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1.
Bioengineered ; 10(1): 425-436, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31564210

RESUMO

Stromal interaction molecule 1 (STIM1) is a calcium-sensing protein localized in the membrane of the endoplasmic reticulum. The expression of STIM1 has been shown to be closely associated with cell proliferation. The aim of the present study was to investigate the role of STIM1 in the regulation of cancer progression and its clinical relevance. The data demonstrated that the expression of the STIM1 was significantly higher in non-small-cell lung cancer (NSCLC) tissues than in benign lesions and was associated with advanced NSCLC T stage. Knockdown of STIM1 expression in NSCLC cell lines A549 and SK-MES-1 significantly inhibited cell proliferation and induces A549 and SK-MES-1 cell arrest at the G2/M and S phases of the cell cycle. Western blotting showed that the expression of cyclin-dependent kinase (CDK) 1 and CDK2 were reduced while knockdown of STIM1 expression. Furthermore, knockdown of STIM1 in NSCLC cells significantly reduced the levels of xenograft tumor growth in nude mice. These data indicate that aberrant expression of the STIM1 protein may contribute to NSCLC progression. Future studies should focus on targeting STIM1 as a novel strategy for NSCLC therapy.

2.
Org Lett ; 21(9): 3265-3270, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30986070

RESUMO

A traceless ß-mercaptan-assisted α-selective ligation of N-terminal lysine-containing peptides has been developed. In this ligation-desulfurization-based protocol, the ε-amine of lysine is free of protection, thus improving the overall synthetic efficiency and avoiding harsh reactions in preparing large peptides and proteins. The applicability of this methodology has been demonstrated in the synthesis of an acid-labile therapeutic protein, interferon gamma, and the anticancer activity of synthetic protein has also been evaluated.


Assuntos
Antineoplásicos/síntese química , Interferon gama/síntese química , Lisina/química , Aminas/química , Antineoplásicos/farmacologia , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Interferon gama/farmacologia , Conformação Proteica , Técnicas de Síntese em Fase Sólida , Compostos de Sulfidrila/química
3.
Chem Commun (Camb) ; 55(2): 253-256, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30534737

RESUMO

We describe the preparation of a cancer vaccine candidate by conjugating a MUC1 peptide antigen to the ß-glucan polysaccharide, which serves both as a carrier and an immune activator. In contrast to amorphous polysaccharides, peptide-ß-glucan conjugates form uniform nanoparticles that facilitate the delivery of antigens and binding to myeloid cells, thus leading to the activation of both innate and adaptive immunity.


Assuntos
Adenocarcinoma/imunologia , Vacinas Anticâncer/imunologia , Portadores de Fármacos/química , Mucina-1/imunologia , Fragmentos de Peptídeos/imunologia , beta-Glucanas/química , Imunidade Adaptativa/imunologia , Sequência de Aminoácidos , Animais , Vacinas Anticâncer/síntese química , Vacinas Anticâncer/química , Humanos , Imunidade Ativa/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Interferon gama/metabolismo , Interleucina-6/metabolismo , Células MCF-7 , Camundongos Endogâmicos C57BL , Mucina-1/química , Fragmentos de Peptídeos/química , Vacinas de Subunidades/síntese química , Vacinas de Subunidades/química , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia
4.
Org Lett ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30451505

RESUMO

The cypemycin decarboxylase CypD is investigated by using a synthetic oligopeptide, which contains the to-be-cyclized dehydroalanine (Dha) residue. It was shown that CypD efficiently catalyzes the decarboxylation of this Dha-containing peptide, but the expected AviCys ring is not formed in the product, suggesting that CypD alone is not enough to form the AviCys ring. It was also shown that the Dha-containing peptide is a better substrate than two similar peptides with a Ser or a Cys residue, supporting that, in cypemycin biosynthesis, Dha formation is prior to decarboxylation of the C-terminal Cys.

5.
Chem Sci ; 9(7): 1940-1946, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29675240

RESUMO

Peptidyl thioesters or their surrogates with C-terminal ß-branched hydrophobic amino acid residues usually exhibit poor reactivities in ligation reactions. Thus, activation using exogenous additives is required to ensure an acceptable reaction efficiency. Herein, we report a traceless ligation at Val-Xaa sites under mild thiol additive-free reaction conditions, whereby the introduction of ß-mercaptan on the C-terminal valine residue effectively activates the otherwise unreactive N-acyl-benzimidazolinone (Nbz), and enables the use of a one-pot ligation-desulfurization strategy to generate the desired peptide products. The orthogonality between ß-thiovaline-Nbz and a conventional alkyl thioester, as well as the convenient access to the former from readily available penicillamine, also allowed expedited assembly of the peptidic hormone ß-LPH and hPTH analogues, based on a kinetically controlled one-pot three-segment ligation and desulfurization strategy.

