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1.
Cancer Commun (Lond) ; 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34738326

RESUMO

BACKGROUND: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. METHODS: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. RESULTS: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. CONCLUSIONS: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.

3.
J Environ Sci (China) ; 105: 33-43, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34130837

RESUMO

Disposal of the pollutants arising from farming cattle and other livestock threatens the environment and public safety in diverse ways. Herein, we report on the synthesis of engineered biochars using cow dung as raw material, and investigating these biochars as antibacterial agents for water decontamination. By coating the biochars with N-halamine polymer and loading them with active chlorine (i.e., Cl+), we were able to regulate them on demand by tuning the polymer coating and bleaching conditions. The obtained N-halamine-modified biochars were found to be extremely potent against Escherichia coli and Staphylococcus aureus. We also investigated the possibility of using these N-halamine-modified biochars for bacterial decontamination in real-world applications. Our findings indicated that a homemade filter column packed with N-halamine-modified biochars removed pathogenic bacteria from mining sewage, dairy sewage, domestic sewage, and artificial seawater. This proposed strategy could indicate a new way for utilizing livestock pollutants to create on-demand decontaminants.


Assuntos
Antibacterianos , Descontaminação , Animais , Antibacterianos/farmacologia , Bovinos , Carvão Vegetal , Escherichia coli , Staphylococcus aureus
4.
J Obstet Gynaecol Res ; 47(8): 2720-2728, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34036681

RESUMO

AIM: We aimed to explore the application of PAX1 methylation and human papillomavirus (HPV) E6/E7 mRNA detection in cervical cancer screening and to compare the efficacy with high-risk (HR)-HPV detection. PATIENTS AND METHODS: The cervical exfoliative cytology samples of 337 patients were collected, including 70 cases of cervical inflammation, 72 cases of low-grade squamous intraepithelial lesions, 97 cases of high-grade squamous intraepithelial lesions, and 98 cases of cervical carcinoma. The PAX1 gene methylation (PAX1) status was detected by multiple quantitative PCR, HPV E6/E7 mRNA (E6/E7) was detected by QuantiVirus detection, and HR-HPV (HPV) was detected by the Cobas 4800 detection system. The sensitivities, specificities, and accuracies were validated in the testing set. RESULTS: The sensitivities of the HPV, HPV E6/E7, and PAX1 testing were 89.23%, 84.10%, and 86.67%, respectively, which all maintained a high level. In contrast, the specificities of the HPV, E6/E7, and PAX1 testing were only 19.10%, 37.32%, and 97.18% (in pairwise comparisons, p = 0.000). The AUC of PAX1 (0.919) was significantly larger than that of HPV (0.541) and E6/E7 detection (0.607) (p < 0.0001). In addition, the AUC areas of all combined parallel testing were lower than that of single PAX1 test (p < 0.05). CONCLUSION: The diagnostic efficacy of E6/E7 detection and PAX1 detection was better than that of HPV detection, especially for PAX1 detection.


Assuntos
Neoplasia Intraepitelial Cervical , Proteínas Oncogênicas Virais , Fatores de Transcrição Box Pareados/metabolismo , Infecções por Papillomavirus , Neoplasias do Colo do Útero , DNA Viral , Detecção Precoce de Câncer , Feminino , Humanos , Metilação , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , RNA Mensageiro/metabolismo , RNA Viral , Neoplasias do Colo do Útero/diagnóstico
5.
Inorg Chem ; 59(21): 16027-16034, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33064476

RESUMO

To estimate the effect of bisphosphine ligands on the formation of the isomeric core structures of gold nanoclusters, the different ligation of bisphosphine ligands is usually used to participate in the construction of gold nanoclusters. Here, the selection of the different bisphosphine ligands, DPEphos and Xantphos, is performed to construct two novel gold nanoclusters, [Au11(DPEphos)4Cl2]Cl (1) and [Au11(Xantphos)4Cl2]Cl(2), which have been characterized by IR, 1H and 31P NMR, ESI-MS, XRD, SEM, XPS, TG, UV-vis, and X-ray crystal structure analysis. The structural analyses indicate that the ligation of bisphosphine ligands play a crucial role in the formation of the fascinating Au11 cores: gold nanocluster 1 includes a birdcage-shaped Au11 core with eight electrons, while gold nanocluster 2 contains a crown-shaped Au11 core with eight electrons. Meanwhile, DOS and PDOS studies indicate that the Au11 cores have a strong effect on the composition of HOMO and LUMO orbitals of gold nanoclusters. Furthermore, the different Au11 core structures lead to different optical absorption characteristics (1: 456 nm; 2: 427 nm). All these demonstrate that the ligation of bisphosphine ligands may have an important influence on constructing the stability of the isomeric core structures of gold nanoclusters.

