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1.
Chin J Physiol ; 64(4): 202-209, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34472451

RESUMO

Gamma-linolenic acid (GLA), a natural fatty acid obtained from oils of various vegetables and seeds, has been demonstrated as an anticancer agent. In this work, we investigated the anticancer effects of GLA on breast cancer BT-474 cells. GLA at 30 µM, a concentration reportedly within the range of circulating concentrations in clinical studies, caused apoptotic cell death. GLA caused an elevation in mitochondrial Ca2+ level and a decrease in mitochondrial membrane potential. GLA treatment depleted cyclopiazonic acid (CPA)-sensitive Ca2+ store and triggered substantial Ca2+ influx. Intracellular Ca2+ release triggered by GLA was suppressed by 3 µM xestospongin C (XeC, IP3 receptor-channel blocker) and 100 µM ryanodine (ryanodine receptor-channel blocker), suggesting that the Ca2+ release was via IP3 receptor-channel and ryanodine receptor-channel. Increased expressions of p-eIF2α and CHOP were observed in GLA-treated cells, suggesting GLA-treated cells had increased expressions of p-eIF2α and CHOP, which suggest endoplasmic reticulum (ER) stress. In addition, GLA elicited increased production of reactive oxygen species. Taken together, our results suggest a basal level of GLA induced apoptotic cell death by causing Ca2+ overload, mitochondrial dysfunction, Ca2+ store depletion, ER stress, and oxidative stress. This is the first report to show that GLA caused Ca2+ store depletion and ER stress. GLA-induced Ca2+ store depletion resulted from opening of IP3 receptor-channel and ryanodine receptor-channel.


Assuntos
Neoplasias da Mama , Ácido gama-Linolênico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Estresse Oxidativo , Ácido gama-Linolênico/metabolismo
2.
J Immunother Cancer ; 8(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32718986

RESUMO

PURPOSE: This randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC). METHODS: At 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety. RESULTS: Of 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5-10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3-11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74-1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3-17.6)) versus those with titers <1:160 (5.5 months (95% CI: 3.7-5.6); HR=0.52; p<0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer <1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%). CONCLUSION: AS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated.NCT01516307.

3.
Adv Cancer Res ; 147: 375-428, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593406

RESUMO

The discovery of the HER2 molecules has embarked a series of investigations on the efficacy and safety of different types of anti-HER2 therapies for treating breast cancer, with the clinical pathway requiring a more detailed, more precise, and more dynamics therapeutic approaches due to the heterogeneity of the disease. As the "do more" and "do less" approaches are becoming more important to personalize treatment for early HER2-positive breast cancer, recent advances aim at tackling the advanced stage of the disease by using novel therapeutic agents and combination strategies. There are also important points of consideration on prognosis and choice of therapies, including HER2 gene copy number, HER2 heterogeneity, tissue biomarkers, blood-based biomarkers, and HER2 mutation and its treatment. Altogether, these could potentially play a vital role in the journey of HER2-positive breast cancer patient to achieve greater survival benefit and potentially a cure for the disease.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Pesquisa Biomédica , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais
4.
Z Naturforsch C J Biosci ; 75(3-4): 65-73, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32092040

RESUMO

Intracellular polyamines such as spermine and spermidine are essential to cell growth in normal and especially in cancer cells. However, whether extracellular polyamines affect cancer cell survival is unknown. We therefore examined the actions of extracellular polyamines on breast cancer BT474 cells. Our data showed that spermine, spermidine, and putrescine decreased cell viability by apoptosis. These polyamines also elicited Ca2+ signals, but the latter were unlikely triggered via Ca2+-sensing receptor (CaSR) as BT474 cells have been demonstrated previously to lack CaSR expression. Spermine-elicited Ca2+ response composed of both Ca2+ release and Ca2+ influx. Spermine caused a complete discharge of the cyclopiazonic acid (CPA)-sensitive Ca2+ pool and, expectedly, endoplasmic reticulum (ER) stress. The Ca2+ influx pore opened by spermine was Mn2+-impermeable, distinct from the CPA-triggered store-operated Ca2+ channel, which was Mn2+-permeable. Spermine cytotoxic effects were not due to oxidative stress, as spermine did not trigger reactive oxygen species formation. Our results therefore suggest that spermine acted on a putative polyamine receptor in BT474 cells, causing cytotoxicity by Ca2+ overload, Ca2+ store depletion, and ER stress.


