RESUMEN
Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.
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Neoplasias de la Mama , Linaje de la Célula , Células Clonales , Evolución Molecular , Mutagénesis , Mutación , Adolescente , Adulto , Femenino , Humanos , Adulto Joven , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Linaje de la Célula/genética , Células Clonales/metabolismo , Células Clonales/patología , Epigénesis Genética , Células Epiteliales/citología , Células Epiteliales/metabolismo , Epitelio/patología , Microdisección , Tasa de Mutación , Premenopausia , Microambiente TumoralRESUMEN
T-cell recruitment to skin tissues is essential for inflammation in different cutaneous diseases; however, the mechanisms by which these T cells access the skin remain unclear. High endothelial venules expressing peripheral node address in (PNAd), an L-selectin ligand, are located in secondary lymphoid organs and are responsible for increasing T-cell influx into the lymphoid tissues. They are also found in non-lymphoid tissues during inflammation. However, their presence in different common inflammatory cutaneous diseases and their correlation with T-cell infiltration remain unclear. Herein, we explored the mechanisms underlying the access of T cells to the skin by investigating the presence of PNAd-expressing vessels in different cutaneous diseases, and its correlation with T cells' presence. Skin sections of 43 patients with different diseases were subjected to immunohistochemical and immunofluorescence staining to examine the presence of PNAd-expressing vessels in the dermis. The correlation of the percentage of these vessels in the dermis of these patients with the severity/grade of CD3+ T-cell infiltration was assessed. PNAd-expressing vessels were commonly found in the skin of patients with different inflammatory diseases. A high percentage of these vessels in the dermis was associated with increased severity of CD3+ T-cell infiltration (Pâ <â 0.05). Additionally, CD3+ T cells were found both around the PNAd-expressing vessels and within the vessel lumen. PNAd-expressing vessels in cutaneous inflammatory diseases, characterized by CD3+ T-cell infiltration, could be a crucial entry point for T cells into the skin. Thus, selective targeting of these vessels could be beneficial in cutaneous inflammatory disease treatment.
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Piel , Linfocitos T , Humanos , Vénulas , Inflamación , DermisRESUMEN
Antibody-secreting cells (ASCs) produce immunoglobulin (Ig) G and IgE autoantibodies in secondary lymphoid organs. Evidence also suggests their existence in the skin in various chronic inflammatory conditions, and in association with CXCL12 and CXCL13, they regulate the recruitment/survival of ASCs and germinal center formation to generate ASCs, respectively. However, the presence of IgG and IgE in bullous pemphigoid (BP) lesions needs to be addressed. Here, we aimed to analyse BP skin for the presence of IgG and IgE and the factors contributing to their generation, recruitment, and persistence. Skin samples from 30 patients with BP were stained to identify ASCs and the immunoglobulin type they expressed. The presence of tertiary lymphoid organ (TLO) elements, which generate ASCs in non-lymphoid tissues, and the chemokines CXCL12 and CXCL13, which regulate the migration/persistence of ASCs in lymphoid tissues and formation of TLOs, respectively, were evaluated in BP skin. BP skin harboured ASCs expressing the two types of antibodies IgG and IgE. ASCs were found in high-grade cellular aggregates containing TLO elements: T cells, B cells, CXCL12+ cells, CXCL13+ cells and high endothelial venules. IgG+ ASCs were detected among these aggregates, whereas IgE+ ASCs were dispersed throughout the dermis. CXCL12+ fibroblast-like cells were located close to ASCs. The inflammatory microenvironment of BP lesions may contribute to the antibody load characteristic of the skin of patients with BP by providing a site for the presence of ASCs. CXCL13 and CXCL12 expression may contribute to the generation and recruitment/survival of ASCs, respectively.