6.
J Microbiol Methods ; 168: 105801, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31811904

RESUMO

The species Karenia mikimotoi is a common nearshore red tide alga that can secrete hemolytic exotoxin and ichthyotoxin, which can induce the death of fish and shellfish, causing severe economic losses. In this study, loop-mediated isothermal amplification (LAMP) was employed in combination with the lateral flow dipstick (LFD) visual detection method to establish the LAMP-LFD rapid detection method for K. mikimotoi. The internal transcribed spacer ITS1-5.8S-ITS2 of K. mikimotoi was used as the target sequence and was amplified with specific primers designed in this study. The results indicated that the amplification optimal reaction conditions for LAMP in this paper were for 20 min at 65 °C. Moreover, LAMP had excellent specificity, showing negative results for other common red tide causing algal species. In field samples, we successfully reduced the total time, with only 23 min needed from LAMP amplification to LFD result display, which was shorter than that of conventional PCR. Consequently, LAMP-LFD should be useful for rapid field detection of low-density K. mikimotoi and for the early prevention of red tide induced by such algae.


Assuntos
Cromatografia/métodos , Dinoflagelados/isolamento & purificação , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Baías , China , Cromatografia/instrumentação , Primers do DNA/genética , DNA Intergênico/genética , Dinoflagelados/genética , Proliferação Nociva de Algas , Sensibilidade e Especificidade
7.
Mol Cancer Res ; 17(10): 2015-2028, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31308149

RESUMO

Semaphorins are a large family of evolutionarily conserved morphogenetic molecules that are associated with repelling axonal guidance. Intriguingly, recent researches indicate that semaphorins are involved in cancer progression. Semaphorin 4C (SEMA4C) has long been considered a neuronal migration gene, but we detected that it is also highly expressed in many malignant human cancers. During an investigation of subcutaneous tumor models, we found that SEMA4C expression promoted tumor growth and progression. We discovered that SEMA4C was involved in maintaining tumor cell self-renewal, likely by regulating the p53 pathway. Inhibiting the expression of endogenous SEMA4C in tumor cells impaired growth and induced senescence and cell-cycle arrest in the G2-phase. In addition, we found that SEMA4C induced the production of angiogenin and colony-stimulating factor-1 (CSF-1) in tumor cells by activating the NF-κB pathway in a plexinB2-dependent manner. In conclusion, SEMA4C expression in breast cancer cells promotes cancer cell proliferation, macrophage recruitment, and angiogenesis. Thus, inhibition of SEMA4C activity may be a novel therapeutic strategy for human breast cancer. IMPLICATIONS: In breast cancer, therapeutic targeting of the SEMA4C pathway may prevent tumor growth, angiogenesis, metastasis, and progression.


Assuntos
Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Semaforinas/metabolismo , Células A549 , Adenofibroma/irrigação sanguínea , Adenofibroma/genética , Adenofibroma/metabolismo , Adenofibroma/patologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Células HT29 , Células HeLa , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Proteínas do Tecido Nervoso/metabolismo , Semaforinas/biossíntese , Semaforinas/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
8.
Zhongguo Dang Dai Er Ke Za Zhi ; 20(7): 529-533, 2018 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-30022752

RESUMO

This article reports the results of tandem mass spectrometry and the mutation features of the ETFDH gene for an infant with multiple acyl-CoA dehydrogenase deficiency. The results of tandem mass spectrometry showed that C14 : 1, C8, C6, C10, and C12 increased. Exon sequencing was performed on this infant and his parents and revealed double heterozygous mutations in the ETFDH gene of the infant: c.992A>T and c.1450T>C. The former was inherited from his mother, and the latter was inherited from his father. c.1450T>C was shown to be the pathogenic mutation in the HGMD database. PolyPhen2, SIFT, and PROVEAN all predicted that the novel mutation c.992A>T might be pathogenic, and the mutant amino acids were highly conserved across various species. The findings expand the mutation spectrum of the ETFDH gene, and provide molecular evidence for the etiological diagnosis of the patient with multiple acyl-CoA dehydrogenase deficiency as well as for the genetic counseling and prenatal diagnosis in the family.


