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1.
Platelets ; : 1-9, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32614630

RESUMO

Intracranial hemorrhage (ICH) is a devastating complication of immune thrombocytopenia (ITP). However, information on ICH in ITP patients under the age of 60 years is limited, and no predictive tools are available in clinical practice. A total of 93 adult patients with ITP who developed ICH before 60 years of age were retrospectively identified from 2005 to 2019 by 27 centers in China. For each case, 2 controls matched by the time of ITP diagnosis and the duration of ITP were provided by the same center. Multivariate analysis identified head trauma (OR = 3.216, 95%CI 1.296-7.979, P =.012), a platelet count ≤ 15,000/µL at the time of ITP diagnosis (OR = 1.679, 95%CI 1.044-2.698, P =.032) and severe/life-threatening bleeding (severe bleeding vs. mild bleeding, OR = 1.910, 95%CI 1.088-3.353, P =.024; life-threatening bleeding vs. mild bleeding, OR = 2.620, 95%CI 1.360-5.051, P =.004) as independent risk factors for ICH. Intraparenchymal hemorrhage (OR = 5.191, 95%CI 1.717-15.692, P =.004) and a history of severe bleeding (OR = 4.322, 95%CI 1.532-12.198, P =.006) were associated with the 30-day outcome of ICH. These findings may facilitate ICH risk stratification and outcome prediction in patients with ITP.

2.
JAMA Netw Open ; 3(6): e206628, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32589229

RESUMO

Importance: The associations of lifestyle factors with gastric cancer (GC) are still underexplored in populations in China. Long-term nutritional supplementation may prevent GC in high-risk populations, but the possible effect modification by lifestyle factors remains unknown. Objective: To evaluate how lifestyle factors, including smoking, alcohol intake, and diet, may change the risk of GC incidence and mortality and whether the effects of vitamin and garlic supplementation on GC are associated with major lifestyle factors. Design, Setting, and Participants: This is a secondary analysis of the Shandong Intervention Trial, a masked, randomized, placebo-controlled trial that aimed to assess the effect of vitamin and garlic supplementations and Helicobacter pylori treatment on GC in a factorial design with 22.3 years of follow-up. The study took place in Linqu County, Shandong province, China, a high-risk area for GC. Data were collected from Jully 1995 to December 2017. Overall, 3365 participants aged 35 to 64 years identified in 13 randomly selected villages who agreed to undergo gastroscopy were invited to participate in the trial and were included in the analysis. Data analysis was conducted from March to May 2019. Interventions: Participants received vitamin and garlic supplementation for 7.3 years, H pylori treatment for 2 weeks (among participants with H pylori ), or placebo. Main Outcomes and Measures: The primary outcomes were GC incidence and GC mortality (1995-2017). We also examined the progression of gastric lesions (1995-2003) as a secondary outcome. Results: Of the 3365 participants (mean [SD] age, 47.1 [9.2] years; 1639 [48.7%] women), 1677 (49.8%) were randomized to receive active vitamin supplementation, with 1688 (50.2%) receiving placebo, and 1678 (49.9%) receiving active garlic supplementation, with 1687 (50.1%) receiving placebo. Overall, 151 GC cases (4.5%) and 94 GC deaths (2.8%) were identified. Smoking was associated with increased risk of GC incidence (odds ratio, 1.72; 95% CI, 1.003-2.93) and mortality (hazard ratio [HR], 2.01; 95% CI, 1.01-3.98). Smoking was not associated with changes to the effects of vitamin or garlic supplementation. The protective effect on GC mortality associated with garlic supplementation was observed only among those not drinking alcohol (never drank alcohol: HR, 0.33; 95% CI, 0.15-0.75; ever drank alcohol: HR, 0.92; 95% CI, 0.55-1.54; P for interaction = .03), and significant interactions were only seen among participants with H pylori (never drank alcohol: HR, 0.31; 95% CI, 0.12-0.78; ever drank alcohol: HR, 0.91; 95% CI, 0.52-1.60; P for interaction = .04). No significant interactions between vitamin supplementation and lifestyle factors were found. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, smoking was associated with an increased risk of GC incidence and mortality. Not drinking alcohol was associated with a stronger beneficial effect of garlic supplementation on GC prevention. Our findings provide new insights into lifestyle intervention for GC prevention, suggesting that mass GC prevention strategies may need to be tailored to specific population subgroups to maximize the potential beneficial effect. Trial Registration: ClinicalTrials.gov Identifier: NCT00339768.

