RESUMO
Wnt signaling is relevant for a wide range of biological processes, including reproductive function. The function of Wnt10a in female fertility, however, remains obscure. In the present study, we explored the structure and function of the female reproductive organs in Wnt10a knockout (KO) mice. The expression of ß-catenin signaling was significantly lower in the ovaries of the Wnt10a KO mice compared with wild-type (WT) mice. In addition, the estrous cycles were disrupted, ovarian follicles were diminished, and endometria were thinner, accompanied by lower serum estrogen levels, and higher testosterone and progesterone levels in Wnt10a KO mice. The expression of the ovarian cytochrome P450 family 19 subfamily A member 1 (Cyp19a1) was significantly lower in Wnt10a KO mice. We detected no significant changes in the levels of the gonadotropins between WT and KO mice. Together, our findings indicate that deficiency of Wnt10a causes female infertility through ß-catenin and Cyp19a1signaling pathways in mice.
Assuntos
Infertilidade Feminina , Proteínas Wnt , beta Catenina , Animais , Aromatase/genética , Aromatase/metabolismo , Feminino , Humanos , Infertilidade Feminina/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Ovário , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Sarcoidosis is a systemic granulomatous disease. In pulmonary sarcoidosis, granulomatous vascular involvement is a common feature that occurs in all types of vessels, including large elastic arteries to venules, but sarcoidosis complicated with pulmonary infarction has not been reported. We report a case of a 60 years old female, who was operated on a clinical diagnosis of lung cancer, and histological examination revealed a pulmonary infarction and sarcoidosis. In the pulmonary elastic arteries, granulomas infiltrated the adventitia and media, and caused elastic fiber collapse and destruction. Arterial occlusion by granulomas was observed in the edge of the infarcted area. It was considered that the arterial sarcoidosis granuloma involvement was the cause of pulmonary infarction. Sarcoidosis is a significant risk factor for cardiovascular events. However, pulmonary infarction is an extremely rare complication of sarcoidosis. Our case suggests that sarcoidosis may cause vascular events in the lungs.
Assuntos
Infarto Pulmonar , Sarcoidose , Feminino , Granuloma/diagnóstico , Granuloma/patologia , Humanos , Pulmão/patologia , Pneumopatias/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Artéria Pulmonar/patologia , Infarto Pulmonar/etiologia , Infarto Pulmonar/patologia , Sarcoidose/diagnóstico , Sarcoidose/patologiaRESUMO
AIMS: Pulmonary tumour thrombotic microangiopathy (PTTM) is a fatal disease of patients with cancer that causes progressive pulmonary hypertension (PH). Its pathology is characterised by fibrocellular intimal proliferation and thrombosis caused by tumour emboli in microscopic pulmonary arteries. However, such PTTM-like lesions often appear incidentally. We sought to identify features that distinguished PTTM from incidental pulmonary tumour emboli, and to gain an overall picture of PTTM morphology in terms of its pathogenesis. METHODS AND RESULTS: Twenty-five PTTM cases were classified into two groups: (i) a definite group (n = 14), clinically diagnosed with PH; and (ii) a suspicious group (n = 11) with respiratory symptoms but without a clinical evidence of PH. As a control group, autopsy cases with PTTM-like lesions lacking progressive respiratory symptoms were selected (n = 7). PTTM-like lesions in these groups were studied and a diagnostic guide for PTTM formulated as follows: PTTM-like lesions with >17 affected vessels observed in a 1-cm2 area of lung specimen, and the absence of pulmonary metastatic nodules. PTTM due to gastric cancers was shown to have a significantly shorter course and larger arterial involvement than cases with non-gastric cancers. Serial sections revealed a PTTM lesion to be a longitudinal obstruction that accumulated in microscopic pulmonary arteries and that showed a proximal extension via supernumerary arteries. CONCLUSION: We suggest novel pathological diagnostic characteristics for PTTM deduced from a study of 25 autopsy cases. This includes PTTM-like lesions with >17 affected vessels in a 1-cm2 area of lung specimen and the absence of pulmonary metastatic nodules.
