP22 -rearranged ALCLs, 21 p-STAT3 + double-negative (DN) ALCLs (both ALK and DUSP22 rearrangement negative), and 15 p-STAT3 - DN-ALCLs. Morphologically, p-STAT3 + DN-ALCLs exhibited sheet-like neoplastic cells and sometimes showed large pleomorphic cells scattered in a lymphocyte-rich background more frequently than those in other ALK - ALCLs subtypes. Phenotypically, the p-STAT3 + DN-ALCLs frequently expressed cytotoxic molecules, epithelial membrane antigen, and programmed death-ligand 1, whereas CD3 and CD5 expression was not observed. Clinically, patients with p-STAT3 + DN-ALCLs had a better prognosis than those with p-STAT3 - DN-ALCLs. These observations suggest that p-STAT3 + DN-ALCLs represent a distinct subtype of ALK - ALCLs. Identifying ALK - ALCL subtypes by using p-STAT3 staining and DUSP22 rearrangement is a promising approach that may contribute to risk stratification and better treatment decisions in the future clinical practice.
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Linfoma Anaplásico de Células Grandes , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Receptores Proteína Tirosina Quinases/genética , Imuno-Histoquímica , Prognóstico , Fator de Transcrição STAT3/genéticaRESUMO
OBJECTIVE: To compare the clinical efficacies of two surgical methods in the treatment of medial tibial-femoral osteoarthritis. METHODS: Between October 2007 and June 2010, a total of 22 cases (25 knees) with severe osteoarthritis in medial tibial-femoral compartment underwent minimally invasive unicompartmental knee arthroplasty (UKA) with Sled prosthesis after arthroscopic procedure. And its clinical efficacy was compared with that of 22 cases (25 knees) undergoing total knee arthroplasty (TKA) with Gemini MKII prosthesis almost simultaneously. RESULTS: There were no significant difference in general data between 2 groups (P > 0.05). Compared with the TKA group, the UKA group had a smaller blood loss ((148 ± 26) vs (278 ± 36) ml), a shorter operative duration ((68 ± 12) vs (86 ± 12) min), a faster progress of resuming 90° flexion ((3.18 ± 1.8) vs (9.1 ± 2.2) d) and an earlier off-bed time (P < 0.05). All patients were followed up for 6 - 34 months. There was no significant difference in KSS (Knee Society Score), function score or WOMAC (Western Ontario and McMaster Universities) score between 2 groups at the last follow-up (P > 0.05). CONCLUSION: The treatment of medial tibial-femoral osteoarthritis with minimally invasive UKA is superior to that with TKA in that it is less invasive, there is a faster recovery of joint functions and no significant difference exists in the mid-term clinical efficacies between them.
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Articulação do Joelho/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos , Osteoartrite do Joelho/cirurgia , Artroplastia do Joelho , Feminino , Humanos , Prótese do Joelho , Masculino , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the mechanism of macrophage-stimulating protein (MSP)-mediated inhibition of inflammatory cytokine and chemokine production in rheumatoid arthritis synovial fibroblasts (RASF). MATERIALS AND METHODS: RASF were treated with different concentrations (0, 0.5, 1, 5 and 10 ng/ml) of MSP with or without 1 µg/mL lipopolysaccharide (LPS). The protein expressions of IL-1ß, TNF-α, IL-18, MIP-1, MCP-1, RANTES and PGE(2) were analyzed by enzyme-linked immunosorbent assays (ELISA). The total nitric oxide (NO) concentration was determined using the Griess reaction. The protein expressions of iNOS, COX-2, NF-κB(p-p65), IKB-α, IKB-ß, p-P38, p-Erk1/2 (P-P42/44) and p-AKT were detected by Western blotting. RESULTS: MSP markedly inhibited expression of inflammatory cytokines (IL-1ß, TNF-α and IL-18), chemokines (MIP-1, MCP-1 and RANTES) and iNOS, NO, COX-2 and PGE(2) in RASF stimulated by LPS. MSP treatment decreased expressions of p-IκBα, p-IKBß and p-P65 in RASF in a concentration-dependent manner. Expressions of p-AKT, p-p38 and p-Erk1/2 were also inhibited markedly in RASF stimulated by LPS after treatment with MSP in a concentration-dependent manner. CONCLUSION: MSP could inhibit the inflammatory cycle by suppressing inflammatory mediators and activation of NF-κB as well. The inhibitory effect of MSP on LPS-stimulated RASF may act through suppression of multiple signals such as the PI3K/AKT and/or MAPK pathways.
