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1.
Nat Commun ; 15(1): 4497, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802357

RESUMO

Silicon-based quantum emitters are candidates for large-scale qubit integration due to their single-photon emission properties and potential for spin-photon interfaces with long spin coherence times. Here, we demonstrate local writing and erasing of selected light-emitting defects using femtosecond laser pulses in combination with hydrogen-based defect activation and passivation at a single center level. By choosing forming gas (N2/H2) during thermal annealing of carbon-implanted silicon, we can select the formation of a series of hydrogen and carbon-related quantum emitters, including T and Ci centers while passivating the more common G-centers. The Ci center is a telecom S-band emitter with promising optical and spin properties that consists of a single interstitial carbon atom in the silicon lattice. Density functional theory calculations show that the Ci center brightness is enhanced by several orders of magnitude in the presence of hydrogen. Fs-laser pulses locally affect the passivation or activation of quantum emitters with hydrogen for programmable formation of selected quantum emitters.

2.
Mater Horiz ; 9(6): 1602-1622, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35467689

RESUMO

Thermoelectric (TE) materials have received much attention due to their ability to harvest waste heat energy. TE materials must exhibit a low thermal conductivity (κ) and a high power factor (PF) for efficient conversion. Both factors define the figure of merit (ZT) of the TE material, which can be increased by suppressing κ without degrading the PF. Recently, binary chalcogenides such as SnSe, GeTe, and PbTe have emerged as attractive candidates for thermoelectric energy generation at moderately high temperatures. These materials possess simple crystal structures with low κ in their pristine forms, which can be further lowered through doping and other approaches. Here, we review the recent advances in the temperature-dependent behavior of phonons and their influence on the thermal transport properties of chalcogenide-based TE materials. Because phonon anharmonicity is one of the fundamental contributing factors for low thermal conductivity in SnSe, Sb-doped GeTe, and related chalcogenides, we discuss complementary experimental approaches such as temperature-dependent Raman spectroscopy, inelastic neutron scattering, and calorimetry to measure anharmonicity. We further show how data gathered using multiple techniques helps us understand and engineer better TE materials. Finally, we discuss the rise of machine learning-aided efforts to discover, design, and synthesize TE materials of the future.

3.
Kathmandu Univ Med J (KUMJ) ; 19(74): 195-199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34819435

RESUMO

Background With increasing age, the older population becomes more susceptible to mental disorders. It is important to recognize and develop an understanding of psychiatric morbidity particularly among the residents of geriatric homes in resource-poor settings. Objective To assess the prevalence and associated factors of dementia symptoms among Nepalese senior citizens living in geriatric homes of Kathmandu valley. Method A cross-sectional study was conducted among 304 senior citizens living in geriatric homes of Kathmandu valley. Cognitive Impairment Test (CIT), was used to assess dementia symptoms. Bivariate and multivariate logistic regressions were performed. All the variables that were significant at p < 0.05 level in the bivariate analysis were included in the multivariate regression model and statistical significance was declared at p < 0.05 with a 95.00% confidence interval (CI). Result This study showed 75.65%, of the participants, had dementia symptoms. In the multivariate logistic regression analysis, female respondents (AOR=2.94, 95% CI=1.31-6.57), respondents never received geriatric allowances (AOR=2.46, 95% CI=1.22-4.98), respondent's history of alcohol consumption habits (AOR=2.04, 95% CI=1.01-4.11) and non-vegetarian diet habits (AOR= 2.31, 95% CI=1.12-4.76) were found more likely to had higher dementia symptoms whereas, literate participants (AOR=0.19, 95% CI=0.08-0.43) were less likely to had dementia symptoms. Conclusion The high prevalence of dementia symptoms among senior citizens living in geriatric homes in the Kathmandu valley indicates an urgent need for early diagnosis and treatment of mental disorders among senior citizens to improve their quality of life and well-being.