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Penfigoide Ampolloso , Humanos , Inmunoglobulina E/metabolismo , Vesícula , Autoanticuerpos/metabolismo , Inmunoglobulina G/fisiología , Linfocitos B , Dermis/metabolismo , Autoantígenos , Colágenos no FibrilaresRESUMEN
Medication waste may be caused by medication oversupply; however, the degree of medication oversupply in Japan is unclear. This study aimed to quantify the degree of oversupply of chronic disease medications per patient, the proportion of oversupplied patients, and the excess days and costs of the oversupplied medications in Japan. This retrospective nationwide cohort study using a large insurance claims database from Japan was conducted in patients aged ≥55 years who received one or a combination of the following five classes of medications dispensed in FY 2019: third-generation calcium antagonists, angiotensin 2 receptor blockers, statins, dipeptidyl peptidase-4 inhibitors, and biguanides. Medications with the same ingredient having the same specification were treated as the same medication. Medication oversupply was defined as a medication possession ratio (MPR) during persistence >1.0. The proportions of oversupplied patients and excessively oversupplied patients with ≥30 excess days/year were approximately 16 and 1-2% for all drug classes, respectively. Three-quarters of the oversupplied patients had fewer excess day (≤14/year), and the median oversupplied medication cost was less than 1000 yen/year for all classes. However, there was a patient with oversupplied medication estimated as 983 excess days per year and a patient with oversupplied medication costs of nearly 90000 yen per year. Using the MPR and excess days as indicators, it is necessary to accelerate estimation of the oversupply per patient, as well as the development of patient intervention strategies and a national system to reduce medication oversupply.
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Costos de los Medicamentos , Humanos , Japón , Anciano , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Enfermedad Crónica/tratamiento farmacológico , Anciano de 80 o más Años , Cumplimiento de la Medicación/estadística & datos numéricos , Bases de Datos FactualesRESUMEN
The purpose of this paper is to understand the milk processing system practiced in the Mongolian nomadic Khalkha groups of Su'qbaatar and Dornod Provinces in eastern Mongolia through a field survey, to compare it with surrounding areas of Qentiy and Dundgowi Provinces, and then to analyze the transmission of processing techniques by further comparison with those of Syria, Jordan, Iran and Iraq in West Asia. The milk processing techniques of fermentation, cream separation and additive coagulation are all used in Su'qbaatar and Dornod Provinces. In fermentation processes, the technique of alcohol fermentation with churning is mainly used for cow milk to process alcoholic sour milk, followed by further processing to spirit, butter oil and non-matured dry cheese. In cream separation processes, the technique of heating/cream separation is used, in which cream is first separated from milk and non-matured dry cheese is processed from skim milk. In additive coagulation processes, the technique of fermented milk coagulation which utilizes lactic acid fermented whey as a coagulant is used to process non-matured dry cheese. These techniques are widely shared in the eastern part of Mongolia. It is characteristic of Su'qbaatar Province that the processing of cow milk is dominated by the technique of fermentation processes, mainly alcohol fermentation with churning. It is presumed that the technique of churning sour milk transmitted from West Asia to eastern Mongolia, and then the function of churning originally for butter processing was converted to allow for alcohol fermentation under the cooler environment in North Asia.
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Fermentación , Manipulación de Alimentos , Leche , Animales , Mongolia , Leche/química , Manipulación de Alimentos/métodos , Bovinos , Queso/análisis , Asia Occidental , MigrantesRESUMEN
Multiplex immunohistochemistry/multiplex immunofluorescence (mIHC/mIF) enables the simultaneous detection of multiple markers in a single tissue section by visualizing the markers in different colors. Currently, tyramide signal amplification (TSA) is the most commonly used method because it is heat resistant to multiplexing. SPiDER-ßGal (6'-(diethylamino)-4'-(fluoromethyl)spiro[isobenzofuran-1(3H),9'-[9H]xanthen]-3'-yl ß-D-galactopyranoside), a novel fluorogenic substrate of ß-galactosidase (ß-gal) was reported recently. Its properties are favorable for application in sensitive mIF based on quinone methide chemistry. Combining SPiDER-ßGal with its related substrates, a novel, sensitive fluorescent IHC method for formalin-fixed paraffin-embedded (FFPE) sections was developed, named the galactosidase-catalyzed fluorescence amplification method (GAFAM). Evaluation of GAFAM indicated the following characteristics: (1) the entire GAFAM procedure was complete within a few hours; (2) the optimal working concentration of the substrates was 20 µM; (3) the fluorescent product was heat resistant; (4) the GAFAM exhibited sensitivity comparable with that of TSA, which was higher than that of conventional IF; and (5) the GAFAM was applicable to mIF and multispectral imaging. GAFAM is expected to be applicable to IF (or mIF in combination with TSA), and is a promising tool for facilitating morphological research in various fields of life science.
