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BACKGROUND: Cyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive. METHODS: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC. RESULTS: CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer. CONCLUSIONS: Our findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients. KEY POINTS: CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.
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Quinases Ciclina-Dependentes , Ferroptose , Neoplasias de Próstata Resistentes à Castração , Animais , Humanos , Masculino , Camundongos , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/metabolismo , Quinases Ciclina-Dependentes/genética , Progressão da Doença , Ferroptose/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Oxidiazóis/farmacologia , Piperidinas/farmacologiaRESUMO
Ferroptosis has attracted much attention for tumor treatment. It has been recently identified that castration-resistant prostate cancer (CRPC) is vulnerable to ferroptosis inducers. Notably, chemodynamic therapy (CDT), triggered by metal ions, could easily induce ferroptosis via a Fenton/Fenton-like reaction, but its efficiency was highly dependent on the intracellular H2O2 concentration, posing significant changes for its clinical translation. Herein, we attached glucose oxidase (GOx) onto the surface of manganese sulfide (MnS) and developed therapeutic nanocomposites (Lpo@MnS-GOx) after encapsulating with liposome. Upon internalization by cancer cells, the released GOx could transform glucose into gluconic acid (GA) and H2O2. Notably, the generated GA stimulates the degradation of MnS, followed by the promotion of the release of H2S and Mn2+, whereas the produced H2O2 can amplify the Fenton-like response initiated by Mn2+. The enhanced CDT combined with the gas therapy effect could simultaneously promote the accumulation of reactive oxygen species and finally induce ferroptosis and exhibit an excellent anti-tumor effect. Consequently, these Lpo@MnS-GOx NPs with enhanced ferroptosis-induced effect will find great potential for CRPC cancer treatment.
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ABSTRACT: A 37-year-old man was admitted to our hospital after experiencing syncope. An MRI of his head revealed multiple foci of abnormal signal, which could potentially be metastases. The patient then underwent a 68 Ga-FAPI-04 PET/MRI examination, which revealed multiple FAPI-avid foci in the brain. Upon analyzing the cerebrospinal fluid, it was found that the patient had a Staphylococcus aureus infection. The results suggest that 68 Ga-FAPI-04 PET has the potential to be a valuable tool in the visualization of intracranial infectious lesions.
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Infecções Estafilocócicas , Staphylococcus aureus , Masculino , Humanos , Adulto , Infecções Estafilocócicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18RESUMO
BACKGROUND: Androgen deprivation therapy (ADT) is one of the main treatment modalities for prostate cancer (PCa); however, almost all patients treated with ADT eventually progress into castration-resistant PCa (CRPC). Although second-generation androgen receptor (AR) antagonists, such as enzalutamide, have been approved for CRPC treatment, AR signaling in CRPC cells is reactivated through multiple mechanisms, resulting in resistance to treatment and tumor progression with a very poor prognosis. The present study aimed to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with AR degrader IU1 on PCa cells. METHODS: The joint effects of enzalutamide and IU1 on PCa cell proliferation and apoptosis and associated cell signaling were evaluated in vitro. Mechanistically, the ubiquitination level and half-life of AR were examined under the combination treatment. The binding of IU1 and enzalutamide to AR was further verified using cellular thermal shift analysis and isothermal dose-response curve fingerprinting. RESULTS: The combination of IU1 and three AR antagonists showed synergistic effects in different prostate cell lines. IU1 and enzalutamide synergistically promoted the degradation of AR and AR-V7 proteins, as well as suppressed the expression levels of AR and AR-V7 downstream target genes at the transcriptional and protein levels. The combination also synergistically blocked the PCa cell cycle and promoted apoptosis in PCa cell lines. Mechanistically, the combination promoted increased levels of AR ubiquitination. In CRPC cell lines and in the presence of increased androgen concentrations, enzalutamide was still able to bind AR competitively with androgens, reducing the stability of AR and thus promoting the degradation effect of IU1 on AR, synergistically producing an inhibitory effect on PCa cells. CONCLUSION: Taken together, our findings suggest that the combination of AR degrader and enzalutamide potentially represents a new therapeutic strategy for CRPC.