3.
Knee ; 27(3): 731-739, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32563430

RESUMO

BACKGROUND: Biomechanical study is fundamental for the preclinical evaluation of knee prostheses. However, there are few reports on the contact characteristic investigation in the hinged knee prosthesis. The purpose of this study was to investigate the contact characteristics of a novel hinged knee prosthesis. METHODS: All of the component models were designed and assembled using Solidworks. A comparison of the contact area and ultra-high-molecular-weight polyethylene (UHMWPE) deformation using the experimental method (EM) and finite-element analysis (FEA) under 3000 N with the prosthesis at different flexions was performed. The peak contact pressure and von Mises stress on tibial insert and bushing were investigated under nine specific samples that were extracted from a gait cycle using FEA (according to ISO 14243-1: 2009). RESULTS: The largest contact area and UHMWPE deformation were 100.78 ± 8.71 mm2 and 0.085 ± 0.015 mm in the EM, and 96.68 mm2 and 0.096 mm in FEA. The peak contact pressure and von Mises stress on the tibial insert were 26.3071 MPa and 10.5115 MPa at 13% of the gait cycle and on bushing were consistently 0 MPa. The contact pressures were distributed at the posterior of the insert. CONCLUSION: The finite-element model was validated to be applicable for predicting the real prosthesis behavior based on the good correlation of the results using the EM and FEA. The model can help to identify contact characteristics and be can used in optimization studies of this novel prosthesis during the design phase.

4.
J Arthroplasty ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32482479

RESUMO

BACKGROUND: Megaprosthetic replacement is one of the main methods for reconstructing mega bone defects after tumor resection. However, the incidences of complication associated with tumor prostheses were 5-10 times higher than that of conventional total knee arthroplasty. The objective of this study is to establish and validate a nomogram model which can assist doctors and patients in predicting the prosthetic survival rates. METHODS: Data on cancer patients treated with tumor prosthesis replacements at our institution from November 2001 to November 2017 were collected. The potential risk factors which were well-studied and shown to be associated with megaprosthetic failure were analyzed. A nomogram model was established using independent risk factors screened out by multivariate regression analysis. The concordance index and calibration curve were selected for internal validation of the predictive accuracy of nomogram. RESULTS: The 3-, 5-, 10-, and 15-year prosthetic survival rates were 92.8%, 88.6%, 74.1%, and 48.3%, respectively. The prosthetic motion mode, body mass index, type of reconstruction, type of prosthesis, and length of bone resection were independent risk factors for tumor prosthetic failure. A nomogram model was established using these significant predictors, with a concordance index of 0.77 and a favorable consistency between predicted and actual prosthetic failure rate according to the internal validation, indicating that the nomogram model had acceptable predictive accuracy. CONCLUSION: The prediction model identifies high-risk patients for whom attached preventive measures are required. Future studies regarding reduction in incidence of prosthetic failure should attach importance to these high-risk patients.

5.
Int Orthop ; 44(7): 1427-1433, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32435955

RESUMO

PURPOSE: Aseptic loosening is a common prosthetic failure mode. The purpose of this study was to identify dose-response relationship between length of femoral stem and aseptic loosening. METHODS: We collected data of patients who underwent distal femoral prosthetic replacements at our institution from 2001 to 2017. Cox regression and two-piecewise regression model were used to analyze the associations between stem length and aseptic loosening. RESULTS: Significant association of length of femoral stem with aseptic loosening was observed in multivariate model and a non-linear relationship could be found from the smoothed curve. In two-piecewise model, an inflection point was calculated to be 143 mm. On the left of the inflection point, every 1 mm increase in the length of stem indicated that the risk of aseptic loosening could be reduced by 6%. CONCLUSION: There was a significant non-linear relationship between the length of femoral stem and aseptic loosening, and the inflection point was 143 mm.

