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1.
Immunol Invest ; : 1-17, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34486463

RESUMO

Although immune checkpoint inhibitors (ICIs) have emerged as new therapeutic options for refractory cancer, they are only effective in select patients. Tumor antigen-pulsed dendritic cell (DC) vaccine therapy activates tumor-specific cytotoxic T lymphocytes, making it an important immunotherapeutic strategy. Salivary ductal carcinoma (SDC) carries a poor prognosis, including poor long-term survival after metastasis or recurrence. In this study, we reported a case of refractory metastatic SDC that was treated with a tumor lysate-pulsed DC vaccine followed by a single injection of low-dose nivolumab, and a durable complete response was achieved. We retrospectively analyzed the immunological factors that contributed to these long-lasting clinical effects. First, we performed neoantigen analysis using resected metastatic tumor specimens obtained before treatment. We found that the tumor had 256 non-synonymous mutations and 669 class I high-affinity binding neoantigen peptides. Using synthetic neoantigen peptides and ELISpot analysis, we found that peripheral blood mononuclear leukocytes cryopreserved before treatment contained pre-existing neoantigen-specific T cells, and the cells obtained after treatment exhibited greater reactivity to neoantigens than those obtained before treatment. Our results collectively suggest that the rapid and long-lasting effect of this combination therapy in our patient may have resulted from the presence of pre-existing neoantigen-specific T cells and stimulation and expansion of those cells following tumor lysate-pulsed DC vaccine and ICI therapy.

2.
Anticancer Res ; 41(8): 4047-4052, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281873

RESUMO

BACKGROUND/AIM: Tropomyosin-related kinase B (TrkB)/brain-derived neurotrophic factor (BDNF) signaling plays a role in inducing malignant phenotypes in several aggressive types of cancers. To create a conclusive therapy targeting TrkB/BDNF signaling in solid refractory cancers, the biological significance of TrkB/BDNF signaling was analyzed in pancreatic ductal adenocarcinoma (PDAC) cells. MATERIALS AND METHODS: Three PDAC cell lines were used as target cells to investigate proliferation and invasiveness. Small interfering RNA (siRNA) and the TrkB tyrosine kinase inhibitor k252a were used as TrkB/BDNF signaling inhibitors. RESULTS: All PDAC cell lines expressed TrkB and BDNF. When TrkB and BDNF were inhibited by siRNA or k252a, the invasiveness of PANC-1 and SUIT-2 cells significantly decreased. When TrkB was inhibited by siRNA or k252a, proliferation was significantly inhibited in PDAC cells. CONCLUSION: TrkB/BDNF signaling may be a new therapeutic target for PDAC. Therapies targeting TrkB/BDNF signaling may be a conclusive cancer therapy for refractory solid cancer.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor trkB/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Carbazóis/farmacologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Alcaloides Indólicos/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Transdução de Sinais/efeitos dos fármacos
3.
FEBS Open Bio ; 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115931

RESUMO

There are no human cancer cell lines of external auditory canal origin available for research use. This report describes the establishment of a culture condition for external auditory canal squamous cell carcinoma, derived from human tumor tissue. Successive squamous cell carcinoma colonies were dissociated by trypsin, subcultured, and maintained on a feeder layer (MMC-TIG-1-20), yielding a clonally proliferating cell culture. Two morphological types of colony were observed: (a) densely packed colonies and (b) colonies with indistinct boundaries characterized by cell-cell complexes with fibroblast feeder cells. The SCC-like characteristics of these cells were evidenced by positivity for p53, SCCA1/2, cytokeratin, and vimentin, and cancer stem cell properties were indicated by positivity for CD44, CD133, Oct3/4, and alkaline phosphatase (ALP). One of the unique properties of cell cultures is their tendency to form steric colonies in vitro on feeder layer cells. In addition, in the presence of fresh macrophages, the cells very slowly transform to break away from colonies as free cells, a process that resembles the epidermal-mesenchymal transition, whereby cell-cell interactions are weakened and migration activity is enhanced. These factors are purported to play a key role in cancer cell metastasis.

