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1.
Front Immunol ; 13: 779574, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35173715

RESUMO

Decidualization of endometrial stromal cells and the presence of immunocompetent cells, including human mast cells, play important roles in the establishment of pregnancy. In the present study, the effects of decidualization of endometrial stromal cells on the function of decidual mast cells were elucidated. The in vitro assay revealed that decidualization of an endometrial stromal cell line, T HESCs, increased stem cell factor (SCF) mRNA expression. Decidualization of T HESCs enhanced the production of leukemia inhibitory factor (LIF), and the migration of LAD2 cells when co-cultured with T HESCs and LAD2 cells. In addition, decidualization of T HESCs enhanced cell migration in a human trophoblast cell line, HTR-8/SVneo, increased CD9 expression, a marker for extravillous trophoblast (EVT) differentiation, and decreased the secretion of ß human chorionic gonadotropin (hCG), a marker for syncytiotrophoblast (ST) differentiation, when co-cultured with T HESCs, LAD2 cells, and HTR-8/SVneo cells, in a LIF-dependent manner. Histological samples from uterine pregnancies, including decidual stromal cells, showed increased SCF mRNA expression, mast cell numbers and LIF mRNA expression thereof compared with tubal pregnancy. SCF produced by decidual stromal cells enhanced the migration and LIF production of mast cells, and promoted the migration and differentiation of trophoblasts to increase the likelihood of successful human pregnancy.


Assuntos
Decídua/metabolismo , Fator Inibidor de Leucemia/metabolismo , Mastócitos/metabolismo , Fator de Células-Tronco/metabolismo , Células Estromais/metabolismo , Adulto , Diferenciação Celular , Linhagem Celular , Movimento Celular , Técnicas de Cocultura , Decídua/citologia , Feminino , Humanos , Fator Inibidor de Leucemia/genética , Gravidez , Trofoblastos/metabolismo
2.
J Invest Dermatol ; 142(3 Pt A): 571-582.e9, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34560074

RESUMO

Surfactant-induced cumulative irritant contact dermatitis (ICD) is a common and clinically important skin disorder. CCL2 is known to mediate inflammation after tissue damage in various organs. Thus, we investigated whether and how CCL2 contributes to the development of murine cumulative ICD induced by a common surfactant, SDS. Wild-type mice treated topically with SDS for 6 consecutive days developed skin inflammation that recapitulated the features of human cumulative ICD, including barrier disruption, epidermal thickening, and neutrophil accumulation. CCL2 was upregulated in SDS-treated skin, and local CCL2 blockade attenuated SDS-induced ICD. SDS-induced ICD and neutrophil accumulation were also attenuated in mice deficient in CCR2, the receptor for CCL2. Neutrophil depletion alleviated SDS-induced ICD, suggesting that impaired neutrophil accumulation was responsible for the amelioration of ICD in CCR2-deficient mice. In RNA-sequencing analyses of SDS-treated skin, the expression levels of Il1b in Ccr2-deficient mice were highly downregulated compared with those in wild-type mice. Furthermore, the intradermal administration of IL-1ß in the SDS-treated skin of CCR2-deficient mice restored the local accumulation of neutrophils and the development of ICD. Collectively, our results suggest that CCL2‒CCR2 signaling in the skin critically promotes the development of SDS-induced ICD by inducing IL-1ß expression for neutrophil accumulation.

3.
Cancer Sci ; 113(2): 529-539, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34902205

RESUMO

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph+ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph+ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph+ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph+ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph+ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph+ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph+ ALL.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/genética , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Mutação , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/farmacologia
4.
Tohoku J Exp Med ; 255(1): 27-31, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34497165