6.
Br J Haematol ; 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32452543

RESUMO

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological emergency. Although therapeutic plasma exchange together with corticosteroids achieve successful outcomes, a considerable number of patients remain refractory to this treatment and require early initiation of intensive therapy. However, a method for the early identification of refractory iTTP is not available. To develop and validate a model for predicting the probability of refractory iTTP, a cohort of 265 consecutive iTTP patients from 17 large medical centres was retrospectively identified. The derivation cohort included 94 patients from 11 medical centres. For the validation cohort, we included 40 patients from the other six medical centres using geographical validation. An easy-to-use risk score system was generated, and its performance was assessed using internal and external validation cohorts. In the multivariable logistic analysis of the derivation cohort, three candidate predictors were entered into the final prediction model: age, haemoglobin and creatinine. The prediction model had an area under the curve of 0·886 (95% CI: 0·679-0·974) in the internal validation cohort and 0·862 (95% CI: 0·625-0·999) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. In conclusion, we developed and validated a highly accurate prediction model for the early identification of refractory iTTP. It has the potential to guide tailored therapy and is a step towards more personalized medicine.

7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 547-552, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319394

RESUMO

OBJECTIVE: To investigate clinical characteristics of multiple myeloma(MM) patients with two different results of blood separation in vacum blood collection tubes containing separator gels after centrifugation, and evaluate the prognostic value of these two results. METHODS: The clinical data of 168 patients with newly diagnosed MM treated in our hospital from March 2009 to December 2017 were retrospectively analyzed. The blood samples were divided into control group(the order from top to bottom is serum,separator gel and red blood cell) and abnormal group(the order from top to bottom is serum, red blood cell, separator gel and red blood cell) according to the results of blood separation in vacum blood collection tubes containing separator gels after centrifugation. The differences of age, sex, biochemical indexes (total protein, albumin, immunoglobulin, ß2microglobulin, calcium, lactate dehydrogenase, creatinine), blood routine indexes(hemoglobin, Plt), immunophenotyping and clinical staging of patients were compared; and the relationship between the results of blood separation and efficacy was analyzed and the difference of overall survival (OS) time between the two groups was compared. RESULTS: There was significant difference in total protein, albumin, immunoglobulin, ß2 microglobulin, hemoglobin, immunophenotyping, clinical stage between control group and abnormal group (P<0.05). However the differences of sex, age, calcium, lactate dehydrogenase, creatinine, Plt showed no statistically significant (P>0.05). Patients in abnormal group obtained complete remission (CR) or very good partial remission (VGPR) showed normal results in blood separation after treatment. Patients obtained partial remission(PR) showed partly normalized and partly unchanged, while patients obtained less than PR showed unchanged. Patients in control group obtained less than PR partly showed abnormal results in blood separation after treatment; Patients with normal results in blood separation showed long OS time, while patients with abnormal results of blood separation showed obviously short OS time. CONCLUSION: Abnormal separation phenomenon is found after centrifugation in patients with multiple myeloma, which associates with total protein, albumin, immunoglobulin, ß2 microglobulin, hemoglobin, immunophenotyping, clinical staging and prompts more tumor burden. The result of normal blood separation suggests a better prognosis, while the result of abnormal blood separation suggests a poor prognosis.


Assuntos
Mieloma Múltiplo , Humanos , Imunofenotipagem , Prognóstico , Indução de Remissão , Estudos Retrospectivos
8.
Zootaxa ; 4722(2): zootaxa.4722.2.5, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-32230633

RESUMO

Morphological and molecular analyses have determined that there is a new species of Tardigrada found in China. Diphascon wuyingensis sp. nov., has smooth cuticle, pharyngeal apophyses, three rod-shaped macroplacoids (increasing in length from first to third, with the second macroplacoid clearly longer than the first) and lacks microplacoids and septulum. The new species has a very small drop-shaped formation and small claws of the Hypsibius type, but no pseudolunules or other cuticular thickenings. Three individual specimens and a group of four specimens were used for DNA isolation and 18S rRNA and COI sequencing; the p-distances to another three Diphascon species used for comparison varied in ranges of 8.8-10.2% (18S rRNA) and 24.2-26.7% (COI).


Assuntos
Tardígrados , Animais , China , Faringe
9.
Orthop Surg ; 12(2): 631-638, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32159285