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Artrite Reumatoide/imunologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fator de Crescimento de Hepatócito/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Proteínas Proto-Oncogênicas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/citologia , Artrite Reumatoide/patologia , Células Cultivadas , Quimiocinas/imunologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/imunologia , Dinoprostona/imunologia , Fibroblastos/citologia , Fibroblastos/fisiologia , Fator de Crescimento de Hepatócito/imunologia , Humanos , Proteínas I-kappa B/metabolismo , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidor de NF-kappaB alfa , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Proto-Oncogênicas/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/imunologia , Fator de Transcrição RelA/metabolismoRESUMO
OBJECTIVE: To explore the therapeutic effects of aspirin on postmenopausal osteoporosis and understand its action mechanism. METHODS: Forty three-month-old female SD rats were randomly divided into 5 groups (n = 8 each): sham group, OVX group and aspirin groups (A1, A2 & A3). The OVX and aspirin groups were ovariectomized (OVX). All rats underwent BMD (bone mineral density) scan at the time of OVX and 3 months after OVX. After the animal model of osteoporosis was established, aspirin groups were intragastrically administered at a dose of 8.93 mg×kg(-1)×d(-1) (A1), 26.79 mg×kg(-1)×d(-1) (A2) and 80.36 mg×kg(-1)×d(-1) (A3) daily in OVX rats. Three months later, the BMD and micro-architecture of vertebrae were measured by dual-energy X-ray absorptiometry and microtomography. Alkaline phosphatase and osteocalcin were measured in peripheral blood. The trabecular architecture changes were observed by histomorphology. Axial compression tests were used to evaluate the mechanical properties of vertebral specimens and three-point bending tests used for femur shaft. RESULTS: Three months after ovariectomy, BMD was significantly lower than preoperative. BMD in aspirin treated groups was significantly higher than that in OVX group. Alkaline phosphatase in peripheral blood decreased significantly in aspirin groups than those in OVX, but osteocalcin had no significant difference between aspirin and OVX groups. The microtomography reconstruction analysis also showed that the trabecular thickness, trabecular number and BMD increased significantly in aspirin groups than those in OVX. And there was no significant difference between A3 and sham groups. The results of biomechanical test showed that the maximum compression load of lumbar spine and three-point bending load of femur shaft were significantly higher in aspirin groups than those in OVX group. CONCLUSION: Aspirin can promote trabecular bone remodeling, improve three-dimensional structure of trabecular bone and increase bone density of cancellous in osteoporotic rats by stimulating bone formation. It may become a new drug for the treatment of osteoporosis.
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Aspirina/uso terapêutico , Osteoporose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Ovariectomia , Ratos , Ratos Sprague-DawleyRESUMO
Two new phenylpropanoids, named (2'R*,3'R*)-2',3'-dihydroxy-4'-methoxy-caffeoyl butyrate (1), 9-acetoxy syringin (2), and a new dihydrostilbene, named (8'R)-4',5-dihydroxy-4,8'-dimethoxy-2-hydroxyethyl diphenylethane (3), together with five analogues (4-8), were isolated from the flower buds of Magnolia biondii Pamp. Their structures were elucidated by extensive spectroscopic analyses and comparison with literature data. The absolute configurations were deduced by comparison of experimental and calculated gauge-independent atomic orbital (GIAO) 1 D NMR data. Moreover, the isolated compounds (1-8) were evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activities.