6.
BMC Cancer ; 17(1): 884, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29268708

RESUMO

BACKGROUND: The primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim. METHODS: The patients were treated with the vaccine at 1 × 106, 1 × 107and the maximum dose 8 × 107 at day 7, 14, and 21 after characterization of the vaccine phenotype by flow cytometry. The safety of the vaccine was assessed by adverse events, and the efficacy by the levels of several specific tumor markers and the patient quality of life. RESULTS: The vaccine was well tolerated without dose-limiting toxicity even at higher doses. The most common adverse event reported was just grade 1 flu-like symptoms without unanticipated or serious adverse event. A significant decrease in CD3 + CD4 + CD25 + Foxp3+ T regulatory (Treg) cell number and increase in TNF-α and IL-6 were observed in two patients. Two patients showed 15% and 64% decrease in carcino-embryonic antigen and CYFRA21, respectively. The vaccination with the maximum dose significantly improved the patients'quality of life when administered at the highest dose. More importantly, in the long-term follow-up until February 17, 2017, 1 patient had no recurrence, 1 patients had a progressive disease (PD), and 1 patient was died in the low dose group. In the middle dose group, all 3 patients had no recurrence. In the high dose group, 1 patient was died, 1 patient had a PD, and the other 7 patients had no recurrence. CONCLUSIONS: We provide preliminary data on the safety and efficacy profile of a novel vaccine against non-small cell lung cancer, which was reasonably well tolerated, induced modest antitumor activity without dose-limiting toxicity, and improved patients' quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence. Our findings on the safety and efficacy of the vaccine in this phase I trial warrant future phase II/III clinical trial.


Assuntos
Vacinas Anticâncer/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/prevenção & controle , Células Dendríticas/imunologia , Neoplasias Pulmonares/prevenção & controle , Qualidade de Vida , Adenocarcinoma/imunologia , Adenocarcinoma/prevenção & controle , Adenocarcinoma/secundário , Adolescente , Adulto , Idoso , Autoantígenos , Carcinoma de Células Grandes/imunologia , Carcinoma de Células Grandes/prevenção & controle , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/prevenção & controle , Carcinoma de Células Escamosas/secundário , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Vacinação , Adulto Jovem
7.
Med Sci Monit ; 22: 3113-23, 2016 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-27587310

RESUMO

BACKGROUND Transplantation with allogeneic cells has become a promising modality for cancer therapy, which can induce graft-versus-tumor (GVT) effect. This study was aimed at assessing the safety, efficacy, and tissue type GVT (tGVT) response of transplantation with allogeneic skin tumors to treat chemically-induced skin tumors in mice. MATERIAL AND METHODS FVB/N and ICR mice were exposed topically to chemicals to induce skin tumors. Healthy ICR mice were transplanted with allogeneic skin tumors from FVB/N mice to test the safety. The tumor-bearing ICR mice were transplanted with, or without, allogeneic skin tumors to test the efficacy. The body weights (BW), body condition scores (BCS), tumor volumes in situ, metastasis tumors, overall survival, and serum cytokines were measured longitudinally. RESULTS Transplantation with no more than 0.03 g allogeneic skin tumors from FVB/N mice to healthy ICR mice was safe. After transplantation with allogeneic skin tumors to treat tumor-bearing mice, it inhibited the growth of tumors slightly at early stage, accompanied by fewer metastatic tumors at 24 days after transplantation (21.05% vs. 47.37%), while there were no statistically significant differences in the values of BW, BCS, tumor volumes in situ, metastasis tumors, and overall survival between the transplanted and non-transplanted groups. The levels of serum interleukin (IL)-2 were significantly reduced in the controls (P<0.05), but not in the recipients, which may be associated with the tGVT response. CONCLUSIONS Our results suggest that transplantation with allogeneic skin tumors is a safe treatment in mice, which can induce short-term tGVT response mediated by IL-2.