Assuntos
Flavoproteínas Transferidoras de Elétrons/genética , Proteínas Ferro-Enxofre/genética , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Sequência de Bases , Éxons , Humanos , Recém-Nascido , Masculino , Deficiência Múltipla de Acil Coenzima A Desidrogenase/enzimologia , Mutação
9.
Int J Oncol ; 50(5): 1693-1700, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28393199

RESUMO

SMAD4 is a critical co-smad in signal transduction pathways activated in response to transforming growth factor-ß (TGF-ß)-related ligands, regulating cell growth and differentiation. The roles played by SMAD4 inactivation in tumors highlighted it as a tumor-suppressor gene. Herein, we report that loss of SMAD4 expression in vascular endothelial cells promotes ovarian cancer invasion. SiRNA transfer of this gene in the HUVEC reduced SMAD4 protein expression and function. Although it reduced the vessel endothelial cell tubule formation in vitro and in vivo, it did not affect the tumor growth significantly in vivo. However, it weakened the barrier integrity in endothelial cells and increased vessel permeability and the ovarian cancer liver metastasis. We documented reduced angiogenesis and increased invasion histologically and by intravital microscopy, and gained mechanistic insight at the messenger and gene level. Finally, we found a negative reciprocal regulation between SMAD4 and FYN. FYN is one of the Src family kinases (SFK), activation of which can cause dissociation of cell-cell junctions and adhesion, resulting in paracellular hypermeability. Upon SMAD4 deletion, we detected high expression levels of FYN in vessel endothelial cells, suggesting the mechanism of the ovarian tumor cells cross the endothelial barrier and transform to an invasive phenotype.


Assuntos
Neoplasias Hepáticas/genética , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas c-fyn/biossíntese , Proteína Smad4/biossíntese , Animais , Vasos Sanguíneos/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Células Endoteliais/patologia , Feminino , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-fyn/genética , Proteína Smad4/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Clin Cancer Res ; 23(1): 214-224, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27401250

RESUMO

PURPOSE: Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis. EXPERIMENTAL DESIGN: In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC). Gene expression levels and activity of signaling pathways were measured by real-time RT-PCR, ELISA, or immunoblotting. Lymphangiogenesis was assessed by IHC. Lymph node metastasis was measured using fluorescence imaging. The effects of SEMA4C on lymphangiogenesis in vitro were evaluated using migration assay and tube-formation assay of LECs. RESULTS: Tumor-associated LECs are molecularly and functionally different from their normal counterparts. In addition to expressing high levels of membrane-bound SEMA4C, tumor-associated LECs also produced soluble SEMA4C (sSEMA4C). Increased serum sSEMA4C was detected in patients with breast cancer and cervical cancer. Patients with metastasis had much higher levels of serum sSEMA4C. sSEMA4C promoted lymphangiogenesis by activating PlexinB2-ERBB2 signaling in LECs, and promoted the proliferation and migration of tumor cells by activating PlexinB2-MET signaling, thus promoting lymphatic metastasis. Although the SEMA4C signaling pathways differ between LECs and tumor cells, RHOA activation was necessary for the effects of SEMA4C in both types of cells. CONCLUSIONS: Tumor-associated LECs produce sSEMA4C to promote lymphatic metastasis of tumors. Our results suggest that SEMA4C and RHOA might be potential therapeutic targets, and that higher serum sSEMA4C could be a marker for breast cancer and cervical cancer. Clin Cancer Res; 23(1); 214-24. ©2016 AACR.