Assuntos
Demência , Qualidade de Vida , Idoso , Estudos Transversais , Demência/epidemiologia , Feminino , Humanos , Modelos Logísticos , Prevalência
5.
Case Rep Dent ; 2020: 6513210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32257453

RESUMO

Maxillectomy defects can result in oroantral communication that causes difficulty in mastication and deglutition, impaired speech, and facial disfigurement. The prosthodontist plays an important role in the rehabilitation of such defects with obturators. This paper describes a clinical report of fabricating a definitive obturator with a cast metal framework using a single flask and one-time processing method for an acquired maxillary defect. A tripodal design was selected for this case. Rest was placed on the premolars and molars of both quadrants of the maxilla. Complete palate as the major connector was designed to ensure maximum distribution of the functional load to the tissue. Indirect retainer was planned on the right first premolar. Direct retention was provided by the I-bar clasp placed on the left first premolar, circumferential clasp on the right first premolar, and embrasure clasp between the right first and second molars. Thus, this definitive prosthesis rehabilitated the patient by providing better masticatory efficiency, improving the clarity of speech and quality of life of the patient.

6.
Cell Prolif ; 48(4): 421-35, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26096843

RESUMO

OBJECTIVES: Aberrant c-Myc activity plays a central role in cancer transformation. γ-tocotrienol is a member of the vitamin E family that displays potent anti-cancer activity. Here, studies were conducted to determine the role of c-Myc in mediating anti-proliferative effects of γ-tocotrienol in mammary cancer cells. MATERIALS AND METHODS: Treatment effects on mouse +SA and human MCF-7 mammary cancer cell proliferation were determined by MTT assay and Ki-67 staining. Protein expression was determined by western blot analysis. Immunofluorescence staining and qRT-PCR were used to characterize cellular c-Myc and MYC levels respectively. RESULTS: Anti-proliferative effects of γ-tocotrienol were associated with reduction in total c-Myc and phosphorylated-c-Myc-serine 62, and increase in phosphorylated-c-Myc-threonine 58 levels. γ-tocotrienol also reduced PI3K/Akt/mTOR and Ras/MEK/Erk mitogenic signalling, cyclin D1 and cyclin-dependent kinase 4 levels, and increased p27 levels. However, γ-tocotrienol had no effect on MYC mRNA levels. γ-tocotrienol also increased levels of FBW7 (E3 ligase that initiates ubiquitination of c-Myc), but had no effect on serine/threonine phosphatase PP2A or isomerase Pin 1 levels. Combined treatment with GSK3α/ß inhibitor LiCl or proteasome inhibitor MG132 blocked γ-tocotrienol-induced reductions in c-Myc. CONCLUSIONS: These findings indicate that anti-proliferative effects of γ-tocotrienol are associated with reduction in c-Myc that results from increase in GSK-3α/ß-dependent ubiquitination and degradation, rather than from reduction in c-Myc synthesis in +SA and MCF-7 mammary cancer cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Cromanos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Vitamina E/análogos & derivados , Animais , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-myc/análise , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitamina E/farmacologia , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/farmacologia
7.
JNMA J Nepal Med Assoc ; 50(180): 267-72, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-22049888

RESUMO

INTRODUCTION: Substance use including tobacco and alcohol is the most important cause of preventable morbidity, disability, and premature mortality. The study aims to specify the prevalence and the pattern of use of different substance. METHODS: A cross sectional study was performed amongst first year and final year students in four medical colleges in Kathmandu using self administered anonymous questionnaire.Data collectedfrom 446 students were analyzed. RESULTS: Prevalence of substance use was found to be 60.3% among the medical students. Alcohol (57.6%) was the substance most prevalently used followed by tobacco (27.58%) and cannabis (12.8%). Mean age of first exposure was 17.94 (Confidence interval: 17.91-17.97). There was significant difference in the useof tobacco and cannabis amongst final year students than first year students. Male and female differed significantly in use of every substance except for benzodiazepine. Medical college, college and school were place of first exposure in 17.26%, 15.92% and 13.23% of the cases respectively. Family history was associated with substance use in medical students and was statistically significant (P<0.0001).Experimentation was the major reason for the use of most of the substances. CONCLUSIONS: Substance use is prevalent in male medical students of both first and final year. Hence steps should be initiated early in school, college and medical college to prevent substance use.


Assuntos
Estudantes de Medicina , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adolescente , Adulto , Distribuição de Qui-Quadrado , Estudos Transversais , Feminino , Humanos , Masculino , Nepal/epidemiologia , Prevalência
8.
J Ethnopharmacol ; 99(2): 199-202, 2005 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-15894127

RESUMO

Sikkim and Darjeeling Himalayan region is characterized by a rich floral diversity and an equally rich ethnomedicinal tradition. Herbal medicine is the dominant system of medicine practiced by the local tribes of this region for the treatment of diabetes. During the course of the present studies it was found that 37 species of plants belonging to 28 families are used as antidiabetic agents in the folk medicinal practices in the region and 81% of these plants are hitherto unreported as hypoglycemic agents. This finding may lead to serious research towards developing new and efficient drugs for diabetes.