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Colorantes Fluorescentes , Galactosidasas , Inmunohistoquímica , Colorantes Fluorescentes/química , beta-Galactosidasa , CatálisisRESUMEN
Recent evidence indicates that RNA-dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates expression of target genes and is directly involved in tumor formation in a telomere-independent manner. Non-canonical function of hTERT has been considered as a therapeutic target for cancer therapy. We have previously shown that hTERT phosphorylation at threonine 249 (p-hTERT), which promotes RdRP activity, is an indicator of an aggressive phenotype and poor prognosis in liver and pancreatic cancers, using two cohorts with small sample sizes with polyclonal p-hTERT antibody. To clarify the clinical relevance of p-hTERT, we developed a specific monoclonal antibody and determined the diagnostic and prognostic value of p-hTERT in cancer specimens using a large cohort. A monoclonal antibody for phosphorylated hTERT (p-hTERT) at threonine 249 was developed and validated. The antibody was used for the immunohistochemical staining of formalin-fixed, paraffin-embedded specimens from 1523 cases of lung, colon, stomach, pancreatic, liver, breast, and kidney cancers. We detected elevated p-hTERT expression levels in cases with a high mitotic activity, high pathological grade, and high nuclear pleomorphism. Elevated p-hTERT expression was an independent prognostic factor for lung, pancreatic, and liver cancers. Furthermore, p-hTERT expression was associated with immature and aggressive features, such as adenosquamous carcinoma (lung and pancreas), invasive type of cancer (lung), high serum alpha-fetoprotein level (liver), and triple-negative status (breast). In conclusion, RdRP activity indicated by p-hTERT expression predicts aggressive cancer phenotypes in various types of cancer. Thus, p-hTERT is a novel biomarker for the diagnosis of aggressive cancers with a poor prognosis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias , Telomerasa , Anticuerpos Monoclonales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Humanos , Neoplasias/genética , Neoplasias/patología , Fosforilación , Pronóstico , ARN Polimerasa Dependiente del ARN , Telomerasa/genética , Treonina/metabolismoRESUMEN
Myxofibrosarcoma (MFS) is a rare subtype of sarcoma, whose genetic basis is poorly understood. We analyzed 69 MFS cases using whole-genome (WGS), whole-exome (WES) and/or targeted-sequencing (TS). Newly sequenced genomic data were combined with additional deposited 116 MFS samples. WGS identified a high number of structural variations (SVs) per tumor most frequently affecting the TP53 and RB1 loci, 40% of tumors showed a BRCAness-associated mutation signature, and evidence of chromothripsis was found in all cases. Most frequently mutated/copy number altered genes affected known disease drivers such as TP53 (56.2%), CDKN2A/B (29.7%), RB1 (27.0%), ATRX (19.5%) and HDLBP (18.9%). Several previously unappreciated genetic aberrations including MUC17, FLG and ZNF780A were identified in more than 20% of patients. Longitudinal analysis of paired diagnosis and relapse time points revealed a 1.2-fold mutation number increase accompanied with substantial changes in clonal composition over time. Our study highlights the genetic complexity underlying sarcomagenesis of MFS.
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Fibrosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Variaciones en el Número de Copia de ADN , Exoma , Fibrosarcoma/genética , Humanos , Mutación , Recurrencia Local de Neoplasia/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Secuenciación del ExomaRESUMEN
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.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Proteínas de Fusión bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animales , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mesilato de Imatinib/farmacología , Ratones , Mutación , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Malignancy of medulloblastoma depends on its molecular classification. Sonic Hedgehog (SHH)-type medulloblastoma with p53 mutation was recognized as one of the most aggressive types of tumors. We developed a novel drug, chlorambucil-conjugated PI-polyamides (Chb-M'), which was designed to compete with the RUNX consensus DNA-binding site. Chb-M' specifically recognizes this consensus sequence and alkylates it to inhibit the RUNX transcriptional activity. In-silico analysis showed all the RUNX families were upregulated in the SHH-type medulloblastoma. Thus, we tested the anti-tumor effects of Chb-M' in vitro and in vivo using Daoy cell lines, which belong to SHH with p53 mutation. Chb-M' inhibited tumor growth of Daoy cells by inducing apoptosis. The same inhibitory effect was also observed by knocking down of RUNX1 or RUNX2, but not RUNX3. Apoptosis array analysis showed that Chb-M' treatment induced phosphorylation of p53 serine 15 residues. In a subcutaneous tumor model, intratumoral injection of Chb-M' induced tumor growth retardation. Chb-M' mediated inhibition of RUNX1 and RUNX2 can be a novel therapeutic strategy for SHH-type medulloblastoma with p53 mutation.