Assuntos
Efeito Enxerto vs Tumor/imunologia , Transplante de Neoplasias/imunologia , Transplante de Neoplasias/métodos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Animais , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/terapia , Feminino , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Distribuição Aleatória , Transplante Homólogo/métodos
8.
J Am Chem Soc ; 138(14): 4890-9, 2016 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-26982082

RESUMO

Prolyl thioesters have shown significantly lower reactivities in native chemical ligation (NCL) in comparison to that of the alanyl thioester. This report describes a mild and efficient internal activation protocol of peptidyl prolyl thioesters in NCL without using any thiol-based additives, where the introduction of a 4-mercaptan substituent on the C-terminal proline significantly improves the reactivity of prolyl thioesters via the formation of a bicyclic thiolactone intermediate. The kinetic data indicate that the reaction rate is comparable to that of the reported data of alanyl thioesters, and the mechanistic studies suggest that the ligation of two peptide segments proceeds through an NCL-like pathway instead of a direct aminolysis, which ensures the chemoselectivity and compatibility of various amino acid side chains. This 4-mercaptoprolyl thioester-based protocol also allows an efficient one-pot ligation-desulfurization procedure. The utility of this method has been further demonstrated in the synthesis of a proline-rich region of Wilms tumor protein 1.


Assuntos
Peptídeos/química , Prolina/química , Compostos de Sulfidrila/química , Aminoácidos/química , Cinética , Proteínas WT1/química
9.
Am J Pathol ; 185(9): 2412-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26362716

RESUMO

Gastric cancer is one of the most common malignancies in developing countries. We examined the possible role of miR-506 in gastric cancer, investigated its associations with the clinical outcomes of gastric cancer patients, and explored its potential role in angiogenesis and the metastasis of gastric cancer cells. We found that miR-506 expression was a useful marker for stratifying patients from early to advanced clinical stages and for overall survival prediction. miR-506 overexpression inhibited the epithelial-to-mesenchymal transition of gastric cancer cells; however, depletion of miR-506 promoted it. In addition, miR-506 suppressed gastric cancer angiogenesis and was associated with decreased matrix metalloproteinase-9 expression. We also found that ETS1 was a miR-506 target, and it was expressed in 71.10% of gastric cancer tissue samples. Moreover, ETS1 expression was associated with matrix metalloproteinase-9 expression (P < 0.001). In conclusion, miR-506 was identified as an ETS1 targeting suppressor of metastatic invasion and angiogenesis in gastric cancer.


Assuntos
Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/patologia
10.
Oncotarget ; 6(13): 10964-77, 2015 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-25844602

RESUMO

The Wnt/ß-catenin signalling pathway is known to play a vital role in the maintenance of cancer stem cells (CSCs), which are reported to be the origin of malignant cancers, and result in poor prognosis of multiple kinds of cancer. Therefore, it is of great importance to illuminate the mechanism by which the Wnt/ß-catenin pathway regulates the cancer stem cell-like traits in cancers. Here, we report that miR-942 is significantly upregulated in esophageal squamous cell carcinoma (ESCC), and miR-942 levels are associated with poor prognosis in ESCC patients. Overexpression of miR-942 promotes, whereas inhibition of miR-942 decreases, the tumor sphere formation, the CD90+ subpopulation cells and the expression of pluripotency associated markers. Moreover, in vivo assay shows that miR-942 overexpressing cells form larger tumors and display higher tumourigenesis. Furthermore, we demonstrate that miR-942 upregulates the Wnt/ß-catenin signaling activity via directly targeting sFRP4, GSK3ß and TLE1, which are multiple level negative regulators of the Wnt/ß-catenin signaling cascade. In addition, our results indicate that c-myc directly binds to the miR-942 promoter and promotes its expression. Taken together, our findings establish an oncogenic role of miR-942 in ESCC and indicate that miR-942 might be an effective therapeutic target for ESCC.


Assuntos
Carcinoma de Células Escamosas/secundário , Transformação Celular Neoplásica/patologia , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Via de Sinalização Wnt/genética , Animais , Apoptose , Western Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Proliferação de Células , Células Cultivadas , Imunoprecipitação da Cromatina , Estudos de Coortes , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Esôfago/metabolismo , Esôfago/patologia , Citometria de Fluxo , Humanos , Metástase Linfática , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Hematol Oncol ; 8: 22, 2015 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-25887760