Assuntos
Hipoglicemiantes/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Plantas Medicinais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Índia , Medicina Tradicional , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico
9.
Cancer Res ; 61(22): 8227-34, 2001 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11719454

RESUMO

We examined the ability of immunization with sequential adenovirus/plasmid DNA vectors expressing human wild-type p53 to stimulate a type 1 T-cell response and induce protection against challenge from a metastatic tumor that expresses mutated murine p53. We found that tumor protection and an antigen (Ag)-specific immune response were enhanced by prior injection of Flt3 ligand (Flt3L) at a dose and schedule that significantly increased dendritic cell (DC) number and frequency. Preliminary studies using enzyme-linked immunospot and Winn assays suggested that Ag-specific CD8 cells, with their significant increase in IFN-gamma-secreting activity (Tc1 cells), were responsible for the tumor protection. The delayed-type hypersensitivity response to p53 was increased in mice immunized with p53 alone or p53 and Flt3L compared with a negative control. In contrast, spleen cells from mice immunized with p53 and Flt3L exhibited a higher Ag-specific proliferative response than mice immunized with p53 alone. The frequencies of Ag-specific IFN-gamma and interleukin (IL)-4-secreting cells were determined using an enzyme-linked immunospot assay, which demonstrated that the frequency of IFN-gamma-secreting cells was significantly higher in mice immunized with p53 and Flt3L than in mice receiving Flt3L, excipient, or p53 treatment alone. In contrast, the frequency of IL-4-secreting cells did not differ significantly among these groups. We also observed an increased frequency of IL-12 and IFN-gamma-secreting cells (but not IL-4 or IL-10) in the spleens of mice immediately after 10 days of Flt3L treatment, which was also the day of p53 priming. This observation supports the likelihood that there are multiple mechanisms of Flt3L adjuvant activity, including expansion of DC and type 1 T-cell number. Overall, these results suggest that immunization with p53 genetic sequences after in vivo expansion of DC, using Flt3L, provides a useful strategy to induce p53-specific, and protective, type 1 T-cell responses.


Assuntos
Epitopos de Linfócito T/imunologia , Genes p53/imunologia , Proteínas de Membrana/imunologia , Linfócitos T/imunologia , Adenoviridae/genética , Animais , Células Dendríticas/imunologia , Feminino , Genes p53/genética , Humanos , Hipersensibilidade Tardia/imunologia , Imunização , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Ativação Linfocitária/imunologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Plasmídeos/genética , Plasmídeos/imunologia , Baço/citologia , Baço/imunologia , Baço/metabolismo
10.
Exp Hematol ; 29(10): 1185-93, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11602320

RESUMO

OBJECTIVE: Mechanisms of T-cell stimulation by Flt3 ligand (Flt3L) and granulocyte-macrophage colony-stimulating factor (GM-CSF) remain unclear. Herein, we compared the effects of Flt3L and GM-CSF on the expansion of dendritic cells (DC) and T-cell subsets and cytokine expression. METHODS: Naïve and effector/memory T cells were analyzed by flow cytometry (FC). CD4(+) and CD8(+) T cells and CD11c(+)CD11b(dull/-)(DC1) and CD11c(+)CD11b(+) (DC2) subsets were isolated and the frequency of IFN-gamma-, IL-12- (type 1) and IL-4-, IL-10 (type 2)-producing cells and cytokine mRNA expression evaluated. RESULTS: Flt3L expanded both DC1 and DC2 subsets with a significantly higher percentage and number of DC1 than DC2, while GM-CSF preferentially expanded the DC2 subset. Isolated DC1 from Flt3L-injected mice had significantly higher levels of IL-12 (p40) than IL-10, while the converse occurred with DC2. The numbers of naïve and memory T cells were elevated in mice that received Flt3L or GM-CSF. However, the number of memory CD4(+) and CD8(+) T cells was significantly increased in Flt3L as compared to GM-CSF cohorts. While GM-CSF increased the frequency of both type 1 and type 2 cytokine-producing cells, Flt3L significantly augmented the frequency of type 1 T cells. CONCLUSIONS: In contrast to GM-CSF, Flt3L preferentially induces the expansion of type 1 T cells. The mechanism of Flt3L-induced T-cell stimulation is associated with the expansion of the IL-12 (p40)-producing DC1 and memory T cells.