4.
Transl Oncol ; 14(9): 101152, 2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34134073

RESUMO

In our previous study, we found that inhibition of protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is expressed in lymphocytes, enhances lymphocyte activation, suggesting PTPN3 may act as an immune checkpoint molecule. However, PTPN3 is also expressed in various cancers, and the biological significance of PTPN3 in cancer cells is still not well understood, especially for lung neuroendocrine tumor (NET).Therefore, we analyzed the biological significance of PTPN3 in small cell lung cancer and examined the potential for PTPN3 inhibitory treatment as a cancer treatment approach in lung NET including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Experiments in a mouse xenograft model using allo lymphocytes showed that PTPN3 inhibition in SCLC cells enhanced the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In addition, PTPN3 was associated with increased vascularization, decreased CD8/FOXP3 ratio and cellular immunosuppression in SCLC clinical specimens. Experiments in a mouse xenograft model using autocrine lymphocytes also showed that PTPN3 inhibition in LCNEC cells augmented the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In vitro experiments showed that PTPN3 is involved in the induction of malignant traits such as proliferation, invasion and migration. Signaling from PTPN3 is mediated by MAPK and PI3K signals via tyrosine kinase phosphorylation through CACNA1G calcium channel. Our results show that PTPN3 suppression is associated with lymphocyte activation and cancer suppression in lung NET. These results suggest that PTPN3 suppression could be a new method of cancer treatment and a major step in the development of new cancer immunotherapies.

5.
Oncol Rep ; 45(3): 997-1010, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33650666

RESUMO

We previously reported that Hedgehog (Hh) signal was enhanced in gallbladder cancer (GBC) and was involved in the induction of malignant phenotype of GBC. In recent years, therapeutics that target Hh signaling have focused on molecules downstream of smoothened (SMO). The three transcription factors in the Hh signal pathway, glioma­associated oncogene homolog 1 (GLI1), GLI2, and GLI3, function downstream of SMO, but their biological role in GBC remains unclear. In the present study, the biological significance of GLI1, GLI2, and GLI3 were analyzed with the aim of developing novel treatments for GBC. It was revealed that GLI2, but not GLI1 or GLI3, was involved in the cell cycle­mediated proliferative capacity in GBC and that GLI2, but not GLI1 or GLI3, was involved in the enhanced invasive capacity through epithelial­mesenchymal transition. Further analyses revealed that GLI2 may function in mediating gemcitabine sensitivity and that GLI2 was involved in the promotion of fibrosis in a mouse xenograft model. Immunohistochemical staining of 66 surgically resected GBC tissues revealed that GLI2­high expression patients had fewer numbers of CD3+ and CD8+ tumor­infiltrating lymphocytes (TILs) and increased programmed cell death ligand 1 (PD­L1) expression in cancer cells. These results suggest that GLI2, but not GLI1 or GLI3, is involved in proliferation, invasion, fibrosis, PD­L1 expression, and TILs in GBC and could be a novel therapeutic target. The results of this study provide a significant contribution to the development of a new treatment for refractory GBC, which has few therapeutic options.

6.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33468653

RESUMO

Chemical modifications of histones, such as lysine acetylation and ubiquitination, play pivotal roles in epigenetic regulation of gene expression. Methods to alter the epigenome thus hold promise as tools for elucidating epigenetic mechanisms and as therapeutics. However, an entirely chemical method to introduce histone modifications in living cells without genetic manipulation is unprecedented. Here, we developed a chemical catalyst, PEG-LANA-DSSMe 11, that binds with nucleosome's acidic patch and promotes regioselective, synthetic histone acetylation at H2BK120 in living cells. The size of polyethylene glycol in the catalyst was a critical determinant for its in-cell metabolic stability, binding affinity to histones, and high activity. The synthetic acetylation promoted by 11 without genetic manipulation competed with and suppressed physiological H2B ubiquitination, a mark regulating chromatin functions, such as transcription and DNA damage response. Thus, the chemical catalyst will be a useful tool to manipulate epigenome for unraveling epigenetic mechanisms in living cells.


