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Here, we investigated the effect of Th1 polarization in the tumor microenvironment (TME) on tumor-associated macrophage (TAM) maturation and activation. In our immunotherapy mouse model, with a Th1-dominant TME, tumors regressed in all cases, with complete regression in 80% of the cases. Monocyte-derived dendritic cells and activated CD4+ and CD8+T-cells increased in the tumor-draining lymph node, and correlated with each other in the therapeutic model. However, the cytotoxicity of tumor-infiltrating CD8+T-cells was slightly inhibited, whereas the number of T-cells significantly increased. Moreover, the number of TAMs increased; their maturation was inhibited; and nitrotyrosine (NT) production, as well as iNOS and arginase I expression, was increased, suggestive of the myeloid-derived suppressor cell-like immunosuppressive function of TAMs. IFN-γ knockout in the therapeutic model decreased NT production and induced macrophage maturation. Hence, Th1 polarization in the IFN-γ-dominant condition induces T-cell immune responses; however, it also enhances the immunosuppressive activity of TAMs.
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Macrófagos/inmunología , Células Supresoras de Origen Mieloide/inmunología , Neoplasias Experimentales/inmunología , Células TH1/inmunología , Microambiente Tumoral/inmunología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Escape del Tumor/inmunologíaRESUMEN
OBJECTIVE: The morphological features of nuclei in cytological and histological specimens were compared and examined for the presence of BRAFV600E mutation and the appearance rate of intranuclear cytoplasmic inclusions (NI). METHODS: BRAFV600E mutation was identified using a mutation-specific antibody (clone; VE1) in 103 thyroid papillary carcinoma cases at Gunma University Hospital. The nuclear area, perimeter, and roundness of the corresponding cytological specimens and haematoxylin and eosin-stained specimens were analysed using image analysis software, and the appearance rate of NI was calculated and compared. RESULTS: BRAFV600E mutation was detected in 71 (69%) cases. The appearance rate of NI was significantly higher in the BRAFV600E mutation-positive group in cytological and histological specimens (P = .0070 and .0184, respectively). Significant differences were observed between the BRAFV600E mutation-negative and -positive groups in the average nuclear area and average nuclear perimeter in cytological specimens (P = .0137 and .0152, respectively). In addition, nuclear enlargement was correlated with the appearance rate of NI regardless of the presence of BRAFV600E mutation in cytological specimens. In the BRAFV600E mutation-negative group, the nuclear area and perimeter were significantly smaller in the lymph node metastasis-positive cases (P = .0182 and .0260, respectively). CONCLUSION: This study found that the appearance rate of NI was positively correlated with the nuclear area and perimeter and negatively correlated with nuclear roundness in cytological specimens. Furthermore, these results were observed regardless of the existence of BRAFV600E mutation. These results have never been previously reported and clearly demonstrate the usefulness of cytological specimens in computer-assisted image analysis.
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Núcleo Celular/patología , Procesamiento de Imagen Asistido por Computador/métodos , Cuerpos de Inclusión/patología , Proteínas Proto-Oncogénicas B-raf/genética , Cáncer Papilar Tiroideo , Femenino , Humanos , Masculino , Mutación , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Glándula Tiroides/citología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patologíaRESUMEN
Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are both key immunosuppressive cells that contribute to tumor growth. Metabolism and immunity of tumors depend on the tumor microenvironment (TME). However, the intracellular metabolism of MDSCs and TAMs during tumor growth remains unclear. Here, we characterized CD11b+ cells isolated from a tumor-bearing mouse model to compare intratumoral TAMs and intrasplenic MDSCs. Intratumoral CD11b+ cells and intrasplenic CD11b+ cells were isolated from tumor-bearing mice at early and late stages (14 and 28 days post-cell transplantation, respectively). The cell number of intrasplenic CD11b+ significantly increased with tumor growth. These cells included neutrophils holding segmented leukocytes or monocytes with an oval nucleus and Gr-1hi IL-4Rαhi cells without immunosuppressive function against CD8 T cells. Thus, these cells were classified as MDSC-like cells (MDSC-LCs). Intratumoral CD11b+ cells included macrophages with a round nucleus and were F4/80hi Gr-1lo IL-4Rαhi cells. Early stage intratumoral CD11b+ cells inhibited CD8 T cells via TNFα. Thus, this cell population was classified as TAMs. Metabolomic analyses of intratumoral TAMs and MDSC-LCs during tumor growth were conducted. Metabolic profiles of intratumoral TAMs showed larger changes in various metabolic pathways, e.g., glycolysis, TCA cycle, and glutamic acid pathways, during tumor growth compared with MDSL-LCs. Our findings demonstrated that intratumoral TAMs showed an immunosuppressive capacity from the early tumor stage and underwent intracellular metabolism changes during tumor growth. These results clarify the intracellular metabolism of TAMs during tumor growth and contribute to our understanding of tumor immunity.