Assuntos
Células Dendríticas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Proteínas de Membrana/farmacologia , Fator de Células-Tronco/farmacologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Separação Celular/métodos , Citocinas/genética , Células Dendríticas/classificação , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-12/genética , Interleucina-4/biossíntese , Interleucina-4/genética , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos
11.
Cancer Lett ; 165(2): 179-84, 2001 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-11275367

RESUMO

Ganglioside GM2 is one of the major gangliosides expressed on the cell surface of human tumors including lung cancer. We have previously reported that a mouse-human chimeric monoclonal antibody (mAb), KM966, against GM2 promotes the lysis of lung cancer cells by human blood mononuclear cells (MNC) of healthy donors. In this study, we examined antibody-dependent cell-mediated cytotoxicity (ADCC) of MNC, using KM966 mAb and its humanized counterpart, KM8969, in 16 lung cancer patients and 18 control patients. The ADCC activity was assessed by 4-h (51)Cr release from GM2 positive SBC-3 small cell lung cancer cells. MNC from lung cancer patients exhibited similar ADCC activity to those from control patients when KM966 and KM8969 were used as mAb. Moreover, effective ADCC activity was observed even in MNC from advanced lung cancer patients. These observations suggest the potential activity of humanized anti-GM2 mAb (KM8969), as well as chimeric KM966, in biological therapy for lung cancer patients.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Gangliosídeo G(M2)/imunologia , Leucócitos Mononucleares/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Pequenas/metabolismo , Estudos de Casos e Controles , Cromo/metabolismo , Humanos , Leucócitos Mononucleares/citologia , Camundongos , Pessoa de Meia-Idade , Fatores de Tempo , Células Tumorais Cultivadas
12.
J Hematother Stem Cell Res ; 9(5): 711-20, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11091495

RESUMO

The hematopoietic sequelae of intramuscular administration of flt-3 ligand (FL) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alone, or in combination, were compared in BALB/c mice. Changes in hematopoiesis were measured in the marrow, spleen and blood using an in vitro colony-forming unit (CFU) assay and flow cytometrically (expression of CD34 and stem cell antigen (Sca)-1). FL administration was associated with a significant increase in the absolute number of CFU and CD34+ cells in the marrow and CFU, CD34+, Sca-1+, and CD34+ Sca-1+ cells in the spleen and blood. These data demonstrate that FL expands and mobilizes a range of hematopoietic progenitors. By comparison, GM-CSF administration was associated with a significant increase in the number of CFU in the spleen and a significant reduction in marrow CD34+, Sca-1+, and CD34+Sca-1+ cells. These data suggest that GM-CSF-driven expansion of CFU may be at the expense of more primitive cells. The pattern of progenitor cell expansion associated with FL + GM-CSF administration was similar to that of FL alone with the following exceptions. The numbers of spleen and blood CFU were significantly greater and the number of marrow CD34+Sca-1+ cells were significantly less, than with FL alone. These data suggest that co-administration of these cytokines may combine the expansion of the more primitive cell populations (associated with FL) with the expansion of the more mature CFU population (associated with GM-CSF) to yield a greater overall CFU expansion and elevation of CFU in the blood. However, increasing the expansion and mobilization of the relatively mature, rather than the more primitive, hematopoietic progenitors, may be of limited value as a mobilization strategy, if the goal is the expansion and isolation of increased numbers of "high-quality," primitive cells for transplantation.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hematopoese/fisiologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Proteínas de Membrana/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Interações Medicamentosas , Citometria de Fluxo , Hematopoese/efeitos dos fármacos , Humanos , Injeções Intramusculares , Ligantes , Proteínas de Membrana/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/farmacologia , Baço/citologia , Baço/efeitos dos fármacos
13.
Int J Immunopharmacol ; 22(11): 865-76, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11090695