Assuntos
Epigenoma , Glicoconjugados/química , Histonas/química , Lisina/química , Polietilenoglicóis/química , Processamento de Proteína Pós-Traducional , Acetilação , Catálise , Engenharia Química/métodos , Epigênese Genética , Células HeLa , Histonas/metabolismo , Humanos , Lisina/metabolismo , Nucleossomos/química , Nucleossomos/metabolismo , Oligopeptídeos/química , Ubiquitinação
7.
Cell Immunol ; 358: 104237, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33137650

RESUMO

We previously reported that protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is upregulated in activated lymphocytes, acts as an immune checkpoint. However, the mechanism by which PTPN3 expression is enhanced in activated lymphocytes is unknown. In this study, we analyzed the mechanism of PTPN3 expression in activated lymphocytes with a view for developing a novel immune checkpoint inhibitor that suppresses PTPN3. Through the activation process, lymphocytes showed enhanced NFκB activation as well as increased PTPN3 expression. NFκB enhanced proliferation, migration, and cytotoxicity of lymphocytes. Furthermore, NFκB enhanced PTPN3 expression and tyrosine kinase activation. TGFß reduced PTPN3 expression and NFκB activation in the cancer microenvironment, and suppressed the biological activity of lymphocytes. The results of this study are expected to provide significant implications for improving existing immunotherapy and developing novel immunotherapy.


Assuntos
NF-kappa B/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Ativação Linfocitária/imunologia , Linfócitos/metabolismo , NF-kappa B/fisiologia , Fosforilação/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 3/genética , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta/fisiologia
8.
Nucleic Acids Res ; 48(12): 6583-6596, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32479628

RESUMO

The nucleolus is a membrane-less nuclear structure that disassembles when cells undergo mitosis. During mitosis, nucleolar factors are thus released from the nucleolus and dynamically change their subcellular localization; however, their functions remain largely uncharacterised. Here, we found that a nucleolar factor called nucleolar protein 11 (NOL11) forms a protein complex with two tryptophan-aspartic acid (WD) repeat proteins named WD-repeat protein 43 (WDR43) and Cirhin in mitotic cells. This complex, referred to here as the NWC (NOL11-WDR43-Cirhin) complex, exists in nucleoli during interphase and translocates to the periphery of mitotic chromosomes, i.e., perichromosomal regions. During mitotic progression, both the congression of chromosomes to the metaphase plate and sister chromatid cohesion are impaired in the absence of the NWC complex, as it is required for the centromeric enrichment of Aurora B and the associating phosphorylation of histone H3 at threonine 3. These results reveal the characteristics of a novel protein complex consisting of nucleolar proteins, which is required for regulating kinetochores and centromeres to ensure faithful chromosome segregation.


Assuntos
Aurora Quinase B/metabolismo , Segregação de Cromossomos , Mitose , Proteínas Nucleares/metabolismo , Células HeLa , Humanos , Proteínas Nucleares/genética , Ligação Proteica
9.
J Immunother ; 43(4): 121-133, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31834207

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy. As a factor of resistance, the dense fibrosis of this cancer acts as a barrier to inhibit immune cell infiltration into a tumor. We examined the influence of a Hedgehog signal inhibitor, Patched 1-interacting peptide, on fibrosis, infiltration of immune cells, and immunotherapeutic effects on PDAC. We found that this peptide inhibited proliferation and migration of cancer-associated fibroblasts and cancer cells. Furthermore, this peptide reduced the production of extracellular matrix and transforming growth factor ß1 in cancer-associated fibroblasts and induced expression of HLA-ABC in PDAC cells and interferon-γ in lymphocytes. In vivo, the peptide suppressed fibrosis of PDAC and increased immune cell infiltration into tumors. The combination of this peptide and an anti-programmed death-1 antibody augmented the antitumor effect, and this combination showed the same effect in experiments using cancer cells and autologous lymphocytes. These results indicate that, in addition to the direct effect of tumor suppression, the Patched 1-interacting peptide increases the infiltration of immune cells by reducing fibrosis of PDAC and consequently enhances the effect of immunotherapy. Therefore, treatment with this peptide may be a novel therapy with 2 different mechanisms: direct tumor suppression and enhancing the immune response against PDAC.

