RESUMO
Currently, cancer is the second leading cause of death worldwide, and potential targeted drugs and molecular pathways for cancer development and progression have been a hot research topic worldwide. In recent years, the importance of the kinase superfamily in diseases has been well demonstrated by studies on various molecular mechanisms of kinases and the successful application of their inhibitors in diseases. Pseudokinases are members of the kinase superfamily, which have been increasingly documented to play a crucial role in cancers year after year. As a member of pseudokinases, tribbles homolog 3 (TRIB3) also exerts diverse functions in different cancers through different interacting proteins and molecular pathways, especially in tumor immunity, stemness, drug resistance, metabolism, and autophagy. In addition, peptide drugs targeting TRIB3 have high specificity in preclinical studies, which shows great promise for TRIB3 application in diseases including cancers. In this review, we dissect diverse functions played by TRIB3 in different cancers, describing the underlying mechanisms in detail. Notably, inhibitors and agonists currently available for TRIB3 are discussed, indicating the potential for TRIB3 as a therapeutic target.
Assuntos
Proteínas de Ciclo Celular , Neoplasias , Proteínas Serina-Treonina Quinases , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Animais , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Terapia de Alvo Molecular/métodos , Autofagia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Resistencia a Medicamentos AntineoplásicosRESUMO
A hemorrhagic aortopulmonary artery sheath (HAPS) is an infrequent and critical complication of aortic dissection (AD), which is caused by a hematoma extending through the ruptured aortic wall into the aortopulmonary artery sheath. The adventitial hematoma might narrow or even occlude the lumen of the pulmonary arteries and extend into the pulmonary interstitium and alveoli. The prompt and accurate recognition of HAPS on computed tomography (CT) is crucial and might assist in the diagnosis of unidentifiable AD. HAPS was manifested as high attenuation areas surrounded the pulmonary arteries without enhancement on CT; even thickened bronchovascular sheath and ground-glass consolidations surrounded bronchovascular distribution, which might be associated with the prognosis. Aggressive and effective surgical treatment is the primary determinant of short-term survival.
Assuntos
Dissecção Aórtica , Humanos , Dissecção Aórtica/complicações , Dissecção Aórtica/diagnóstico por imagem , Hemorragia/diagnóstico por imagem , Hemorragia/etiologia , Aorta , Artéria Pulmonar/diagnóstico por imagem , Hematoma/complicações , Hematoma/diagnóstico por imagemRESUMO
Herein, we proposed an innovative visual quantitative sensing strategy based on thiol-ene click chemistry and the capillary action principle. A triethoxyvinylsilane (VTEO)- or mercaptopropylsilatrane (MPS)-modified interface was prepared for analyte recognition. Target analyte molecules containing thiol groups or CâC double bonds are coupled to the VTEO- or MPS-modified inner surface of the glass capillary tube via a thiol-ene click reaction, respectively. Then, the molecular recognition events were transformed into the wettability change of the inner wall of the glass capillary. The concentration of the target molecules was quantified by reading the height change of the water column in the capillary tube. As a proof of concept, this strategy was successfully used to build visual quantitative sensors for detecting glutathione and cholesterol. In addition, this strategy showed a good anti-interference ability to complex biological fluids and realized sensitive glutathione (GSH) and cholesterol detection in real human blood samples.
Assuntos
Glutationa , Compostos de Sulfidrila , Colesterol , Química Click , Humanos , MolhabilidadeRESUMO
BACKGROUND: High incidence of venous thromboembolic complications in coronavirus disease 2019 (COVID-19) patients was noted recently. OBJECTIVE: This study aimed to explore the factors associated with prevalence of venous thromboembolism (VTE) in COVID-19 patients. METHODS: A literature search was conducted in several online databases. Fixed effects meta-analysis was performed for the factors associated with prevalence of VTE in COVID-19 patients. RESULTS: A total of 39 studies were analysed in this analysis. The incidence of pulmonary embolism and VTE in severe COVID-19 patients were 17% (95% CI, 13-21%) and 42% (95% CI, 25-60%), respectively. VTE were more common among individuals with COVID-19 of advance age. Male COVID-19 patients are more likely to experience VTE. Higher levels of white blood cell (WBC; WMD = 1.34 × 109/L; 95% CI, 0.84-1.84 × 109/L), D-dimer (WMD = 4.21 µg/ml; 95% CI, 3.77-4.66 µg/ml), activated partial thromboplastin time (APTT; WMD = 2.03 s; 95% CI, 0.83-3.24 s), fibrinogen (WMD = 0.49 µg/ml; 95% CI, 0.18-0.79 g/L) and C-reactive protein (CRP; WMD = 21.89 mg/L; 95% CI, 11.44-32.34 mg/L) were commonly noted in COVID-19 patients with VTE. Patients with lower level of lymphocyte (WMD = -0.15 × 109/L; 95% CI, -0.23--0.07 × 109/L) was at high risk of developing VTE. The incidence of severe condition (OR = 2.66; 95% CI, 1.95-3.62) was more likely to occur among COVID-19 patients who developed VTE. CONCLUSION: VTE is a common complication in severe COVID-19 patients and thromboembolic events are also associated with adverse outcomes.