RESUMO

Liposomes and Flt3 ligand (Flt3L), a ligand for the fms-like tyrosine kinase receptor Flt3/ FLK2, can augment the immune response to an HIV peptide vaccine. The HGP-30 peptide used in these studies is a synthetic peptide that corresponds to a highly conserved region of HIV-1 p17 gag (amino acids 86-115). Mice were immunized with HGP-30 or HGP-30 conjugated to keyhole limpet hemocyanin (KLH) and delayed-type hypersensitivity (DTH) responses, antibody (IgG) amount and antigen-specific proliferative responses by spleen cells were used to monitor the immune response. Daily injections of Flt3L prior to HGP-30 administration enhanced significantly an antigen-specific lymphocyte proliferation response when compared with Flt3L, HGP-30 alone or HGP-30 containing liposomes. Intravenous administration of HGP-30 was superior to intramuscular (i.m.) immunization for the induction of DTH responses. The HGP-30/KLH containing liposomes enhanced both DTH and antibody responses, while liposomes containing HGP-30 peptide elicited only T cell responses. In these studies, either Flt3L or liposomes increased DTH responses compared with the i.m. injection of the HGP-30 vaccine alone.


Assuntos
Vacinas contra a AIDS/imunologia , Produtos do Gene gag/imunologia , Antígenos HIV/imunologia , HIV-1/imunologia , Proteínas de Membrana/farmacologia , Proteínas Virais , Sequência de Aminoácidos , Animais , Células Dendríticas/fisiologia , Anticorpos Anti-HIV/sangue , Hipersensibilidade Tardia , Lipossomos/administração & dosagem , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Linfócitos T Citotóxicos/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana
14.
Oncol Res ; 12(4): 173-9, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11341466

RESUMO

Interferons are known to modulate several cellular functions by the induction of various proteins. In this study, we demonstrated that human interferon-gamma (HuIFN-gamma) enhanced the expression of ganglioside GM2 (GM2), which is a kind of tumor-associated antigen substantially expressed in human lung cancer and that human lung cancer cells expressing GM2 became more susceptible to anti-GM2 monoclonal antibody (mAb)-dependent tumor cell killing mediated by human effector cells after HuIFN-gamma treatment. GM2 expression on human lung cancer cells treated with or without HuIFN-gamma was measured by flow cytometry. The antibody-dependent cellular cytotoxicity (ADCC) activity was assessed by 4-h 51Cr release assay. HuIFN-gamma enhanced GM2 expression on human small-cell lung cancer (SCLC), SBC-3, and human non-small-cell lung cancer (NSCLC), A549 cells in a dose-dependent manner. The optimal concentration of HulIFN-gamma was 1,000 U/ml. The effect of HulFN-gamma reached maximum after 4 days of culture. HulFN-gamma did not have any effect to enhance the expression of other gangliosides in SBC-3 cells. No other cytokines used in this study modulated GM2 expression in SBC-3 cells. Anti-GM2 mAb-dependent ADCC activities induced by lymphocytes and monocytes were more potent against IFN-gamma-treated SBC-3 and A549 cells than nontreated cells. Taken together, HulFN-gamma combined with anti-GM2 mAb may be useful for immunotherapy against GM2-positive human lung cancer.


Assuntos
Anticorpos Monoclonais/metabolismo , Gangliosídeo G(M2)/imunologia , Gangliosídeo G(M2)/metabolismo , Interferon gama/farmacologia , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/metabolismo , Relação Dose-Resposta a Droga , Citometria de Fluxo , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos/metabolismo , Monócitos/metabolismo , Fatores de Tempo , Células Tumorais Cultivadas
15.
Oncol Res ; 11(5): 219-24, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10608616

RESUMO

We examined the effect of a novel topoisomerase I and II (topo I and II) inhibitor, TAS-103, on P-glycoprotein (P-gp)-expressing and -nonexpressing drug-resistant human small-cell lung cancer (SCLC) cells in vitro and in vivo. We observed that TAS-103 was effective in inhibiting in vitro proliferation of human SCLC (SBC-3 and H69) cells and their drug-resistant variants SBC-3/ADM or SBC-3/CDDP and H-69/VP, respectively. SBC-3/ADM and H-69/VP expressed high P-gp, whereas SBC-3/CDDP did not. TAS-103 also effectively reduced the tumor growth (more than 50% inhibition) of the parental as well as MDR SCLC cells grown SC in nude mice. Adriamycin (ADM) and cisplatin (CDDP), on the other hand, were effective only against the parental cells, while these drugs failed to inhibit the respective drug-resistant variants in vitro or in vivo. TAS-103 was observed to induce apoptosis dose dependently in the parental as well as drug-resistant SCLC cells as analyzed after 48 h of in vitro treatment, suggesting that the stabilization of cleavable topo I- or II-DNA complexes by topo I and II inhibitors like TAS-103 is followed by apoptosis of the cells. Overall, our study suggests that TAS-103 may have clinical application against drug-resistant human SCLC.