RESUMO

BACKGROUND: During tumor formation and expansion, increasing glucose metabolism is necessary for unrestricted growth of tumor cells. Expression of key glycolytic enzyme alpha-enolase (ENO1) is controversial and its modulatory mechanisms are still unclear in non-small cell lung cancer (NSCLC). METHODS: The expression of ENO1 was examined in NSCLC and non-cancerous lung tissues, NSCLC cell lines, and immortalized human bronchial epithelial cell (HBE) by quantitative real-time reverse transcription PCR (qRT-PCR), immunohistochemistry, and Western blot, respectively. The effects and modulatory mechanisms of ENO1 on cell glycolysis, growth, migration, invasion, and in vivo tumorigenesis and metastasis in nude mice were also analyzed. RESULTS: ENO1 expression was increased in NSCLC tissues in comparison to non-cancerous lung tissues. Similarly, NSCLC cell lines A549 and SPCA-1 also express higher ENO1 than HBE cell line in both mRNA and protein levels. Overexpressed ENO1 significantly elevated NSCLC cell glycolysis, proliferation, clone formation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo by regulating the expression of glycolysis, cell cycle, and epithelial-mesenchymal transition (EMT)-associated genes. Conversely, ENO1 knockdown reversed these effects. More importantly, our further study revealed that stably upregulated ENO1 activated FAK/PI3K/AKT and its downstream signals to regulate the glycolysis, cell cycle, and EMT-associated genes. CONCLUSION: This study showed that ENO1 is responsible for NSCLC proliferation and metastasis; thus, ENO1 might serve as a potential molecular therapeutic target for NSCLC treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ligação a DNA/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Neoplasias Pulmonares/patologia , Fosfopiruvato Hidratase/metabolismo , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Glicólise/fisiologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Transfecção
12.
Autoimmunity ; 47(1): 46-56, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24191684

RESUMO

BACKGROUND: The development of protocols for the ex vivo generation of dendritic cells (DCs) has led to intensive research into their potential use in immunotherapy in the treatment of cancer. In this study, we examined the efficacy of dendritic cell-tumor cell fusion hybrid vaccines in eliciting an immune response against Lewis lung carcinoma (LLC) cells, as compared to other types of tumor vaccines. In addition, we also tested whether the efficacy of the vaccines was affected by the route of administration. Four different tumor vaccines were compared: (1) HC (hybrid cell), consisting of DC/LLC hybrids; (2) DC+LLC (DCs pulsed with apoptotic LLCs); (3) DC without antigen loading/pulsing; (4) LLC (apoptotic/irradiated tumor cells). We also compared four different routes of administration for each vaccine: (1) Preimmunization; (2) Vaccination therapy; (3) Adoptive immunotherapy; (4) Vaccination therapy combined with adoptive immunotherapy. Anti-tumor immunity was assessed in vivo and the CTL (cytotoxic T lymphocyte) response as well as the expression of key cytokines, IFN-γ and IL-10 were further evaluated using in vitro assays. RESULTS: Our data demonstrate that vaccination with HC hybrids provides more effective anti-tumor protective immunity and significantly greater therapeutic immunity than vaccination with DC+LLC, DC or LLC. Most remarkably, vaccination therapy with HC hybrids was more successful than combination (vaccination + adoptive) therapy for the induction of anti-tumor responses. Splenocytes harvested from mice immunized with HC hybrids demonstrated the greatest cytotoxic T lymphocyte (CTL) activity and their production of IFN-γ was high, while their production of IL-10 was very low. CONCLUSIONS: Our results suggest that vaccination therapy with DC-tumor cell fusion hybrids provides more effective protection against lung cancer.


Assuntos
Vacinas Anticâncer/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Células Dendríticas/imunologia , Células Híbridas/imunologia , Animais , Carcinoma Pulmonar de Lewis/mortalidade , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Lewis/terapia , Linhagem Celular Tumoral , Terapia Combinada , Células Dendríticas/metabolismo , Feminino , Células Híbridas/metabolismo , Imunoterapia Adotiva , Camundongos , Carga Tumoral
13.
Science ; 342(6164): 1357-1360, 2013 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-24337294

RESUMO

Erythropoietin is a signaling glycoprotein that controls the fundamental process of erythropoiesis, orchestrating the production and maintenance of red blood cells. As administrated clinically, erythropoietin has a polypeptide backbone with complex dishomogeneity in its carbohydrate domains. Here we describe the total synthesis of homogeneous erythropoietin with consensus carbohydrate domains incorporated at all of the native glycosylation sites. The oligosaccharide sectors were built by total synthesis and attached stereospecifically to peptidyl fragments of the wild-type primary sequence, themselves obtained by solid-phase peptide synthesis. The glycopeptidyl constructs were joined by chemical ligation, followed by metal-free dethiylation, and subsequently folded. This homogeneous erythropoietin glycosylated at the three wild-type aspartates with N-linked high-mannose sialic acid-containing oligosaccharides and O-linked glycophorin exhibits Procrit-level in vivo activity in mice.