Assuntos
COVID-19 , Tromboembolia Venosa , Idoso , Testes de Coagulação Sanguínea/métodos , COVID-19/sangue , COVID-19/complicações , COVID-19/diagnóstico , Humanos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiologiaRESUMO
OBJECTIVE: Two-dimensional electrophoresis (2-DE) and MALDI-TOF/TOF mass spectrometry were performed to compare the proteomic alterations of lycorine-treated and control cells to further investigate the anti-multiple myeloma (MM) mechanisms of lycorine. RESULTS: Mass spectrometry results showed that after lycorine treatment of MM cells, 42% of the differentially expressed proteins had subcellular localization, mainly, on mitochondria. Voltage-dependent anion-selective channel protein 2 (VDAC2), the most abundant protein in the outer mitochondrial membrane, was up-regulated after treatment with lycorine and was subsequently verified by western blot analysis. Further studies on mitochondria found that lycorine was able to increase abnormal mitochondria and increase mitochondrial membrane potential. CONCLUSIONS: Lycorine can achieve the effect of resisting multiple myeloma by acting on VDAC2 and causing mitochondrial abnormalities.
Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Mieloma Múltiplo/metabolismo , Fenantridinas/farmacologia , Proteoma/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Canal de Ânion 2 Dependente de Voltagem/metabolismo , Antineoplásicos/farmacologia , Eletroforese em Gel Bidimensional , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Proteoma/análiseRESUMO
Chronic myelomonocytic leukemia (CML) is a myeloid tumor characterized by MDS (myelodysplastic syndrome) and MPN (myeloproliferative neoplasms). Allogeneic hematopoietic stem cell transplantation, chemotherapy, interferon, and targeted therapy are the main treatment methods for CML. Tyrosine kinase inhibitors (TKIs) are also a treatment option, and patients are currently recommended to take these drugs throughout their lives to prevent CML recurrence. Therefore, there is a need to investigate and identify other potential chemotherapy drugs. Currently, research on CML treatment with a single drug has shown little progress. Fingolimod (FTY720), an FDA-approved drug used to treat relapsing multiple sclerosis, has also shown great potential in the treatment of lymphocytic leukemia. In our study, we find that FTY720 and curcumol have a significant inhibitory effect on K562 cells, K562/ADR cells, and CD34+ cells from CML patients. RNAseq data analysis shows that regulation of apoptosis and differentiation pathways are key pathways in this process. Besides, BCR/ABL-Jak2/STAT3 signaling, PI3K/Akt-Jnk signaling, and activation of BH3-only genes are involved in CML inhibition. In a K562 xenograft mouse model, therapy with curcumol and FTY720 led to significant inhibition of tumor growth and induction of apoptosis. To summarize, curcumol and FTY720 synergistically inhibit proliferation involved in differentiation and induce apoptosis in CML cells. Therefore, synergistic treatment with two drugs could be the next choice of treatment for CML.