Assuntos
Pneumopatias/diagnóstico , Pneumopatias/etiologia , Neoplasias/complicações , Células Neoplásicas Circulantes/patologia , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia , Adenocarcinoma/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Background: We recently reported that WNT10A plays a pivotal role in wound healing by regulating collagen expression/synthesis, as the depletion of WNT10A dramatically delays skin ulcer formation. WNT signaling also has a close correlation with the cancer microenvironment and proliferation, since tumors are actually considered to be 'unhealing' or 'overhealing' wounds. To ascertain the in vivo regulatory functions of WNT10A in tumor growth, we examined the net effects of WNT10A depletion using Wnt10a-deficient mice (Wnt10a -/-). Methods and Results: We subjected C57BL/6J wild-type (WT) or Wnt10a -/- mice to murine melanoma B16-F10 cell transplantation. Wnt10a -/- mice showed a significantly smaller volume of transplanted melanoma as well as fewer microvessels and less collagen expression and more necrosis than WT mice. Conclusions: Taken together, our observations suggest that critical in vivo roles of Wnt10a-depleted anti-stromagenesis prevent tumor growth, in contrast with true wound healing/scarring.
Assuntos
Colágeno/metabolismo , Melanoma Experimental/patologia , Proteínas do Tecido Nervoso/genética , Neoplasias Cutâneas/patologia , Proteínas Wnt/genética , Animais , Linhagem Celular Tumoral , Feminino , Deleção de Genes , Masculino , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/metabolismo , Microvasos/patologia , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/metabolismo , Células Estromais/patologia , Proteínas Wnt/metabolismoRESUMO
Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase (MAP3K), is ubiquitously expressed and situated in an important upstream position of many signal transduction pathways. ASK1 plays a pivotal role in stressor-induced cell survival and inflammatory reactions. To ascertain the regulatory functions of ASK1 in bile duct ligation (BDL)-induced liver injury, we examined the net effects of ASK1 depletion on hepatic necroinflammation and/or fibrosis. We subjected C57BL/6 wild-type (WT) or ASK1-deficient (ASK1(-/-)) mice to sham or BDL surgery for 14 days. In day 3 BDL animals, ASK1(-/-) mice had significantly fewer bile infarcts along with more reduced interlobular or portal inflammatory infiltrate of various immune cells, including neutrophils, compared with WT mice in which ASK1 expression was markedly activated. Morphologically apoptotic hepatocytes or cholangiocytes were negligible in both the sham and BDL animals. In contrast, ASK1(-/-) mice had significantly less proliferating activity of not only hepatocytes but also large cholangiocytes than WT mice. Day 14 BDL ASK1(-/-) mice manifested potential antifibrogenic aspects of ASK1 deficiency, characterized by significantly fewer activated peribiliary fibrogenic cells and peribiliary fibrosis. These observations indicate that ASK1-mediated hepatic necroinflammation and proliferation, but not apoptosis, are closely linked to liver fibrosis and fibrogenesis. A specific ASK1 pathway blocker or inhibitor might offer a therapeutic strategy against human cholestatic diseases.
Assuntos
Apoptose , Cirrose Hepática/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Transdução de Sinais , Animais , Ductos Biliares/patologia , Proliferação de Células , Colestase/patologia , Hepatócitos/metabolismo , Inflamação , Fígado/metabolismo , Cirrose Hepática/patologia , MAP Quinase Quinase Quinase 5/genética , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Deleção de SequênciaRESUMO
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-α-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model.