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Inibidores da Colinesterase/farmacologia , Di-Hidroestilbenoides , Magnolia , Propionatos/farmacologia , Acetilcolinesterase , Inibidores da Colinesterase/isolamento & purificação , Di-Hidroestilbenoides/isolamento & purificação , Di-Hidroestilbenoides/farmacologia , Flores/química , Magnolia/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Propionatos/isolamento & purificaçãoRESUMO
BACKGROUND: Anaplastic large cell lymphoma (ALCL) is a rare non-Hodgkin lymphoma. A comprehensive understanding of the genetic and clinical heterogeneity of ALCL may help to improve the clinical management of patients with ALCL. However, due to the rarity of the disease, the genetic heterogeneity of ALCL has not been well elucidated. This study aimed to comprehensively elucidate the mutational landscape of tumor tissue samples from patients with systemic ALCL. METHODS: Thirty-six patients with systemic ALCL were enrolled in this retrospective study. Immunohistochemistry (IHC) was performed on tumor tissues at baseline to identify anaplastic lymphoma kinase (ALK) fusions. Capture-based targeted next-generation sequencing (NGS) with a panel spanning 112 lymphoma-related genes, including ALK rearrangements, was also performed on tumor tissue samples. RESULTS: A total of 102 mutations were identified in the entire cohort. Among the 36 patients included in this analysis, 14 (38.8%) were ALK positive, as determined by IHC, while NGS showed 12 patients (33.3%) to harbor ALK rearrangements. Younger patients were more likely to have ALK-positive ALCL (P=0.011). Patients with wild-type (WT) ALK were more likely to have single-nucleotide variants (SNVs) and insertions or deletions (INDELs) than patients with ALK rearrangements (P=0.027). Among the 22 patients with WT ALK, the most commonly mutated genes were TP53 (n=6, 27.3%), followed by NOTCH1 (n=5, 22.7%), KMT2D (n=3, 13.6%), KRAS (n=3, 13.6%), TET2 (n=3, 13.6%), and JAK1 (n=2, 9.1%). Mutations in PRDM1, a commonly mutated gene in ALK-negative patients, were not detected in our ALK-negative cohort. Start-loss of beta-2-microglobulin (B2M) was detected in another patient; this patient had a favorable prognosis, with an overall survival exceeding 19 months. CONCLUSIONS: Our study revealed the unique genomic profiles of Chinese ALCL patients and represents an incremental step in deepening the understanding of the genetic heterogeneity of ALCL patients.
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OBJECTIVE: To observe effect of "Zhibian (BL 54) through Shuidao (ST 28)" acupuncture for quality of life of female patients with stress urinary incontinence. METHODS: A total of 90 female patients were randomly divided into an observation group and a control group, 45 cases in each group. The patients in the observation group were treated with "Zhibian (BL 54) through Shuidao (ST 28)" acupuncture method, and the patients in the control group were treated with non-permeable sham acupuncture at Zhibian (BL 54). The needles were retained for 30 min in both groups, once a day, and the treatment was totally given 10 times. The score of urinary incontinence quality of life questionnaire (I-QOL) was recorded before and after treatment and during the follow-up 1 month after treatment in the two groups, and the 1 h urine pad test and the 72 h urination diary card were used to evaluate the 1 h urine leakage and the 24 h urine leakage frequency of the two groups. RESULTS: After treatment and during follow-up, the I-QOL scores in the observation group were higher than those before treatment (P<0.05), and were higher than those in the control group (P<0.05). After treatment and during follow-up, the 1 h urine leakage and the 24 h urine leakage frequency in the observation group were lower than those before treatment (P<0.05), and less than those in the control group (P<0.05). CONCLUSION: Acupuncture of "Zhibian (BL 54) through Shuidao (ST 28)" can improve the quality of life of female patients with stress urinary incontinence, and improve the volume and frequency of urine leakage.