10.
Cancer Immunol Immunother ; 68(10): 1649-1660, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31562536

RESUMO

It has been shown that protein tyrosine phosphatase non-receptor type (PTPN) 3 inhibits T-cell activation. However, there is no definitive conclusion about how the inhibition of PTPN3 in lymphocytes affects immune functions in human lymphocytes. In the present study, we showed that PTPN3 inhibition significantly contributes to the enhanced activation of activated human lymphocytes. The PTPN3 expression of lymphocytes was significantly increased through the activation process using IL-2 and anti-CD3 mAb. Interestingly, inhibiting the PTPN3 expression in activated lymphocytes significantly augmented the proliferation, migration, and cytotoxicity through the phosphorylation of zeta-chain-associated protein kinase 70 (ZAP-70), lymphocyte-specific protein tyrosine kinase (LCK), and extracellular signal-regulated kinases (ERK). Lymphocyte activation by PTPN3 inhibition was observed only in activated CD3+ T cells and not in NK cells or resting T cells. In therapy experiments using autologous tumors and lymphocytes, PTPN3 inhibition significantly augmented the number of tumor-infiltrated lymphocytes and the cytotoxicity of activated lymphocytes. Our results strongly imply that PTPN3 acts as an immune checkpoint in activated lymphocytes and that PTPN3 inhibitor may be a new non-antibody-type immune checkpoint inhibitor for cancer therapy.


Assuntos
Pontos de Checagem do Ciclo Celular , Ativação Linfocitária , Neoplasias Ovarianas/prevenção & controle , Proteína Tirosina Fosfatase não Receptora Tipo 3/antagonistas & inibidores , Linfócitos T/imunologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Feminino , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína-Tirosina Quinase ZAP-70/metabolismo
11.
ACS Chem Biol ; 14(6): 1102-1109, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117394

RESUMO

Cell biology is tightly regulated by post-translational modifications of proteins. Methods to modulate post-translational modifications in living cells without relying on enzymes or genetic manipulation are, however, largely underexplored. We previously reported that a chemical catalyst (DSH) conjugated with a nucleosome-binding ligand can activate an acyl-CoA and promote site-selective lysine acylation of histones in test tubes. In-cell acylation by this catalyst system is challenging, however, mainly due to the low cell permeability of acyl-CoA and the propensity of DSH to form inactive disulfide. Here, we report a new catalyst system effective for in-cell acylation, comprising a cell-permeable acyl donor and pro-drugged DSH. Using E. coli dihydrofolate reductase and trimethoprim as a model protein and ligand pair, the catalyst system enabled site-selective acylation of the target protein in living cells. The findings will lead to the development of useful chemical biology tools and new therapeutic strategies capable of synthetically modulating post-translational modifications.


Assuntos
Proteínas/metabolismo , Acetilação , Acil Coenzima A/metabolismo , Acilação , Catálise , Permeabilidade da Membrana Celular , Escherichia coli/enzimologia , Células HEK293 , Humanos , Ligantes , Tetra-Hidrofolato Desidrogenase/metabolismo
12.
Sci Adv ; 4(6): eaap7777, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29881774

RESUMO

The nucleolus is a dynamic nuclear body that has been demonstrated to disassemble at the onset of mitosis; the relationship between cell cycle progression and nucleolar integrity, however, remains poorly understood. We studied the role of nucleolar proteins in mitosis by performing a global analysis using small interfering RNAs specific to nucleolar proteins; we focused on nucleolar protein 11 (NOL11), with currently unknown mitotic functions. Depletion of NOL11 delayed entry into the mitotic phase owing to increased inhibitory phosphorylation of cyclin-dependent kinase 1 (Cdk1) and aberrant accumulation of Wee1, a kinase that phosphorylates and inhibits Cdk1. In addition to effects on overall mitotic phenotypes, NOL11 depletion reduced ribosomal RNA (rRNA) levels and caused nucleolar disruption during interphase. Notably, mitotic phenotypes found in NOL11-depleted cells were recapitulated when nucleolar disruption was induced by depletion of rRNA transcription factors or treatment with actinomycin D. Furthermore, delayed entry into the mitotic phase, caused by the depletion of pre-rRNA transcription factors, was attributable to nucleolar disruption rather than to G2/M checkpoint activation or reduced protein synthesis. Our findings therefore suggest that maintenance of nucleolar integrity during interphase is essential for proper cell cycle progression to mitosis via the regulation of Wee1 and Cdk1.