Assuntos
Apoptose , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , MAP Quinase Quinase Quinase 5/deficiência , Miócitos de Músculo Liso/patologia , Neointima/enzimologia , Neointima/patologia , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Aorta/patologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Becaplermina , Artérias Carótidas/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperplasia , Imuno-Histoquímica , Inflamação/genética , Inflamação/patologia , Ligadura , MAP Quinase Quinase Quinase 5/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-sis/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Estresse Fisiológico/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
High-mobility group box (HMGB) proteins are ubiquitous, abundant nuclear non-histone chromosomal proteins that play a critical role in binding to distorted DNA structures and subsequently regulating DNA transcription, replication, repair, and recombination. Both HMGB1 and HMGB2 exhibit a high expression in several human cancers and are closely associated with tumor progression and a poor prognosis. However, the expression patterns of these molecules in pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. As most cases of postoperative relapse of PDAC occur within the first 2 years, the clinical significance of accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical HMGB1 and HMGB2 expression and the clinicopathological characteristics and prognosis using 62 paraffin-embedded tumor samples obtained from patients with surgically resected PDAC. The HMGB1/2 expression was considered to be positive when 10 % or more of the cancer cells showed positive nuclear, not merely cytoplasmic, staining. Consequently, the expression of HMGB1/2 was observed in 54 (87.1 %) and 31 (50.0 %) patients, respectively. Unexpectedly, a positive HMGB1 expression was found to have a significantly close relationship with a negative HMGB2 expression. The univariate and multivariate analyses demonstrated that the patients with a HMGB1+ and HMGB2- status had markedly lower disease-specific survival rates, especially within the first 2 years postoperatively, whereas those with a HMGB1+ status alone did not. Therefore, the combination of a HMGB1+ and HMGB2- expression potentially predicts a poor prognosis in patients with PDAC, and these new biomarkers may be useful parameters for clinical management in the early postoperative phase.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/patologia , Proteína HMGB1/biossíntese , Proteína HMGB2/biossíntese , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Linhagem Celular Tumoral , Feminino , Imunofluorescência , Proteína HMGB1/análise , Proteína HMGB2/análise , Humanos , Imuno-Histoquímica , Imunoprecipitação , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , RNA Interferente Pequeno , TransfecçãoRESUMO
Pseudo-Meigs' syndrome accompanied by massive ascites in uterine leiomyoma is rare. We encountered a rare case of a 37-year-old, nulliparous woman with a lower abdominal tumor and severe abdominal distention due to massive ascites. Serum cancer antigen 125 and vascular endothelial growth factor levels were elevated to 1007.9 U/mL and 103 pg/mL, respectively. She was tentatively diagnosed with ovarian cancer. Emergency concentrated ascites re-infusion therapy was performed to improve dyspnea, abdominal pain, and her preoperative respiratory condition. Concentrated ascites re-infusion therapy eliminated dyspnea and abdominal discomfort without decreasing serum albumin levels. The patient underwent laparotomy, which revealed a fist-sized pedunculated uterine leiomyoma arising from the right uterine fundus. Myomectomy was performed. Pseudo-Meigs' syndrome mimics advanced ovarian cancer due to massive ascites and markedly elevated serum cancer antigen 125 and vascular endothelial growth factor levels. Concentrated ascites re-infusion therapy was effective in improving the subjective symptoms of pseudo-Meigs' syndrome and the patient's preoperative condition.