RESUMO

Langerhans cell neoplasms, which include Langerhans cell histiocytosis and Langerhans cell sarcoma, are tumors that originate from dendritic cells. Langerhans cell sarcoma is defined as a high-grade neoplasm with overtly malignant cytological features and the Langerhans cell-like phenotype, and generally has a poorer prognosis and more aggressive phenotype than Langerhans cell histiocytosis. Insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types; its expression is often associated with a poor prognosis and aggressive phenotype. Here, we used immunohistochemistry to evaluate IGF2BP3 expression in Langerhans cell neoplasms. IGF2BP3 expression was scored as negative (< 1%) or positive (≥ 1%) by immunohistochemistry. All 4 patients with Langerhans cell sarcoma (100%) and 6 of 22 pediatric (age < 18 years) patients with Langerhans cell histiocytosis (27.3%) had positive results for IGF2BP3; however, 16 of 22 pediatric patients with Langerhans cell histiocytosis (72.7%) and all 15 adult (age ≥ 18 years) patients with Langerhans cell histiocytosis (100%) had a negative result. Among patients with Langerhans cell histiocytosis, IGF2BP3 expression was independent of sex, location, prognosis, and BRAF V600E staining results. Taken together, these results indicate that IGF2BP3 expression may be a helpful marker for distinguishing Langerhans cell sarcoma from Langerhans cell histiocytosis in adult patients.


Assuntos
Histiocitose de Células de Langerhans/metabolismo , Sarcoma de Células de Langerhans/metabolismo , Proteínas de Ligação a RNA/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Histiocitose de Células de Langerhans/diagnóstico , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Sarcoma de Células de Langerhans/diagnóstico , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Jpn J Radiol ; 39(9): 857-867, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34021462

RESUMO

Granulocyte colony-stimulating factor (G-CSF)-producing tumors have an aggressive clinical course. Here, we report five cases of G-CSF-producing tumors and review the literature, focusing on imaging findings related to tumor-produced G-CSF. In addition to our cases, we identified 30 previous reports of G-CSF-producing tumors on which 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT, bone scintigraphy, or evaluation of bone marrow MR findings was performed. White blood cell count, serum C-reactive protein, and serum interleukin-6 were elevated in all cases for which these parameters were measured. G-CSF-producing tumors presented large necrotic masses (mean diameter 83.2 mm, range 17-195 mm) with marked FDG uptake (mean maximum standardized uptake value: 20.09). Diffuse FDG uptake into the bone marrow was shown in 28 of the 31 cases in which FDG-PET/CT was performed. The signal intensity of bone marrow suggested marrow reconversion in all seven MRI-assessable cases. Bone scintigraphy demonstrated no significant uptake, except in two cases with bone metastases. Splenic FDG uptake was increased in 8 of 10 cases in which it was evaluated. These imaging findings may reflect the effects of tumor-produced G-CSF. The presence of G-CSF-producing tumors should be considered in patients with cancer who show these imaging findings and marked inflammatory features of unknown origin.


Assuntos
Neoplasias Ósseas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Fator Estimulador de Colônias de Granulócitos , Humanos , Tomografia Computadorizada por Raios X
6.
Sci Rep ; 11(1): 10112, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980938

RESUMO

This study aimed to evaluate the predictions of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for prognosis of triple-negative breast cancer (TNBC), especially with residual disease (RD) after preoperative chemotherapy. This retrospective analysis included 74 TNBC patients who received preoperative chemotherapy. DCE-MRI findings from three timepoints were examined: at diagnosis (MRIpre), at midpoint (MRImid) and after chemotherapy (MRIpost). These findings included cancer lesion size, washout index (WI) as a kinetic parameter using the difference in signal intensity between early and delayed phases, and time-signal intensity curve types. Distant disease-free survival was analysed using the log-rank test to compare RD group with and without a fast-washout curve. The diagnostic performance of DCE-MRI findings, including positive predictive value (PPV) for pathological responses, was also calculated. RD without fast washout curve was a significantly better prognostic factor, both at MRImid and MRIpost (hazard ratio = 0.092, 0.098, p < 0.05). PPV for pathological complete remission at MRImid was 76.7% by the cut-off point at negative WI value or lesion size = 0, and 66.7% at lesion size = 0. WI and curve types derived from DCE-MRI at the midpoint of preoperative chemotherapy can help not only assess tumour response but also predict prognosis.