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Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Androgênios/metabolismo , Antagonistas de Androgênios/uso terapêutico , Receptores Androgênicos/metabolismo , Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Antagonistas de Receptores de Andrógenos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos AntineoplásicosRESUMO
OBJECTIVE: Acetaminophen (APAP) is one of the world's popular and safe painkillers, and overdose can cause severe liver damage and even acute liver failure. The effect and mechanism of the xanthohumol on acetaminophen-induced hepatotoxicity remains unclear. METHODS: The hepatoprotective effects of xanthohumol were studied using APAP-induced HepG2 cells and acute liver injury of mouse, seperately. RESULTS: In vitro, xanthohumol inhibited H2O2- and acetaminophen-induced cytotoxicity and oxidative stress. Xanthohumol up-regulated the expression of Nrf2. Further mechanistic studies showed that xanthohumol triggered Nrf2 activation via the AMPK/Akt/GSK3ß pathway to exert a cytoprotective effect. In vivo, xanthohumol significantly ameliorated acetaminophen-induced mortality, the elevation of ALT and AST, GSH depletion, MDA formation and histopathological changes. Xanthohumol effectively suppressed the phosphorylation and mitochondrial translocation of JNK, mitochondrial translocation of Bax, the activation o cytochrome c, AIF secretion and Caspase-3. In vivo, xanthohumol increased Nrf2 nuclear transcription and AMPK, Akt and GSK3ß phosphorylation in vivo. In addition, whether xanthohumol protected against acetaminophen-induced liver injury in Nrf2 knockout mice has not been illustated. CONCLUSION: Thus, xanthohumol exerted a hepatoprotective effect by inhibiting oxidative stress and mitochondrial dysfunction through the AMPK/Akt/GSK3ß/Nrf2 antioxidant pathway.
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Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Animais , Camundongos , Acetaminofen/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Transdução de Sinais , Glicogênio Sintase Quinase 3 beta/metabolismo , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo , Fígado , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismoRESUMO
PURPOSE: This study aimed to investigate the correlations and identify the relationships between the resilience, perception of illness and body image of women with breast cancer in the 5-year-or-above survivorship. METHODS: We used convenient sampling to recruit from an outpatient department 106 women with breast cancer. The inclusion criteria were participants aged >20 years currently in a stable condition and were able to understand the Chinese language. Those women with mental health illness were excluded. All participants completed questionnaires on the following: demographic information, revision of illness perception (IPQ-R), body image scale (BIS), Eysenck personality questionnaire (EPQ), and resilience scale (RS). We conducted the structural equation modeling (SEM) to explore the factor structure. RESULTS: SEM results showed a good fit to the data (comparative fit index = 0.97, Tucker-Lewis index = 0.94). Findings F indicated the existence of significant relationships between resilience and either illness perception or body image. Personality had a direct association with illness perception (ß = 0.73, P < 0.05). Body image had an indirect effect on the relationship between resilience and illness perception (coefficient = -2.52; 95% bootstrapping CI = -31.36, -0.62). CONCLUSIONS: Results indicated that illness perception is a crucial predictor for better resilience as mediated through body image. To provide adequate information to women with breast cancer can improve their perception of breast cancer more positively. Hence, their body image and their way of coping with survival life turn better.
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Imagem Corporal , Neoplasias da Mama , Humanos , Feminino , Imagem Corporal/psicologia , Neoplasias da Mama/psicologia , Adaptação Psicológica , Inquéritos e Questionários , Saúde MentalRESUMO
A safe and effective vaccine is urgently needed to control the unprecedented COVID-19 pandemic. Four adenovirus-vectored vaccines expressing spike (S) protein have been approved for use. Here, we generated several recombinant chimpanzee adenovirus (AdC7) vaccines expressing S, receptor-binding domain (RBD), or tandem-repeat dimeric RBD (RBD-tr2). We found vaccination via either intramuscular or intranasal route was highly immunogenic in mice to elicit both humoral and cellular immune responses. AdC7-RBD-tr2 showed higher antibody responses compared to either AdC7-S or AdC7-RBD. Intranasal administration of AdC7-RBD-tr2 additionally induced mucosal immunity with neutralizing activity in bronchoalveolar lavage fluid. Either single-dose or two-dose mucosal administration of AdC7-RBD-tr2 protected mice against SARS-CoV-2 challenge, with undetectable subgenomic RNA in lung and relieved lung injury. AdC7-RBD-tr2-elicted sera preserved the neutralizing activity against the circulating variants, especially the Delta variant. These results support AdC7-RBD-tr2 as a promising COVID-19 vaccine candidate.
