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1.
Artigo em Inglês | MEDLINE | ID: mdl-32223928

RESUMO

Although most EGFR-mutant lung adenocarcinomas initially respond to EGFR inhibitors, disease progression almost inevitably occurs. We previously reported that two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, contain subpopulations of cells that display an epithelial-to-mesenchymal phenotype and can thrive independently of EGFR signaling. In this study, we explored to what extent these two sublines, HCC827 GR2 and H1975 WR7, depended on the anti-apoptotic BCL2 family members, Bcl-xL and/or MCL1, for survival. Although HCC827 GR2 cells were hardly affected by Bcl-xL or MCL1 knockdown alone, dual inhibition of Bcl-xL and MCL1 caused the cells to undergo apoptosis, resulting in decreased viability. In H1975 WR7 cells, not only dual inhibition, but also MCL1 silencing alone, induced the cells to undergo apoptosis. Interestingly, the two sublines markedly declined in number when autophagy flux was suppressed, because they depend, in part, on active autophagy for survival. However, autophagy inhibition was inferior to dual inhibition of Bcl-xL plus MCL1 for GR2 cells, or MCL1 inhibition alone, for decreasing the viability of WR7 cells. Collectively, these findings suggest that inhibiting Bcl-xL plus MCL1, or MCL1 alone, may represent a new approach to treat EGFR-independent EGFR-mutant cancer cells.

2.
Cancer Sci ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32237253

RESUMO

Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in TTF-1/NKX2-1-positive terminal respiratory unit (TRU) types and rarely in non-TRU types. To elucidate the molecular characteristics of the major subtypes of non-TRU-type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non-TRU types). A characteristic of non-TRU-type cell lines was the strong expression of TFF-1 (trefoil factor-1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF-1 was positive in 31 cases (13%). TFF-1 expression was frequently detected in invasive mucinous(14/15,93%), enteric(2/2,100%), and colloid(1/1,100%) adenocarcinomas, less frequent in acinar(5/24,21%), papillary(7/120,6%), and solid(2/43,5%) adenocarcinomas, and negative in micropapillary(0/1,0%), lepidic(0/23,0%), and microinvasive adenocarcinomas or adenocarcinoma in situ(0/9,0%). TFF-1 expression correlated with the expression of HNF4alpha and MUC5AC (p<0.0001, p<0.0001, respectively) and inversely correlated with that of TTF-1/NKX2-1 (p<0.0001). These results indicate that TFF-1 is characteristically expressed in non-TRU-type adenocarcinomas with gastrointestinal features. TFF-1-positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. TFF-1 expression correlated with tumor spread through air space (STAS), and a poor prognosis in advanced stages. Moreover, the knockdown of TFF-1 inhibited cell proliferation and soft-agar colony formation and induced apoptosis in a TFF-1-high and KRAS-mutated lung adenocarcinoma cell line. These results indicate that TFF-1 is not only a biomarker, but also a potential molecular target for non-TRU-type lung adenocarcinomas.

3.
Med Mol Morphol ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907620

RESUMO

We herein report a variant case of desmoplastic small round cell tumor (DSRCT) showing limited desmoplasia and confusing immunohistochemical findings. A 26-year-old male was referred for multiple abdominal masses. Laparoscopic biopsy showed only the solid proliferation of small round cells, and he was initially diagnosed with small cell carcinoma. At autopsy, the tumor spread diffusely throughout the abdominal and pelvic cavities. Although the tumor was composed of a predominantly solid pattern of small round cells, multiple samples revealed a fibrous stroma in limited areas only. While immunohistochemistry showed the diffuse expression of desmin, CD99, and bcl-2, epithelial differentiation was unclear with few cytokeratin-positive cells and no staining for the epithelial membrane antigen. Although fluorescence in situ hybridization analysis indicated the EWSR1 gene rearrangement, we were unable to exclude Ewing sarcoma considering the morphological and immunohistochemical findings. The diagnosis of DSRCT was confirmed with a reverse transcription-polymerase chain reaction for EWSR1-WT1 fusion transcripts. DSRCT must be included in a differential diagnosis of small round cell tumors even if desmoplasia is not immediately detected, and thorough sampling and a molecular analysis are mandatory.