Assuntos
Cloridrato de Fingolimode/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Apoptose , Diferenciação Celular , Proliferação de Células , Modelos Animais de Doenças , Cloridrato de Fingolimode/farmacologia , Humanos , Camundongos , Sesquiterpenos/farmacologia , Transdução de SinaisRESUMO
Multiple myeloma stem-like cells (MMSCs) are responsible for initiation and relapse, though novel treatment paradigms that effectively eradicate MMSCs are yet to be developed. Selective inhibition of the cell cycle regulatory kinase Wee1 by MK1775 is being explored as a potential anti-cancer therapeutic. We report that higher expression of Wee1 is correlated with poor survival in multiple myeloma (MM). The MM models and patient-derived CD138+ plasma cells are particularly sensitive to the growth-inhibitory effects of the Wee1 inhibitor MK1775. MK1775 induces Mus81-Eme1 endonuclease-mediated DNA damage in S-phase cell cycle that results in a blockade of replication and then apoptosis. Furthermore, MK1775 strongly suppresses the features of stemness in vitro, in vivo and in primary CD138+ cells by decreasing ALDH1+ cell fraction and the expression of ALDH1. In addition, co-treatment of MK1775 with bortezomib is synergistic in vitro and in vivo. Bortezomib, although it enhances ALDH1+ cells, when combined with MK1775 abrogates this stimulatory effect on stemness. Considering MM as an invariably incurable malignancy due to the presence of heterogenic myeloma stem-like cells, our study presents inhibition of Wee1 as a promising targeted therapy for MM and provides a compelling rationale to further investigate the activity of MK1775 against myeloma in clinical settings.
Assuntos
Bortezomib/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Mieloma Múltiplo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Animais , Bortezomib/agonistas , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/enzimologia , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirazóis/agonistas , Pirimidinonas/agonistas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Multiple myeloma (MM) is characterised by the proliferation and accumulation of malignant plasma cells in the bone marrow. Despite the progress in treatment over the last few years, MM remains incurable and the majority of patients relapse. MM stem-like cells (MMSCs) have been considered as the main reason for drug resistance and eventual relapse. Currently, therapeutic agents are not enough to eradicate MMSCs, and finding effective strategies to eradicate MMSCs may improve the outcome of patients. Here we showed that lycorine, a natural compound from the Amaryllidaceae species, effectively inhibits the proliferation of myeloma cells from cell lines or patients, mainly through decreasing ALDH1+ cells. Mechanistically, lycorine decreases the MMSC population through inhibition of the Wnt/ß-catenin pathway by reducing the ß-catenin protein level. Moreover, lycorine could overcome the increasing proportion of ALDH1+ cells caused by bortezomib (BTZ) treatment, and a combination BTZ and lycorine have a synergistic effect on anti-myeloma cells. Furthermore, we found a similar reduction of MMSC characteristics by lycorine in BTZ-resistant MM cells and primary CD138+ plasma cells. Collectively, our findings indicate lycorine as a promising agent to target MMSCs to overcome the drug resistance of BTZ, and that, alone or in combination with BTZ, lycorine is a potential therapeutic strategy for MM treatments.
Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Mieloma Múltiplo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas , Fenantridinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Linhagem Celular Tumoral , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologiaRESUMO
Cisplatin is a main chemotherapeutic drug used to treat non-small-cell lung cancer patients. However, these patients commonly face cisplatin resistance. The roles and underlying mechanisms of gemcitabine, irinotecan, pemetrexed and docetaxel used as single agents or combined with cisplatin for overcoming cisplatin-resistant non-small-cell lung cancer were explored in this study. MTT assays showed that gemcitabine alone exhibited stronger cytotoxicity on cisplatin-resistant A549 cells than irinotecan, pemetrexed and docetaxel. Meanwhile, gemcitabine combined with cisplatin showed a synergistic inhibitory effect on cisplatin-resistant cells. RNA sequencing and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis showed that cell cycle signaling pathways and trx-interacting protein were factors in the efficacy of the cotreatment. Flow cytometry and Western blot results showed that when cisplatin-resistant A549 cells were cotreated with gemcitabine and cisplatin, G0/G1 phase arrest occurred, and trx-interacting protein was upregulated. Silencing trx-interacting protein attenuated the response of the resistant cells to the drug combination. A trx-interacting protein agonist together with cisplatin showed an additive cytotoxic effect on the resistant cells compared with cisplatin alone. The gemcitabine and cisplatin combination, compared to gemcitabine or PBS alone, markedly suppressed the growth of cisplatin-resistant A549 tumors in vivo, accompanied by an increase in trx-interacting protein and a decrease in Ki67 expression. Therefore, we concluded that gemcitabine and cisplatin, as an FDA-approved combination, is a viable therapy for cisplatin-resistant non-small-cell lung cancer ex vivo and in vivo.