Assuntos
Ascite/terapia , Líquido Ascítico , Hidratação , Leiomioma/cirurgia , Terapias em Estudo , Neoplasias Uterinas/cirurgia , Adulto , Ascite/diagnóstico , Ascite/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Infusões Parenterais , Japão , Leiomioma/diagnóstico , Leiomioma/patologia , Síndrome de Meigs/diagnóstico , Terapia Neoadjuvante , Derrame Pleural/diagnóstico , Derrame Pleural/fisiopatologia , Índice de Gravidade de Doença , Síndrome , Resultado do Tratamento , Carga Tumoral , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologiaRESUMO
A female in her 60's presented with a left-sided breast mass. A core needle biopsy specimen showed diffuse proliferation of a round cell tumor, which was positive for vimentin, NKX2.2, BCOR, and focal CD99 on immunohistochemistry (IHC). No fusion genes of the Ewing family sarcomas were detected. With a tentative diagnosis of primary breast sarcoma (PBS), total mastectomy was performed after chemotherapy. The resected tissues showed proliferation of round or spindle-shaped tumor cells with a high nuclear-to-cytoplasmic ratio, exhibiting solid and fascicular arrangements but no epithelial component or organoid pattern. While IHC indicated no particular histological diagnosis, genomic examination revealed gene alterations in MED12 p.G44D, MLL2 (KMT2D) p.T1496fs*27, and EGFR variant III (vIII). Moreover, a retrospective IHC study showed overexpression of EGFRvIII. A malignant phyllodes tumor (PT) with extensive sarcomatous overgrowth was indicated as an integrative diagnosis. This is a rare case of a malignant PT harboring EGFRvIII. The present case provides an importance of accurate diagnosis and genomic analysis of rare breast tumors, as malignant PT and PBS are different in its treatment strategy and prognosis.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Receptores ErbB , Imuno-Histoquímica , Mutação , Tumor Filoide , Humanos , Feminino , Tumor Filoide/genética , Tumor Filoide/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Receptores ErbB/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Proteína Homeobox Nkx-2.2 , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio , Proteínas Nucleares , Complexo Mediador , Fatores de Transcrição , Proteínas de NeoplasiasRESUMO
Sclerosing mucoepidermoid carcinoma with eosinophilia (SMCE) of the salivary gland is a rare variant of mucoepidermoid carcinoma. We report a case of SMCE in the right submandibular gland of a 79-year-old man. Fine needle aspiration cytology revealed cohesive clusters of atypical squamous epithelial cells admixed with cells containing intracytoplasmic mucin and eosinophils. Histologically, the tumor was composed of epithelial nests with keratinizing cells occasionally present at the center, as well as peripherally located atypical basaloid cells, and some mucin-containing cells embedded in a fibrosclerotic stroma, which were accompanied by a prominent lymphoplasmacytic and eosinophilic infiltrate. Inflammatory infiltrate and stromal fibrosclerosis also were seen in the non-neoplastic salivary gland tissue adjacent to the tumor. Immunohistochemically, many plasma cells were IgG4-positive. The postoperative serum IgG4 level was elevated. Our reverse transcription-polymerase chain reaction using formalin-fixed, paraffin-embedded tumor tissue failed to detect any fusion-gene transcripts which are specifically identified in ordinary mucoepidermoid carcinoma. The findings of the present case suggest that this rare type of salivary gland carcinoma may be associated with a chronic inflammatory condition such as IgG4-related sclerosing disease. Only 23 cases of sclerosing mucoepidermoid carcinoma with or without eosinophilic infiltratie have been reported to date in such an anatomical location.
Assuntos
Carcinoma Mucoepidermoide/patologia , Eosinofilia/patologia , Neoplasias da Glândula Submandibular/patologia , Idoso , Carcinoma Mucoepidermoide/imunologia , Carcinoma Mucoepidermoide/metabolismo , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/metabolismo , Masculino , Esclerose , Neoplasias da Glândula Submandibular/imunologia , Neoplasias da Glândula Submandibular/metabolismoRESUMO
An 87-year-old man consulted a former doctor with a complaint of black stool and was admitted to hospital because of anemia and multiple gastric ulcers. The laboratory findings showed that his hepatobiliary enzyme levels and inflammatory response were elevated. Computed tomography showed hepatosplenomegaly and enlarged intra-abdominal lymph nodes. Two days later, he was transferred to our hospital due to deterioration of his liver function. Since he had low level of consciousness and his ammonia level was high, we diagnosed him with acute liver failure (ALF) with hepatic coma, and started on-line hemodiafiltration. As the cause of ALF, we suspected hepatic involvement of a hematologic tumor because of high lactate dehydrogenase and soluble interleukin-2 receptor levels and large abnormal lymphocyte-like cells in the peripheral blood. Because of his poor general condition, bone marrow and other histological examinations were difficult, and he died on the third day of hospitalization. Pathological autopsy showed marked hepatosplenomegaly and the proliferation of large abnormal lymphocyte-like cells in the bone marrow, liver, spleen, and lymph nodes. Immunostaining revealed aggressive natural killer-cell leukemia (ANKL).We herein report a rare case of the development of ALF with coma due to ANKL with a review of the relevant literature.