4.
iScience ; 22: 240-255, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31786520

RESUMO

Endogenous extracellular Galectins constitute a novel mechanism of membrane protein organization at the cell surface. Although Galectins are also highly expressed intracellularly, their cytosolic functions are poorly understood. Here, we investigated the role of Galectin-9 in dendritic cell (DC) surface organization and function. By combining functional, super-resolution and atomic force microscopy experiments to analyze membrane stiffness, we identified intracellular Galectin-9 to be indispensable for plasma membrane integrity and structure in DCs. Galectin-9 knockdown studies revealed intracellular Galectin-9 to directly control cortical membrane structure by modulating Rac1 activity, providing the underlying mechanism of Galectin-9-dependent actin cytoskeleton organization. Consequent to its role in maintaining plasma membrane structure, phagocytosis studies revealed that Galectin-9 was essential for C-type-lectin receptor-mediated pathogen uptake by DCs. This was confirmed by the impaired phagocytic capacity of Galectin-9-null murine DCs. Together, this study demonstrates a novel role for intracellular Galectin-9 in modulating DC function, which may be evolutionarily conserved.

5.
Am J Surg Pathol ; 43(11): 1526-1535, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31600177

RESUMO

Atypical polypoid adenomyoma (APA) is a polypoid lesion that is comprised of atypical endometrial glands and fibromuscular stroma, which pathologists often confuse with myoinvasive endometrioid carcinoma. Here, we characterized the immunohistochemical and molecular features of the stromal components of APA to find distinct markers between APA and myoinvasive endometrioid carcinoma. First, we examined the immunohistochemical expression and gene mutations that were previously investigated in uterine and breast fibroepithelial lesions using 12 cases of APA. α-smooth muscle actin was diffusely positive in the stromal component in all cases, whereas desmin and h-caldesmon were focally expressed in 8 cases. Positive expression was also observed in 9 cases for CD10, 12 cases for estrogen receptor, 3 cases for HMGA2, and 3 cases for MDM2. All cases showed normal p53 expression and negative staining of HMGA1 and nuclear ß-catenin. No mutations in MED12 exon 2 and the TERT promoter were found in any cases. p16 was positive in all cases and showed diffuse expression in 10 cases. We assessed stromal p16 expression in 84 cases of myoinvasive endometrioid carcinoma. The stromal p16 status was negative in all myoinvasive carcinomas, but there was 1 case with focal staining. There was a significant difference in stromal p16 expression between APA and myoinvasive endometrioid carcinoma (P<0.001). Stromal p16 expression was more suggestive of APA than myoinvasive endometrioid carcinoma among endometrial fibroepithelial lesions.

6.
Oncoimmunology ; 8(8): 1601482, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413910

RESUMO

Galectin-9 has emerged as a promising biological target for cancer immunotherapy due to its role as a regulator of macrophage and T-cell differentiation. In addition, its expression in tumor cells modulates tumor cell adhesion, metastasis, and apoptosis. Malignant mesothelioma (MM) is an aggressive neoplasm of the mesothelial cells lining the pleural and peritoneal cavities, and in this study, we found that both human MM tissues and mouse MM cells express high levels of galectin-9. Using a novel monoclonal antibody (mAb) (Clone P4D2) that binds the C-terminal carbohydrate recognition domain (CRD) of galectin-9, we demonstrate unique agonistic properties resulting in MM cell apoptosis. Furthermore, the P4D2 mAb reduced tumor-associated macrophages differentiation toward a protumor phenotype. Importantly, these effects exerted by the P4D2 mAb were observed in both human and mouse in vitro experiments and not observed with another antigalectin-9 specific mAb (clone P1D9) that engages the N-terminus CRD of galectin-9. In syngeneic murine models of MM, P4D2 mAb treatment inhibited tumor growth and improved survival, with tumors from P4D2-treated mice exhibited reduced infiltration of tumor-associated M2 macrophages. This was consistent with an increased production of inducible nitric oxide synthase, which is a major enzyme-regulating macrophage inflammatory response to cancer. These data suggest that using an antigalectin 9 mAb with agonistic properties similar to those exerted by galectin-9 may provide a novel multitargeted strategy for the treatment of mesothelioma and possibly other galectin-9 expressing tumors.