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Terapia por Acupuntura , Incontinência Urinária por Estresse , Pontos de Acupuntura , Feminino , Humanos , Qualidade de Vida , Resultado do Tratamento , Incontinência Urinária por Estresse/terapia , MicçãoRESUMO
BACKGROUND: Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL-N) is an aggressive lymphoma typically diagnosed by examining small biopsy specimens. Flow cytometry is very valuable for the diagnosis and classification of several kinds of hematolymphoid neoplasms but has not been widely used for diagnosing ENKTL-N. METHODS: We systematically investigated the flow cytometry characteristics of 26 solid tissue biopsy specimens of ENKTL-N at initial diagnosis and compared the results with those from reactive NK-cells in the nasal/nasopharyngeal region and peripheral blood. RESULTS: Our study revealed seven flow cytometry (FCM)-based characteristics for distinguishing between the neoplastic cells and reactive NK-cells, including (1) the proportion of NK-cells among total lymphocytes >10%; (2) forward scatter >105 ; (3) mean fluorescence intensity of CD56 > 5,000; (4) aberrant antigen expression or loss; (5) skewed killer cell immunoglobulin-like receptor repertoire; (6) homogenously positive for CD38; and (7) positive for CD30 or CD336. FCM-based immunophenotyping is a potentially feasible and convenient approach for discriminating cellular lineages, evaluating the activation status of NK-cells, and selecting potential therapy targets of ENKTL-N. CONCLUSIONS: Flow cytometry is very valuable for facilitating routine diagnosis, confirming clonality, predicting the cellular lineage, and guiding individual treatment for ENKTL-N. © 2019 International Clinical Cytometry Society.
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Citometria de Fluxo/métodos , Imunofenotipagem/métodos , Células Matadoras Naturais/patologia , Linfoma Extranodal de Células T-NK/diagnóstico , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Idoso , Biópsia/métodos , Antígeno CD56/metabolismo , Linhagem da Célula/fisiologia , Feminino , Humanos , Antígeno Ki-1/metabolismo , Células Matadoras Naturais/metabolismo , Linfoma Extranodal de Células T-NK/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Estudos RetrospectivosRESUMO
OBJECTIVE: To expose the spectrum and frequency of GJB2, GJB3, SLC26A4 and MT-RNR1 in northwest China and to investigate the underlying causative genes in patients without common mutations. METHODS: We analyzed the mutation screening results of GJB2, GJB3, SLC26A4 and MT-RNR1 in 398 unrelated severe-to-profound probands with bilateral, symmetrical sensorineural hearing loss. Subsequently, we selected 10 probands with a significant family history of inherited hearing loss (HL) that did not have the above four common gene mutations to perform next-generation sequencing (NGS) of 139 known deafness genes, followed by co-segregation analysis of all available family members. RESULTS: Among the 398 patients, 69 (17.34%) had the biallelic GJB2 gene mutations, and the most common mutations were c.235delC, c.109G>A and c.299_300delAT, with allele frequencies of 12.31%, 3.38% and 3.89%, respectively. A total of 63 (15.83%) cases with biallelic SLC26A4 mutations were detected, and the most common pathogenic alleles were c.919-2A>G, c.2168A>G and c.1174A>T, with allele frequencies of 9.17%, 2.26% and 0.88%, respectively. Mitochondrial gene mutations were detected in 9 (2.26%) patients, with 5 cases of mitochondrial DNA (mtDNA) m.1555A>G mutation and 4 cases of mtDNA m.1095T>C mutation. In 10 probands with a clear family history of HL, NGS showed two novel pathogenic variants in 2 families, including c.4129C>T/c.3268C>T in LOXHD1, c.334G>A/c.2968G>T in CDH23. Sanger sequencing confirmed that these variants segregated with the HL in each family. CONCLUSIONS: Our results showed that GJB2 and SLC26A4 were the two major HL-causing genes in northwest China. The most common mutation alleles in GJB2 were c.235delC, c.109G>A and c.299_300delAT, and those in SLC26A4 were c.919-2A>G, c.2168A>G and c.1174A>T. In addition, both genes and their loci can be used as the first selection of deafness gene screening. Additionally, for patients who did not have mutations of these common genes, NGS provided an efficient diagnosis for increasing known deafness genes.