RESUMO

OBJECTIVES: To investigate the contact stress and the contact area o tibial inserts and bushings with respect to different congruency designs in a spherical center axis and rotating bearing hinge knee prosthesis under gait cycle loading conditions using finite element analysis. METHODS: Nine prostheses with different congruency (different degrees of tibiofemoral conformity and different distances between the spherical center and the bushing) designs were developed with the same femoral and tibial components. The models were transferred to finite element software. The peak contact stresses and contact areas on tibial inserts and bushings under the gait cycle loading conditions were investigated and compared. RESULTS: For tibial insert, the peak contact stress was the highest in the low conformity-long group (61.4486 MPa), and it was 1.88 times higher than that in the group with the lowest stress (moderate conformity-short group, 32.754 MPa). The contact area was the largest in the low conformity-long group (420.485 mm2 ), and it was 1.19 times larger than that in the group with the smallest area (moderate conformity-middle group, 352.332 mm2 ). For bushing, the peak contact stress was the highest in the high conformity-long group (72.8093 MPa), and it was 3.21 times higher than that in the group with the lowest stress (high conformity-short group, 22.6928 MPa). The contact area was the largest in the low conformity-short group (2.41 mm2 ), and it was 2.27 times larger than that in the group with the smallest area (high conformity-middle group, 1.063 mm2 ). CONCLUSION: The results of our study showed that the congruency of the tibiofemoral surface and bushing surface should be considered carefully in the design of the spherical center axis and rotating bearing hinge knee prosthesis. Different levels of contact performance were observed with different congruency designs. In addition, the influence of contact stress and contact area on the polyethylene wear of rotating hinge knee prostheses should be confirmed with additional laboratory tests.

10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 82-87, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027257

RESUMO

OBJECTIVE: To provide clinical basis for the diagnosis and treatment of chronic neutrophilic leukemia (CNL) and to provide possible molecular targets for the treatment. METHODS: By summarizing the clinical data of 14 patients with CNL, the clinical characteristics, gene mutation types and possible prognostic factors were analyzed. RESULTS: Among the 14 patients with CNL, males (9 cases) were more than females (5 cases), with a median age of 57 years old. The detection rate of CSF3R mutation was 92.86% (13/14), including 12 cases (85.71%) with T318I mutation and 1 case of Y799X mutation, and only 1 case was not detected for mutation of CSF3R. The ASXL1 mutation was detected in 42.86% (6/14) of the patients, all of which were nonsense mutations, including 4 cases with R693X and 2 cases with E705X, and 14.29% (2/14) of the patients was detected for SETBP1 mutation, all of which were with D868N mutation. No patients with simultaneous ASXL1 and SETBP1 mutations were found, and JAK2 and CALR mutations were not detected. All of the patients had normal karyotypes. These patients' median survival time was 30 months (95%CI 13.19-46.80), and the influence of age over 60 years old was statistically significant (21.83 months vs 35.35 months) (P<0.05). CONCLUSION: It is difficult to diagnose CNL. CSF3R T618I mutation is its specific mutation, and ASXL1 mutation and SETBP1 mutation have auxiliary diagnostic significance for CNL. The age>60 years old at diagnosis is a factor of unfavourable prognosis.


Assuntos
Leucemia , Neutrófilos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Receptores de Fator Estimulador de Colônias
11.
BMJ ; 366: l5016, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511230

RESUMO

OBJECTIVE: To assess the effects of Helicobacter pylori treatment, vitamin supplementation, and garlic supplementation in the prevention of gastric cancer. DESIGN: Blinded randomized placebo controlled trial. SETTING: Linqu County, Shandong province, China. PARTICIPANTS: 3365 residents of a high risk region for gastric cancer. 2258 participants seropositive for antibodies to H pylori were randomly assigned to H pylori treatment, vitamin supplementation, garlic supplementation, or their placebos in a 2×2×2 factorial design, and 1107 H pylori seronegative participants were randomly assigned to vitamin supplementation, garlic supplementation, or their placebos in a 2×2 factorial design. INTERVENTIONS: H pylori treatment with amoxicillin and omeprazole for two weeks; vitamin (C, E, and selenium) and garlic (extract and oil) supplementation for 7.3 years (1995-2003). MAIN OUTCOME MEASURES: Primary outcomes were cumulative incidence of gastric cancer identified through scheduled gastroscopies and active clinical follow-up through 2017, and deaths due to gastric cancer ascertained from death certificates and hospital records. Secondary outcomes were associations with other cause specific deaths, including cancers or cardiovascular disease. RESULTS: 151 incident cases of gastric cancer and 94 deaths from gastric cancer were identified during 1995-2017. A protective effect of H pylori treatment on gastric cancer incidence persisted 22 years post-intervention (odds ratio 0.48, 95% confidence interval 0.32 to 0.71). Incidence decreased significantly with vitamin supplementation but not with garlic supplementation (0.64, 0.46 to 0.91 and 0.81, 0.57 to 1.13, respectively). All three interventions showed significant reductions in gastric cancer mortality: fully adjusted hazard ratio for H pylori treatment was 0.62 (95% confidence interval 0.39 to 0.99), for vitamin supplementation was 0.48 (0.31 to 0.75), and for garlic supplementation was 0.66 (0.43 to 1.00). Effects of H pylori treatment on both gastric cancer incidence and mortality and of vitamin supplementation on gastric cancer mortality appeared early, but the effects of vitamin supplementation on gastric cancer incidence and of garlic supplementation only appeared later. No statistically significant associations were found between interventions and other cancers or cardiovascular disease. CONCLUSIONS: H pylori treatment for two weeks and vitamin or garlic supplementation for seven years were associated with a statistically significant reduced risk of death due to gastric cancer for more than 22 years. H pylori treatment and vitamin supplementation were also associated with a statistically significantly reduced incidence of gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00339768.