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Macrófagos/inmunología , Macrófagos/metabolismo , Neoplasias Experimentales/inmunología , Escape del Tumor/fisiología , Microambiente Tumoral/fisiología , Animales , Antígeno CD11b/inmunología , Línea Celular Tumoral , Masculino , Metabolómica , Ratones , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Trasplante de Neoplasias , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patologíaRESUMEN
Several antitumour drugs have been isolated from natural products and many clinical trials are underway to evaluate their potential. There have been numerous reports about the antitumour effects of astaxanthin against several tumours but no studies into its effects against glioblastoma. Astaxanthin is a red pigment found in crustaceans and fish and is also synthesized in Haematococcus pluvialis; adonixanthin is an intermediate product of astaxanthin. It is known that both astaxanthin and adonixanthin possess radical scavenging activity and can confer a protective effect on several damages. In this study, we clarified the antitumour effects of astaxanthin and adonixanthin using glioblastoma models. Specifically, astaxanthin and adonixanthin showed an ability to suppress cell proliferation and migration in three types of glioblastoma cells. Furthermore, these compounds were confirmed to transfer to the brain in a murine model. In the murine orthotopic glioblastoma model, glioblastoma progression was suppressed by the oral administration of astaxanthin and adonixanthin at 10 and 30 mg/kg, respectively, for 10 days. These results suggest that both astaxanthin and adonixanthin have potential as treatments for glioblastoma.
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Neoplasias Encefálicas/tratamiento farmacológico , Carotenoides/farmacología , Glioblastoma/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Carotenoides/administración & dosificación , Línea Celular Tumoral , Progresión de la Enfermedad , Glioblastoma/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Xantófilas/administración & dosificación , Xantófilas/farmacologíaRESUMEN
Glycoprotein nonmetastatic melanoma protein B (GPNMB), which is involved in invasion and metastasis, was found to be overexpressed in various cancers. High levels of GPNMB and Na+/K+-ATPase α subunits are associated with a poor prognosis in glioblastoma patients. We showed that GPNMB interacts with Na+/K+-ATPase α subunits to activate PI3K/Akt and MEK/ERK pathways. However, it remains unclear whether the interaction of GPNMB and Na+/K+-ATPase α subunits is involves in progression of glioma. The tumor size induced by the injection of glioma GL261 cells was larger in transgenic mice overexpressing GPNMB when compared with wild-type mice. Additionally, the interaction of GPNMB and Na+/K+-ATPase α subunits was identified in the murine glioma model and in the tumors of glioblastoma patients. Ouabain, a Na+/K+-ATPase inhibitor, suppressed the glioma growth induced by the injection of glioma cells in the transgenic mice overexpressing GPNMB and blocked the GPNMB-induced migration of glioma cells. These findings indicate that GPNMB promotes glioma growth via Na+/K+-ATPase α subunits. Thus, the interaction between GPNMB and Na+, K+-ATPase α subunits represents a novel therapeutic target for the treatment of brain glioblastomas.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proteínas del Ojo/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patología , Glicoproteínas de Membrana/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Anciano , Animales , Línea Celular Tumoral , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Invasividad NeoplásicaRESUMEN
The effects of hyperbaric oxygen (HBO) on mouse skin two-stage chemical carcinogenesis were examined. Six-week-old inbred CD-1 female mice were divided into the following five groups: group 1, normoxia and application of 25 nmol 7,12-dimethylbenz[a]anthracene (DMBA) and 8.5 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) (n=19); group 2, HBO and DMBA/TPA (n=21); group 3, HBO and DMBA/acetone (n=3); group 4, normoxia and acetone (n=3); and group 5, non-treatment group (n=5). HBO was started at the same time as DMBA. Mice were euthanized at 23 weeks after the start of the experiment. Mice in group 2 showed the occurrence of tumors at 8 weeks after the beginning