Assuntos
Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/metabolismo , Semaforinas/genética , Semaforinas/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Imuno-Histoquímica , Linfangiogênese , Metástase Linfática , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Camundongos Nus , Neoplasias/patologia , Receptor ErbB-2/metabolismo , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo
11.
Toxicol Lett ; 265: 131-139, 2017 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-27923599

RESUMO

Pegylated liposomal doxorubicin (PLD) has been approved to treat patients with various types of cancers because it rarely caused side effects, such as cardiotoxicity, in comparison to doxorubicin, but it frequently results in hand-foot syndrome (HFS). This may affect the quality of life and require a reduction in the PLD dose. The pathophysiology of HFS was not well understood. This study was aimed at exploring the mechanism of HFS induced by PLD. We compared the effects of different doses of PLD on the proliferation inhibition and apoptosis in vitro in HaCaT cells and analyzed the skin changes and skin cell DNA damage in vivo using a zebrafish model. The results suggested that very low doses of PLD show a proliferation inhibition (cell cycle arrest at G2/M phase) and an apoptosis phenotype characterized by the ATM/Chk/P53 pathway that mediates DNA damage in vitro in HaCaT cells. In addition, PLD enhanced zebrafish skin pigmentation from the head to the trunk and induced DNA damage (phospho-H2AX staining) and cell death in the skin of zebrafish. The results of the present study suggested potential applications to provide a better understanding of the apoptosis of PLD-treated skin cells and described a simple methodology for detecting a PLD-induced DNA damage response in zebrafish, which may be helpful in preventing and treating HFS.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA , Doxorrubicina/análogos & derivados , Síndrome Mão-Pé , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Síndrome Mão-Pé/etiologia , Síndrome Mão-Pé/genética , Síndrome Mão-Pé/metabolismo , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Polietilenoglicóis/toxicidade , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra
12.
Differentiation ; 92(4): 161-168, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27477184

RESUMO

Transforming growth factor-beta (TGF-beta) regulates cellular functions and plays key roles in development and carcinogenesis. Smad4 is the central intracellular mediator of TGF-beta signaling and plays crucial roles in tissue regeneration, cell differentiation, embryonic development, regulation of the immune system and tumor progression. To clarify the role of smad4 in development, we examined both the pattern of smad4 expression in zebrafish embryos and the effect of smad4 suppression on embryonic development using smad4-specific antisense morpholino-oligonucleotides. We show that smad4 is expressed in zebrafish embryos at all developmental stages examined and that embryonic knockdown of smad4 results in pericardial edema, decreased heartbeat and defects in the trunk structure. Additionally, these phenotypes were associated with abnormal expression of the two heart-chamber markers, cmlc2 and vmhc, as well as abnormal expression of three makers of myogenic terminal differentiation, mylz2, smyhc1 and mck. Furthermore, a notable increase in apoptosis was apparent in the smad4 knockdown embryos, while no obvious reduction in cell proliferation was observed. Collectively, these data suggest that smad4 plays an important role in heart and skeletal muscle development.


Assuntos
Diferenciação Celular/genética , Desenvolvimento Embrionário/genética , Desenvolvimento Muscular/genética , Proteína Smad4/genética , Proteínas de Peixe-Zebra/genética , Animais , Apoptose/genética , Miosinas Cardíacas/genética , Proliferação de Células/genética , Regulação da Expressão Gênica no Desenvolvimento , Coração/crescimento & desenvolvimento , Músculo Esquelético/crescimento & desenvolvimento , Cadeias Leves de Miosina/genética , Fator de Crescimento Transformador beta , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
13.
Virology ; 496: 28-34, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27240146

RESUMO

Enterovirus 71 (EV71) infection can cause severe diseases, and is becoming increasingly common in children. In the current study, we carried out yeast two-hybrid assays to screen human proteins that could interact with 3A protein of EV71. Human ß3 subunit of Na(+)/K(+)-ATPase (ATP1B3) protein was demonstrated to interact with the 3A protein of EV71. Although 3A protein had no effect on the expression of ATP1B3, EV71 infection resulted in elevated expression of ATP1B3 in RD cell line, both on messenger RNA (mRNA) and protein levels. Interestingly, knockdown of ATP1B3 could significantly increase the replication of EV71, whereas overexpression of ATP1B3 significantly suppressed the replication of EV71 in RD cells. Furthermore, we demonstrated that the expression of ATP1B3 could induce the production of type-I interferons. Our study demonstrated that ATP1B3 inhibit EV71 replication by enhancing the production of type-I interferons, which could act as a potential therapeutic target in EV71 infection.