Assuntos
Proteína Quinase CDC2/metabolismo , Nucléolo Celular/metabolismo , Interfase , Mitose , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Ativação Enzimática , Células HeLa , Humanos , Proteínas Nucleares/metabolismo , Transporte Proteico , Proteínas Tirosina Quinases/metabolismo
13.
Anticancer Res ; 37(12): 6649-6654, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29187440

RESUMO

BACKGROUND/AIM: In pancreatic cancer, where the microenvironment is extremely hypoxic, analyzing signal transduction under hypoxia is thought to be significantly important. By investigating microarray analysis of pancreatic cancer cells cultured under both normoxia and hypoxia, we found that the expression of leukocyte common antigen-related (LAR)-interacting protein (liprin)-α4 was extremely increased under hypoxia compared to under normoxia. MATERIALS AND METHODS: In the present study, the biological significance of liprin-α4 in pancreatic cancer was investigated and whether liprin-α4 has potential as a therapeutic target for pancreatic cancer was estimated. RESULTS: Suppression of liprin-α4 reduced proliferation of pancreatic cancer cells both in vitro and in vivo. Inhibition of liprin-α4 also reduced invasiveness through the suppression of endothelial-mesenchymal transition. Stimulation by liprin-α4 was through phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways. CONCLUSION: Liprin-α4 plays a pivotal role in inducing malignant phenotypes such as increased proliferation and invasion in pancreatic cancer, and that liprin-α4 could be a new effective therapeutic target for pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Hipóxia , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Interferência de RNA , Transdução de Sinais , Transplante Heterólogo
14.
Anticancer Res ; 37(2): 561-565, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179302

RESUMO

The role of cluster of differentiation (CD) 24 in breast cancer remains unclear; previously, we showed that CD24 suppresses malignant phenotypes by inactivating Hedgehog signaling through signal transducer and activator of transcription (STAT) 1 inhibition. In this study, we examined how CD24 affects chemosensitivity in breast cancer cells. The CD44+CD24+ breast cancer cell line MCF-7 was transfected with CD24 with/without STAT1 siRNA, and chemosensitivity to 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum (CDDP) was measured. CD24 inhibition reduced chemosensitivity to 5-FU, while STAT1 inhibition did not affect chemosensitivity to 5-FU in CD24 siRNA-transfected cells. Conversely, CD24 inhibition did not affect chemosensitivity to CDDP, while STAT1 inhibition reduced chemosensitivity to CDDP in CD24 siRNA-transfected cells. STAT1 inhibition, but not CD24 inhibition, reduced expression of the ATP-binding cassette (ABC) transporter genes, ABCB1 and ABCG2. In conclusion, CD24 inhibition may modulate chemosensitivity according to drug type, but ABC transporter expression appears not to contribute to this mechanism. This study contributes to determining the role of CD24 in breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Antígeno CD24/metabolismo , Transportador 1 de Cassete de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Neoplasias da Mama/genética , Antígeno CD24/genética , Feminino , Fluoruracila/farmacologia , Humanos , Células MCF-7 , Proteínas de Neoplasias/biossíntese , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Fator de Transcrição STAT1/antagonistas & inibidores , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transfecção
15.
Cell Immunol ; 310: 199-204, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27522179

RESUMO

We investigated whether hypoxia-induced activation of Hh signaling contributes to PDL-1 expression in cancer and whether it affects the anti-tumor function of activated lymphocytes. Hypoxia augmented PDL-1 expression and inhibition of Hh signaling reduced PDL-1 expression under hypoxia. When activated lymphocytes were cocultured with cancers treated with a Hh inhibitor, activated lymphocyte cell numbers increased under hypoxia. In contrast, this increase was abrogated when cancer cells were treated with a PDL-1 neutralizing antibody. These results suggest that Hh signaling is one of regulatory pathways of PDL-1 expression under hypoxia and that inhibiting Hh signaling may induce lymphocyte anti-tumor activity.