of the experiment, while the occurrence of tumors in mice in group 1 was observed beginning at 9 weeks. There was a difference in occurrence among low-grade papillomas, high-grade papillomas and SCCs in both groups 1 and 2 by the χ (2)-test at end of the experiment (p<0.05). The Ki-67 labeling indices of tumors revealed that the percentages of positive cells in low-grade papillomas in groups 1 and 2 were 15.27 ± 2.54% and 29.67 ± 2.82%, respectively (p<0.01). The results suggested that the tumors in group 2, which was treated with HBO, were more progressive than those in group 1, which was not treated with HBO. In this study, HBO accelerated tumor cell proliferation and advanced tumor progression in skin carcinogenesis by DMBA/TPA.
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We measured section thickness (ST) after slicing using a film thickness meter and investigated the relationship between ST and the percent area of positive staining using computer-assisted image analysis. METHODS: Sections were prepared from a paraffin-only block and formalin-fixed paraffin-embedded (FFPE) blocks containing fish sausage and human liver specimens. The ST was compared between the sections prepared with cooling using an ice pack (IP) or a continuous cooling device (CCD) paired with a sliding microtome set at an ST of 4 µm. The sections were stained with eosin or aniline blue, and the association between the percent area of positive staining and ST was determined using computer-aided analysis of images captured with a whole slide scanner. RESULTS: The average STs of the paraffin-only block sections measured by four practitioners were 5.01-5.41 and 4.09-4.33 µm in samples prepared using an IP and a CCD, respectively. Therefore, subsequent analyses included sections prepared using the CCD. The ST of the tissue surface was significantly thinner than that of the paraffin surrounding the tissue section. Furthermore, the percent areas of positive staining for eosin and aniline blue were significantly correlated with ST in both the fish sausage and liver sections. The analysis of the ST and percent area of positive staining in 60 sections of the same block, which were categorized into quantiles based on ST, revealed a significant difference in the percent area of positive staining between the thicker and thinner sections. DISCUSSION: Specimen sectioning should be performed with a CCD, ST should be measured before the staining of pathologic specimens prepared for quantitative analysis, and histologic examination should be performed using specimens with uniform ST.
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Emerin and lamins not only influence nuclear morphology but are also involved in differentiation. We herein examined 82 resected cases of invasive lung adenocarcinoma using computer-assisted image analysis of nuclear morphology on Feulgen-stained and immunohistochemical sections of lamin A, B1, B2, and emerin (four proteins) to calculate the rank sum of the cell positivity rates for these four proteins. The rank sum of four proteins showed weak negative correlations with the nuclear area and perimeter and a weak positive correlation with the nuclear shape factor. Interestingly, the top three cases with the highest rank sum were papillary adenocarcinoma, and the bottom three cases were acinar adenocarcinomas containing cribriform patterns. We compared the rank sum for grading (differentiation: G1, G2, and G3) and predominant histological subtypes and found that the rank sum of G3 was lower than that of G1 and G2. Furthermore, the rank sum was lower for acinar adenocarcinoma with >20â¯% cribriform pattern (acinar+cribri) and solid adenocarcinoma than for lepidic and papillary adenocarcinoma. Individual examination of the four proteins revealed that emerin expression was lower in G3 than in G1, and lamin B2 expression was lower in G3 than in G1 and G2. Compared with lepidic adenocarcinoma, acinar+cribri showed significantly lower expression of all four proteins among histological subtypes. These data indicated that the expression of lamin A, B1, B2, and emerin was markedly decreased in poorly differentiated adenocarcinoma (i.e., G3), especially in acinar+cribri. Our data suggested that changes in these four proteins can not only affect nuclear morphology but also histological structure in lung adenocarcinoma.