Assuntos
Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Indenos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Células Tumorais Cultivadas
16.
J Leukoc Biol ; 65(6): 764-70, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10380897

RESUMO

Dendritic cells (DC) play a key role in the initiation of immune response by stimulating the naive T cells. The fate of DC after the initiation of immune response is not clearly understood. Although there are few reports implicating natural killer (NK) cells in the elimination of DC, killing of DC by LAK cells, and specifically by T cells, has not been studied. In this study, we observed that DC, generated from monocytes, in vitro in the presence of granulocyte-macrophage colony-stimulating factor, interleukin-4 (IL-4), and tumor necrosis factor alpha were susceptible to cytolysis by lymphokine-activated killer (LAK) cells induced in the presence of IL-2 and IL-15 but not IL-12 alone. However, LAK cells induced by a combination of IL-12 and suboptimal dose of IL-2 were cytotoxic to DC. When purified lymphocytes were activated with IL-2, the CD8+/CD57- fraction (T-LAK), but not the CD8-/CD57+ fraction (NK-LAK) was cytotoxic to autologous DC. However, when unseparated peripheral blood mononuclear cells were used to generate LAK cells, both T-LAK and NK-LAK fractions showed equal cytotoxicity against autologous DC. Monoclonal antibodies against CD54, CD11a, and CD18 significantly inhibited the cytolysis, indicating that the killing involves the engagement of CD54 with its ligands.


Assuntos
Citotoxicidade Imunológica , Células Dendríticas/imunologia , Células Matadoras Ativadas por Linfocina/imunologia , Anticorpos Bloqueadores/farmacologia , Anticorpos Monoclonais/farmacologia , Antígenos CD18/biossíntese , Citotoxicidade Imunológica/efeitos dos fármacos , Células Dendríticas/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/imunologia , Interleucina-12/farmacologia , Interleucina-2/farmacologia , Células Matadoras Naturais/fisiologia , Leucócitos Mononucleares/citologia , Antígeno-1 Associado à Função Linfocitária/biossíntese , Antígeno-1 Associado à Função Linfocitária/imunologia , Macrófagos/metabolismo , Linfócitos T/fisiologia
17.
Oncol Res ; 10(6): 295-300, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9848100

RESUMO

We investigated the regulatory effect of interleukin (IL) 10 on IL-12-inducible killer activity of blood mononuclear cells (MNC) of healthy subjects. IL-10 suppressed non-MHC-restricted killer activity induced by IL-12 in a dose-dependent manner. Cytotoxicity against Daudi cells of blood MNC activated with optimal dose (100 U/ml) of IL-12 was significantly suppressed from 36.6 +/- 6.8% (mean +/- SE) to 26.0 +/- 5.0% by 100 ng/ml of IL-10 (n = 5; P < 0.05) at an E/T ratio of 20. IL-10, however, did not suppress killer induction by IL-2 from blood MNC. On the other hand, IL-4, a known inhibitor of IL-2-mediated killer induction, had no effect on IL-12-mediated killer induction from blood MNC. Moreover, production of interferon-gamma by IL-12-stimulated MNC was suppressed by IL-10. Because the presence of IL-10 is reported in the tumor-growing site, these observations suggest that IL-10 acts as a key cytokine in the suppression of IL-12-mediated antitumor response in situ.


Assuntos
Interleucinas/farmacologia , Células Matadoras Ativadas por Linfocina/efeitos dos fármacos , Células Matadoras Ativadas por Linfocina/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Células Cultivadas , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Interferon gama/biossíntese , Interleucina-10/farmacologia , Interleucina-12/farmacologia , Interleucina-2/farmacologia , Células Matadoras Ativadas por Linfocina/metabolismo , Células Matadoras Naturais , Leucócitos Mononucleares/metabolismo , Linfócitos
18.
Cancer Chemother Pharmacol ; 42(6): 483-90, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9788575