Assuntos
Leucemia , Falência Hepática Aguda , Masculino , Humanos , Idoso de 80 Anos ou mais , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/patologia , Baço/patologia , Hepatomegalia , Esplenomegalia , Células Matadoras Naturais/patologia , Leucemia/patologiaRESUMO
Endometrial cancers are classified into mismatch repair (MMR) deficient- (MMRd), p53 mutation- (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP) subtypes according to The Cancer Genome Atlas (TCGA). The distinction between POLEmut and NSMP subtypes is made on the basis of molecular analysis because the specific histological and immunohistochemical features of these two subtypes are still unknown. In this study, we analyzed histological features by scoring the presence of a mucinous pool, giant cells, clear cells, keratinization, neutrophilic abscess, and surface proliferating pattern in 82 cases of endometrial cancers in which an integrative diagnosis was confirmed by immunohistochemistry and genomic profiles showing POLE mutations, tumor mutation burden, and microsatellite instability. In contrast to the hierarchical branching of micropapillary proliferation observed in serous carcinoma, POLEmut-subtype endometrioid carcinomas often showed a surface epithelial slackening (SES) pattern in the tumor cells facing the uterine surface. The POLEmut subtype exhibited higher scores for clear cells and SES patterns than the other three subtypes. The scores for giant cells, clear cells, and the SES pattern were significantly higher in the POLEmut subtype than in the NSMP subtype, suggesting that these morphometric parameters are useful for differentiating POLEmut- and NSMP-subtype endometrioid carcinomas, although genomic profiling is still necessary for a definite molecular diagnosis.
Assuntos
Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Neoplasias do Endométrio , Feminino , Humanos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Biomarcadores Tumorais/genética , Cistadenocarcinoma Seroso/patologia , Mutação , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) is a rare type of sarcoma which is observed in the soft tissue of proximal extremities, typically in young and middle-aged adults. It consists of a solid proliferation of bland spindle cells within collagenous and myxoid stroma. CASE REPORT: Herein, we report a case of LGFMS with massive degeneration and hyalinization. A 30-year-old man presented with a well-circumscribed mass measuring 15 cm in diameter in his left biceps femoris muscle. Marginal tumor resection was performed under the clinical diagnosis of an ancient schwannoma or chronic expanding hematoma (CEH). The resected tissue revealed a well-demarcated tumor mass with massive degeneration and hyalinization with focal calcification. Proliferation of spindle tumor cells with abundant collagenous stroma, which resembled the fibrous capsule of CEH, was observed exclusively in a small area of the periphery of the tumor. No nuclear palisading, myxoid stroma, or collagen rosettes were identified. Immunohistochemical analysis demonstrated that the spindle tumor cells expressed mucin 4 and epithelial membrane antigen. Reverse transcriptase-polymerase chain reaction analysis detected mRNA expression of fused in sarcoma::CAMP-responsive element binding protein 3-like protein 2 (FUS::CREB3L2) fusion gene. Thus, a final diagnosis of LGFMS with massive degeneration and FUS::CREB3L2 fusion was made. CONCLUSION: The recognition of massive degeneration and hyalinization as unusual features of LGFMS might be helpful to differentiate it from CEH and other benign spindle-cell tumors.
Assuntos
Fibrossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Pessoa de Meia-Idade , Masculino , Humanos , Biomarcadores Tumorais/genética , Fibrossarcoma/diagnóstico , Fibrossarcoma/genética , Fibrossarcoma/cirurgia , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/patologiaRESUMO
OBJECTIVE: The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis. METHODS AND RESULTS: We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1(-/-)/apoE(-/-)) and analyzed atherosclerosis in ASK1(-/-)/apoE(-/-) mice fed a high-cholesterol diet for 12 weeks. ASK1(-/-)/apoE(-/-) mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE(-/-) mice. Bone marrow transplantation from ASK1(-/-) or wild-type to apoE(-/-) mice confirmed the above observation that the recipient mice of ASK1(-/-) donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors. CONCLUSIONS: These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development.
