RESUMO
BACKGROUND: Although considered one of the most important prognostic factors for lung cancer patients, the health-related quality of life (HRQOL) of the newly diagnosed lung cancer population remains scarcely focused on in the literature. Therefore, we aimed to identify the determinants of HRQOL among newly diagnosed lung cancer patients in Taiwan. METHODS: Two hundred and fifty patients newly diagnosed with lung cancer were recruited from a medical center in northern Taiwan through convenience sampling. Four structured questionnaires, including the Taiwanese version of the MD Anderson symptom inventory (MDASI-T), the Taiwanese version of the Pittsburgh Sleep Quality Index (PSQI-T), the International Physical Activity Questionnaire-Short Form (IPAQ-SF), and the World Health Organization Quality of Life-BREF (WHOQOL-BREF), were used to collect data. Further, a multivariate stepwise linear regression was conducted to determine the independent risk factors for HRQOL. A p value of less than 0.05 was considered statistically significant. RESULTS: The patients (mean age was 61.04 years, 51.2% male, 94.0% non-small-cell lung cancer, 56.4% stage IIIB-IV) had moderate levels of HRQOL among the physical, psychological, social, and environmental domains, as well as overall QOL. HRQOL was not correlated with married status, religion, and comorbidity. Gender, age, family income, smoking status, cancer stage, ECOG PS scores, PA, symptom burden (severity and interference), and PSQI global scores were correlated with HRQOL. Notably, symptom severity was the dominant negative predictor affecting the psychological and environmental domains of QOL (ß = -4.313 and -3.500, respectively), accounting for 23.2% and 14.6% of the variance, respectively. On the other hand, symptom interference was the dominant negative predictor affecting the physical and social domains of QOL, as well as overall QOL (ß = -3.592, -1.984, and -0.150, respectively), accounting for 44.4%, 15.0%, and 24.1% of the variance, respectively. CONCLUSION: Newly diagnosed lung cancer patients suffered symptom severity and interference that significantly impaired their HRQOL; particularly, symptom interference affected the physical domain of QOL. Healthcare professionals should pay more attention to cancer-related symptom severity, symptom interference, and HRQOL changes when caring for newly diagnosed lung cancer patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Qualidade de Vida/psicologia , Estudos Transversais , Taiwan , Inquéritos e QuestionáriosRESUMO
Mesenchymal stem cells (MSCs) that display homing and infiltration properties towards tumor cells are a promising cellular targeting vector for brain tumor therapy but are limited to local-regional delivery in current preclinical models. Here, we investigated whether placenta-derived MSCs (P-MSCs) are a superior cellular vector for systemic targeting of glioblastoma stem-like cells (GSCs), with an imaging modality to real-time monitor the trafficking P-MSCs to glioblastoma sites. Results demonstrated that P-MSCs had greater migratory activity towards GSCs and across blood-brain barrier compared with bone marrow-derived MSCs, and this activity was enhanced by hypoxia precondition. Chemokine ligand 5 was identified as a chemoattractant responsible for the glioblastoma tropism of P-MSCs. Polyethylene glycol-coated superparamagnetic iron oxide (PEG-SPIO) was synthesized for cellular labelling and imaging P-MSCs, displaying high cellular uptake and no cytotoxic effect on P-MSCs cell proliferation or stemness property. The homing effects of intravenously administered PEG-SPIO-labelled P-MSCs towards intracerebral GSCs were able to be detected in mice models through T2-weighted magnetic resonance imaging (MRI). This study suggests the possibility of innovative systemic P-MSC-based cell therapy for aggressive GSCs, developing a state-of-the-art theranostic technique for real-time tracking of therapeutic P-MSCs tumor infiltration through cellular MRI.
Assuntos
Neoplasias Encefálicas , Rastreamento de Células/métodos , Meios de Contraste , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/química , Células-Tronco Mesenquimais/metabolismo , Placenta/metabolismo , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Meios de Contraste/química , Meios de Contraste/farmacologia , Feminino , Humanos , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Placenta/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , GravidezRESUMO
This chapter describes an efficient and reproducible method for large-scale propagation of Oncidium and Phalaenopsis protocorm-like bodies (PLBs) using floral stalk sections and seeds, respectively. The propagated PLBs can be used for Agrobacterium-mediated transformation. An advanced transformation system for Oncidium and Phalaenopsis orchids has been established. This protocol demonstrates that the time during which the PLBs are cocultivated with Agrobacterium is the key to promoting transformation efficiency. Modified DNA and RNA extraction methods are also provided to diminish polysaccharide contamination and to improve the quality for further molecular analysis.