7.
Cancer Sci ; 110(9): 3006-3011, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301084

RESUMO

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/metabolismo , Mucinas/metabolismo , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/genética , Idoso , Antígenos CD/genética , Caderinas/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Tomografia Computadorizada por Raios X , Sequenciamento Completo do Exoma
8.
Case Rep Obstet Gynecol ; 2019: 3120921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214368

RESUMO

We describe a patient with bilateral cystic tumors of the pelvis. The left one rapidly grew during pregnancy and combined with the right one, whose clinical course made diagnosis difficult. A pregnant woman with a history of laparotomy was referred to us due to suspected bilateral pelvic cysts. The left-sided cyst had rapidly grown to 27 cm in diameter and merged with the right cyst, forming a large cyst occupying the entire pelvic cavity in the third trimester. Considering this rapid growth, cesarean section and resection of the cyst were performed at 37th week. The resected cyst consisted of two components: a large unilocular cyst containing serous fluid and a multilocular cyst suggestive of ovarian mucinous cystadenoma in the right ovary. The wall of the former largely lacked lining epithelium, but it was partly continuous with the latter mucinous epithelium. Immunohistochemically, estrogen and progesterone receptors were focally positive in the cyst wall, suggesting that pregnancy-associated sex-hormones may have contributed to the rapid growth of the cyst. We diagnosed this condition as a peritoneal inclusion cyst margining with a right ovarian mucinous cystadenoma. Peritoneal inclusion cyst should be considered in the differential diagnosis of a rapidly growing pelvic mass during pregnancy.

9.
Medicine (Baltimore) ; 98(24): e15888, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192921

RESUMO

RATIONALE: Suppression and of cancer metastasis is one of the most important issues in cancer care. Considering the typical clinical course of metastases, cancer cells might prefer certain environments or conditions. However, favorable environments for cancer metastasis have not been clearly identified. We had previously described a case of dual, yet separate, pancreatic and colon cancer, in which the metastatic pancreatic cancer was localized at the invasive portion of the colon cancer. We hypothesized that metastatic pancreatic cancer took over the colon cancer microenvironment. PATIENT CONCERNS: We experienced an another case of double cancer in a 65-year-old man who had lung squamous cell carcinoma and an independent pancreatic adenocarcinoma that metastasized to the liver as well as to the lung cancer lesion and pulmonary fibrotic regions associated with pneumothorax and bronchiolization. INTERVENTIONS: The pneumothorax could not be controlled by conservative treatment. Thus, an emergency surgery with partial resection of the lower lobe of right lung was performed. DIAGNOSES: We found multiple pancreatic cancer metastases in the lung cancer and fibrotic lesions in the surgical specimen. However, we detected no metastasis in normal lung tissues except inside small arteries, although the lung cancer and fibrotic tissue areas were smaller than the normal lung tissue areas in the surgical specimen. OUTCOMES: The patient died 50 days after the surgery. LESSONS: This case may thus provide evidence to strengthen our hypothesis that pancreatic cancer prefers to metastasize to other independent cancer lesions, overtaking the cancer microenvironment constructed by other independent cancers. The lung cancer microenvironment, rich in myofibroblasts and/or cancer-associated fibroblasts, might be suitable for pancreatic carcinoma metastasis. In addition, we propose the hypothesis that compared with normal tissues, noncancerous fibrotic lesions are preferable destinations for cancer metastasis. Furthermore, metastasis of pancreatic carcinoma to lung cancer and fibrotic tissues might be more common, although such cases have not been previously reported.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Neoplasias Pulmonares/cirurgia , Segunda Neoplasia Primária/cirurgia , Neoplasias Pancreáticas/cirurgia , Pneumotórax/cirurgia , Idoso , Carcinoma de Células Escamosas/diagnóstico , Evolução Fatal , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/secundário , Masculino , Segunda Neoplasia Primária/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Pneumotórax/diagnóstico , Pneumotórax/etiologia , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/cirurgia , Microambiente Tumoral
10.
Lung Cancer ; 133: 88-95, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31200834