Assuntos
Neoplasias da Mama/metabolismo , Cálcio/metabolismo , Poliaminas/farmacologia , Receptores de Detecção de Cálcio/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Homeostase , Humanos , Putrescina/farmacologia , Espermidina/farmacologia , Espermina/farmacologia
5.
Cell Mol Life Sci ; 77(13): 2473-2482, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31894358

RESUMO

Voltage-gated K+ (Kv) channel opening repolarizes excitable cells by allowing K+ efflux. Over the last two decades, multiple Kv functions in the nervous system have been found to be unrelated to or beyond the immediate control of excitability, such as shaping action potential contours or regulation of inter-spike frequency. These functions include neuronal exocytosis and neurite formation, neuronal cell death, regulation of astrocyte Ca2+, glial cell and glioma proliferation. Some of these functions have been shown to be independent of K+ conduction, that is, they suggest the non-canonical functions of Kv channels. In this review, we focus on neuronal or glial plasmalemmal Kv channel functions which are unrelated to shaping action potentials or immediate control of excitability. Similar functions in other cell types will be discussed to some extent in appropriate contexts.


Assuntos
Neuroglia/metabolismo , Neurônios/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Potenciais de Ação , Apoptose , Astrócitos/metabolismo , Cálcio/metabolismo , Movimento Celular , Proliferação de Células , Exocitose , Glioma/patologia , Neuritos/fisiologia , Neuroglia/citologia
6.
Future Oncol ; 15(28): 3243-3253, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432689

RESUMO

Aim: To evaluate the safety and efficacy of neratinib-based therapy in Asian patients with HER2-positive metastatic breast cancer (MBC). Patients & methods: We performed a pooled analysis of seven early-phase studies of neratinib given either as monotherapy or in combination with chemotherapeutic agents or trastuzumab in patients with advanced solid tumors. Results: A total of 793 patients with HER2-positive MBC were included in the efficacy analysis (Asia: 271 patients; other regions: 522 patients). The overall response rate in patients from Asia was 66.4% (180/271) and the median progression-free survival was 55.6 weeks. The most common adverse event in patients from Asia was diarrhea (all-grade: 96.3%; grade 3: 27.4%). Conclusion: Neratinib-based therapy is safe and effective in patients with HER2-positive MBC from Asia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Guias de Prática Clínica como Assunto/normas , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Quinolinas/administração & dosagem , Taxa de Sobrevida , Trastuzumab/administração & dosagem , Adulto Jovem
7.
Naunyn Schmiedebergs Arch Pharmacol ; 392(4): 427-436, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30547225

RESUMO

ATP depletion induced by inhibiting glycolysis or mitochondrial ATP production has been demonstrated to cause cancer cell death. Whether ATP depletion can enhance the efficacy and potency of anti-cancer effects of herbal compounds is so far unknown. We examined the enhancing effect of ATP depletion on anti-cancer actions of tetrandrine (TET) in human lung carcinoma A549 cells. A 24-h incubation of A549 cells with tetrandrine caused a concentration-dependent cytotoxic effect (LC50 = 66.1 µM). Co-incubation with 20 mM 2-deoxyglucose (2-DG, glycolysis inhibitor) caused only a very slight enhancement of tetrandrine cytotoxicity. By contrast, inhibiting mitochondrial ATP production with oligomycin (10 µM, ATP synthase inhibitor) and FCCP (30 µM, uncoupling agent) (thus, oligo-FCCP) on its own caused only slight cell cytotoxicity but strongly potentiated tetrandrine cytotoxicity (tetrandrine LC50 = 15.6 µM). The stronger enhancing effect of oligo-FCCP than 2-DG on TET toxicity did not result from more severe overall ATP depletion, since both treatments caused a similar ATP level suppression. Neither oligo-FCCP nor 2-DG synergized with tetrandrine in decreasing mitochondrial membrane potential. TET on its own triggered reactive oxygen species (ROS) production, and oligo-FCCP, but not 2-DG, potentiated TET in causing ROS production. Taken together, our results suggest that inhibiting ATP production from mitochondria, but not from glycolysis, appears to be a very effective means in augmenting TET-triggered ROS production and hence toxicity in A549 cells.