Assuntos
Imageamento por Ressonância Magnética/métodos , Neoplasia Residual/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Idoso , Antineoplásicos/uso terapêutico , Meios de Contraste/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Cinética , Imageamento por Ressonância Magnética/instrumentação , Pessoa de Meia-Idade , Neoplasia Residual/química , Neoplasia Residual/mortalidade , Neoplasia Residual/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
7.
Breast Cancer Res Treat ; 188(1): 117-131, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33763789

RESUMO

PURPOSE: To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients. METHODS: Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety. RESULTS: The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively. CONCLUSIONS: In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina/uso terapêutico , Feminino , Furanos , Recombinação Homóloga , Humanos , Japão , Cetonas , Terapia Neoadjuvante , Paclitaxel/uso terapêutico , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
9.
J Allergy Clin Immunol ; 148(2): 563-573.e7, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33581199

RESUMO

BACKGROUND: The programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8+ T cells. However, just how this regulatory pathway is involved in the pathophysiology of CD8+ T-cell-mediated inflammatory skin diseases remains unclear. OBJECTIVE: Our aim was to elucidate the mechanisms by which the PD-1/PD-L1 pathway exerts its regulatory roles in CD8+ T-cell-mediated cutaneous immune responses. METHODS: PD-L1-deficient (Pdl1-/-) mice were used for the murine contact hypersensitivity model. Inflammatory responses such as IFN-γ production from CD8+ T cells in the skin was evaluated by flow cytometry. RESULTS: Compared with wild-type mice, Pdl1-/- mice exhibited exacerbated ear swelling and increased numbers of IFN-γ+ CD8+ T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant cells in the skin, PD-L1 was most highly expressed on mast cells (MCs) before and after elicitation. Administration of anti-PD-L1 blocking antibody during the elicitation phase significantly enhanced ear swelling responses and increased the number of IFN-γ+CD8+ T cells in the skin of wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-KitW/KitW-v/J and C57BL/6-KitW-sh/W-sh) mice. The high level of expression of PD-L1 on human skin MCs was confirmed by database analysis and immunohistochemical analysis. CONCLUSION: PD-L1 on MCs negatively regulates CD8+ T-cell activation in the skin.


Assuntos
Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Dermatite de Contato/imunologia , Ativação Linfocitária , Pele/imunologia , Animais , Antígeno B7-H1/genética , Linfócitos T CD8-Positivos/patologia , Dermatite de Contato/genética , Dermatite de Contato/patologia , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Pele/patologia
10.
Pathol Int ; 71(3): 191-198, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33497038

RESUMO

The neonatal Fc receptor (FcRn) plays a role in trafficking IgG and albumin and is thought to mediate intravenous immunoglobulin (IVIG) therapy for certain diseases. IVIG can be used for the treatment of human Langerhans cell histiocytosis (LCH); however, the mechanism remains unclear. The expression and function of FcRn protein have not been studied in LCH, though the expression of FcRn messenger RNA (mRNA) have been reported. In this report, we confirmed the expression of FcRn in 26 of 30 pathological cases (86.7%) diagnosed immunohistochemically as LCH. The expression was independent of age, gender, location, multi- or single-system, and the status of BRAFV600E immunostaining. We also confirmed the expression of FcRn mRNA and protein in the human LCH-like cell line, ELD-1. FcRn suppressed albumin consumption and growth of IVIG preparation-treated ELD-1 cells, but not of IVIG preparation-untreated or FcRn-knockdown ELD-1 cells. In addition, FITC-conjugated albumin was taken into Rab11-positive recycle vesicles in mock ELD-1 cells but not in FcRn-knockdown ELD-1 cells. IVIG preparation prolonged this status in mock ELD-1 cells. Therefore, ELD-1 recycled albumin via FcRn and albumin was not used for metabolism. Our results increase our understanding of the molecular mechanism of IVIG treatment of LCH.