Assuntos
Engenharia Genética/métodos , Orchidaceae/crescimento & desenvolvimento , Orchidaceae/genética , Agrobacterium tumefaciens/genética , Agrobacterium tumefaciens/crescimento & desenvolvimento , Southern Blotting , Técnicas de Cocultura , DNA de Plantas/genética , DNA de Plantas/isolamento & purificação , Orchidaceae/citologia , RNA de Plantas/genética , RNA de Plantas/isolamento & purificação , Regeneração , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transformação GenéticaRESUMO
Bone marrow-derived mesenchymal stem cells (MSCs) are able to migrate to tumors, where they promote tumorigenesis and cancer metastasis. However, the molecular phenotype of the recruited MSCs at the tumor microenvironment and the genetic programs underlying their role in cancer progression remains largely unknown. By using a three-dimensional rotary wall vessel coculture system in which human MSCs were grown alone or in close contact with LNCaP, C4-2 or PC3 prostate cancer cell lines, we established in vitro matched pairs of normal and cancer-associated MSC derivatives to study the stromal response of MSCs to prostate cancer. We observed that prostate cancer-associated MSCs acquired a higher potential for adipogenic differentiation and exhibited a stronger ability to promote prostate cancer cell migration and invasion compared with normal MSCs both in vitro and in experimental animal models. The enhanced adipogenesis and the pro-metastatic properties were conferred by the high levels of IL-6 secretion by cancer-associated MSCs and were reversible by functionally inhibiting of IL-6. We also found that IL-6 is a direct target gene for the let-7 microRNA, which was downregulated in cancer-associated MSCs. The overexpression of let-7 via the transfection of let-7 precursors decreased IL-6 expression and repressed the adipogenic potential and metastasis-promoting activity of cancer-associated MSCs, which was consistent with the inhibition of IL-6 3'UTR luciferase activity. Conversely, the treatment of normal MSCs with let-7 inhibitors resulted in effects similar to those seen with IL-6. Taken together, our data demonstrated that MSCs co-evolve with prostate cancer cells in the tumor microenvironment, and the downregulation of let-7 by cancer-associated MSCs upregulates IL-6 expression. This upregulation triggers adipogenesis and facilitates prostate cancer progression. These findings not only provide key insights into the molecular basis of tumor-stroma interactions but also pave the way for new treatments for metastatic prostate cancer.
Assuntos
Células da Medula Óssea/patologia , Interleucina-6/genética , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Regulação para Cima/genética , Animais , Reatores Biológicos , Diferenciação Celular , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Técnicas de Cocultura , Progressão da Doença , Células HEK293 , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Metástase Neoplásica , Fenótipo , Células Estromais/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cell-based carriers were recently exploited as a tumor-targeting tool to improve systemic delivery of oncolytic viruses for cancer therapy. However, the slow clearance of carrier cells from normal organs indicates the need for a controllable system which allows viral delivery only when the carrier cells reach the tumor site. In this study, we sought to develop a pharmaceutically inducible cell-based oncolytic adenovirus delivery strategy for effective targeting and treatment of renal cell carcinoma (RCC), which is one of the most malignant tumor types with an unfavorable prognosis. Herein, we demonstrated the intrinsic tumor homing property of human bone marrow-derived mesenchymal stem cells (hMSCs) to specifically localize primary and metastatic RCC tumors after systemic administration in a clinically relevant orthotopic animal model. The platelet derived growth factor AA (PDGF-AA) secreted from RCC was identified as a chemoattractant responsible for the recruitment of hMSCs. Like endogenous osteocalcin whose barely detectable level of expression was dramatically induced by vitamin D(3), the silenced replication of human osteocalcin promoter-directed Ad-hOC-E1 oncolytic adenoviruses loaded in hMSCs was rapidly activated, and the released oncolytic adenoviruses sequentially killed cocultured RCC cells upon vitamin D(3) exposure. Moreover, the systemic treatment of RCC tumor-bearing mice with hMSC cell carriers loaded with Ad-hOC-E1 had very limited effects on tumor growth, but the loaded hMSCs combined with vitamin D(3) treatment induced effective viral delivery to RCC tumors and significant tumor regression. Therapeutic effects of hMSC-based Ad-hOC-E1 delivery were confirmed to be significantly greater than those of injection of carrier-free Ad-hOC-E1. Our results presented the first preclinical demonstration of a novel controllable cell-based gene delivery strategy that combines the advantages of tumor tropism and vitamin D(3)-regulatable human osteocalcin promoter-directed gene expression of hMSCs to improve oncolytic virotherapy for advanced RCC.