Assuntos
Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Interferon Tipo I/biossíntese , ATPase Trocadora de Sódio-Potássio/metabolismo , Replicação Viral , Linhagem Celular , Células Cultivadas , Infecções por Enterovirus/genética , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Ligação Proteica , ATPase Trocadora de Sódio-Potássio/genética , Proteínas Virais/metabolismo
14.
Int J Clin Exp Med ; 8(9): 15018-29, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26628986

RESUMO

OBJECTIVE: This study was designed to evaluate the response, toxicity and survival of taxanes plus platinum (TP) and CPT-11plus platinum (CP) as neoadjuvant chemotherapies with previously untreated cervical cancer, and to identify prognostic risk factors in these patients. METHODS: A cohort study was performed to evaluate the result of TP and CP regimes in the treatment of cervical cancer patients. RESULTS: The study included 567 patients with locally advanced cervical cancer (LACC) staged as FIGO IB-IIB in our clinical departments. Clinical response was found in 76.1% and 78% of patients in the TP and CP arms, respectively, and no treatment-related deaths were reported. During the follow-up period, disease-free survival (DFS) and overall survival (OS) for the TP and CP arms were not different (P = 0.384 for DFS, P = 0.800 for OS). The CP regime showed higher survival rate for endophytic growth style (P = 0.013 for DFS, P = 0.027 for OS). The CP regime also showed higher DFS and OS for G2 tumor (P = 0.027 for DFS, P = 0.032 for OS). In multivariate cox's proportional hazards regression model, the average death rates were much greater in the non-responder group (HR, 2.68), in the older (> 44 years) group (HR, 2.51), and in the FIGO stage II b patients (HR, 2.84). CONCLUSIONS: The CP regime showed higher survival rate for endophytic growth style or G2 tumor. Clinical response, age and FIGO stage were independent prognostic risk factors in this study for both DFS and OS.

15.
J Huazhong Univ Sci Technolog Med Sci ; 35(5): 629-634, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26489613

RESUMO

Reports of BRCA2 genetic mutations on the prognosis of familial breast cancer (BC) patients have been contradictory. True difference in survival, if it exists, would have important implications for genetic counseling and in treatment of hereditary BC. The purpose of this study was to compare overall survival rate (OSR) among BRCA2 mutation carriers, non-carriers and sporadic BC patients. We searched the PUBMED and EMBASE databases and retrieved 4529 articles using keywords that included breast cancer, BRCA, prognosis and survival. Nine articles were selected for systematic review and among them 6 were included in our meta-analysis. We used the fixed and random effect models to calculate the summary odds ratio (OR) and corresponding 95% confidence interval (CI). BRCA2 mutation carriers had significantly higher long-term OSR than non-carriers (OR=0.69 [95% CI=0.5-0.95]), while both short-term and long-term OSR of BRCA2 mutation carriers did not differ from those of patients with sporadic disease (OR=1.11 [95% CI=0.74-1.65]; 0.85 [95% CI=0.38-1.94], respectively). For BC-specific survival rate (BCSSR), BRCA2 mutation carriers had a similar BCSSR to the non-carriers (OR=0.61 [95% CI=0.28-1.34]). There was no significant difference in disease-free survival (DFS) between BRCA2 mutation carriers and patients with sporadic disease. Our results suggest that BRCA2 mutation increases long-term OSR in hereditary BC, which reminds us a new prospect of management of the disease.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Predisposição Genética para Doença , Mutação , Neoplasias da Mama/patologia , Feminino , Expressão Gênica , Aconselhamento Genético , Humanos , Razão de Chances , Prognóstico , Análise de Sobrevida
16.
Am J Pathol ; 179(6): 2740-50, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21983072