Assuntos
Infecções por Helicobacter/terapia , Lesões Pré-Cancerosas/terapia , Neoplasias Gástricas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiulcerosos/administração & dosagem , Biópsia , China/epidemiologia , Suplementos Nutricionais , Quimioterapia Combinada/métodos , Feminino , Seguimentos , Alho/química , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastroscopia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Inibidores da Bomba de Prótons/administração & dosagem , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Vitaminas/administração & dosagem
12.
Onco Targets Ther ; 12: 6253-6265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496729

RESUMO

Purpose: Oxymatrine, an alkaloid extracted from the Chinese herb Sophora flavescens Aiton, possesses anti-inflammatory, anti-immune, anti-hepatic fibrosis, and anti-cancer properties. However, the effects of oxymatrine on epithelial-mesenchymal transition (EMT) of breast cancer cells are still unclear. Aim: The present study was performed to investigate whether oxymatrine reverses EMT in breast cancer cells and to explore the underlying molecular mechanisms. Materials and methods: MTT assay was performed to evaluate cell viability. Wound-healing assay and transwell chamber assay were used to assess cell migration and invasion, respectively. Immunofluorescence and Western blot were used to study the expression of EMT-related molecules and αⅤß3 integrin/focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling transduction. Fibronectin, a physiologic ligand of αⅤß3 integrin, was used to stimulate αⅤß3 integrin signaling. Results: Our results demonstrated that oxymatrine effectively suppressed the viability of MDA-MB-231 and 4T1 breast cancer cells, and oxymatrine showed less cytotoxicity on normal breast mammary epithelial MCF-10A cells. In addition, oxymatrine reversed EMT in the MDA-MB-231 and 4T1 cells at nontoxic concentrations. Oxymatrine significantly inhibited cell migration and invasion, downregulated the expression of N-cadherin, vimentin, and Snail in MDA-MB-231 and 4T1 cells, but upregulated the expression of E-cadherin in 4T1 cells. The mechanism revealed that oxymatrine decreased the expression of αⅤ and ß3 integrin and their co-localization. It also inhibited αⅤß3 integrin downstream activation by suppressing the phosphorylation of FAK, PI3K, and Akt. Furthermore, oxymatrine prevented fibronectin-induced EMT and αⅤß3 integrin/FAK/PI3K/Akt signaling activation. Conclusion: Our results revealed that oxymatrine effectively reversed EMT in breast cancer cells by depressing αⅤß3 integrin/FAK/PI3K/Akt signaling. Thus, oxymatrine could be a potential therapeutic candidate with anti-metastatic potential for the treatment of breast cancer.