Assuntos
Histiocitose de Células de Langerhans , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoglobulinas Intravenosas , Receptores Fc/metabolismo , Adolescente , Adulto , Albuminas/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Feminino , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/metabolismo , Humanos , Imunoglobulinas Intravenosas/metabolismo , Imunoglobulinas Intravenosas/farmacologia , Lactente , Recém-Nascido , Masculino , Albumina Sérica/metabolismo
11.
Cancer Immunol Immunother ; 70(3): 817-830, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33000417

RESUMO

Among several mechanisms for the resistance of human epidermal growth factor receptor 2-overexpressing (HER2 +) cancer cells to trastuzumab, little is known regarding the mechanism underlying the resistance to trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Cell death due to ADCC is caused by apoptosis of target cells induced by granzymes released from natural killer cells. Because optimal granzyme physiological activity occurs at neutral pH, we assumed that the pH of the intracellular environment influences the cytotoxic effects of granzymes. We established ADCC-resistant cells and compared them with wild-type cells in terms of the expression of intracellular pH-regulating genes. The expression of ATP6V1B1, which encodes a component of vacuolar ATPases, was downregulated in the ADCC-resistant cells. Thus, to functionally characterize ATP6V1B1, we used a CRISPR/Cas9 system to generate ATP6V1B1-knockout SKBR3 and JIMT-1 cells (both HER2 + human breast cancer cell line). The resulting cells exhibited significantly less ADCC than the control SKBR3 and JIMT-1 cells. The intracellular pH of the ATP6V1B1-knockout SKBR3 and JIMT-1 cells was significantly lower than control SKBR3 and JIMT-1cells. An analysis of granzyme dynamics during the ADCC reaction in cancer cells revealed that granzymes degraded intracellularly in the control SKBR3 and JIMT-1 cells and accumulated in ATP6V1B1-knockout cells, but were not cytotoxic. These findings suggest that decreased vacuolar ATPase activity alters the cytoplasmic pH of cancer cells to create an environment that is less suitable for granzyme bioactivity, which adversely affects the induction of apoptosis of cancer cells by NK cells.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , ATPases Vacuolares Próton-Translocadoras/genética , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células , Imunofluorescência , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Concentração de Íons de Hidrogênio , Imuno-Histoquímica , Espaço Intracelular/metabolismo , Terapia Neoadjuvante , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resultado do Tratamento , ATPases Vacuolares Próton-Translocadoras/metabolismo
12.
Clin Cancer Res ; 27(6): 1756-1765, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323405

RESUMO

PURPOSE: Extramammary Paget disease (EMPD) is an uncommon skin malignancy whose genetic alterations are poorly characterized. Previous reports identified mutations in chromatin remodeling genes and PIK3CA. In order to unambiguously determine driver mutations in EMPD, we analyzed 87 EMPD samples using exome sequencing in combination with targeted sequencing. EXPERIMENTAL DESIGN: First, we analyzed 37 EMPD samples that were surgically resected using whole-exome sequencing. Based on several in silico analysis, we built a custom capture panel of putative driver genes and analyzed 50 additional formalin-fixed, paraffin-embedded samples using target sequencing. ERBB2 expression was evaluated by HER2 immunohisotochemistry. Select samples were further analyzed by fluorescence in situ hybridization. RESULTS: A median of 92 mutations/sample was identified in exome analysis. A union of driver detection algorithms identified ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 as likely driver mutations. Copy-number alteration analysis showed regions spanning CDKN2A as recurrently deleted, and ERBB2 as recurrently amplified. ERBB2, ERBB3, and FGFR1 amplification/mutation showed tendency toward mutual exclusivity. Copy-number alteration load was associated with likelihood to recur. Mutational signatures were dominated by aging and APOBEC activation and lacked evidence of ultraviolet radiation. HER2 IHC/fluorescence in situ analysis validated ERBB2 amplification but was underpowered to detect mutations. Tumor heterogeneity in terms of ERBB2 amplification status was observed in some cases. CONCLUSIONS: Our comprehensive, unbiased analysis shows EMPD is characterized by alterations involving the PI3K-AKT pathway. EMPD is distinct from other skin cancers in both molecular pathways altered and etiology behind mutagenesis.