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BACKGROUND: Lamins, located beneath the nuclear membrane, are involved in maintaining nuclear stiffness and morphology. The nuclei of tumor cells are enlarged in serous carcinoma, a histologic subtype of ovarian cancer that is notable for its poor prognosis. The present study investigated the association of lamin A, B1, and B2 expression with nuclear morphology and metastatic route in serous ovarian carcinoma. METHODS: We performed immunohistochemistry for lamins A, B1, and B2 using specimens of patients who underwent surgery for serous ovarian carcinoma in Gunma University Hospital between 2009 and 2020. Following staining, the specimens were scanned using a whole-slide scanner and processed using computer-assisted image analysis. RESULTS: The positivity rates for lamins A and B1 as well as the rank sum of the positivity rates for lamins A, B1, and B2 were negatively correlated with the mean and standard deviation of the nuclear area. Interestingly, the positivity rate for lamin A was significantly higher in metastatic lesions than in primary tumors in cases with lymph node metastasis. DISCUSSION: Previous studies indicated that decreased lamin A led to nuclear enlargement and deformation and that lamin B1 was required to maintain the meshworks of lamins A and B2 to maintain nuclear morphology. The present study findings suggest that decreased lamin A and B1 expression might lead to nuclear enlargement and deformation and raise the possibility that tumor cells maintaining or not losing lamin A expression might metastasize to lymph nodes.
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Lamina Tipo A , Neoplasias Ováricas , Femenino , Humanos , Núcleo Celular/metabolismo , Inmunohistoquímica , Ganglios Linfáticos/metabolismo , Neoplasias Ováricas/metabolismo , Lamina Tipo BRESUMEN
We tried to prevent nonspecific nuclear staining (NS-NS) of picrosirius red (PSR) staining by treating the specimens with one of the heteropoly acids phosphotungstic acid (PTA). We analyzed a total of 35 cases of non-cancerous liver tissue for fibrosis and NS-NS under PSR-alone, phosphomolybdic acid (PMA)-pretreated PSR (PMA + PSR), or PTA-pretreated PSR (PTA + PSR) condition. In addition, we analyzed the photosensitivity of PMA or PTA single stain specimens. PTA + PSR significantly suppressed NS-NS compared with PSR. The color of the specimens did not change into blue by 30 times the exposure to whole slide scanner (WSS) light. The PTA + PSR condition showed the highest correlation with the Ishak score (pathological evaluation of liver fibrosis) compared with other conditions. Furthermore, Sirius Red-positive percentage (SRP%) in PSR was increased in the NS-NS observed cases. SRP% in PMA + PSR was significantly affected by WSS light exposure time. Moreover, the deposition of non-polarized PSR-stained substances (NP-PSR+S) clinging to the collagen fibers potentially explains why SRP% seemed bigger under PSR than PTA + PSR. Our protocol enabled us to analyze the whole slide image of PSR staining by high magnification, which would contribute to the accurate analysis of collagen amount in the tissue sections.
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Compuestos Azo , Colágeno , Ácido Fosfotúngstico , Colágeno/análisis , Coloración y Etiquetado , Compuestos Azo/química , ColorantesRESUMEN
The anti-allergic mechanism of heat-killed Lactobacillus acidophilus strain L-92 has not been fully investigated. Recent studies have reported that CD4(+)CD25(+)Foxp3(+) (forkhead box P3) T regulatory (Treg) cells play important roles in controlling allergic diseases. Hence, we examined the effect of orally administered L-92 on CD4(+)CD25(+)Foxp3(+) cell populations. BALB/c mice were supplemented daily with L-92 by gavage for 5 weeks. 2,4-Dinitrofluorobenzene (DNFB) was used to induce allergic contact dermatitis (ACD) in mice. Fluorescent-activated cell sorter (FACS) analysis was used to determine CD4(+)CD25(+)Foxp3(+) T cell populations in spleen and cervical lymph nodes (CLN). Interleukin-10 (IL-10), transforming growth factor-ß (TGF-ß), and Foxp3 mRNA expressions in mouse ear skin were investigated by real-time reverse transcription-polymerase chain reaction (RT-PCR). The percentage of CD4(+)CD25(+)Foxp3(+) T cell populations were significantly increased in both spleen and CLN of L-92-fed group than vehicle and control. In addition, L-92 produced higher levels of Foxp3, IL-10 and TGF-ß compared to control mice. These results suggest that L-92 can up-regulate the number of Treg cells to suppress the progression of DNFB-induced contact dermatitis in mice.