13.
Biochem Pharmacol ; 166: 33-45, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071331

RESUMO

Triple-negative breast cancer (TNBC) is characterized by elevated metastasis, low survival, and poor response to therapy. Although many specific and effective agents for treating TNBC have been investigated, promising therapeutic options remain elusive. Here, we screened the inhibitory activities of three main components of Lithospermum erythrorhizon Sieb. et Zucc (shikonin, acetylshikonin, and ß,ß-dimethylacrylshikonin) on TNBC cells. The results revealed that shikonin potently decreased the viabilities of TNBC MDA-MB-231 and 4T1 cells but showed less cytotoxicity to normal mammary epithelial MCF-12A cells. Additionally, shikonin reversed the epithelial-to-mesenchymal transition (EMT) in MDA-MB-231 and 4T1 cells. Shikonin depressed cell migration and invasion, upregulated E-cadherin levels, downregulated N-cadherin, vimentin, and Snail levels, and reorganized the cytoskeletal proteins F-actin and vimentin. Shikonin reversed EMT by inhibiting activation of ß-catenin signaling through attenuating ß-catenin expression, nuclear accumulation, binding to T-cell factor consensus oligos, and transcription of its targeted EMT-related genes. Moreover, shikonin upregulated glycogen synthase kinase 3ß (GSK-3ß) levels, leading to enhanced phosphorylation and decreased levels of ß-catenin. Furthermore, shikonin administration significantly inhibited lung metastasis of MDA-MB-231 cells in NOD/SCID mice accompanied by low systemic toxicity. Histological analysis confirmed that shikonin elevated levels of E-cadherin, phosphorylated ß-catenin, and GSK-3ß, and decreased levels of vimentin and ß-catenin in pulmonary metastatic foci. These results indicated that shikonin potently inhibits TNBC metastasis by targeting the EMT via GSK-3ß-regulated suppression of ß-catenin signaling, which highlights the importance of shikonin as a potential candidate for novel anticancer therapeutics against TNBC.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Naftoquinonas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , beta Catenina/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Naftoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Neoplasias de Mama Triplo Negativas/metabolismo , beta Catenina/metabolismo
14.
Cancer Res ; 79(11): 2962-2977, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952634

RESUMO

Targeting microenvironmental factors that foster migratory cell phenotypes is a promising strategy for halting tumor migration. However, lack of mechanistic understanding of the emergence of migratory phenotypes impedes pharmaceutical drug development. Using our three-dimensional microtumor model with tight control over tumor size, we recapitulated the tumor size-induced hypoxic microenvironment and emergence of migratory phenotypes in microtumors from epithelial breast cells and patient-derived primary metastatic breast cancer cells, mesothelioma cells, and lung cancer xenograft cells. The microtumor models from various patient-derived tumor cells and patient-derived xenograft cells revealed upregulation of tumor-secreted factors, including matrix metalloproteinase-9 (MMP9), fibronectin (FN), and soluble E-cadherin, consistent with clinically reported elevated levels of FN and MMP9 in patient breast tumors compared with healthy mammary glands. Secreted factors in the conditioned media of large microtumors induced a migratory phenotype in nonhypoxic, nonmigratory small microtumors. Subsequent mathematical analyses identified a two-stage microtumor progression and migration mechanism whereby hypoxia induces a migratory phenotype in the initialization stage, which then becomes self-sustained through a positive feedback loop established among the tumor-secreted factors. Computational and experimental studies showed that inhibition of tumor-secreted factors effectively halts microtumor migration despite tumor-to-tumor variation in migration kinetics, while inhibition of hypoxia is effective only within a time window and is compromised by tumor-to-tumor variation, supporting our notion that hypoxia initiates migratory phenotypes but does not sustain it. In summary, we show that targeting temporal dynamics of evolving microenvironments, especially tumor-secreted factors during tumor progression, can halt tumor migration. SIGNIFICANCE: This study uses state-of-the-art three-dimensional microtumor models and computational approaches to highlight the temporal dynamics of tumor-secreted microenvironmental factors in inducing tumor migration.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Hipóxia Tumoral , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Neoplasias da Mama/tratamento farmacológico , Caderinas/antagonistas & inibidores , Caderinas/imunologia , Caderinas/metabolismo , Movimento Celular , Feminino , Fibronectinas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos , Modelos Teóricos , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Gastric Cancer ; 22(3): 506-517, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30390154