Assuntos
Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Mutação , Recidiva Local de Neoplasia/genética , Doença de Paget Extramamária/genética , Receptor ErbB-2/metabolismo , Amplificação de Genes , Humanos , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Doença de Paget Extramamária/metabolismo , Doença de Paget Extramamária/patologia , Prognóstico , Receptor ErbB-2/genética , Taxa de Sobrevida , Sequenciamento Completo do Exoma
13.
Pediatr Blood Cancer ; 68(2): e28789, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33180377

RESUMO

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive pediatric malignancy primarily affecting infants and young children. Intensive multimodal therapies currently given to MRT patients are not sufficiently potent to control this highly malignant tumor. Therefore, additive or alternative therapy for these patients with a poor prognosis is necessary. We herein demonstrated that the inhibition of runt-related transcription factor 1 (RUNX1) by novel alkylating conjugated pyrrole-imidazole (PI) polyamides, which specifically recognize and bind to RUNX-binding DNA sequences, was highly effective in the treatment of rhabdoid tumor cell lines in vitro as well as in an in vivo mouse model. Therefore, suppression of RUNX1 activity may be a novel strategy for MRT therapy.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Clorambucila/uso terapêutico , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Tumor Rabdoide/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Clorambucila/análogos & derivados , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Interferência de RNA , RNA Interferente Pequeno/genética , Proteína SMARCB1/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Pathol Int ; 70(11): 888-892, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32936992

RESUMO

Kasai operation is widely performed for biliary atresia (BA), as it improves the prognosis. Biliary tract cancer has rarely been reported as a complication after Kasai operation. A 17-year-old man underwent liver transplantation for progressive jaundice and liver dysfunction after Kasai operation for BA. A macroscopic examination of the explanted liver revealed a 3.6-cm-diameter mass in the hilus of the explanted liver. The tumor consisted of an atypical proliferation of glandular cells in the collagenous stroma. The differential diagnosis included a florid ductular reaction and primary adenocarcinoma. Immunohistochemistry revealed that the glandular cells were diffusely positive for IGF2BP3 and S100P, but negative for CDX2. A diagnosis of extrahepatic cholangiocarcinoma arising from the liver hilus was made. To our knowledge, this is the third case of perihilar cholangiocarcinoma after Kasai operation for BA. The previously reported cases had a poor prognosis, but the current case did not recur during a 15-year follow-up. Cholangiocarcinoma and hepatocellular carcinoma can occur as a late complication of BA after Kasai operation, and early detection and liver transplantation may improve the prognosis.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Atresia Biliar/cirurgia , Tumor de Klatskin/cirurgia , Recidiva Local de Neoplasia/cirurgia , Adolescente , Neoplasias dos Ductos Biliares/complicações , Ductos Biliares Intra-Hepáticos/cirurgia , Atresia Biliar/complicações , Atresia Biliar/diagnóstico , Humanos , Tumor de Klatskin/complicações , Fígado/cirurgia , Masculino , Recidiva Local de Neoplasia/diagnóstico
15.
Diagn Pathol ; 15(1): 26, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32293476

RESUMO

BACKGROUND: Insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types, and its expression is often associated with poor prognosis. IGF2BP3 expression has not been fully settled in vascular lesions. METHODS: We evaluated the expression of IGF2BP3 in malignant (angiosarcoma and epithelioid hemangioendothelioma [EHE]) and benign (hemangioma, granulation tissue cappilaries, and pyogenic granuloma) vascular lesions using immunohistochemistry. IGF2BP3 expression was scored as negative (0% of endothelial/neoplastic cells), equivocal (1-25%), or positive (> 26%). RESULTS: Eight of 30 (26.7%) cases of angiosarcoma and two of five (40%) cases of epithelioid hemangioendothelioma were positive for IGF2BP3. In contrast, hemangiomas (10 cases) and granulation tissue capillaries (12 cases) were all negative for IGF2BP3, and some cases of pyogenic granuloma (six of 14 cases) was scored as equivocal. In angiosarcoma, IGF2BP3 expression was independent of age, gender, location, morphological pattern, prognosis, presence of metastatic foci, and PD-L1 expression. CONCLUSIONS: IGF2BP3 is a useful marker to distinguish between malignant and benign vascular lesions.