Assuntos
Proteínas de Transporte/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Células A549 , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte/metabolismo , Morte Celular/efeitos dos fármacos , Desoxicitidina/farmacologia , Feminino , Fase G1/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
Ubiquitination is an enzymatic post-translational modification that affects protein fate. The ubiquitin-proteasome system (UPS) was first discovered in reticulocytes where it plays important roles in reticulocyte maturation. Recent studies have revealed that ubiquitination is a dynamic and reversible process and that deubiquitylases are capable of removing ubiquitin from their protein substrates. Given the fact that the UPS is highly active in reticulocytes, it is speculated that deubiquitylases may play important roles in erythropoiesis. Yet, the role of deubiquitylases in erythropoiesis remains largely unexplored. In the present study, we found that the expression of deubiquitylase USP7 is significantly increased during human terminal erythroid differentiation. We further showed that interfering with USP7 function, either by short hairpin RNA-mediated knockdown or USP7-specific inhibitors, impaired human terminal erythroid differentiation due to decreased GATA1 level and that restoration of GATA1 levels rescued the differentiation defect. Mechanistically, USP7 deficiency led to a decreased GATA1 protein level that could be reversed by proteasome inhibitors. Furthermore, USP7 interacts directly with GATA1 and catalyzes the removal of K48-linked poly ubiquitylation chains conjugated onto GATA1, thereby stabilizing GATA1 protein. Collectively, our findings have identified an important role of a deubiquitylase in human terminal erythroid differentiation by stabilizing GATA1, the master regulator of erythropoiesis.
Assuntos
Diferenciação Celular/genética , Células Precursoras Eritroides/citologia , Células Precursoras Eritroides/metabolismo , Eritropoese/genética , Fator de Transcrição GATA1/metabolismo , Peptidase 7 Específica de Ubiquitina/genética , Peptidase 7 Específica de Ubiquitina/metabolismo , Biomarcadores , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imunofenotipagem , Modelos Biológicos , Ligação Proteica , Estabilidade Proteica , UbiquitinaçãoRESUMO
BACKGROUND: To determine whether magnetic resonance imaging (MRI)-detected extramural vascular invasion (mrEMVI) status is associated with quantitative perfusion parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) in rectal cancer. METHODS: Seventy-two patients with rectal adenocarcinoma who underwent curative surgery alone within 2 weeks following rectal MRI were enrolled in this retrospective study. mrEMVI status was determined based on high-resolution MRI. The quantitative perfusion parameters (Ktrans, kep and ve) derived from DCE-MRI were calculated from all sections containing tumours. DCE-MRI parameters and clinicopathological variables in patients with different mrEMVI statuses were compared. RESULTS: For patients who were mrEMVI positive, the tumours demonstrated significantly lower kep values (P = 0.012) and higher ve values (P = 0.021) than tumours of patients who were mrEMVI negative, while the Ktrans value displayed no significant difference (P = 0.390). The patients who were mrEMVI positive had larger tumour size, higher pathological tumour stage and increased regional nodal metastases compared to those who were mrEMVI negative (2.9 cm vs. 3.5 cm, P = 0.011; 63.8% vs. 92.0%, P = 0.010; 36.2% vs. 76.0%, P = 0.001; respectively). CONCLUSIONS: This study demonstrated for the first time that tumour microcirculation is altered in mrEMVI-positive patients with rectal adenocarcinoma, as evidenced by significantly lower kep and higher ve values. In addition, these patients were more likely to have a larger tumour size, a higher pathological tumour stage and regional nodal metastases than mrEMVI-negative patients.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Angiografia por Ressonância Magnética/métodos , Microcirculação , Invasividade Neoplásica/diagnóstico por imagem , Dados Preliminares , Neoplasias Retais/diagnóstico por imagem , Idoso , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Neovascularização Patológica/diagnóstico por imagem , Variações Dependentes do Observador , Prognóstico , Radiologistas , Estudos Retrospectivos , Carga Tumoral , Microambiente TumoralRESUMO
OBJECTIVE: The aim of this study was to discriminate metastatic from nonmetastatic regional lymph nodes (LNs) with short-axis diameters of less than 5 mm in rectal cancer using quantitative parameters derived from dynamic contrast-enhanced (DCE) MRI. SUBJECTS AND METHODS: Sixty-five LNs from 122 patients were evaluated, including malignant LNs (n = 27) and benign LNs (n = 38). The following parameters were assessed: the forward volume transfer constant (Ktrans), reverse volume transfer constant (kep), fractional extravascular extracellular space volume (Ve), short-axis diameter, long-axis diameter, and short- to long-axis diameter ratio. ROC curves were used to analyze statistically significant parameters. RESULTS: Metastatic LNs exhibited a lower Ktrans than did nonmetastatic LNs (p < 0.001), but the other parameters were not significantly different between the two groups. The AUC of the Ktrans was 0.732, with a 95% CI of 0.610-0.854, and the diagnostic cutoff value was 0.088 min-1 (sensitivity, 60.5%; specificity, 81.5%). CONCLUSION: Ktrans had moderate diagnostic performance in assessing small regional LNs in rectal cancer and appears to be a useful predictor when distinguishing malignant LNs from benign LNs only by morphology is difficult.