Assuntos
Trifosfato de Adenosina/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Benzilisoquinolinas/farmacologia , Mitocôndrias/efeitos dos fármacos , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Endocr Relat Cancer ; 25(2): 123-130, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29158285

RESUMO

The purpose of the study was to test the efficacy of neoadjuvant palbociclib therapy and to evaluate its impact on cell cycle arrest and changes in EndoPredict (EP) scores before and after treatment. Postmenopausal women with histologically proven ER+ve, HER2-ve invasive breast cancer, 2 cm or greater, were enrolled in an open-label, single-arm study. Twenty eligible patients were given letrozole 2.5 mg per day together with palbociclib 125 mg per day for 3 out of 4 weeks in repeated cycles for 16 weeks (4 cycles) before surgery. The primary end points were clinical response rates (cRR) and preoperative endocrine prognostic index (PEPI). The secondary end points were pathologic response and gene expression testing with EP test on collected tumor samples. The following results were obtained. 17 patients showed a clinical response of 50% or more, including 8 complete responses and 9 partial responses. There was significant reduction in area (P < 0.0001) and volume (P = 0.017) of the cancer. Pathologic complete response (pCR) was achieved in one patient; all cancers were downgraded after treatment. Ki67 (P = 0.044) and EP scores (P < 0.0001) were significantly reduced after treatment. Analysis of the relative gene expression levels showed that all proliferative genes, IL6ST and RBBP8 were decreased after palbociclib treatment. 6 patients with intermediate and three patients with high PEPI risk scores were found to have low EPclin scores. All patients with high PEPI relapse risk score had high EPclin score. In conclusion, effective clinical response was demonstrated by neoadjuvant letrozole in combination with palbociclib. Compared with PEPI, EPclin might be a better parameter to estimate prognosis after neoadjuvant therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptores de Estrogênio , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
9.
Future Oncol ; 11(9): 1297-300, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25952777

RESUMO

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Medicina de Precisão , Gerenciamento Clínico , Feminino , Humanos
10.
Future Oncol ; 11(9): 1301-5, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25952778

RESUMO

Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Medicina de Precisão , Gerenciamento Clínico , Feminino , Humanos
11.
Int J Biol Markers ; 30(2): e252-3, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25684439

RESUMO

A therapeutic strategy, biomarker-driven and response-guided approach has been investigated in cancer therapy where the treatment targets heterogeneous and unstable disease. Neoadjuvant chemotherapy, for instance, is indicated based on tumor stage and subtype and its therapeutic outcomes like pathological responses are associated with the long-term prognostic probability in subgroups such as hormone receptor (HR) negative and HR-positive patients with high-grade cancers. Therefore, it would be reasonable to consider a treatment plan according to the short-time response in the stratified subgroups. It is also applicable for new therapy development, and in fact many clinical trials are under investigation in the post-neoadjuvant setting. In order to increase the therapeutic efficacy, it is recognized as necessary to incorporate biomarkers that enable us to classify conventional subtypes further including genetic mutations and epigenetic phenotypes into the planning of treatment. It is also crucial to analyze tumor biology particularly tumor evolution in the metastasis and the clonal selection by the treatment in these clinical settings.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Humanos , Prognóstico
12.
Int J Biol Markers ; 29(4): e380-6, 2014 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-25385240