Assuntos
Biomarcadores Tumorais/análise , Hemangioendotelioma Epitelioide/diagnóstico , Hemangiossarcoma/diagnóstico , Proteínas de Ligação a RNA/biossíntese , Doenças Vasculares/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/análise , Adulto Jovem
16.
Pathol Int ; 70(7): 413-421, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32304153

RESUMO

Immunohistochemically p16 (CDKN2A)-negative uterine cervical squamous cell carcinoma (SCC) is uncommon, and there are few reports about its pathological features. This study explored the causes of p16 negativity in such cases. We analyzed diagnostic tissue samples of five cases of p16-negative cervical SCC among 107 patients who underwent hysterectomy at Kyoto University Hospital between January 2010 and December 2015. The samples were subjected to immunohistochemical staining, in situ hybridization and a genetic analysis. Two of five cases were positive for human papilloma virus (HPV) by genotyping. One was positive for HPV56 with promoter hypermethylation of CDKN2A and co-existing Epstein-Barr virus infection. Another was positive for HPV6 categorized as low-risk HPV with condylomatous morphology. Among the remaining three cases, one had amplification of the L1 gene of HPV with promoter hypermethylation of CDKN2A and TP53 mutation, and one of the other two HPV-negative cases had a homozygous CDKN2A deletion, while the other was positive for p53 and CK7. p16-negativity of cervical SCC is often associated with an unusual virus infection status and CDKN2A gene abnormality.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia
17.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023940

RESUMO

Killer immunoglobulin-like receptor (KIR) 2DL4 (CD158d) was previously thought to be a human NK cell-specific protein. Mast cells are involved in allergic reactions via their KIT-mediated and FcɛRI-mediated responses. We recently detected the expression of KIR2DL4 in human cultured mast cells established from peripheral blood of healthy volunteers (PB-mast), in the human mast cell line LAD2, and in human tissue mast cells. Agonistic antibodies against KIR2DL4 negatively regulate the KIT-mediated and FcɛRI-mediated responses of PB-mast and LAD2 cells. In addition, agonistic antibodies and human leukocyte antigen (HLA)-G, a natural ligand for KIR2DL4, induce the secretion of leukemia inhibitory factor and serine proteases from human mast cells, which have been implicated in pregnancy establishment and cancer metastasis. Therefore, KIR2DL4 stimulation with agonistic antibodies and recombinant HLA-G protein may enhance both processes, in addition to suppressing mast-cell-mediated allergic reactions.


Assuntos
Mastócitos/metabolismo , Metástase Neoplásica/genética , Receptores KIR2DL4/genética , Receptores KIR2DL4/metabolismo , Feminino , Regulação da Expressão Gênica , Antígenos HLA-G/metabolismo , Humanos , Fator Inibidor de Leucemia/metabolismo , Gravidez , Serina Proteases/metabolismo
18.
Sci Rep ; 10(1): 2505, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054954

RESUMO

Signaling lymphocytic activation molecule family member 8 (SLAMF8) / B-lymphocyte activator macrophage expressed/CD353 is a member of the CD2 family. SLAMF8 suppresses macrophage function but enhances the growth of neoplastic mast cells via SHP-2. In this study, we found that some anaplastic large cell lymphoma (ALCL) samples were immunohistochemically positive for SLAMF8. However, we found no significant differences between SLAMF8-positive and SLAMF8-negative ALCL samples with respect to age, gender, site, or prognosis. We also identified SLAMF8 expression in ALCL cell lines, Karpas299, and SU-DHL-1. SLAMF8 knockdown decreased the activation of SHP-2 and the growth of these cell lines, and increased the apoptosis of these cell lines. In addition, we observed the interaction between SLAMF8 and SHP-2 in these cell lines using the DuoLink in situ kit. Taken together, these results suggest that SLAMF8 may enhance the growth of ALCL via SHP-2 interaction.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Anaplásico de Células Grandes/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Adolescente , Adulto , Idoso , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Criança , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Pessoa de Meia-Idade , Família de Moléculas de Sinalização da Ativação Linfocitária/análise , Adulto Jovem
19.
Breast Cancer Res Treat ; 180(1): 135-146, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31953696