Assuntos
Adenoviridae/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/terapia , Colecalciferol/farmacologia , Colecalciferol/uso terapêutico , Células-Tronco Mesenquimais/citologia , Animais , Carcinoma de Células Renais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia Viral Oncolítica/métodos , Osteocalcina/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Advanced renal cell carcinoma (RCC) frequently develops skeletal metastasis and is highly resistant to conventional therapies. We hypothesized that the osteocalcin (OC) promoter may be a promising gene delivery system for RCC targeted gene therapy because osteotropic tumors gain osteomimetic properties and thrive in the new environment by exhibiting a bone-like gene expression profile. Human OC (hOC) expression is highly regulated by vitamins and hormone. In the present study, we tested the feasibility of vitamin-regulatable hOC promoter for RCC-specific transcriptional targeting, and examined the anti-tumor effect of vitamins C and D3 with hOC-based adenoviral vectors towards RCC. METHODS: Real-time reverse transcriptase-polymerase chain reaction measured OC expression induced by vitamins C and D3, either alone or in combination, in RCC and normal human renal epithelial cells (HRE). The RCC-cytotoxic effects of concomitant vitamins and hOC promoter-based adenoviral vectors, Ad-hOC-TK and Ad-hOC-E1, were evaluated in both cell culture and a xenograft murine model. RESULTS: We found that high doses of vitamin C induced H2O2-dependent apoptosis in RCC but not HRE. Treatment of RCC cells with combined vitamins C and D3 treatment significantly increased OC promoter activity compared to single reagent treatment. Combined vitamin therapy reduced tumor size (85%) and complete tumor regression occurred in 38% of mice co-administrated Ad-hOC-E1. CONCLUSIONS: The results obtained in the present study demonstrate that vitamins C and D3 synergized with the anti-tumor effects of therapeutic genes driven by hOC promoter through direct cytotoxicity as well as transcriptional targeting. This combined gene therapy provides a promising modality for advanced RCC targeted therapy.
Assuntos
Ácido Ascórbico/metabolismo , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Osteocalcina/genética , Vitamina D/metabolismo , Adenoviridae/genética , Animais , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Terapia Genética , Vetores Genéticos , Humanos , Neoplasias Renais/genética , Masculino , Camundongos , Camundongos Knockout , Camundongos Nus , Regiões Promotoras Genéticas , Transcrição Gênica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The L1 cell adhesion molecule (L1CAM) has been implicated in tumor progression of many types of cancers, but its role in oral squamous cell carcinoma (OSCC) has not been investigated. In the present study, we demonstrated overexpression of L1CAM in OSCC cells, but not in normal keratinocytes, using both clinical specimens and cell lines. This overexpression demonstrated a strong correlation with less differentiation and a higher invasion potential of cancer cells, supporting the significance of L1CAM in human OSCC tumor progression. Targeting L1CAM gene expression in SCC4 cells overexpressing L1CAM using a lentivirus-mediated small hairpin RNA (shRNA) led to a significant reduction in cell proliferation in vitro via retardation of cell cycle at the G1 phase. In addition, shRNA knockdown of L1CAM strongly attenuated the migration and invasion of SCC4 cells, and this was also observed to parallel increased E-cadherin levels and decreased levels of vimentin, fibronectin, and Snail-family transcription factors, indicating that L1CAM expression was related to the epithelial-mesenchymal transition. Furthermore, while mice receiving orthotopically placed control SCC4 cells died within 40 days due to invasive tumor growth and regional lymph node metastasis, prolonged animal survival and complete suppression of tumor progression was observed in mice implanted with L1CAM-deficent SCC4 cells, further substantiating the fundamental importance of L1CAM in OSCC pathophysiology. Our findings suggested that L1CAM is a critical mediator of tumor progression in OSCC, and targeting L1CAM using lentivirus-mediated shRNA may be a useful molecular pharmaceutical approach for the treatment of advanced OSCC.