RESUMO

BACKGROUND: This retrospective study investigated the therapeutic benefit of adjuvant endocrine therapy (ET) in breast cancer patients with hormone receptor (HR) status change from positive to negative after neoadjuvant chemotherapy (NAC). METHODS: From December 2000 to November 2010, 97 eligible patients with a positive-to-negative switch of HR status after NAC were identified. All patients were categorized into 2 groups on the basis of the administration of ET: 57 ET-administered patients and 40 ET-naïve patients. Survival analyses were performed to examine the prognostic value of ET administration as well as other clinical and pathologic variables. RESULTS: The administration of ET was significantly associated with improved disease-free survival (p=0.018) in patients with a positive-to-negative switch of HR status. The 5-year disease-free survival rates were 77.0% and 55.5%, respectively, in ET-administered patients and ET-naïve patients. The 5-year overall survival rate for ET-administered patients was also higher than that of ET-naïve patients (81.3% vs. 72.7%, p=0.053), albeit this was statistically insignificant. CONCLUSIONS: This study revealed that patients with HR altered from positive to negative after NAC still benefit from ET. The HR status should be evaluated not only in specimens obtained during post-NAC surgery but also in specimens biopsied before NAC.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos
13.
Int J Biol Markers ; 29(4): e440-4, 2014 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-25385242

RESUMO

We describe a case of postradiation chondrosarcoma after basal cell carcinoma treatment. At the time he presented, the patient was a 35-year-old man who had received radiotherapy at a dose of 70 Gy for 8 weeks. Six months after radiation treatment, a rapidly growing mass at the upper right alveolar ridge of the gums, where radiation had been given, was diagnosed as chondrosarcoma. Generally, chondrosarcoma occurs after a latency period of several years following radiation. However, there are a few relevant reports indicating that maxillofacial chondrosarcoma can develop after radiotherapy for basal cell carcinoma, with a short latency of 6 months. We hypothesize that the dosage and treatment time of radiation may have played a role in the opening/closing of the Hh-signaling pathway in the case of this patient.


Assuntos
Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Ossos Faciais/patologia , Neoplasias Induzidas por Radiação/patologia , Adulto , Neoplasias Ósseas/cirurgia , Carcinoma Basocelular/patologia , Carcinoma Basocelular/radioterapia , Condrossarcoma/cirurgia , Ossos Faciais/efeitos da radiação , Humanos , Masculino , Neoplasias Induzidas por Radiação/cirurgia
14.
Int J Biol Markers ; 29(4): e411-22, 2014 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-25362936

RESUMO

BACKGROUND: Among all neurological tumors, tumor incidence of the neuroepithelial tissue is the highest, where 50% are gliomas. Treatment for gliomas has traditionally included surgery and adjuvant therapy. With advancements in medicine, gene therapy has entered the clinical setting, in which control of tumor growth, tumor volume and decrease of supply of blood to the tumor have been observed. Rat hyperplasia suppressor gene (rHSG) has been proven to inhibit the injury-mediated proliferation of vascular smooth muscle cells. METHODS: A recombinant adenovirus, Adv-rHSG-GFP, was constructed and characterized by in vitro and in vivo studies. The function of rHSG on cell proliferation was determined in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) exclusion assay and plate clone formation, while a C6/Sprague Dawley rat glioma model was established to observe the effect of rHSG in vivo. RESULTS: Overexpression of rHSG displayed a strong effect on suppressing C6 cells proliferation in vitro and growth of glioma in vivo, which suggests the use of rHSG as a possible treatment strategy for glioma. p21Cip1, p27Kip1 and proliferating cell nuclear antigen were found to be involved in the tumor suppression mechanism of rHSG. CONCLUSIONS: rHSG can markedly inhibit of the growth of rat glioma cells. The suppression mechanism of rHSG may be related to cell cycle regulation, which shows that rHSG is a potential therapeutic target of glioma tumor. This preclinical study supports a further in-depth study on the effect of rHSG on cell proliferation, migration and change in the extracellular matrix component of glioma cells.