Assuntos
Antígeno B7-H1/metabolismo , Proteínas Hedgehog/antagonistas & inibidores , Hipóxia/imunologia , Linfócitos/imunologia , Neoplasias/imunologia , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Técnicas de Cocultura , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/terapia , Ativação Linfocitária , Terapia de Alvo Molecular , Neoplasias/terapia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Transativadores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Alcaloides de Veratrum/farmacologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
16.
Anticancer Res ; 36(8): 3945-52, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27466498

RESUMO

Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia. PSK reduced SMO, MAML3 and RBPJ expression in pancreatic cancer cells under hypoxia. PSK also blocked RBPJ-induced invasiveness under hypoxia by inhibiting matrix metalloproteinase expression. Lastly, we showed that PSK attenuated RBPJ-induced proliferation both in vitro and in vivo. These results suggest that PSK suppresses Hedgehog signaling through down-regulation of MAML3 and RBPJ transcription under hypoxia, inhibiting the induction of a malignant phenotype in pancreatic cancer. Our results may lead to development of new treatments for refractory pancreatic cancer using PSK as a Hedgehog inhibitor.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Proteínas Fúngicas/administração & dosagem , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/biossíntese , Proteínas Nucleares/biossíntese , Neoplasias Pancreáticas/tratamento farmacológico , Polissacarídeos/administração & dosagem , Fatores de Transcrição/biossíntese , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Camundongos , Invasividade Neoplásica/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Transativadores , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Auris Nasus Larynx ; 43(2): 192-6, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26165630

RESUMO

OBJECTIVE: In some cases, the exposure and safeguarding of the internal carotid artery (ICA) are not easy by the maxillary swing approach that is used as a mainstay for the removal of nasopharyngeal tumors. To address this issue, we have developed a new combined transcervical and orbitozygomatic approach. METHODS: A nasopharyngeal adenocarcinoma arose in a 52-year-old patient and occupied the right middle skull base extending to the ICA. We first identified and dissected the ICA from the posterolateral part of the tumor using a transcervical approach. Then, the tumor was approached and removed by an orbitozygomatic technique with hemifacial dismasking. The surgical defect was filled using a temporal muscle flap, which was divided into two parts according to the blood supply from either the anterior or the posterior deep temporal artery. RESULTS: The postoperative course was uneventful and favorable cosmetic results were obtained. The patient has been free of carcinoma for more than 40 months after the surgery. CONCLUSION: Our new combined approach might be a good option for selected patients with nasopharyngeal tumors.


Assuntos
Adenocarcinoma/cirurgia , Neoplasias Nasofaríngeas/cirurgia , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Neoplasias da Base do Crânio/cirurgia , Artéria Carótida Interna , Feminino , Humanos , Pessoa de Meia-Idade , Órbita , Zigoma
19.
J Am Med Inform Assoc ; 21(e2): e326-31, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24763677

RESUMO

BACKGROUND AND OBJECTIVE: While the secondary use of medical data has gained attention, its adoption has been constrained due to protection of patient privacy. Making medical data secure by de-identification can be problematic, especially when the data concerns rare diseases. We require rigorous security management measures. MATERIALS AND METHODS: Using secure computation, an approach from cryptography, our system can compute various statistics over encrypted medical records without decrypting them. An issue of secure computation is that the amount of processing time required is immense. We implemented a system that securely computes healthcare statistics from the statistical computing software 'R' by effectively combining secret-sharing-based secure computation with original computation. RESULTS: Testing confirmed that our system could correctly complete computation of average and unbiased variance of approximately 50,000 records of dummy insurance claim data in a little over a second. Computation including conditional expressions and/or comparison of values, for example, t test and median, could also be correctly completed in several tens of seconds to a few minutes. DISCUSSION: If medical records are simply encrypted, the risk of leaks exists because decryption is usually required during statistical analysis. Our system possesses high-level security because medical records remain in encrypted state even during statistical analysis. Also, our system can securely compute some basic statistics with conditional expressions using 'R' that works interactively while secure computation protocols generally require a significant amount of processing time. CONCLUSIONS: We propose a secure statistical analysis system using 'R' for medical data that effectively integrates secret-sharing-based secure computation and original computation.


Assuntos
Segurança Computacional , Registros Eletrônicos de Saúde , Estatística como Assunto , Sistemas Computacionais , Atenção à Saúde/estatística & dados numéricos
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