RESUMO

OBJECTIVES: MCL1 is an anti-apoptotic BCL2 family member that is highly expressed in various malignant tumors. However, little is known about the role of MCL1 in KRAS-mutant lung adenocarcinomas. In this study, we aimed to clarify whether MCL1 could be a therapeutic target in KRAS-mutant lung adenocarcinomas for which no effective molecular targeted drugs are available. MATERIALS AND METHODS: We examined to what extent MCL1 knockdown either alone or in combination with MEK inhibitor trametinib suppressed growth or induced apoptosis in the KRAS-mutant lung adenocarcinoma cell line H441 and EGFR-mutant lung adenocarcinoma cell line H1975. Furthermore, we investigated the therapeutic effects of dual inhibition of MCL1 and Bcl-xL, another anti-apoptotic BCL2 family member, in these two cell lines. RESULTS: MCL1 knockdown alone did not induce apoptosis in H441 or H1975 cells. However, MCL1-depleted H441 and H1975 cells underwent apoptosis and decreased in number in the presence of trametinib. We also confirmed that combined therapy by MCL1 knockdown and trametinib almost completely suppressed the growth of H441 cells in vivo. Moreover, dual knockdown of MCL1 and Bcl-xL induced extensive apoptosis in H441 and H1975 cells. CONCLUSION: These findings suggest that combined treatments of MCL1 knockdown and trametinib or dual inhibition of MCL1 and Bcl-xL would be effective therapies for lung adenocarcinomas including the KRAS-mutant subtype.

11.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146370

RESUMO

Galectin-9 (Gal-9) enhances tumor immunity mediated by T cells, macrophages, and dendritic cells. Its expression level in various cancers correlates with prognosis. Furthermore, Gal-9 directly induces apoptosis in various cancers; however, its mechanism of action and bioactivity has not been clarified. We evaluated Gal-9 antitumor effect against esophageal squamous cell carcinoma (ESCC) to analyze the dynamics of apoptosis-related molecules, elucidate its mechanism of action, and identify relevant changes in miRNA expressions. KYSE-150 and KYSE-180 cells were treated with Gal-9 and their proliferation was evaluated. Gal-9 inhibited cell proliferation in a concentration-dependent manner. The xenograft mouse model established with KYSE-150 cells was administered with Gal-9 and significant suppression in the tumor growth observed. Gal-9 treatment of KYSE-150 cells increased the number of Annexin V-positive cells, activation of caspase-3, and collapse of mitochondrial potential, indicating apoptosis induction. c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) phosphorylation were activated and could be involved in apoptosis. Therefore, Gal-9 induces mitochondria-mediated apoptosis of ESCC and inhibits cell proliferation in vitro and in vivo with JNK and p38 activation.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Galectinas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Esofágicas/tratamento farmacológico , Galectinas/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo
12.
Clin J Gastroenterol ; 12(6): 534-538, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31134449

RESUMO

A 68-year-old male was referred with dysphagia. Endoscopic findings showed circular stenosis with a protruding mass in the lower esophagus. Biopsy showed adenocarcinoma and there was no evidence of distant metastases. A subtotal esophagectomy was performed. The resected specimen revealed a mixed neuroendocrine carcinoma with adenocarcinoma. The adenocarcinoma component was on the surface of the tumor and the neuroendocrine component invaded the deeper portion. Immunohistochemically, the neuroendocrine carcinoma component stained positive for cytokeratin 7 and cytokeratin 20, suggesting that the neuroendocrine carcinoma originated from the adenocarcinoma. The adenocarcinoma component stained positive for MUC2, which suggests that the adenocarcinoma component originated from Barrett's epithelium. Taken together, the neuroendocrine carcinoma may have originated from Barrett's epithelium. A metastasis to the liver was found 2 months after the surgical resection. Chemotherapy was administered, but there was no response. Most esophageal neuroendocrine carcinomas are accompanied by adenocarcinoma or squamous cell components, suggesting that these carcinomas originate from pluripotent cells in squamous or Barrett's epithelium. Appropriate chemotherapy for these lesions should be considered based on the cell of origin.

13.
Cancer Sci ; 110(7): 2284-2295, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31069869

RESUMO

Cell adhesion molecule-1 (CADM1) is a member of the immunoglobulin superfamily that functions as a tumor suppressor of lung tumors. We herein demonstrated that CADM1 interacts with Hippo pathway core kinases and enhances the phosphorylation of YAP1, and also that the membranous co-expression of CADM1 and LATS2 predicts a favorable prognosis in lung adenocarcinoma. CADM1 significantly repressed the saturation density elevated by YAP1 overexpression in NIH3T3 cells. CADM1 significantly promoted YAP1 phosphorylation on Ser 127 and downregulated YAP1 target gene expression at confluency in lung adenocarcinoma cell lines. Moreover, CADM1 was co-precipitated with multiple Hippo pathway components, including the core kinases MST1/2 and LATS1/2, suggesting the involvement of CADM1 in the regulation of the Hippo pathway through cell-cell contact. An immunohistochemical analysis of primary lung adenocarcinomas (n = 145) revealed that the histologically low-grade subtype frequently showed the membranous co-expression of CADM1 (20/22, 91% of low-grade; 61/91, 67% of intermediate grade; and 13/32, 41% of high-grade subtypes; P < 0.0001) and LATS2 (22/22, 100% of low-grade; 44/91, 48% of intermediate-grade; and 1/32, 3% of high-grade subtypes; P < 0.0001). A subset analysis of disease-free survival revealed that the membranous co-expression of CADM1 and LATS2 was a favorable prognosis factor (5-year disease-free survival rate: 83.8%), even with nuclear YAP1-positive expression (5-year disease-free survival rate: 83.7%), whereas nuclear YAP1-positive cases with the negative expression of CADM1 and LATS2 had a poorer prognosis (5-year disease-free survival rate: 33.3%). These results indicate that the relationship between CADM1 and Hippo pathway core kinases at the cell membrane is important for suppressing the oncogenic role of YAP1.