Assuntos
Aorta/enzimologia , Apoptose , Células Espumosas/enzimologia , Hiperlipidemias/enzimologia , MAP Quinase Quinase Quinase 5/deficiência , Macrófagos Peritoneais/enzimologia , Placa Aterosclerótica/enzimologia , Animais , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Peso Corporal , Transplante de Medula Óssea , Colesterol na Dieta , Modelos Animais de Doenças , Tecido Elástico/metabolismo , Células Espumosas/patologia , Hiperlipidemias/etiologia , Hiperlipidemias/genética , Hiperlipidemias/patologia , Imuno-Histoquímica , Lipoproteínas/sangue , MAP Quinase Quinase Quinase 5/genética , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Transdução de SinaisRESUMO
A male infant born prematurely at 31 weeks of gestation weighed 789 g and had mildly brown-colored oral/tracheal aspirates at delivery. The amniotic fluid was also discolored, and its index was below 5. The patient died of hypoxemic respiratory and cardiac failure 2 hours after birth. The maternal profiles showed placenta previa and intrauterine growth restriction (IUGR) at 22 weeks of gestation, and revealed recurrent episodes of antenatal and substantial vaginal bleeding and oligohydramnios, indicating chronic abruption-oligohydramnios sequence. The thickened placenta, weighing 275 g, grossly displayed unevenness and diffuse opacity with green to brown discoloration in the chorioamniotic surface, and revealed chronic massive subchorial hematomas (Breus' mole) with old peripheral blood clot, circumvallation, and infarction. Microscopically, diffuse Berlin-blue staining-positive hemosiderin deposits were readily encountered in the chorioamniotic layers of the chorionic plate, consistent with diffuse chorioamniotic hemosiderosis (DCH) due to Breus' mole, accompanied by diffuse amniotic necrosis. At autopsy, an external examination showed several surface anomalies and marked pulmonary hypoplasia, 0.006 (less 0.012) of lung:body weight ratio. Since Breus' mole has a close relationship with intrauterine hemorrhage, resulting in DCH, IUGR, and/or pulmonary hypoplasia of the newborn, the present features might be typical.
Assuntos
Anormalidades Múltiplas/patologia , Membrana Corioalantoide/patologia , Hematoma/patologia , Hemorragia/patologia , Hemossiderose/patologia , Pneumopatias/patologia , Doenças Placentárias/patologia , Adulto , Córion/patologia , Evolução Fatal , Feminino , Hematoma/complicações , Hemorragia/complicações , Hemossiderose/etiologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/anormalidades , Pulmão/patologia , Pneumopatias/complicações , Masculino , Doenças Placentárias/etiologia , GravidezRESUMO
Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines and is synthesized by monocyte-derived macrophages and dendritic cells (DCs). In this study, we investigate the relationship between monocytes/macrophages and histamine in atherosclerosis and discover that histamine levels regulate various immunologically important molecules and influences atherosclerotic progression. Immunohistochemical analysis of human atherosclerotic lesions revealed that macrophages and DCs express CCL22. The human acute monocytic leukemia cell line (THP-1) adhered to culture plates and morphologically changed to macrophage-like cells when treated with tetradecanoylphorbol-13-acetate (TPA). Macrophage-like cells derived from THP-1 cells and cultivated peripheral blood mononuclear cells (PBMCs) show similar expression of CCL22. Gene expression of CCL22 was also detected in THP-1 cells treated with histamine and the expression of the protein produced by the CCL22 gene is similar in PBMCs and THP-1 cells. In addition, the histamine H2 receptor mediated these reactions. Our results suggest that CCL22 expression in monocytes is regulated by histamine, and that CCL22 is involved centrally in the development of human atherosclerotic lesions. In conclusion, CCL22 is a marker that is a characteristic of the monocytes/ macrophages migrating into atherosclerotic lesions and histamine plays a role in regulating its expression.