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Adenoviridae/genética , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , COVID-19 , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/genética , Chlorocebus aethiops , Feminino , Vetores Genéticos/genética , Células HEK293 , Humanos , Imunogenicidade da Vacina , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos BALB C , Pan troglodytes/virologia , Ligação Proteica , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/administração & dosagem , Glicoproteína da Espícula de Coronavírus/genética , Vacinação , Células VeroRESUMO
BACKGROUND: The 8-item self-report Perceived Stigma toward Substance Users Scale (PSAS) is a commonly used instrument to assess stigma for people with substance use disorders. This study aimed to develop and validate the Taiwan version of the PSAS entitled Perceived Stigma toward People who use Substances - Taiwan version (PSPS-TV) among individuals with substance use disorders. METHODS: Patients with substance use disorders (N = 300; mean age = 45.22; 255 males) completed the PSPS-TV, Self-Stigma Scale-Short (SSS-S), Taiwan Depression Questionnaire (TDQ), and Rosenberg Self-Esteem Scale (RSES). Confirmatory factor analysis was used to test the construct validity and the measurement invariance of the PSPS-TV. Concurrent validity was tested using the correlations between PSPS-TV and SSS-S, TDQ, and RSES scores. RESULTS: The confirmatory factor analysis supported the construct validity and measurement invariance of the PSPS-TV. SSS-S scores explained 13 %, TDQ scores explained 10 % and RSES scores explained 17 % of the PSPS-TV score variance with moderate standardized coefficients (0.38, 0.32 and -0.42, respectively; all p < 0.001). CONCLUSIONS: The PSPS-TV is an appropriate instrument to assess perceived stigma for individuals residing in Taiwan who have substance use disorders. Taiwan healthcare providers may thus consider using the PSPS-TV to assess perceived stigma relating to substance use in Taiwan.
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Alcoolismo/psicologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Dependência de Heroína/psicologia , Percepção , Psicometria/métodos , Estigma Social , Adulto , Alcoolismo/diagnóstico , Alcoolismo/epidemiologia , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Usuários de Drogas/psicologia , Análise Fatorial , Feminino , Dependência de Heroína/diagnóstico , Dependência de Heroína/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/normas , Autorrelato/normas , Inquéritos e Questionários/normas , Taiwan/epidemiologiaRESUMO
C-C chemokine receptor 5(CCR5) is a cell membrane protein from G protein-coupled receptors (GPCR) family, which is an important modulator for leukocyte activation and mobilization. In the 1980s, several reports suggest that lack of the HIV-1 co-receptor, the chemokine receptor CCR5, offers protection against HIV infection. Later, it was shown that CCR5 was confirmed to be the most common co-receptor for the HIV-1 virus R5 strain. In recent years, many studies have shown that CCR5 is closely related to the development of various cancers and inflammations to facilitate the discovery of CCR5 antagonists. There are many types of CCR5 antagonists, mainly including chemokine derivatives, non-peptide small molecule compounds, monoclonal antibodies, and peptide compounds. This review focus on the recent research processes and pharmacological effects of CCR5 antagonists such as Maraviroc, TAK-779 and PRO 140. After focusing on the therapeutic effect of CCR5 antagonists on AIDS, it also discusses the therapeutic prospect of CCR5 in other diseases such as inflammation and tumor.