RESUMO

Cigarette smoke activates the extracellular signal-regulated kinase (ERK) 1/2 mitogen activated-protein kinase pathway, which, in turn, is responsible for early growth response gene-1 (EGR-1) activation. Here we provide evidence that EGR-1 activation can also reactivate ERK 1/2 mitogen activated-protein kinase through a positive feedback loop through its target gene (geranylgeranyl diphosphate synthase) GGPPS. For the first time, the GGPPS gene is identified as a target of EGR-1, as EGR-1 can directly bind to the predicted consensus-binding site in the GGPPS promoter and regulate its transcription. Long-term observations show that there are two ERK 1/2 phosphorylation peaks after cigarette smoke extract stimulation in human lung epithelial Beas-2B cells. The first peak (at 10 minutes) is responsible for EGR-1 accumulation, and the second (at 4 hours) is diminished after the disruption of EGR-1 transcriptional activity. EGR-1 overexpression enhances Ras prenylation and membrane association in a GGPPS-dependent manner, and it augments ERK 1/2 activation. Likewise, a great reduction of the second peak of ERK 1/2 phosphorylation is observed during long-term cigarette smoke extract stimulation in cells where GGPPS is disrupted. Thus, we have uncovered an intricate positive feedback loop in which ERK 1/2-activated EGR-1 promotes ERK 1/2 reactivation through promoting GGPPS transcription, which might affect cigarette smoke-related lung pathological processes.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce/genética , Farnesiltranstransferase/genética , Sistema de Sinalização das MAP Quinases/genética , Prenilação/genética , Fumar/genética , Proteínas ras/metabolismo , Animais , Células Cultivadas , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Retroalimentação Fisiológica , Células HEK293 , Humanos , Camundongos , Camundongos Mutantes , Pneumonia/etiologia , RNA Interferente Pequeno/farmacologia , Fumaça , Fumar/efeitos adversos , Transcrição Genética
17.
Proc Natl Acad Sci U S A ; 108(17): 7058-63, 2011 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-21482757

RESUMO

Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-ß/bone morphogenetic protein (BMP) signaling. Alteration of these signaling pathways leads to lung malformation. We investigated the role of Follistatin-like 1 (Fstl1), a secreted follistatin-module-containing glycoprotein, in lung development. Deletion of Fstl1 in mice led to postnatal lethality as a result of respiratory failure. Analysis of the mutant phenotype showed that Fstl1 is essential for tracheal cartilage formation and alveolar maturation. Deletion of the Fstl1 gene resulted in malformed tracheal rings manifested as discontinued rings and reduced ring number. Fstl1-deficient mice displayed septal hypercellularity and end-expiratory atelectasis, which were associated with impaired differentiation of distal alveolar epithelial cells and insufficient production of mature surfactant proteins. Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin rescued pulmonary atelectasis of Fstl1-deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling.


Assuntos
Proteína Morfogenética Óssea 4/antagonistas & inibidores , Proteína Morfogenética Óssea 4/metabolismo , Proteínas Relacionadas à Folistatina/metabolismo , Alvéolos Pulmonares/embriologia , Transdução de Sinais/fisiologia , Animais , Proteína Morfogenética Óssea 4/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cartilagem/citologia , Cartilagem/embriologia , Linhagem Celular Tumoral , Proteínas Relacionadas à Folistatina/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Camundongos , Camundongos Knockout , Alvéolos Pulmonares/citologia , Surfactantes Pulmonares/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo , Traqueia/citologia , Traqueia/embriologia
18.
Am J Pathol ; 178(1): 110-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21224049

RESUMO

Early growth response 1 (EGR-1) contributes to the development of chronic obstructive pulmonary disease in the lungs of smokers by mediating pulmonary inflammatory responses, but the direct downstream genes of EGR-1 that regulate this process remain unknown. We show that a new EGR-1 target gene, geranylgeranyl diphosphate synthase (GGPPS), which controls protein prenylation, can regulate the proinflammatory function of EGR-1 by activating MAPK signaling. When C57BL/6 mice were exposed to cigarette smoke, EGR-1 and GGPPS levels increased in their lungs, and the inflammatory responses were augmented, whereas these effects could be reversed by the down-regulation of EGR-1 transcription activity. The accumulation of EGR-1 and GGPPS was induced by MAPK/ERK pathway activation when Beas-2B human bronchial epithelial cells were exposed to cigarette smoke extract (CSE). Further examination showed that EGR-1 in turn regulated Erk1/2 activity because inhibition of EGR-1 transcription activity decreased CSE-induced Erk1/2 phosphorylation. Furthermore, EGR-1-promoted Erk1/2 activation was dependent on GGPPS transcription. Knockdown of GGPPS expression with small-interfering RNA abolished the EGR-1-activated Erk1/2 activity. Both EGR-1 transcription inhibition and GGPPS expression knockdown decreased the inflammatory response induced by CSE in Beas-2B cells. Our results reveal a new EGR-1/GGPPS/MAPK signaling pathway that controls cigarette smoke-induced pulmonary inflammation, and this may shed light on our understanding of the mechanism of cigarette smoke-related pulmonary diseases such as chronic obstructive pulmonary disease.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Farnesiltranstransferase/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/efeitos adversos , Tabaco/efeitos adversos , Animais , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/patologia , Transdução de Sinais
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