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Marcadores Genéticos , Perda Auditiva Neurossensorial/genética , Taxa de Mutação , Adolescente , Adulto , Criança , Pré-Escolar , China , Conexina 26 , Conexinas/genética , Análise Mutacional de DNA , Feminino , Genes Mitocondriais , Genes de RNAr , Testes Genéticos , Perda Auditiva Neurossensorial/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , RNA Ribossômico/genética , Transportadores de Sulfato/genética , Adulto JovemRESUMO
Colorectal cancer (CRC) is a common human malignancy, accounting for 600,000 death cases annually worldwide. Chrysophanol is a naturally occurring anthraquinone compound and exhibits anti-neoplastic activities. This study aims to explore the biological effects of chrysophanol on CRC metastasis and the relevant underlying mechanism. Cell proliferation assay, wound scratch assay, and Transwell invasion assay were used to examine the effect of chrysophanol on proliferation, migration, and invasion of CRC cells. Hypoxia-inducible factor-1α (HIF-1α) shRNA was utilized to transfect CRC cells to examine the role of HIF-1α in chrysophanol suppression of hypoxia-induced epithelial to mesenchymal transition (EMT). The suppression effect of chrysophanol on hypoxia-induced EMT in vivo was also validated in xenograft tumor models. In the present study, our findings indicated that chrysophanol has the capability to suppress hypoxia-induced EMT in CRC in vitro and in vivo, and the possible mechanism involved is the inhibition of HIF-1α via modulating PI3k/Akt signaling pathway. Collectively, the results indicated that chrysophanol can be used as an EMT and cancer metastasis inhibitor in the treatment of CRC. Anat Rec, 302:1561-1570, 2019. © 2019 American Association for Anatomy.
Assuntos
Antraquinonas/farmacologia , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hipóxia/fisiopatologia , Mutagênicos/farmacologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: In this study, we investigated the prevalence of CD79B and MYD88 mutations and their relation to clinical characteristics in a cohort of Chinese patients with primary testicular diffuse large B cell lymphoma (PT-DLBCL). PATIENTS AND METHODS: We examined the mutational status of CD79B and MYD88 by Sanger sequencing, and the gene amplification and protein expression of MYD88 in tissue samples from 30 cases of PT-DLBCL by quantitative polymerase chain reaction and immunohistochemistry, respectively. Western blotting was used to analyze phosphorylated STAT3 (p-STAT3) and phosphorylated p65 (p-p65) protein expression in cell lines harboring retroviral constructs for WT MYD88 or MYD88 mutant. RESULTS: Immunophenotypically, MYD88 protein staining was positive in 26/30 (86.67%) cases, and 23/30 (76.7%) cases tested positive for p65 in the nucleus. Genetically, CD79B mutation was found in 13/30 (43.3%) cases, whereas the MYD88 L265P mutation was found in 18/30 (60.0%) cases. Interestingly, CD79B and MYD88 mutations were more prevalent in the non-germinal center B cell (GCB) subtype (83.3% and 76.9%, respectively) and were relatively rare in the GCB subtype (16.7% and 23.1%, respectively). Furthermore, although MYD88 was significantly amplified in PT-DLBCL, the amplification status showed no correlation with its mutational status and protein expression. Clinicopathological comparison between the mutant and wild-type group showed that both CD79B mutation and MYD88 L265P were not significantly correlated with age, anatomical site, Ann Arbor stage, non-GCB/GCB subtype, p65 protein expression, BCL-2 protein expression, or BCL-2/c-MYC double expression (P>0.05). Survival analyses showed that high IPI and advanced stage (stage III-IV) associated with worse outcome (P<0.05). The expression of p-STAT3 and p-p65 protein was upregulated in the mutant group, indicating that MYD88 mutant activated NF-κB and JAK-STAT3 signaling. CONCLUSION: Our results suggest that MYD88 and CD79B mutations are important drivers of immune-privileged site-associated DLBCL and highlight potential therapeutic targets for personalized treatment.