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Dermatitis Alérgica por Contacto/inmunología , Lactobacillus acidophilus , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD4/inmunología , Femenino , Factores de Transcripción Forkhead/inmunología , Interleucina-10/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Ratones , Ratones Endogámicos BALB C , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
A 3-year-old boy presented with tumors in the adrenal gland and the right orbit, and was diagnosed with neuroblastoma. After chemotherapy, the tumors were resected and the pathological diagnoses of ganglioneuroblastoma in the adrenal gland and ganglioneuroma in the orbit were made. The tumor relapsed at the intracranial dura mater 21 years after the initial diagnosis, and was diagnosed as ganglioneuroma from a biopsied sample. This case is very unique in that ganglioneuroma matured from ganglioneuroblastoma or neuroblastoma had the late recurrence with 21 years of tumor dormancy.
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Progresión de la Enfermedad , Ganglioneuroma/patología , Neuroblastoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Preescolar , Ganglioneuroblastoma/diagnóstico , Ganglioneuroblastoma/tratamiento farmacológico , Ganglioneuroblastoma/patología , Ganglioneuroma/diagnóstico , Ganglioneuroma/tratamiento farmacológico , Humanos , Imagen por Resonancia Magnética , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/tratamiento farmacológico , RecurrenciaRESUMEN
OBJECTIVE: Mongolia is a sparsely populated country; however, almost fifty percent of the population lives in the capital city. Medical care services and exceptionally well-organized cervical cancer screening tests are limited in remote areas. To improve cervical cancer screening test coverage, we compared the interest between physicians taking samples and self-sampling among the attendees in this study. METHODS: A total of 175 women participated in this study. The hundred twelve women visited the Gynecology ward, and the sixty-three women were provided with the cervical self-sampling test kit and filled out a questionnaire. Subsequently, the acceptability of physician taking and self-sampling were evaluated using a questionnaire. All specimens were processed using the TACAS LBC system, and the quality of samples was tested by cytology. RESULTS: Regarding the acceptability of self-sampling, the selections for subsequent screening were 36% self-sampling and 64% gynecologist-sampling methods. The acceptability rates were higher in the remote areas than the urban areas. However, 64% of the participants lacked knowledge that the causative agent of cervical cancer is the human papillomavirus, and 66.9% mainly were sexually transmitted. In addition, 82.3% of the women surveyed were unaware that there was a vaccine to prevent cervical cancer, but 88.6% wanted to be vaccinated. Of most women, 44.4% chose self-sampling due to no embarrassment in the gynecological examination. The self-sampling preferences were dominant in the old age group (61.6%). The cytology satisfaction rate in physician-sampling (99.1%) was higher than in the self-sampling group (69.8%). CONCLUSION: The Implementation of the self-sampling tool may be considered a primary screening. The self-sampling test can adopt into the early screening program and may increase the coverage of the screening program and improve the quality.