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Fármacos Anti-HIV/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Antagonistas dos Receptores CCR5/uso terapêutico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Fármacos Anti-HIV/metabolismo , Anti-Inflamatórios/metabolismo , Antineoplásicos/metabolismo , Antagonistas dos Receptores CCR5/metabolismo , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Receptores CCR5/metabolismoRESUMO
BACKGROUND: Currently, the identification of Clara cell and type II alveolar epithelial cell-type cancer cells requires electron microscopy, which is a time-consuming and expensive process involving a complicated tissue sampling procedure. The aim of this study was to identify unique biomarkers for Clara cell and type II alveolar epithelial cell-type lung cancer cells, respectively, with proteomic profiling. METHODS: Six human lung adenocarcinoma cell lines (A549, NCI-H358, NCI-H1650, HCC827, NCI-H1395, and NCI-H1975) were investigated for their ultrastructural characteristics. The differentially expressed proteins (DEPs) were screened between NCI-H358 cells (Clara cell type) and A549 cells (type II alveolar epithelial cell type) using two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS/MS), and then they were validated by western blot. The protein expression levels of endoplasmic reticulum oxidoreductin 1-α (ERO1L), Clara cell 10-kD protein (CC10), and surfactant protein C (SP-C) were also determined in the six cell lines assayed. RESULTS: NCI-H358 cells featured Clara cell differentiation; A549, NCI-H1975, and HCC827 cells had characteristics of type II alveolar epithelial cells; and NCI-H1395 and NCI-H1650 cells had no differentiation characteristics of any lung adenocarcinoma cell type. Five DEPs including ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), cytokeratin 19 (CK19), cytokeratin 8 (CK8), ERO1L, and peroxiredoxin 2 (PRDX2) between NCI-H358 and A549 cells were identified for further validation; however, none of them showed suitability as an effective biomarker. Similarly, CC10 and SP-C were not appropriate biomarkers. CONCLUSIONS: Cytological subtypes of NCI-H1975 and HCC827 cells were identified, but no promising biomarker was discovered in the present study.
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OBJECTIVE: Fear of cancer recurrence (FCR) is the most commonly reported problem and unmet need among breast cancer survivors. The aim of this qualitative study was to explore the experience of recurrence fears among Taiwanese breast cancer survivors. METHODS: Three focus groups were included in this study. A purposive sampling technique was used to recruit 11 recurrence-free women at least 20 years of age from southern Taiwan who were diagnosed with breast cancer within the previous 2 years. Data were analysed and interpreted using content analysis. RESULTS: Three themes reflecting the experience of FCR were extracted from the transcript analyses: "Trapped in insecurity," "Suffering in silence," and "Pretending as if nothing happened." Participants endured a complex set of circumstances akin to silently walking the survival tightrope. Breast cancer survivors were still insecure and suffering, rather than celebrating survival, after the completion of treatment. Fear of cancer recurrence silently dominated their lives. CONCLUSIONS: An avoidance mindset and an unspoken FCR leave survivors insecure, resulting in a silent survival journey. These difficult thoughts and feelings that may impact the reconstruction of post-cancer life should be acknowledged. The development of appropriate survivorship care programs and emotional resilience regarding recurrence is needed for Taiwanese breast cancer survivors.
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Neoplasias da Mama/psicologia , Sobreviventes de Câncer/psicologia , Medo/psicologia , Recidiva Local de Neoplasia/psicologia , Adulto , Feminino , Grupos Focais , Humanos , Pessoa de Meia-Idade , Pesquisa Qualitativa , TaiwanRESUMO
In this paper, the colorimetric sensing of H2O2 related molecules and biothiols based on etching and anti-etching strategy was firstly proposed. Ag/carbon nanocomposite (Ag/C NC) was served as the sensing nanoprobe, which was synthesized via carbon dots (C-dots) as the reductant and stabilizer. The characteristic surface plasmon resonance (SPR) absorbance of Ag nanoparticles (AgNPs) was sensitive to the amount of hydrogen peroxide (H2O2). It exhibited strong optical responses to H2O2 with the solution colour changing from yellow to nearly colourless, which is resulted from the etching of Ag by H2O2. The sensing platform was further extended to detect H2O2 related molecules such as lactate in coupling with the specific catalysis oxidation of L-lactate by lactate oxidase (LOx) and formation of H2O2. It provides wide linear range for detecting H2O2 in 0.1-80µM and 80-220µM with the detection limit as low as 0.03µM (S/N=3). In the presence of biothiols, the etching from the H2O2 can be hampered. Other biothiols exhibit anti-etching effects well. The strategy works well in detecting of typical biothiols including cysteine (Cys), homocysteine (Hcy) and glutathione (GSH). Thus, a simple colorimetric strategy for sensitive detection of H2O2 and biothiols is proposed. It is believed that the colorimetric sensor based on etching and anti-etching strategy can be applied in other systems in chemical and biosensing areas.