Assuntos
Aterosclerose/metabolismo , Quimiocina CCL22/metabolismo , Células Dendríticas/metabolismo , Regulação da Expressão Gênica/genética , Histamina/metabolismo , Receptores Histamínicos H2/metabolismo , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Linhagem Celular Tumoral , Movimento Celular , Quimiocina CCL22/efeitos dos fármacos , Quimiocina CCL22/genética , Quimiocinas/efeitos dos fármacos , Quimiocinas/genética , Quimiocinas/metabolismo , Células Dendríticas/imunologia , Progressão da Doença , Histamina/farmacologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Modelos Moleculares , Monócitos/imunologia , Monócitos/metabolismo , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Regiões Promotoras Genéticas/genética , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
This is a case report of a 65-year-old female with malakoplakia in the urinary bladder. An ultrasound scan showed many tumor-like polyp lesions, where a transurethral resection was performed. Since the lesions revealed gross papillary neoplasms, malignancy was suspected. However, histpathological examination showed an aggregation of many infiltrating histiocytes containing characteristic Michaelis-Gutmann bodies positively reactive with von Kossa staining, indicating a typical case of malakoplakia of the urinary bladder. Immunohistochemical study demonstrated that the cytoplasms of the histiocytes were focally positive for an anti-Escherichia coli antibody. One of the etiologies of malakoplakia is infection by Escherichia coli, which is supported by our data.
Assuntos
Malacoplasia/patologia , Doenças da Bexiga Urinária/patologia , Idoso , Anticorpos Antibacterianos/análise , Escherichia coli/imunologia , Infecções por Escherichia coli/complicações , Feminino , Humanos , Imuno-Histoquímica , Malacoplasia/etiologia , Doenças da Bexiga Urinária/etiologiaRESUMO
The hippocampus plays an important role in maintaining normal cognitive function and is closely associated with the neuropathogenesis of dementia. Wnt signaling is relevant to neuronal development and maturation, synaptic formation, and plasticity. The role of Wnt10a in hippocampus-associated cognition, however, is largely unclear. Here, we examined the morphological and functional alterations in the hippocampus of Wnt10a-knockout (Wnt10a-/-) mice. Neurobehavioral tests revealed that Wnt10a-/- mice exhibited spatial memory impairment and anxiety-like behavior. Immunostaining and Western blot findings showed that the protein expressions of ß-catenin, brain-derived neurotrophic factor, and doublecortin were significantly decreased and that the number of activated microglia increased, accompanied by amyloid-ß accumulation, synaptic dysfunction, and microglia-associated neuroinflammation in the hippocampi of Wnt10a-/- mice. Our findings revealed that the deletion of Wnt10a decreased neurogenesis, impaired synaptic function, and induced hippocampal neuroinflammation, eventually leading to hippocampal neurodegeneration and memory deficit, possibly through the ß-catenin signaling pathway, providing a novel insight into preventive approaches for hippocampus-dependent cognitive impairment.
RESUMO
Extramedullary hematopoiesis (EMH) in adults usually occurs in the liver, spleen, and lymph nodes when bone marrow hematopoiesis fails. EMH has also been recognized in benign or malignant hepatic tumors, such as hepatoblastoma, hepatocellular adenoma, and vascular tumors. However, it is rarely encountered in hepatocellular carcinoma (HCC) in elderly adults, and the molecular mechanism of EMH in hepatic tumors remains unclear. We present a case of a 74-year-old man without any hematopoietic disorders and hepatitis viral infection who underwent hepatic resection for HCC. Histological examination revealed a well-differentiated HCC with trilineage hematopoiesis in the tumor and non-neoplastic liver. The coexistence of HCC and EMH in adult patients with no hematopoietic disorders is very rare and must be distinguished from poorly differentiated or dedifferentiated HCC and hepatoblastoma.