Assuntos
Terapia Genética/métodos , Glioma/genética , Glioma/terapia , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Adenoviridae/genética , Animais , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , GTP Fosfo-Hidrolases , Células HEK293 , Humanos , Masculino , Músculo Liso Vascular/citologia , Antígeno Nuclear de Célula em Proliferação/genética , Ratos , Ratos Sprague-Dawley
15.
Int J Biol Markers ; 29(3): e208-14, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-25041782

RESUMO

OBJECTIVES: This study aimed to compare the epigenetic changes via hypermethylation status of TIMP-3, GSTP-1 and 14-3-3σ genes, between healthy subjects and patients with reversible chronic inflammatory disease, and between healthy subjects and patients with irreversible malignant disease, to highlight the genetic changes that occur in the progression from an inflammatory condition to irreversible genetic changes commonly observed in cancer patients. METHODS: DNA was extracted from the blood of 680 healthy subjects, and tissues and blood of 110 patients with chronic inflammation disease of the gums, as well as neoplastic tissues of 108 breast cancer patients. Methylation-specific polymerase chain reaction (PCR) for TIMP-3, GSTP-1 and 14-3-3σ was performed, and hypermethylation status was analyzed and compared between the 3 groups. RESULTS: The hypermethylation frequencies of TIMP-3 and GSTP-1 of reversible chronic inflammatory gum disease and the control group were similar, but both were significantly lower than those for malignant disease patients (p<0.0001). The methylation frequency of 14-3-3σ in chronic inflammatory gum disease was higher than in the cancer and control groups (p<0.0001). The methylation of CpG islands in TIMP-3 and GSTP-1 in chronic inflammation patients occurred as frequently as in the control group, but less frequently than in breast cancer patients. However, the epigenetic silencing of 14-3-3σ occurred more frequently in the chronic inflammation group than in cancer patients and healthy controls. CONCLUSIONS: The epigenetic silencing of 14-3-3σ might be essential for chronic inflammatory gum disease. The epigenetic changes presented in chronic inflammation patients might demonstrate an irreversible destruction in the tissues or organs similar to cancer.


Assuntos
Proteínas 14-3-3/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Metilação de DNA , Exorribonucleases/genética , Glutationa S-Transferase pi/genética , Inflamação/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Estudos de Casos e Controles , Doença Crônica , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Gengivite/genética , Humanos , Masculino , Pessoa de Meia-Idade
16.
Int J Biol Markers ; 29(3): e193-203, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-24803281

RESUMO

The two most important factors in tumor-stromal interactions are tumor-infiltrating lymphocytes (TIL) and neoangiogenesis (NAng). While changes of these parameters in responders of neoadjuvant chemotherapy (NCTx) have been reported, their correlation with pathological response in breast cancer (BC) patients treated with NCTx have not been described. We therefore evaluated alterations of the TIL subtypes ratio and alterations of NAng using the vasohibin-1-positive ratio (VPR) in BC patients during the course of NCTx. To this aim we used: (i) double immunohistochemistry of CD8 cytotoxic T cells and T regulatory cells (Treg) with Foxp3, determining the CD8+/Foxp3 ratio; (ii) immunostaining of CD31 and vasohibin-1, yielding the VPR, which reflects the NAng status. Changes between the CD8+/Foxp3 ratio and VPR before and after therapy were then correlated with the pathological response of the patients. A concomitant significant decrement of Foxp3 and NAng, represented by VPR, were detected only in NCTx pathological responders (p<0.001 and p=0.044, respectively). The CD8+/Foxp3 ratio increased in both responders and non-responders, but to greater extent in responders (p=0.02). The changes of VPR in the NCTx-treated group differed from those recorded for the patients treated with aromatase inhibitors and shown in our earlier study; this indicates that the reactions of the tumor-stromal interaction to therapy were different among different treatments in BC patients. Changes in Foxp3 and VPR in responders may reflect the dynamic activity of tumor stroma and host immune response to tumor antigens in the tumor microenvironment in response to the NCTx. VPR can be a potential surrogate marker in BC specimens for predicting the response to NCTx, incorporating both features of carcinoma and stromal cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/irrigação sanguínea , Carcinoma Ductal de Mama/tratamento farmacológico , Linfócitos do Interstício Tumoral/imunologia , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Ciclofosfamida/administração & dosagem , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Fatores de Transcrição Forkhead/imunologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Terapia Neoadjuvante , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/imunologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Células Estromais/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Taxoides/administração & dosagem , Microambiente Tumoral
17.
Lancet Oncol ; 15(5): 489-538, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24731404