Assuntos
Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Imageamento por Ressonância Magnética/métodos , Neoplasias Retais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Meios de Contraste , Diagnóstico Diferencial , Gadolínio DTPA , Humanos , Interpretação de Imagem Assistida por Computador , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Intravoxel incoherent motion magnetic resonance imaging (IVIM-MRI) acquires tumor perfusion information without injection of contrast medium, which is promising in tumor assessment. However, its consistency with dynamic contrast-enhanced MRI (DCE-MRI), a more widely used method for tumor perfusion evaluation, is not revealed in rectal cancer. PURPOSE: In this study, we aimed to investigate the correlation of perfusion-sensitive parameters derived from IVIM-MRI with DCE-MRI and measurement reproducibility of IVIM-MRI parameters in rectal cancer. MATERIAL AND METHODS: Forty-seven rectal cancer patients underwent IVIM-MRI with 16 b-values and DCE-MRI. The perfusion fraction ( f), pseudo-diffusion coefficient ( D*), and f· D* were measured by two radiologists independently and correlated with the transfer constant ( Ktrans), reflux constant ( kep), and extravascular extracellular fractional volume ( ve) obtained from DCE-MRI. RESULTS: Pearson's correlation analyses of IVIM-MRI and DCE-MRI parameters showed fair to moderate correlation between f and Ktrans ( r = 0.461, P = 0.001), followed by f and kep ( r = 0.430, P = 0.003), f·D*, and Ktrans ( r = 0.425, P = 0.003), f·D*, and kep ( r = 0.384, P = 0.008). There was no significant correlation between ve and f, ve and D*, ve and f· D*, D* and Ktrans, and D* and kep. The reproducibility of IVIM-MRI measurements was moderate. For parameter f, intraclass correlation coefficient (ICC) = 0.71 (0.53-0.82), coefficient of variation (CV) = 13.05 ± 0.02%, limit of agreement (LoA) = -0.05-0.04; for parameter D*, ICC = 0.55 (0.32-0.72), CV = 20.28 ± 3.23%, LoA = -9.6-8.4. CONCLUSION: Perfusion-sensitive parameters derived from IVIM-MRI correlated fairly to moderately with DCE-MRI in rectal cancer patients and showed moderate measurement reproducibility. IVIM-MRI supplements routine high-resolution MRI without contrast enhancement to provide information of tumor microcirculation.
Assuntos
Meios de Contraste , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Neoplasias Retais/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reto/diagnóstico por imagem , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Hepatocyte growth factor (HGF)/c-met pathway activation has been implicated in the pathogenesis of multiple myeloma (MM), and blocking this pathway has been considered a rational therapeutic strategy for treating MM. Aptamers are single-stranded nucleic acid molecules that fold into complex 3D structures and bind to a variety of targets. Recently, it was reported that DNA aptamer SL1 exhibited high specificity and affinity for c-met and inhibited HGF/c-met signaling in SNU-5 cells. However, as the first c-met-targeted DNA aptamer to be identified, application of SL1 to myeloma treatment requires further investigation. Here, we explore the potential application of SL1 in MM. Our results indicated that c-met expression is gradually increased in MM patients and contributes to poor outcomes. SL1 selectively bound to c-met-positive MM cells but not to normal B cells and suppressed the growth, migration and adhesion of MM cells in vitro in a co-culture model performed with HS5 cells, wherein SL1 inhibited HGF-induced activation of c-met signaling. In vivo and ex vivo fluorescence imaging showed that SL1 accumulated in the c-met positive tumour areas. In addition, SL1 was active against CD138+ primary MM cells and displayed a synergistic inhibition effect with bortezomib. Collectively, our data suggested that SL1 could be beneficial as a c-met targeted antagonist in MM.