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Técnicas Biossensoriais , Cisteína/sangue , Glutationa/sangue , Homocisteína/sangue , Peróxido de Hidrogênio/análise , Nanopartículas Metálicas/química , Carbono/química , Cor , Colorimetria/métodos , Humanos , Ácido Láctico/sangue , Limite de Detecção , Oxigenases de Função Mista/química , Oxirredução , Pontos Quânticos/química , Prata/química , Ressonância de Plasmônio de Superfície/métodosRESUMO
The function of miR-592 has been investigated in many types of cancer, however its roles in breast cancer remain unclear. We therefore investigated the biological function and underlying mechanism of miR-592 in breast cancer. In the present study, a marked downregulation of miR-592 was observed in breast cancer tissues and cell lines compared to the matched adjacent non-tumor tissues and normal breast cell line. Statistical analysis revealed that decreased miR-592 was negatively associated with advanced clinical stage, distant metastasis and lymph node metastases. Function analysis demonstrated that overexpression of miR-592 significantly inhibited cell proliferation, clone formation, migration and invasion in breast cancer cells in vitro, as well as suppressed tumor growth in vivo. Furthermore, transforming growth factor ß-2 (TGFß-2), a known oncogene, was identified as a direct target of miR-592, and its mRNA expression level was inversely correlated with the expression level of miR-592 in human breast cancer specimens. Restoration of TGFß-2 expression rescued the inhibitory effect in breast cancer cells caused by miR-592. Collectively, these data suggest that miR-592 may exert it suppressive role in breast cancer, at least in part, by targeting TGFß-2, and that miR-592 may be a novel target for breast cancer treatment.
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Neoplasias da Mama/genética , Proliferação de Células/genética , MicroRNAs/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Lung cancer is one of the most common non-AIDS-defining malignancies among HIV-infected patients. The incidence of lung cancer has significantly increased in the HIV-positive population in recent years. The purpose of this study was to summarize the incidence and risk of lung cancer in published population-based studies of people with HIV/AIDS. METHODS: Published literature from PubMed, Embase, the Web of Science, and Google Scholar was retrieved. Sixty-five publications were selected and assessed for the following parameters: research coverage and location; continent; study period; duration of follow-up; lung cancer cases; HIV cases; incidence rate; and overall SIR or adjusted IRR. In addition, the risk of lung cancer was compared based on age, gender, HIV exposure category, CD4 count, and periods with highly active antiretroviral therapy (HAART). RESULTS: Lung cancer risk was greater among HIV-infected individuals compared with the general population. SIRs or adjusted IRRs were 1.5-3.4 in Europe, 0.7-6.9 in the USA, and 5.0 in Africa. Most, but not all studies did not observe a significant change in the incidence and risk of lung cancer between the pre-HAART and HAART eras. In most studies, the risk of lung cancer was higher among women, younger individuals, and injection drug users (IDUs), but the incidence of lung cancer was higher among men and the elderly. No significant trend in lung cancer risk across CD4 cell count categories was reported among the selected articles. CONCLUSION: Our study suggests an increase in the incidence and risk of lung cancer in HIV/AIDS population is worldwide. The effect of HAART on the incidence and risk of lung cancer is in dispute. The risk of lung cancer based on gender differences, especially among females, as well as IDUs, requires further investigation.
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Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/epidemiologia , Humanos , IncidênciaRESUMO
Angiogenesis is crucial for solid tumor growth. By secreting angiogenic factors, tumor cells induce angiogenesis. However, targeting these angiogenic factors for cancer therapy is not always successful, suggesting that other factors may be involved in tumor angiogenesis. This work shows that 25 protein spots were differentially expressed by two-dimensional gel electrophoretic analysis when HepG2 cells induced endothelial cell differentiation to tube in vitro, and most of them were upregulated. Twenty-one proteins were identified with MALDI-TOF-MS, and the other four were identified by LTQ-MS/MS. Keratins were identified as one class of these upregulated proteins. Further study indicated that the expression of keratin 17 in cultured endothelial cells is likely microenvironment regulated, because its expression can be induced by HepG2 cells and bFGF as well as serum in culture media. Increased expression of keratins in endothelial cells, such as keratin 17, may contribute to the angiogenesis induced by HepG2 cells.