RESUMO

PURPOSE AND METHODS: To develop a clinically useful approach to circumvent P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MDR human small-cell lung cancer (SCLC), we examined the ability of a novel quinoline compound, MS-209, to reverse MDR by inhibition of P-gp function in combination with other MDR-reversing drugs using a cytotoxicity assay. RESULTS: We established MDR human SCLC cells by culture in medium with gradually increasing concentrations of adriamycin (ADM). Compared with the parental human SCLC cells, SBC-3, the MDR variant SBC-3 cells obtained (SBC-3/ADM) were highly resistant to various chemotherapeutic agents due to P-gp expression. MS-209 reversed the resistance to ADM and vincristine (VCR) of SBC-3/ADM and H69/VP cells in a dose-dependent manner. Moreover, MS-209 in combination with cyclosporin A (CsA) or verapamil (VER) synergistically enhanced the antitumor effects of ADM and VCR on SBC-3/ADM cells. MS-209 restored ADM incorporation and this effect was enhanced by CsA and VER, suggesting that these synergistic effects were due to competitive inhibition of P-gp function. CONCLUSION: MS-209 in combination with CsA or VER might increase the efficacy of these chemotherapeutic agents against MDR human SCLC cells.


Assuntos
Carcinoma de Células Pequenas/tratamento farmacológico , Ciclosporina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Quinolinas/uso terapêutico , Verapamil/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Ciclosporina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Quinolinas/farmacologia , Células Tumorais Cultivadas , Verapamil/farmacologia
19.
J Med Invest ; 44(3-4): 205-10, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9597810

RESUMO

Recently, the use of macrolides is suggested to be therapeutically effective in prolonging the survival of patients with inoperable non-small cell lung cancer. The purpose of this study was to examine therapeutic effects of a macrolide, clarythromycin (CAM) on the metastastic developments of two different human non-small cell lung cancers (squamous cell lung carcinoma RERF-LC-AI, and adenocarcinoma PC-14) in severe combined immunodeficient (SCID) mice depleted or undepleted of natural killer (NK) cells, respectively. CAM, injected subcutaneously at doses of 5 and 10 mg/kg body weight/day from day 7 to 41 after i.v. inoculation of human lung cancer cells, was not effective in inhibiting their distant organ metastases in SCID mice. CAM at concentrations of less than 10 micrograms/ml did not have a direct influence on the proliferation of these tumor cells in vitro. Although CAM alone was not effective in augmenting NK activity, it augmented the IL-2-induced killer (LAK) activity against Daudi cells in vitro. These results suggest that CAM alone may not be enough to control the spread of non-small cell lung cancer in the patient with T cell dysfunction.


Assuntos
Antibacterianos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Animais , Humanos , Macrolídeos , Camundongos , Camundongos SCID , Metástase Neoplásica , Transplante de Neoplasias
20.
Tumour Biol ; 18(2): 104-12, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9222308

RESUMO

The effect of the ascitic growth of Dalton's lymphoma (DL), a T cell lymphoma, on the immune responses of the host mice to exogenous antigens, with respect to the humoral response, delayed-type hypersensitivity (DTH) response and the antigen-presenting ability of macrophages was investigated. The humoral immune response to sheep red blood cells (SRBC) as well as the antigen-presenting ability of macrophages (with keyhole limpet hemocyanin as the standard antigen) in the DL-bearing mice were consistently higher than in the normal mice, although the magnitude showed a decline during later tumor stages. However, the DTH response to SRBC was suppressed in the DL-bearing mice compared with the response in the normal mice. The possible mechanisms are discussed. In vivo administration of FK565, a synthetic biological response modifier, enhanced the humoral immune response as well as the antigen-presenting ability of the macrophages in the normal and early DL-bearing mice, whereas these immune responses n the later tumor-bearing animals were found to be nonresponsive to FK565 treatment. In contrast, the DTH response in the normal as well as in the DL-bearing mice was suppressed on FK565 administration. This is the first study of its kind regarding the effect of the ascitic growth of any T cell lymphoma on various aspects of the immune response to exogenous antigens and the correlation thereof with an immunomodulator.


Assuntos
Formação de Anticorpos , Ascite/patologia , Imunidade Celular , Linfoma de Células T/imunologia , Linfoma de Células T/patologia , Adjuvantes Imunológicos/farmacologia , Animais , Células Apresentadoras de Antígenos/imunologia , Feminino , Hipersensibilidade Tardia/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Oligopeptídeos/farmacologia , Organismos Livres de Patógenos Específicos
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