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Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Clorambucilo/farmacología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Meduloblastoma/metabolismo , Mutación , Nylons/química , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
A 39-year-old man had an intracranial tumour without infiltration into the surrounding cerebral tissue. The tumour recurred seven times in 11 years but maintained a well-demarcated character. Histopathological examination of the 4th surgical specimens showed nests of tumour cells surrounding small blood vessels. The tumour cells harboured amphophilic cytoplasm and small round nuclei with fine chromatin, and perinuclear haloes and clear borders were frequently observed, which was unclassifiable histology. By the Deutsches Krebsforschungszentrum methylation classifier, the tumour was not classified into any of the methylation classes. mRNA sequencing identified a novel SREBF1::NACC1 gene fusion. This intracranial tumour could be a novel tumour entity with NACC1 rearrangement showing characteristic histological and diagnostic imaging findings.
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Neoplasias Encefálicas , Fusión Génica , Masculino , Humanos , Adulto , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Proteínas de Neoplasias , Proteínas RepresorasRESUMEN
BACKGROUND: The oncofetal protein insulin-like growth factor 2 mRNA binding protein-3 (IMP3) is expressed in various cancers. In this study, we examined the diagnostic utility of IMP3 immunohistochemistry in the context of intravascular large B-cell lymphoma (IVL). METHODS: We obtained 25 skin biopsy (SB) specimens diagnosed as IVL and nine IVL-negative SB specimens from 27 IVL patients. Additionally, 27 negative SB specimens from 26 non-IVL patients were obtained from our pathology archives. We performed IMP3 immunohistochemistry on these 61 SB specimens, considering IMP3 expression in any mononuclear cell as positive. In selected cases, triple immunostaining for IMP3, PAX5, and CD34 was performed to analyze the origin and location of IMP3-positive cells. RESULTS: IMP3 was expressed in most intravascular lymphoma cells in all the 25 SB specimens diagnosed as IVL. Furthermore, our evaluation revealed the presence of intravascular IMP3-positive B-cells in five of the nine negative SB specimens from IVL patients; however, this was not observed in the 27 SB specimens from non-IVL patients. CONCLUSION: IMP3 was expressed in most IVL cells, and IMP3 immunohistochemistry could serve as a sensitive diagnostic aid for detecting IVL cells in SB.
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Linfoma de Células B Grandes Difuso , Biomarcadores de Tumor/análisis , Biopsia , Humanos , Inmunohistoquímica , Linfocitos/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Piel/patologíaRESUMEN
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.
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Citotoxicidad Celular Dependiente de Anticuerpos , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , ATPasas de Translocación de Protón Vacuolares/genética , Biomarcadores , Línea Celular Tumoral , Proliferación Celular , Técnica del Anticuerpo Fluorescente , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Concentración de Iones de Hidrógeno , Inmunohistoquímica , Espacio Intracelular/metabolismo , Terapia Neoadyuvante , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Resultado del Tratamiento , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
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.
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Antineoplásicos Alquilantes/uso terapéutico , Clorambucilo/uso terapéutico , Subunidad alfa 2 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Tumor Rabdoide/tratamiento farmacológico , Animales , Línea Celular Tumoral , Clorambucilo/análogos & derivados , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteína SMARCB1/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Desmoid-type fibromatosis (DF) is a locally aggressive but non-metastatic (myo)fibroblastic neoplasm. A hallmark of the tumor is nuclear positivity for beta-catenin in immunohistochemistry due mostly to CTNNB1 mutations. However, a recent study has reported that even beta-catenin 'nuclear-negative' DFs can harbor CTNNB1 mutations and that the positive ratio of nuclear beta-catenin in DF is different among antibodies. Here, we reviewed soft tissue lesions for which the possibility of DF was considered and compared the sensitivity and specificity of nuclear beta-catenin for the diagnosis of DF among commonly used anti-beta-catenin antibodies, i.e., clone beta-catenin 1, 17C2 and 14. We analyzed 26 cases of DF, 28 cases of benign fibroblastic lesions, and 27 cases of other soft tissue tumors. The sensitivity and specificity of nuclear beta-catenin for the diagnosis of DF were different among antibodies; 54% and 98% in clone beta-catenin 1, 85% and 84% in 17C2, and 96% and 62% in 14. IHC of LEF1 showed comparable results with IHC of beta-catenin, with a sensitivity of 88% and specificity of 76%. Additionally, when beta-catenin 1 was used, DFs showed characteristic dotted cytoplasmic staining, often appearing as rings. Our results might be helpful for making a correct diagnosis of DF.