Assuntos
Eritropoetina/administração & dosagem , Eritropoetina/síntese química , Sequência de Aminoácidos , Animais , Ácido Aspártico/química , Células Cultivadas , Sequência Consenso , Relação Dose-Resposta a Droga , Contagem de Eritrócitos , Eritropoetina/química , Glicoforina/química , Glicosilação , Injeções Subcutâneas , Manose/química , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Ácido N-Acetilneuramínico/química , Oligossacarídeos/química , Reticulócitos/efeitos dos fármacos
14.
Angew Chem Int Ed Engl ; 52(30): 7646-65, 2013 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-23775885

RESUMO

The total synthesis of a homogeneous erythropoietin (EPO), possessing the native amino acid sequence and chitobiose glycans at each of the three wild-type sites of N glycosylation, has been accomplished in our laboratory. We provide herein an account of our decade-long research effort en route to this formidable target compound. The optimization of the synergy of the two bedrock sciences we now call biology and chemistry was central to the success of the synthesis of EPO.


Assuntos
Eritropoetina/síntese química , Eritropoetina/metabolismo , Polissacarídeos/metabolismo , Sequência de Aminoácidos , Glicosilação , Dados de Sequência Molecular , Estrutura Molecular
15.
J Am Chem Soc ; 134(48): 19782-7, 2012 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-23110297

RESUMO

A rhodium-catalyzed dehydrogenation protocol for the conversion of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones has been developed. With this protocol, analogues of the cytotoxic agent chamaecypanone C have been synthesized via Diels-Alder cycloaddition between the cyclopentadienones and in situ-generated o-quinols. Biological evaluation of these analogues revealed a compound with higher activity as a microtubule inhibitor and cytotoxic agent in comparison with the parent structure.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Ciclopentanos/química , Ciclopentanos/farmacologia , Ródio/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Compostos Bicíclicos com Pontes/química , Catálise , Microtúbulos/efeitos dos fármacos , Estrutura Molecular , Moduladores de Tubulina/química
19.
J Am Chem Soc ; 134(8): 3912-6, 2012 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-22332757

RESUMO

Application of native chemical ligation logic to the case of an N-terminal proline is described. Two approaches were studied. One involved incorporation of a 3R-substituted thiyl-proline derivative. Improved results were obtained from a 3R-substituted selenol function, incorporated in the context of an oxidized dimer.


Assuntos
Prolina/química , Eritropoetina/síntese química , Eritropoetina/química , Estrutura Molecular , Prolina/análogos & derivados , Estereoisomerismo
20.
Mol Diagn Ther ; 15(4): 211-9, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21913743

RESUMO

OBJECTIVE: This study was designed to analyze expression patterns of estrogen receptor (ER), human epidermal growth factor receptor-2 (HER2/ERBB2), and nonmetastatic protein 23 (NM23-H1/NME1) proteins in patients with invasive ductal carcinoma and different menopausal status to identify their relationships with axillary lymph node metastasis. MATERIALS AND METHODS: 213 pre-menopausal and 177 post-menopausal women diagnosed with invasive ductal carcinoma were evaluated for ER, HER2, and NM23-H1 protein expression by immunohistochemistry. When HER2 immunoreactivity was equivocal (category 2+), specimens were confirmed by fluorescence in situ hybridization. RESULTS: ER expression showed no correlation with menopausal status or lymph node metastasis (each p > 0.05). However, expression of ER was associated with negative expression of HER2 (r = -0.214, p < 0.05) and positive expression of NM23-H1 (r = 0.137, p < 0.05) in the pre-menopausal group. Over-expression of HER2 was correlated with menopausal status (r = -0.107, p < 0.05) and lymph node metastasis in the ER-negative post-menopausal group (r = 0.222, p < 0.05). NM23-H1 was associated with less lymph node metastasis in the ER-positive pre-menopausal group (r = -0.237, p < 0.05). CONCLUSION: Our results indicated that expression patterns of ER, NM23-H1, and HER2 in primary breast cancer lesions warn that cells might have metastatic potential, which could assist clinicians to provide a more accurate prognosis and tailor therapeutic management for individual patients.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Menopausa , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/secundário , Feminino , Genes erbB-2 , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Metástase Linfática , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptores Estrogênicos/genética
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