Assuntos
Molécula 1 de Adesão Celular/metabolismo , Membrana Celular/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Células NIH 3T3 , Gradação de Tumores , Fosforilação , Prognóstico , Análise Serial de Tecidos
14.
Front Immunol ; 10: 267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30842775

RESUMO

Endogenous plasma levels of the immunomodulatory carbohydrate-binding protein galectin-9 (Gal-9) are elevated during HIV infection and remain elevated after antiretroviral therapy (ART) suppression. We recently reported that Gal-9 regulates HIV transcription and potently reactivates latent HIV. However, the signaling mechanisms underlying Gal-9-mediated viral transcription remain unclear. Given that galectins are known to modulate T cell receptor (TCR)-signaling, we hypothesized that Gal-9 modulates HIV transcriptional activity, at least in part, through inducing TCR signaling pathways. Gal-9 induced T cell receptor ζ chain (CD3ζ) phosphorylation (11.2 to 32.1%; P = 0.008) in the J-Lat HIV latency model. Lck inhibition reduced Gal-9-mediated viral reactivation in the J-Lat HIV latency model (16.8-0.9%; P < 0.0001) and reduced both Gal-9-mediated CD4+ T cell activation (10.3 to 1.65% CD69 and CD25 co-expression; P = 0.0006), and IL-2/TNFα secretion (P < 0.004) in primary CD4+ T cells from HIV-infected individuals on suppressive ART. Using phospho-kinase antibody arrays, we found that Gal-9 increased the phosphorylation of the TCR-downstream signaling molecules ERK1/2 (26.7-fold) and CREB (6.6-fold). ERK and CREB inhibitors significantly reduced Gal-9-mediated viral reactivation (16.8 to 2.6 or 12.6%, respectively; P < 0.0007). Given that the immunosuppressive rapamycin uncouples HIV latency reversal from cytokine-associated toxicity, we also investigated whether rapamycin could uncouple Gal-9-mediated latency reactivation from its concurrent pro-inflammatory cytokine production. Rapamycin reduced Gal-9-mediated secretion of IL-2 (4.4-fold, P = 0.001) and TNF (4-fold, P = 0.02) without impacting viral reactivation (16.8% compared to 16.1%; P = 0.2). In conclusion, Gal-9 modulates HIV transcription by activating the TCR-downstream ERK and CREB signaling pathways in an Lck-dependent manner. Our findings could have implications for understanding the role of endogenous galectin interactions in modulating TCR signaling and maintaining chronic immune activation during ART-suppressed HIV infection. In addition, uncoupling Gal-9-mediated viral reactivation from undesirable pro-inflammatory effects, using rapamycin, may increase the potential utility of recombinant Gal-9 within the reversal of HIV latency eradication framework.