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Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/prevención & control , Frotis Vaginal/métodos , Detección Precoz del Cáncer/métodos , Mongolia/epidemiología , Papillomaviridae , Manejo de Especímenes/métodos , Infecciones por Papillomavirus/diagnóstico , Tamizaje Masivo/métodos , Autocuidado/métodosRESUMEN
OBJECTIVE: In this study, we focused on five microRNAs (miRNAs) that have been reported to regulate phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene expression, namely miR-182, miR-183, miR-200a, miR-200b, and miR-205, and examined their relationships with PTEN protein expression in endometrial cancer tissues. METHODS: By utilizing paraffin-embedded blocks of normal endometrium (NE) and endometrial carcinoma (EC) tissue (40 cases each), we measured the expression of miRNAs by real-time PCR. Conversely, we examined PTEN protein expression by immunohistochemistry and computer-assisted image analysis. RESULTS: The expression of all five miRNAs was significantly higher in the EC group than in the NE group (all P ≤ 0.0001). There was no inverse correlation between PTEN positivity in glandular and/or stromal areas and the expression of the five miRNAs in both groups. Conversely, miR-182, miR-183, miR-200a, and miR-200b displayed similar expression patterns in the EC group, whereas miR-205 displayed moderate correlations with the other four miRNAs. CONCLUSION: Using endometrial cancer tissues, we found for the first time that miR-182, miR-183, miR-200a, and miR-200b were strongly correlated with each other, whereas miR-205 was not strongly correlated with the other four miRNAs. In addition, the five miRNAs examined in this study only had weak effects on PTEN protein expression based on the lack of clear inverse correlations.
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Neoplasias Endometriales , MicroARNs , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunohistoquímica , MicroARNs/genética , MicroARNs/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The nuclear lamina protein, Lamin A and inner nuclear membrane protein, emerin participate in maintaining nuclear morphology. However, their correlations with the nuclear shape in the four representative ovarian epithelial cancer subtypes, high-grade serous carcinoma (HGSCa), clear cell carcinoma (CCCa), endometrioid carcinoma (EMCa) and mucinous carcinoma (MUCa), remains unclear. The present study aimed to investigate the association between nuclear morphology and nuclear membrane protein expression in four histological subtypes of ovarian epithelial cancer. A total of 140 surgically resected ovarian cancer specimens were subjected to Feulgen staining to evaluate nuclear morphology, and immunohistochemistry analysis to assess Lamin A and emerin expression. The histological images were analyzed via computer-assisted image analysis (CAIA). The results demonstrated that the mean nuclear area of EMCa was significantly smaller compared with CCCa (P=0.0009). The standard deviation of the mean nuclear area was used to assess nuclear size variation, and the results indicated that EMCa lesions were significantly smaller than CCCa lesions (P=0.0006). Regarding the correlation between the Lamin A-positive rate and nuclear morphological factors, positive correlations were observed with nuclear area in CCCa and EMCa (R=0.2855 and R=0.2858, respectively) and nuclear perimeter in CCCa, EMCa and MUCa (R=0.2409, R=0.4054 and R=0.2370, respectively); however, a negative correlation with nuclear shape factor was observed in HGSCa and EMCa (R=-0.2079 and R=-0.3707, respectively). With regards to the correlation between emerin positivity and nuclear morphological factors, positive correlations were observed with nuclear shape factor in HGSCa (R=0.2673) and nuclear area in CCCa (R=0.3310). It is well-known that HGSCa and CCCa have conspicuous nuclear size variation, and EMCa has small nuclei without strong atypia. These findings were verified in the present study via CAIA. Taken together, the results of the present study suggest that Lamin A strongly contributes to the maintenance of nuclear morphology in ovarian epithelial cancer compared with emerin, although their contributions differ based on tumor subtype.
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Background: The nuclear laminar protein Lamin A and inner nuclear membrane protein Emerin plays important role in sustaining nuclear structure. However, They have not investigated the significance of these proteins for development of pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods: We examined pancreatic IPMN specimens for nuclear morphology and nuclear protein expression pattern of Lamin A and Emerin. Forty-two IPMN specimens were included, with 30 classified as intraductal papillary mucinous adenoma (IPMA) and 12 as intraductal papillary mucinous carcinoma (IPMC). Results: Classification according to histological subtype revealed that 26 specimens were of the gastric subtype (1 IPMC case), 8 were pancreatobiliary (6 IPMC cases), 6 were intestinal (3 IPMC cases), and 2 were oncocytic (all cases were IPMC). The frequency of IPMN subtypes in this study seemed to agree with those in previous reports. We analyzed Feulgen staining sections for nuclear morphological analysis using computer-assisted image analysis. Nuclear area and perimeter were significantly larger in IPMC than in IPMA. Finally, we examined the positive ratios of Lamin A and Emerin in immunohistochemical staining sections by image analysis. We found a negative correlation between the nuclear size and Lamin A-positive ratio, which was significantly lower in IPMC than that in IPMA. However, no significant correlation was observed between nuclear size and Emerin expression was observed, and no differences were found in the Emerin-positive ratio between IPMA and IPMC. Conclusion: Our results suggest that a decreased Lamin A positive ratio induces nuclear enlargement in adenomas, which thereby induce promotion to carcinomas. Furthermore, Lamin A expression can be a reliable biomarker for distinguishing between IPMC and IPMA.