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Queratina-17/isolamento & purificação , Queratina-17/fisiologia , Neoplasias/irrigação sanguínea , Neovascularização Patológica/metabolismo , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/metabolismo , Humanos , Queratina-17/genética , Queratina-17/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neovascularização Patológica/genética , Proteômica/métodosRESUMO
OBJECTIVE: To assess the effects of honokiol on proliferation and apoptosis of human cervical carcinoma cell line Hela in vitro. METHODS: Cultured HeLa cells were treated with different concentrations of honokiol for the varieties of period (24, 48, 72, 96 h). Cell proliferation was assessed by MTT colorimetric assay. Cell apoptosis was determined by flow cytometry (FCM), Hoechst 33258 fluorescent staining and DNA ladder respectively. RESULTS: MTT assay demonstrated that the proliferation of Hela cells were suppressed significantly by honokiol in dose-and time-dependent manner. FCM analysis showed that the apoptosis rates of Hela cells treated with 10 microg/mL and 20 microg/mL honokiol for 24 h were 22.5% and 62.2%, respectively, while that of the control group cells was 8.7%. After treatment with honokiol, typically morphologic changes of apoptosis were observed by Hoechst 33258 fluorescence staining; Genomic DNA from Hela cells treated with honokiol displayed a characteristic ladder pattern on agarose gel electrophoresis. CONCLUSION: honokiol can inhibit the proliferation and induce apoptosis of human cervical carcinoma cell line Hela.
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Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Proliferação de Células/efeitos dos fármacos , Lignanas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Citometria de Fluxo , Células HeLa , Humanos , Fatores de TempoRESUMO
BACKGROUND: Honokiol is a major bioactive compound extracted from Magnolia. The present study was designed to determine whether liposomal honokiol has the antitumor activity against human lung cancer as well as potentiates the antitumor activity of cisplatin in A549 lung cancer xenograft model, if so, to examine the possible mechanism in the phenomenon. METHODS: human A549 lung cancer-bearing nude mice were treated with liposomal honokiol, liposomal honokiol plus DDP or with control groups. Apoptotic cells and vessels were evaluated by fluorescent in situ TUNEL assay and by immunohistochemistry with an antibody reactive to CD31 respectively. RESULTS: The present study showed that liposomal honokiol alone resulted in effective suppression of the tumor growth, and that the combined treatment with honokiol plus DDP had the enhanced inhibition of the tumor growth and resulted in a significant increase in life span. The more apparent apoptotic cells in the tumors treated with honokiol plus DDP was found in fluorescent in situ TUNEL assay, compared with the treatment with control groups. In addition, the combination of honokiol and DDP apparently reduced the number of vessels by immunolabeling of CD31 in the tissue sections, compared with control groups. CONCLUSION: In summary, our data suggest that honokiol alone had the antitumor activity against human lung cancer in A549 lung cancer xenograft model, and that the combination of honokiol with DDP can enhance the antitumor activity, and that the enhanced antitumor efficacy in vivo may in part result from the increased induction of the apoptosis and the enhanced inhibition of angiogenesis in the combined treatment. The present findings may be of importance to the further exploration of the potential application of the honokiol alone or the combined approach in the treatment of lung carcinoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos de Bifenilo/farmacologia , Cisplatino/administração & dosagem , Lignanas/farmacologia , Lipossomos/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Animais , Apoptose , Compostos de Bifenilo/administração & dosagem , Linhagem Celular Tumoral , Humanos , Marcação In Situ das Extremidades Cortadas , Lignanas/administração & dosagem , Camundongos , Transplante de Neoplasias , Neovascularização Patológica , Extratos Vegetais/farmacologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossínteseRESUMO
Honokiol, a novel antitumor agent, could induce apoptosis and inhibit the growth of vascular endothelium in several tumor cell lines and xenograft models. It has been suggested that the antitumor effect of chemotherapy could be increased by combining it with an antiangiogenesis agent in anticancer strategy. The present study explored the potential to increase the antitumor effect of adriamycin by combining it with honokiol in mouse 4T1 breast cancer models, and the underlining mechanism was investigated. Honokiol was encapsulated in liposomes to improve the water insolubility. In vitro, liposomal honokiol inhibited the proliferation of 4T1 cells via apoptosis and significantly enhanced the apoptosis of 4T1 cells induced by adriamycin. In vivo, the systemic administration of liposomal honokiol and adriamycin significantly decreased tumor growth through increased tumor cell apoptosis compared with either treatment alone. Collectively, these findings suggest that liposomal honokiol may augment the induction of apoptosis in 4T1 cells in vitro and in vivo, and this combined treatment has shown synergistic suppression in tumor progression according to the analysis of isobologram. The present study may be important in future exploration of the potential application of the combined approach in the treatment of breast cancer.