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Anticuerpos Antineoplásicos , Fibromatosis Agresiva , beta Catenina , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Fibromatosis Agresiva/diagnóstico , Fibromatosis Agresiva/patología , Humanos , Inmunohistoquímica , Lactante , Masculino , Persona de Mediana Edad , Mutación , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/patología , Adulto Joven , beta Catenina/genética , beta Catenina/inmunología , beta Catenina/metabolismoRESUMEN
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.
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Histiocitosis de Células de Langerhans , Antígenos de Histocompatibilidad Clase I/metabolismo , Inmunoglobulinas Intravenosas , Receptores Fc/metabolismo , Adolescente , Adulto , Albúminas/metabolismo , Línea Celular , Niño , Preescolar , Femenino , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/metabolismo , Humanos , Inmunoglobulinas Intravenosas/metabolismo , Inmunoglobulinas Intravenosas/farmacología , Lactante , Recién Nacido , Masculino , Albúmina Sérica/metabolismoRESUMEN
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 FcÉRI-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 FcÉRI-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.
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Mastocitos/metabolismo , Metástasis de la Neoplasia/genética , Receptores KIR2DL4/genética , Receptores KIR2DL4/metabolismo , Femenino , Regulación de la Expresión Génica , Antígenos HLA-G/metabolismo , Humanos , Factor Inhibidor de Leucemia/metabolismo , Embarazo , Serina Proteasas/metabolismoRESUMEN
Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti-programmed death ligand-1 (PD-L1) is a well-studied biomarker for response to anti-programmed death-1 PD-1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3-dioxygenase (IDO) is correlated to a response to anti-CTLA-4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti-PD-1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD-L1 expression with response to anti-PD-1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti-PD-1 antibody from the perspective of IDO and PD-L1 expression levels by immunohistochemistry (IHC). Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression-free survival (HR = 0.33, 95% CI = 0.13-0.81, P = 0.016), whereas PD-L1 expression on tumors was not associated with progression-free survival. Significantly lower expression of IDO in tumors was found in non-responders compared to responders. Assessment of the IDO expression could be useful for the identification of suitable candidates for anti-PD-1 therapy among acral and mucosal melanomas patients. Further validation study is needed to estimate the clinical utility of our findings.
Asunto(s)
Antígeno CTLA-4/antagonistas & inhibidores , Inmunoterapia , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Melanoma/enzimología , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Cutáneas/enzimología , Anciano , Pueblo Asiatico , Femenino , Humanos , Japón , Estimación de Kaplan-Meier , Masculino , Melanoma/mortalidad , Melanoma/patología , Melanoma/terapia , Persona de Mediana Edad , Mutación , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
The involvement of mast cells in the establishment of pregnancy is unclear. Herein, we found that human mast cells are present in the decidual tissues of parous women and expressed a human-specific protein killer cell Ig-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen G expressed on human trophoblasts. In contrast, decreased numbers of decidual mast cells and reduced KIR2DL4 expression were observed in these cells of infertile women who had undergone long-term corticosteroid treatment. Co-culture of the human mast cell line, LAD2, and human trophoblast cell line, HTR-8/SVneo, accelerated the migration and tube formation of HTR-8/SVneo cells in a KIR2DL4-dependent manner. These observations suggest the possible involvement of human mast cells in the establishment of pregnancy via KIR2DL4 and that long-term corticosteroid treatment may cause infertility by influencing the phenotypes of decidual mast cells.