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Adenocarcinoma Mucinoso , Adenocarcinoma Papilar , Carcinoma Ductal Pancreático , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Lamina Tipo A , Carcinoma Ductal Pancreático/patología , Lámina Nuclear/metabolismo , Lámina Nuclear/patología , Adenocarcinoma Mucinoso/patología , Neoplasias Pancreáticas/patología , Adenocarcinoma Papilar/patologíaRESUMEN
OBJECTIVE: This study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/ß-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC). DESIGN: An open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PBC classified as stage III or higher according to the Scheuer classification by liver biopsy between 4 September 2019 and 21 September 2021 were enrolled. Seven patients received intravenous OP-724 infusions at escalating dosages of 280 and 380 mg/m2/4 hours two times weekly for 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). The secondary endpoints were the incidence of AEs and the improvement in the modified Histological Activity Index (mHAI) score. RESULTS: Seven patients (median age, 68 years) were enrolled. Of these seven patients, five completed twelve cycles of treatment, one discontinued prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2). Consequently, the recommended dosage was determined to be 280 mg/m2/4 hours. SAEs did not occur. The most common AEs were abdominal discomfort (29%) and abnormal hepatic function (43%). OP-724 treatment was associated with histological improvements in the fibrosis stage (2/5 (40%)) and mHAI score (3/5 (60%)) on histological analysis. CONCLUSION: Administration of intravenous OP-724 infusion at a dosage of 280 mg/m2/4 hours two times weekly for 12 weeks was well tolerated by patients with advanced PBC. However, further evaluation of antifibrotic effects in patients with PBC is warranted. TRIAL REGISTRATION NUMBER: NCT04047160.
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Proteína de Unión a CREB , Cirrosis Hepática Biliar , Humanos , Anciano , beta Catenina , Estudios de Factibilidad , InvestigadoresRESUMEN
BACKGROUND: We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/ß-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis. METHODS: This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child-Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m2/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at ClinicalTrials.gov (no. NCT03620474). FINDINGS: Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level. INTERPRETATION: Intravenous administration of 280 mg/m2/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted. FUNDING: AMED, Ohara Pharmaceutical.
Asunto(s)
Enfermedad Hepática en Estado Terminal , Hepatitis C Crónica , Hepatitis C , Herpesvirus Cercopitecino 1 , Antivirales/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes , Enfermedad Hepática en Estado Terminal/inducido químicamente , Hepacivirus , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/tratamiento farmacológico , Pirimidinonas , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , beta CateninaRESUMEN
RNF8 is a nuclear protein having an N-terminal forkhead-associated (FHA) domain and a C-terminal RING-finger (RF) domain. Depletion of RNF8 caused cell growth inhibition and cell cycle arrest at not only S but also G2/M phases. In addition, cell death was frequently observed in RNF8-depleted cells. Analyses of time-lapse microscopy revealed that the cells died in mitosis and interphase. To elucidate the RNF8 function in M phase, the Plk1 content in RNF8-depleted cells was examined. The amount of RNF8 decreased time-dependently, whereas Plk1 reciprocally increased by transfection of RNF8 siRNA. Protein contents of RNF8 and Plk1 among various cell lines were also compared. RNF8 in normal cell lines was much higher than that in many cancer cell lines. Conversely, Plk1 in normal cell lines was lower than in cancer cell lines. These results suggest that RNF8 is downregulated in many cancer cells and inversely correlated with Plk1.