RESUMO

PURPOSE: The standard of care in the neoadjuvant setting for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is dual HER2-targeted therapy. However, a need to minimize treatment-related toxicity and improve pathological complete response (pCR) rates, particularly in luminal HER2-positive disease, exists. METHODS: Neopeaks, a randomized, phase 2 study, compared docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP; 6 cycles; group A), TCbHP (4 cycles) followed by trastuzumab emtansine + pertuzumab (T-DM1+P; 4 cycles; group B), and T-DM1+P (4 cycles; group C) regimens in HER2-positive primary breast cancer patients; concurrent hormone therapy with T-DM1+P was administered in case of estrogen receptor positivity (ER+). Based on tumor shrinkage, nonresponders in group C were switched to 5-fluorouracil + epirubicin + cyclophosphamide (FEC; 4 cycles). Primary endpoint was pCR (comprehensive pCR ypN0 [ypT0-TisypN0]). RESULTS: Of 236 patients enrolled, 204 were randomized to groups A (n = 51), B (n = 52), and C (n = 101). In group C, 80 (79%) patients continued T-DM1+P following favorable response, whereas 21 (21%) nonresponders switched to FEC. pCR rate was numerically higher with the TCbHP → T-DM1+P regimen (71%) versus the standard TCbHP (57%) and T-DM1+P (57%) regimens. The rate in group C was higher among responders continuing T-DM1+P (63%) versus nonresponders who switched to FEC (38%). pCR rates after initial 4 cycles of T-DM1+P (group C; 57%) and standard TCbHP regimen (57%) were equivalent. pCR rate in patients with ER+ was significantly higher in group B (69%) than groups A (43%) and C (51%), but was comparable in patients with ER- (67-76%). Compared with the T-DM1-based arm, the incidence of adverse events was higher in the taxane-based arms. CONCLUSION: In the neoadjuvant setting, the pCR rate with the standard TCbHP → T-DM1+P regimen was numerically better than the TCbHP regimen alone and significantly better in patients with ER+. Personalization of the T-DM1+P regimen could serve as a reasonable approach to minimize toxicity while maintaining efficacy. Trial registration ID: UMIN-CTR: UMIN000014649.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Carboplatina/administração & dosagem , Terapia Combinada , Feminino , Humanos , Imageamento por Ressonância Magnética , Maitansina/administração & dosagem , Terapia Neoadjuvante , Receptor ErbB-2/genética , Retratamento , Trastuzumab/administração & dosagem , Resultado do Tratamento
20.
Pathol Int ; 70(11): 881-887, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33410565

RESUMO

Langerhans cell sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytological features and a Langerhans cell phenotype. The underlying genetic features are poorly understood, and only a few alterations, such as those of the MARK pathway-related genes, CDKN2A and TP53 have been reported. Here we present a 70-year-old male with LCS on the scalp and pulmonary metastasis. The multinodular tumor, 3.0 cm in diameter, consisted of diffusely proliferated pleomorphic cells with numerous mitoses (53/10 HPFs). Immunohistochemically, the tumor cells were positive for CD1a, Langerin and PD-L1, and the Ki-67 labeling index was 50%. These pathological features were consistent with LCS, and were also observed in the metastatic tumor. Whole-exome sequencing revealed that both the primary and metastatic tumors harbored a large number of mutations (>20 mutations/megabase), with deletion of CDKN2A and TP53 mutation, and highlighted that the mutational signature was predominantly characteristic of ultraviolet (UV) exposure (W = 0.828). Our results suggest, for the first time, that DNA damage by UV could accumulate in Langerhans cells and play a role in the pathogenesis of LCS. The high mutational burden and PD-L1 expression in the tumor would provide a rationale for the use of immune checkpoint inhibitors for treatment of unresectable LCS.


Assuntos
Histiocitose de Células de Langerhans/patologia , Sarcoma de Células de Langerhans/patologia , Sequenciamento Completo do Exoma , Idoso , Antígenos CD1/metabolismo , Biomarcadores Tumorais/genética , Histiocitose de Células de Langerhans/diagnóstico , Humanos , Sarcoma de Células de Langerhans/diagnóstico , Masculino , Mutação/genética , Couro Cabeludo/metabolismo , Couro Cabeludo/patologia , Sequenciamento Completo do Exoma/métodos
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