Assuntos
Aptâmeros de Nucleotídeos/uso terapêutico , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Aptâmeros de Nucleotídeos/farmacologia , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Adesão Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Fluorescência , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sindecana-1/metabolismo , Distribuição Tecidual/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND Comprehensive and precise assessment of rectal carcinoma is crucial before surgery to plan an individual treatment strategy. New functional techniques, such as intravoxel incoherent motion (IVIM), have emerged and could lead to more detailed information. The aim of this study was to evaluate the difference between the rectal tumor parenchyma and normal wall by IVIM and to explore the correlations of IVIM parameters and histopathology. MATERIAL AND METHODS We prospectively enrolled 128 patients with pathologically proven rectal non-mucinous carcinoma with differentiation degree and 16 patients with mucinous carcinoma. All patients underwent routine MR examination and IVIM sequence. The IVIM maps were automatically generated and 3 ROIs were drawn on the maximal rectal tumor parenchyma and normal rectal wall. The Wilcoxon signed rank test, t test, Mann-Whitney U test, and Spearman's rank correlation test were performed. RESULTS All IVIM parameters demonstrated the difference between rectal tumor parenchyma and normal wall (PD<0.001; PD*=0.014; Pf<0.001). Poorly differentiated carcinoma had a significantly lower f value (Pf=0.049) than well/moderately-differentiated carcinoma. In addition, mucinous carcinoma had a higher D (PD=0.001) and a lower D* value (PD*=0.001) than non-mucinous carcinoma. Correlation analysis between IVIM parameters and histopathology showed that D (|r|=0.538, PD=0.000) and D* (|r|=0.267, PD*=0.001) had statistically significant correlations with histological type and f (|r|=0.175, Pf=0.048) was significantly correlated with differentiation degree. CONCLUSIONS The IVIM parameters of rectal tumor parenchyma and normal wall were significantly different. D appears to be a valid and promising parameter to indicate histological features of rectal carcinoma.
Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reto/diagnóstico por imagem , Reprodutibilidade dos TestesRESUMO
The membrane-cytoskeletal protein 4.1N has recently been proposed as a tumor suppressor in a number of cancers of epithelial origin, including non-small-cell lung cancer (NSCLC). However, the molecular mechanism associated with 4.1N tumor suppression remains has not been thoroughly characterized. In this study, 4.1N was shown to directly interact with the lipid raft marker flotillin-1 through its FERM and U2 domains in several different NSCLC cell lines using immunoprecipitation, co-immunoprecipitation and pull-down assays. Moreover, 4.1N silencing/overexpression experiments in paired 95C/95D cells that are of homologous origin but varying endogenous 4.1N expression (high expression in 95C cells, low expression in 95D cells) indicated that 4.1N is involved in the suppression of cell proliferation and migration through a flotillin-1/ß-catenin/Wnt pathway. Taken together, the findings of this study help to elucidate the novel tumor suppressor role of 4.1N in NSCLC.
Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Proteínas do Citoesqueleto/genética , Proteínas de Membrana/genética , Neuropeptídeos/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Sequência de Aminoácidos , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas do Citoesqueleto/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Neuropeptídeos/metabolismo , Ligação Proteica , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , beta Catenina/metabolismoRESUMO
Lycorine, a natural alkaloid, has been widely reported to possess potential efficacy against cancer. However, the anti-multiple myeloma mechanism of lycorine is not fully understood. In this study, the results demonstrated that lycorine is effective against multiple myeloma cell line ARH-77 via inducing programmed necrosis. The mechanisms of lycorine on the multiple myeloma cell line ARH-77 are associated with G1 phase cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) generation, ATP depletion, and DNA damage. Our results elucidate the new mechanism of lycorine against multiple myeloma.
Assuntos
Alcaloides de Amaryllidaceae/administração & dosagem , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Fenantridinas/administração & dosagem , Alcaloides de Amaryllidaceae/química , Caspases/biossíntese , Linhagem Celular Tumoral , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Necrose/induzido quimicamente , Necrose/patologia , Fenantridinas/química , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Espécies Reativas de Oxigênio/metabolismoRESUMO
Autophagy is a process that leads to the degradation of unnecessary or dysfunctional cellular components and long-lived protein aggregates. Erythropoiesis is a branch of hematopoietic differentiation by which mature red blood cells (RBCs) are generated from multi-potential hematopoietic stem cells (HSCs). Autophagy plays a critical role in the elimination of mitochondria, ribosomes and other organelles during erythroid terminal differentiation. Here, the modulators of autophagy that regulate erythroid differentiation were summarized, including autophagy-related (Atg) genes, the B-cell lymphoma 2 (Bcl-2) family member Bcl-2/adenovirus E1B 19 kDa interacting protein 3-like (Nix/Binp3L), transcription factors globin transcription factor 1 (GATA1) and forkhead box O3 (FoxO3), intermediary factor KRAB-associated protein1 (KAP1), and other modulators, such as focal adhesion kinase family-interacting protein of 200-kDa (FIP200), Ca2+ and 15-lipoxygenase. Understanding the modulators of autophagy in erythropoiesis will benefit the autophagy research field and facilitate the prevention and treatment of autophagy-related red blood cell disorders.