RESUMO

Cancer is one of the major non-communicable diseases posing a threat to world health. Unfortunately, improvements in socioeconomic conditions are usually associated with increased cancer incidence. In this Commission, we focus on China, India, and Russia, which share rapidly rising cancer incidence and have cancer mortality rates that are nearly twice as high as in the UK or the USA, vast geographies, growing economies, ageing populations, increasingly westernised lifestyles, relatively disenfranchised subpopulations, serious contamination of the environment, and uncontrolled cancer-causing communicable infections. We describe the overall state of health and cancer control in each country and additional specific issues for consideration: for China, access to care, contamination of the environment, and cancer fatalism and traditional medicine; for India, affordability of care, provision of adequate health personnel, and sociocultural barriers to cancer control; and for Russia, monitoring of the burden of cancer, societal attitudes towards cancer prevention, effects of inequitable treatment and access to medicine, and a need for improved international engagement.


Assuntos
Neoplasias/terapia , Idoso , Idoso de 80 Anos ou mais , Alcoolismo/epidemiologia , Neoplasias da Mama/diagnóstico , China , Neoplasias Colorretais/diagnóstico , Características Culturais , Detecção Precoce de Câncer/tendências , Desenvolvimento Econômico/tendências , Poluição Ambiental/efeitos adversos , Grupos Étnicos , Feminino , Serviços de Saúde/economia , Acesso aos Serviços de Saúde/tendências , Mão de Obra em Saúde/tendências , Disparidades em Assistência à Saúde/tendências , Humanos , Índia , Masculino , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Neoplasias/prevenção & controle , Serviços de Saúde Rural/tendências , Federação Russa/epidemiologia , Sexismo , Fumar , Estigma Social , Serviços Urbanos de Saúde/tendências
18.
Arch Oral Biol ; 59(5): 513-23, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24632094

RESUMO

OBJECTIVES: This present study was designed to investigate the effects of Angiotensin II on mitochondrial functions, ROS generation and c-jun N-terminal kinases (JNK) signalling pathway-mediated cell apoptosis in mouse calvaria osteoblasts. METHODS: Calvaria osteoblast were isolated and cultured. The cells were separated into two groups-control and treated groups-where the latter was stimulated with angiotensin II (Ang II). Mitochondrial reactive oxygen species (ROS) and superoxide production were measured. Intracellular ATP levels were also detected. The cell proliferation rate was determined for the two groups. Protein production such as Anti-Bax, Bcl-2, COX IV and activation of c-jun N-terminal kinases signal (JNK) pathway was measured by enzyme-linked immunosorbent assay (ELISA) methods and Western blotting in this study. RESULTS: Ang II treated cells showed significantly higher levels of superoxide production compared to the control group (p<0.05). Conversely, Ang II induced inhibitory effects on mitochondrial respiratory enzyme complexes, cause membrane potential dissipation, ATP loss and promote ROS generation, cell apoptosis in cultured osteoblasts. In addition, JNK phosphorylations were involved in activating the mitochondria-dependent apoptotic pathway following Ang II stimulation, as pre-treatment of JNK-specific inhibitor SP600125 could rescue osteoblast cells from apoptosis by enhancing the anti-apoptotic protein Bcl-2 expressions, suppressing the translocation of Bax from cytosol into mitochondria, blocking cytochrome C release and caspase-3 activation. CONCLUSIONS: Ang II stimulates osteoblast apoptosis via suppression of the mitochondrial respiratory enzymes, membrane potential and cellular ATP productions. Clinical application with Ang II-stimulated osteoblast could be used for modelling or bone resorption in the oral region.


Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Osteoblastos/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocromos c/metabolismo , Ensaio de Imunoadsorção Enzimática , Marcação In Situ das Extremidades Cortadas , Potenciais da Membrana , Camundongos , Mitocôndrias/metabolismo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Crânio/citologia , Superóxidos/metabolismo
19.
Int J Biol Markers ; 28(4): e348-56, 2013 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-24338719

RESUMO

BACKGROUND: Short-term memory (STM) decline in breast cancer patients resulting from chemotherapy was evaluated by means of blood biomarkers, a questionnaire, and a computerized STM test. METHODS: This study was conducted from January 2013 to June 2013, recruiting 90 subjects: 30 breast cancer patients beginning the 3rd of 4th cycles of docetaxel and cyclophosphamide chemotherapy, 30 recovered patients (who completed 4 cycles of docetaxel for a minimum of 6 months), and 30 healthy subjects (disease-free females). The levels of hemoglobin, red and white blood cells, and cortisol in serum, and a computerized STM test were analyzed to estimate the effects of chemotherapy on STM. A questionnaire was given to all subjects to assess quality of life. RESULTS: Statistically significant differences were observed for the blood parameters (hemoglobin, red and white blood cells, and cortisol levels) between healthy and on-treatment subjects (respectively 13.47 ± 0.96 g/dL vs 5.37 ± 0.38 g/dL, 4.58 ± 0.41 10(12)/L vs 2.07 ± 0.13 10(12)/L, and 6.15 ± 1.03 10(9)/L vs 0.86 ± 0.41 10(9)/L). Scores of the STM test were significantly lower for patients compared to healthy subjects. As indicated by the results of the questionnaire, breast cancer patients had a higher tendency to forget than healthy controls (X(2)=3.15; p<0.0001) and recovered subjects (X(2)=3.15; p<0.0001). CONCLUSION: We found depleted levels of hemoglobin, red and white blood cells as a result of chemotherapy, and elevated levels of stress correlated with poor performances in the computerized STM test. A higher cortisol level might be an important precursor of STM deterioration. Monitoring cortisol would be beneficial for evaluating the quality of life of breast cancer patients on chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Hemoglobinas/metabolismo , Hidrocortisona/sangue , Transtornos da Memória/etiologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Neoplasias da Mama/psicologia , Estudos de Casos e Controles , Ciclofosfamida/administração & dosagem , Docetaxel , Contagem de Eritrócitos , Feminino , Humanos , Contagem de Leucócitos , Transtornos da Memória/sangue , Transtornos da Memória/induzido quimicamente , Projetos Piloto , Qualidade de Vida , Inquéritos e Questionários , Taxoides/administração & dosagem , Resultado do Tratamento , Adulto Jovem
20.
Int J Biol Markers ; 28(2): 168-73, 2013 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-23709344

RESUMO

BACKGROUND: This study was designed to assess oral ulcerative mucositis, C-reactive protein, blood pressure, heart rate and thyroid function in breast cancer patients in relation to the occurrence of posttraumatic stress disorder (PTSD). METHODS: A total of 120 female breast cancer patients and women 100 healthy subjects were enrolled in this study. PTSD status was assessed by questionnaire. Before and after treatment (modified radical mastectomy and chemotherapy), serum samples were collected and measured for levels of triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH) and high-sensitivity C-reactive protein (hs-CRP) by ELISA. Oral ulcerative mucositis was evaluated by the number and duration of oral ulcers and the degree of pain. RESULTS: Breast cancer patients experienced long-term PTSD and had elevated serum T3 and T4 levels. Patients experienced more severe pain and longer duration of oral ulcers compared with the healthy group. Oral ulcers were significantly associated with PTSD score in terms of the number of ulcers (p=0.0025), the degree of pain (p<0.0001) and the duration of ulcers (p<0.0001). CONCLUSION: These findings support that thyroid function is altered in breast cancer patients with PTSD. Elevation of T3 and T4 and oral ulcerative mucositis might be indicative of the emotional status of breast cancer patients.


Assuntos
Neoplasias da Mama/fisiopatologia , Úlceras Orais/fisiopatologia , Estomatite/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Pressão Sanguínea , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , Proteína C-Reativa/genética , Feminino , Humanos , Pessoa de Meia-Idade , Úlceras Orais/complicações , Úlceras Orais/genética , Estomatite/complicações , Estomatite/genética , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/psicologia , Testes de Função Tireóidea , Tireotropina/sangue , Tri-Iodotironina/sangue
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