RESUMO
Rationale: Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3). RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression. We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice. Methods: Tissues from colorectal cancer patients were examined for RIP3 expression. CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice. Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses. Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively. Results: RIP3 expression was upregulated in mouse CAC and human colon cancer. RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis. Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype. RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis. RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC. The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3-/- mice. Conclusion: Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression. These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.
Assuntos
Imunidade Adaptativa , Quimiocina CXCL1/metabolismo , Neoplasias Colorretais/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Animais , Antracenos/farmacologia , Apoptose/fisiologia , Carcinogênese , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL1/efeitos dos fármacos , Colite/complicações , Colite/patologia , Colo/patologia , Neoplasias do Colo/complicações , Neoplasias do Colo/patologia , Neoplasias Colorretais/complicações , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Expressão Gênica , Técnicas de Inativação de Genes , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Necroptose/fisiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Linfócitos T/metabolismoRESUMO
Myopia development has been extensively studied from different perspectives. Myopia recovery is also considered important for understanding the development of myopia. However, despite several previous studies, retinal proteomics during recovery from myopia is still relatively unknown. Therefore, the aim of the present study was to investigate the changes in protein profiles of chicken retinas during early recovery from lensinduced myopia to evaluate the signals involved in the adjustment of this refractive disorder. Threeday old chickens wore glasses for 7 days (10D lens over the right eye and a plano lens as control over the left eye), followed by 24 h without lenses. Protein expression in the retina was measured by twodimensional fluorescence difference gel electrophoresis (2DDIGE). ProQ Diamond phosphoprotein staining 2D gel electrophoresis was used to analyze phosphoprotein profiles. Protein spots with significant differences (P<0.05) were analyzed by mass spectrometry. The minus lenstreated eye became myopic, however following 24 h recovery, less myopia was observed. 2DDIGE proteomic analysis demonstrated that three identified protein spots were upregulated at least 1.2fold in myopic recovery retinas compared with those of the controls, Ras related protein Rab11B, Santigen retina and pineal gland and 26S proteasome nonATPase regulatory subunit 14. ProQ Diamond images further revealed three protein spots with significant changes (at least 1.8fold): ßtubulin was downregulated, while peroxiredoxin 4 and ubiquitin carboxylterminal hydrolaseL1 were upregulated in the recovery retinas compared with the control eye retinas. The present study detected previously unreported protein changes in recovering eyes, therefore revealing their potential involvement in retinal remodeling during eye ball reforge.
Assuntos
Proteínas Aviárias/metabolismo , Proteínas do Olho/metabolismo , Miopia/metabolismo , Proteômica , Retina/metabolismo , Animais , Galinhas , Modelos Animais de Doenças , Miopia/patologia , Retina/patologiaRESUMO
Surface treatment with Fenton was applied to flotation separation of acrylonitrile-butadienestyrene (ABS) and polyvinylchloride (PVC). After treatment, the floatability of ABS has a dramatic decrease, while the floatability of PVC is not affected. Fourier transform infrared spectroscopy (FT-IR) spectra and X-ray photoelectron spectroscopy (XPS) spectra were recorded to ascertain the mechanism of Fenton treatment. FT-IR and XPS analysis confirms that the introduction of oxygen-containing group occurs on the surface of ABS. The optimum conditions are molar ration (H2O2:Fe2+) 10000, H2O2 concentration 0.4M/L, pH 5.8, treatment time 2min and temperature 25°C, frother concentration 15mg/L and flotation time 3min. Particle sizes and mixing ratios were also investigated. Plastic mixtures of ABS and PVC with different particle sizes and mixing ratios can be effectively separated. The purity of ABS and PVC are up to 100% and 99.78%, respectively; the recovery of ABS and PVC are up to 99.89% and 100%, respectively. A practical, environmentally friendly and effective reagent, namely Fenton, was originally applied to surface treatment of ABS and PVC waste plastics for flotation separation of their mixtures.