15.
Pathol Int ; 69(2): 86-93, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30729623

RESUMO

Bile duct cancer is known to contain numerous fibroblasts, and reported to recruit cancer- associated fibroblasts by secreting platelet-derived growth factor-D (PDGF-D) which needs serine proteases, such as matriptase, to behave as a ligand. However, their expression pattern, and prognostic value have not been clarified. In this study, we investigated the clinicopathological significance of PDGF-D and matriptase expression in patients with extrahepatic bile duct cancer. The samples were obtained from 256 patients who underwent the surgical resection between 1991 and 2015, and the expression levels of PDGF-D and matriptase were evaluated immunohistochemically. Staining intensities and distribution were scored, and finally classified into low and high expression groups in cancer cells and stroma respectively. High expression of matriptase in the cancer stroma was detected in 91 tumors (40%). The high stromal matriptase expression was significantly associated with shorter recurrence-free survival (RFS) and overall survival (OS) (P = 0.0027 and 0.0023, respectively). Multivariate analyses also demonstrated that the stromal matriptase expression level was an independent influential factor in RFS (P = 0.0050) and OS (P = 0.0093). Our findings suggest that the high stromal matriptase expression was strongly associated with tumor progression, recurrence and poor outcomes in patients with extrahepatic bile duct cancer.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/análise , Colangiocarcinoma/patologia , Serina Endopeptidases/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/mortalidade , Ductos Biliares Extra-Hepáticos/patologia , Colangiocarcinoma/enzimologia , Colangiocarcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfocinas/biossíntese , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Derivado de Plaquetas/biossíntese , Prognóstico
16.
Intern Med ; 58(9): 1335-1339, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30626819

RESUMO

Ewing's sarcoma (ES)/primitive neuroectodermal tumors (PNETs) are highly malignant neoplasms that usually affect the bones and soft tissues in children and young adults. ES/PNET of the lung is very rare and is associated with a poor prognosis. We herein report a case of ES/PNET of the left lung in a 45-year-old man. He was treated with neoadjuvant chemotherapy and pneumonectomy, but unfortunately his disease recurred 1.5 months after surgery. He was started on pazopanib, which resulted in a five-month progression-free survival. To our knowledge, this is the first demonstration of pazopanib efficacy in ES/PNET of the lung.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Pirimidinas/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Sulfonamidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Evolução Fatal , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Pneumonectomia/métodos , Intervalo Livre de Progressão , Sarcoma de Ewing/cirurgia , Resultado do Tratamento
17.
Clin J Gastroenterol ; 12(3): 223-230, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30617852

RESUMO

Congenital hepatic fibrosis (CHF), a fibropolycystic disease, is characterized by bile duct malformation, periportal fibrosis, and renal polycystic disease. Although cholangiocellular carcinoma is the primary tumor arising from fibropolycystic diseases, hepatocellular carcinoma (HCC) is extremely rare. In addition, no algorism for determining the optimum HCC treatment has yet been available in cases of fibropolycystic disease due to variations in the background liver and renal conditions. We herein report a patient with HCC arising from CHF that was successfully treated using radiofrequency ablation (RFA) under laparoscopic assistance. A 37-year-old man with CHF was admitted to our hospital for treatment of HCC in 2014. Imaging revealed HCC located in hepatic segments II and VIII with diameters of 28 and 24 mm, respectively. There had been no histories of recurrent cholangitis or renal failure after when CHF was diagnosed in 2003. In addition, esophageal varices were well controlled. We achieved sufficient ablation using a bipolar ablation system without any complications. The post-operative course was uneventful, and the patient was free from HCC for 4 years. Thus, locoregional therapy, including RFA, is acceptable for the treatment of HCC arising from CHF when the background liver and kidney are preserved.


Assuntos
Carcinoma Hepatocelular/cirurgia , Doenças Genéticas Inatas/complicações , Cirrose Hepática/complicações , Neoplasias Hepáticas/cirurgia , Ablação por Radiofrequência , Adulto , Carcinoma Hepatocelular/etiologia , Humanos , Laparoscopia , Neoplasias Hepáticas/etiologia , Masculino
18.
CEN Case Rep ; 8(2): 95-100, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30565047

RESUMO

Measurement of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio may be clinically useful to discriminate systemic lupus erythematosus (SLE) from preeclampsia. Here, we present a pregnant woman with new-onset SLE with hypertension, with the measurement of the sFlt-1/PlGF ratio during pregnancy. A 31-year-old Japanese nulliparous woman, who had been diagnosed with idiopathic thrombocytopenic purpura at 10 years, had a systolic blood pressure of 120 mmHg and was negative for proteinuria at 12+1 weeks. Since her blood pressure increased to 159/86 mmHg with 3+ proteinuria at 25+4 weeks, preeclampsia was suspected. Deterioration of the kidney function (creatinine: 0.58 mg/dL at 24+6 weeks to 0.83 mg/dL at 33+6 weeks) necessitated cesarean section at 33+6 weeks. After delivery, she still showed increased creatinine and proteinuria. Therefore, she was transferred to a nephrology specialist in a tertiary center and was finally diagnosed with SLE with lupus nephritis class IV-G(A) (diffuse lupus nephritis). The serum levels of sFlt-1 and the sFlt-1/PlGF ratio, which are usually elevated in preeclampsia, were within normal reference ranges at 27+6, 28+1, and 28+6 weeks of gestation, although the serum levels of PlGF were slightly lower than the normal reference range. In conclusion, measurement of the sFlt-1/PlGF ratio may be clinically useful to discriminate lupus nephritis from preeclampsia.