RESUMO

BACKGROUND: The new 8th TNM system attributes AEG Siewert type II to esophageal classification system. However, the gastric and esophageal classification system which was more suitable for type II remains in disputation. This study aimed to illuminate the 8th TNM-EC or TNM-GC system which was more rational for type II, especially for patients underwent transhiatal approaches. METHODS: We collected the database of patients with AEG who underwent radical surgical resection from two high-volume institutions in China: West China Hospital (N = 773) and Xi Jing Hospital of Fourth Military University (N = 637). The cases were randomly matched into 705 training cohort and 705 validation cohort. All the cases were reclassified by the 8th edition of TNM-EC and TNM-GC. The distribution of patients in each stage, the hazard ratio of each stage, and the separation of the survival were compared. Multivariate analysis was performed using the Cox proportional hazard model. Comparisons between the different staging systems for the prognostic prediction were performed with the rcorrp.cens package in Hmisc in R (version 3.4.4. http://www.R-project.org/ ). The validity of these two systems was evaluated by Akaike information criterion (AIC) and concordance index (C-index). RESULTS: By univariate analysis, the HRs from stage IA/IB to stage IV/IVB were monotonously increased according to TNM-GC scheme in both cohorts (training 2.63, 3.91, 5.02, 8.64, 15.51 and 29.64; validation 1.54, 3.55, 4.91, 7.14, 11.67, 18.71 and 48.32) whereas only a fluctuating increased tendency was found when staged by TNM-EC. After the multivariate analysis, TNM-GC (P < 0.001), TNM-EC (P = 0.001) in training cohort and TNM-GC (P < 0.001) TNM-EC (P < 0.001) in the validation cohort were both independent prognostic factors. The C-index value for the TNM-GC scheme was larger than that of TNM-EC system in both training (0.721 vs. 0.690, P < 0.001) and validation (0.721 vs. 0.696, P < 0.001) cohorts. After stratification analysis for Siewert type II, the C-index for TNM-GC scheme was still larger than that of TNM-EC in both training (0.724 vs. 0.694, P = 0.005) and validation (0.723 vs. 0.699, P < 0.001) cohorts. CONCLUSIONS: The 8th TNM-GC scheme is superior to TNM-EC in predicting the prognosis of AEG especially for type II among patients underwent transhiatal approaches.


Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Estadiamento de Neoplasias/normas , Neoplasias Gástricas/patologia , Adenocarcinoma/classificação , Adenocarcinoma/cirurgia , China , Neoplasias Esofágicas/classificação , Neoplasias Esofágicas/cirurgia , Esofagectomia , Junção Esofagogástrica/cirurgia , Feminino , Seguimentos , Gastrectomia , Hospitais com Alto Volume de Atendimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/classificação , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida
16.
Chem Asian J ; 13(21): 3281-3284, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30152148

RESUMO

A highly efficient rhodium(III)-catalyzed direct oxidative annulation of acrylic acid with alkynes to form α-pyrones was developed. Various substituted acrylic acids were compatible in this transformation, affording the corresponding products in moderate to excellent yields under mild conditions.

17.
J Pharm Pharmacol ; 70(11): 1513-1520, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30159900

RESUMO

OBJECTIVES: The purpose of this study was to further clarify the role and underlying mechanism of miR-324-5p in gastric cancer. METHODS: The expressions of miR-324-5p and TSPAN8 as determined by qRT-PCR or Western blot were compared between the gastric cancer tissues and normal tissues. Human gastric cancer cell line SGC-7901 was cultured and transfected with miR-324-5p mimic/inhibitor or pcDNA-TSPAN8. The cell survival was assessed by the cell viability and apoptosis. Luciferase reporter gene assays were performed to explore the interaction between miR-324-5p and TSPAN8 in SGC-7901 cells. KEY FINDINGS: MiR-324-5p was decreased in human gastric carcinoma tissues (n = 33), but TSPAN8 protein expression was increased in the gastric carcinoma tissues (n = 33). Moreover, miR-324-5p inhibited the viability and induced the apoptosis of gastric cancer cells in vitro. TSPAN8 is a functional target of miR-324-5p in gastric cancer. MiR-324-5p was further confirmed to reduce gastric cancer cell viability and induce apoptosis via downregulating TSPAN8 in SGC-7901 cells in vitro. Additionally, miR-324-5p overexpression markedly inhibited the tumorigenesis of gastric cancer cells in vivo, as shown by the smaller tumour volume compared with the control. CONCLUSIONS: This study suggested a novel, probable mechanism of miR-324-5p in gastric cancer context and revealed that miR-324-5p inhibited gastric cancer cell survival by targeting TSPAN8.