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Lentivirus/genética , Neoplasias Bucais/tratamento farmacológico , Molécula L1 de Adesão de Célula Nervosa/imunologia , RNA Interferente Pequeno/farmacologia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lentivirus/imunologia , Camundongos , Camundongos Nus , Neoplasias Bucais/genética , Neoplasias Bucais/imunologia , Molécula L1 de Adesão de Célula Nervosa/biossíntese , Molécula L1 de Adesão de Célula Nervosa/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
There is currently no effective treatment method available for liver fibrosis. We therefore evaluated the use of Wharton's jelly stem cells (WJSCs; the major umbilical cord stem cell population) to treat chemically induced liver fibrosis via intraperitoneal injection of thioacetamide. WJSCs were transplanted into liver-damaged rats via the portal vein and the treatment was evaluated by assessing serum biochemistry and histopathology. Transplanted WJSCs were distributed in the fibrotic area and around blood vessels, and hepatic recovery was accelerated. Serum prothrombin time significantly recovered, and serum albumin also improved at 21 days posttransplantation; collagen accumulation also decreased at 14 days. Thus, human WJSCs promoted recovery after chronic liver damage. Using immunohistochemical analyses, we determined that transplanted WJSCs produce albumin, hepatocyte growth factor (HGF), and metalloproteinase (MMP) after transplantation to chemically injured liver, indicating that WJSC may help to decrease liver collagen and thus may be useful for treating liver fibrosis.
Assuntos
Cirrose Hepática/terapia , Transplante de Células-Tronco , Células-Tronco/citologia , Cordão Umbilical/citologia , Animais , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Cirrose Hepática/induzido quimicamente , Masculino , Metaloproteases/metabolismo , Ratos , Ratos Wistar , Albumina Sérica/metabolismo , Tioacetamida/toxicidadeRESUMO
The purpose of this study was to investigate the chemopreventive effect of carotenoids on proliferating cell nuclear antigen (PCNA) and cyclin D(1) expression in betel (Areca catechu) quid extract (BQE)-induced hamster oral cancer and human KB cell models, respectively. In the in vivo animal study, 41 hamsters were divided into six groups and treated with 0.3 ml of 0.5% 9,10-dimethyl-1,2-benz[a]-anthracene, BQE, alpha-tocopherol, beta-carotene, lycopene, lutein and mixed carotenoids for 12 weeks. After treatment, the pouches were excised and graded using an immunohistochemical assay of PCNA. In the in vitro cell experiment, KB cells were cultured, and the inhibitory effect of carotenoids (beta-carotene, lycopene and lutein) on cell proliferation was evaluated. Cyclin D(1) and PCNA were evaluated in terms of cell differentiation. In the results, most of the animal lesions showed no overexpression of PCNA. However, in dysplastic lesions, PCNA expressions by the beta-carotene, lutein, lycopene, mixed and vitamin E groups were less than that of the control group. In papilloma lesions, PCNA expressions by the beta-carotene, mixed and vitamin E groups were less severe than that of the control group. PCNA expression by the vitamin E-treated group was less severe than that of the control group. No carcinoma was found in the lycopene or mixed groups. In the cell study, all carotenoids exerted a significant inhibitory effect on KB cell proliferation. Although lycopene suppressed KB cell proliferation at the G(0)/G(1) phase with a significant decrease in PCNA expression, beta-carotene and lutein possessed less of an inhibitory effect and even exhibited elevated cell proliferation at the G(2)/M phase. These results indicate that different carotenoids present various suppressive abilities against PCNA and cyclin D(1) expressions in cell proliferation. In conclusion, carotenoids suppressed the carcinogenesis of induced hamster oral cancer and a cancer cell line by acting as a suppressor which inhibited the expressions of PCNA and cyclin D(1).