19.
Medicine (Baltimore) ; 97(49): e13466, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30544433

RESUMO

Little is known concerning the prognostic significance of the degree of lymphatic vessel invasion in pancreatic head cancer. To address this gap in knowledge, we retrospectively examined 60 patients with locally advanced, surgically resectable pancreatic head cancer who underwent pancreaticoduodenectomy and lymph node (LN) dissection.All cases were histopathologically diagnosed as ductal adenocarcinoma, stage II (25 pT3N0 cases, 35 pT3N1 cases). The following variables were investigated: age; sex; neoadjuvant therapy; adjuvant therapy; tumor size; tumor grade; invasion into the serosa, retropancreatic tissue, duodenum, bile duct, portal venous system and perineural area; cut margins; LN metastasis; and the number of invaded lymphatic vessels (LVI-score).Univariate analysis demonstrated that LN metastasis and an LVI-score ≥5 were significantly associated with poor disease-free survival. Multivariate Cox regression analysis confirmed that LN metastasis and an LVI-score ≥7 were significantly associated with poor disease-free survival. Additionally, LVI-scores ≥9 and ≥10 were comparable to or surpassed the significance of LN metastasis based on the hazard ratio. Univariate analysis demonstrated that tumor size >30 mm, duodenal invasion, LN metastasis and an LVI-score ≥2 were significantly associated with poor overall survival. Multivariate Cox regression analysis confirmed that LN metastasis and LVI-scores ≥9 and ≥10 were significantly associated with poor overall survival, and an LVI-score ≥10 was comparable to or surpassed the significance of LN metastasis based on the hazard ratio.Our study strongly suggests that a high degree of lymphatic vessel invasion is associated with a poor prognosis in patients with locally advanced, surgically resectable pancreatic head cancer.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/cirurgia , Metástase Linfática/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia , Prognóstico , Estudos Retrospectivos
20.
Cell Physiol Biochem ; 50(5): 1856-1868, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30396167

RESUMO

BACKGROUND/AIMS: Galectin-9 is a soluble immune modulator with versatile functions, including a role as an immune checkpoint molecule. Therefore, the amount of galectin-9 in the blood may reflect an individual's immunological balance. Many studies have conducted galectin-9 measurements; however, the reported galectin-9 concentration in the blood varies greatly, even within healthy controls. This study investigates the variation between the reported and actual concentrations of galectin-9. METHODS: A GalPharma ELISA and an R&D Systems ELISA kit were directly compared using the same set of plasma and a series of recombinant galectins, including degraded galectin-9. Furthermore, galectin-9 in plasma was concentrated using anti-galectin-9 antibody-conjugated beads, and subjected to western blotting to estimate the quantity and integrity of galectin-9 and assess the consistency of ELISA measurements. RESULTS: The R&D Systems' ELISA indicated a 50-fold higher median concentration of plasma galectin-9 than that indicated by the GalPharma ELISA. This variation is due to aberrantly enhanced reactivity of the R&D Systems' ELISA to degraded galectin-9 present in small quantities in the plasma. The GalPharma ELISA could detect only intact galectin-9 and its results correlated well with the plasma galectin-9 level obtained by western blotting. CONCLUSION: ELISA kits from R&D Systems reacts aberrantly higher against degraded galectin-9 than the intact galectin-9. Therefore, the existence of a small amount of degraded galectin-9 in a test sample hinders the quantification. As galectin-9 is a fragile protein, this is a serious concern when using this kit. Based on quantifications from the GalPharma ELISA, the median (25th-75th percentiles) galectin-9 concentration in healthy subjects in the current study cohort was calculated as 110 pg/mL (67 -154 pg/mL).


Assuntos
Galectinas/sangue , Falência Hepática Aguda/sangue , Ensaio de Imunoadsorção Enzimática , Galectinas/metabolismo , Humanos , Limite de Detecção , Falência Hepática Aguda/diagnóstico , Kit de Reagentes para Diagnóstico
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