Assuntos
Apoptose , MicroRNAs/metabolismo , Neoplasias Gástricas/metabolismo , Tetraspaninas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Tetraspaninas/genética , Carga Tumoral
18.
J Int Med Res ; 46(10): 4092-4099, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30014762

RESUMO

Background To investigate the relationship between the levels of nuclear factor (NF)-κB p50 and NF-κB p65 and tumour characteristics in patients with thyroid carcinoma. Methods This prospective study enrolled consecutive patients with thyroid carcinoma. Tumour samples were collected and the levels of NF-κB p50 and NF-κB p65 protein and mRNA were measured using immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Results A total of 73 patients with thyroid carcinoma were included in the study (20 males; 53 females; mean ± SD age, 44.8 ± 12.7 years, range, 18-76 years). There were no significant differences in sex, age and pathological type between the NF-κB p50 positive group and the NF-κB p50 negative group, but tumour diameter and lymph node metastasis were significantly higher in the NF-κB p50 positive group compared with the NF-κB p50 negative group. Similar findings were observed for NF-κB p65. The levels of NF-κB p50 were positively correlated with NF-κB p65 in samples of thyroid carcinoma ( rs = 0.653). Conclusion The levels of NF-κB p50 and NF-κB p65 in samples of thyroid carcinoma were positively associated with tumour diameter and the presence of lymph node metastasis.


Assuntos
Subunidade p50 de NF-kappa B/sangue , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/patologia , Fator de Transcrição RelA/sangue , Adolescente , Adulto , Idoso , China , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Glândula Tireoide/metabolismo , Adulto Jovem
19.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(2): 508-515, 2018 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-29665924

RESUMO

OBJECTIVE: To examine one young female patient with hereditary FVII deficiency and her family members, to observe the gene mutation and clinical phenotype, and to investigate the molecular mechanism of the dysfunction. METHODS: Prothrombin time (PT), activated partial thromoploastin time (APTT), fibrinogen (Fg) and FVII activity (FVII:C) and FVII antigen (FVII:Ag) were tested. The gene mutations were sought by DNA sequencing for all of the exons and flanks, 5' and 3' non-translation region of F7 gene. To confirm the role of the found gene mutation, the reverse sequence were determined with Chromas software. To infer the influence of the mutation on the synthesis and function of FVII protein, the FVII protein molecule model containing the found mutation was constructed and the function prediction was performed by the signal peptide prediction database. RESULTS: Compared with the normal population, the proband's PT value was significantly prolonged, and the ratio % FVII:C and that of FVII:Ag were significantly decreased by 1.1% and 0.9%, respectively. The PT, APTT, FVII:C and FVII:Ag of the proband's parents were both normal. Heterozygous 556th nucleotide mutations T/G were found in the proband's and his father's exon lA of F7 gene, with codon CTG turning into CGG, corresponding leucine (L) into arginine (R), i.e Leu12Arg. Function prediction showed that L12R mutations affected the segmentation of different parts of the signal peptide and its corresponding function, which could result in the decline in the mature protein synthesis and its activity obviously. In addition, a spontaneous 3' untranslated region c11814-insAA heterozygous mutation was detected in the proband's F7 gene, while her parents didn't possess this mutation. CONCLUSION: A new hererozygous mutation (L12R) located in signal peptide of F7 gene is the primary molecular basis of the case with hereditary FVII deficiency. At the same time, the proband's spontaneous 3' non-translation region c11814-insAA mutation may lead to the further reduetion of the FVII synthesis.


Assuntos
Mutação , Fator VII , Deficiência do Fator VII , Feminino , Humanos , Linhagem , Fenótipo , Sinais Direcionadores de Proteínas
20.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(1): 77-82, 2018 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29397822

RESUMO

OBJECTIVE: To screen and identify potential biomarkers specific for T-cell acute lymphoblastic leukemia (T-ALL). METHODS: Sera were collected from 20 newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients and 20 T-ALL patients. Proteins were extracted, purified and digested with trypsin. All specimens were analyzed by isobaric tags for relative and absolute quantification (iTRAQ) and two-dimensional liquid chromatography-tandem mass spectrometry (2DLC-MS/MS) in a data-dependent mode. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression of serum soluble L-selectin (sL-selectin). RESULTS: A total of 468 proteins were identified from distinct peptides. Compared with B-ALL group, 31 proteins were significantly differentially up-regulated while 7 proteins were significantly down-regulated in T-ALL group, sL-selectin was the higher up-regulated in these differential expression proteins. The overexpression of sL-selectin in T-ALL was verified by ELISA. CONCLUSION: There are the differentially expressed proteins between T-ALL and B-ALL, and the sL-selectin is specific for T-ALL, which can not only become a new biomarker for the diagnosis and prognosis of T-ALL, but also can be used as a potential target for therapy of this leukemia.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Biomarcadores , Humanos , Proteômica , Linfócitos T , Espectrometria de Massas em Tandem
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