Assuntos
Autofagia , Eritropoese , Araquidonato 15-Lipoxigenase/metabolismo , Eritrócitos/citologia , Eritrócitos/metabolismo , Células-Tronco Hematopoéticas/citologia , Humanos , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fatores de Transcrição/metabolismo , Talassemia beta/metabolismo , Talassemia beta/patologiaRESUMO
The aptamer TY04 is a single-stranded DNA. However, its biological function has not been elucidated. Here, we found that TY04 specifically bound to multiple myeloma cells MM.1S, and some membrane proteins on the surface of MM.1S cells constituted the target molecules of TY04. TY04 inhibited the growth of multiple myeloma cell lines, induced cell cycle arrest in mitosis, and resulted in a significant accumulation of binucleated cells. Following TY04 treatment, a concomitant increase in CDK1 and cyclin B1 expression occurred. In addition, TY04 treatment also resulted in a significant downregulation of γ-tubulin. Considering the unique advantages of aptamers, TY04 shows great potential as a drug candidate to treat multiple myeloma.
Assuntos
Aptâmeros de Nucleotídeos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Proteína Quinase CDC2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/genética , Quinases Ciclina-Dependentes/genética , Humanos , Proteínas de Membrana/metabolismo , Mitose/efeitos dos fármacos , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologiaRESUMO
BACKGROUND: The psychological health and sleep quality of intensive care unit (ICU) patients and their families have health implications, and greater attention should be devoted to developing effective interventions to address these concerns. Due to an increasing amount of evidence on ICU diary interventions, their comparative effectiveness should be evaluated. AIMS: This systematic review and meta-analysis aimed to evaluate the effect of ICU diaries on psychological disorders and sleep quality in critically ill patients and on psychological disorders in their family members. METHODS: The PubMed, Embase, Web of Science, Cochrane Library, China Biomedical Literature Database, China National Knowledge Network, Wanfang Database, and Weipu Chinese Journal databases were searched up to November 2023 to identify randomized controlled trials. We used the Cochrane Risk of Bias Tool for quality assessment, and we used Review Manager 5.4 software to conduct meta-analysis. RESULTS: Eleven studies with a total of 1682 patients met the inclusion criteria. PATIENTS: PTSD (7 studies, 1015 patients): OR 0.63 (95%CI 0.45-0.87), p = 0.005; Anxiety (6 studies, 546 patients): OR 0.52 (95%CI 0.22-1.27), p = 0.15; Depression (6 studies, 546 patients): OR 0.62 (95%CI 0.39-0.97), p = 0.04; sleep quality (2 studies, 203 patients): OR -3.97 (95%CI -7.71-0.23), p = 0.04. Family members: PTSD (2 studies, 652 patients): OR 0.81 (95%CI 0.37-1.79), p = 0.60; Anxiety (2 studies, 650 family members): OR 1.09 (95%CI 0.79-1.49), p = 0.62; Depression (2 studies, 650 patients): OR 1.03 (95%CI 0.71-1.50), p = 0.87. The pooled results of the meta-analysis showed that ICU diaries reduced the incidence of depression and post-traumatic stress disorder and improved sleep quality in patients, but had no significant effects on patients' anxiety status or family members' psychological disorders. Three of the included studies had a high quality, and the remaining eight studies had a moderate quality. CONCLUSIONS: For patients, ICU diaries can improve their depression and post-traumatic stress disorder, improve sleep quality, but has no significant effect on anxiety; For family members, ICU diaries were not significant. Due to the existence of bias and the limited sample size, the results should be interpreted with caution. Researchers need to further elucidate the multidisciplinary collaborative process of diary-based treatment in ICUs and its impact on psychological disorders in family members. Furthermore, large-scale, multicentre, robust studies should be conducted in the future.