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The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3, also called cryopyrin) inflammasome is an intracellular innate immune complex, which consists of the pattern-recognition receptor NLRP3, the adaptor apoptosis-assciated speck-like protein containing a caspase recruitment domain, and procaspase-1. Aberrant activation of the NLRP3 inflammasome causes an autoinflammatory disease called cryopyrin-associated periodic syndrome (CAPS). CAPS is caused by gain-of-function mutations in the NLRP3-encoding gene CIAS1; however, the mechanism of CAPS pathogenesis has not been fully understood. Thus, unknown regulators of the NLRP3 inflammasome, which are associated with CAPS development, are being investigated. To identify novel components of the NLRP3 inflammasome, we performed a high-throughput screen using a human protein array, with NLRP3 as the bait. We identified a NLRP3-binding protein, which we called the cryopyrin-associated nano enhancer (CANE). We demonstrated that CANE increased IL-1ß secretion after NLRP3 inflammasome reconstitution in human embryonic kidney 293T cells and formed a "speck" in the cytosol, a hallmark of NLRP3 inflammasome activity. Reduced expression of endogenous CANE decreased IL-1ß secretion upon stimulation with the NLRP3 agonist nigericin. To investigate the role of CANE in vivo, we developed CANE-transgenic mice. The PBMCs and bone marrow-derived macrophages of CANE-transgenic mice exhibited increased IL-1ß secretion. Moreover, increased autoinflammatory neutrophil infiltration was observed in the s.c. tissue of CANE-transgenic versus wild-type mice; these phenotypes were consistent with those of CAPS model mice. These findings suggest that CANE, a component of the NLRP3 inflammasome, is a potential modulator of the inflammasome and a contributor to CAPS pathogenesis.
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Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Animais , Inflamassomos/metabolismo , Inflamassomos/imunologia , Camundongos , Humanos , Células HEK293 , Síndromes Periódicas Associadas à Criopirina/imunologia , Síndromes Periódicas Associadas à Criopirina/genética , Camundongos Endogâmicos C57BL , Interleucina-1beta/metabolismo , Camundongos KnockoutRESUMO
Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced recruitment of fibroblasts and immune cells, which reflect morphological features of IDCP, may influence the aggressiveness of high-grade prostate cancer.
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Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata , Microambiente Tumoral , Masculino , Humanos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Microambiente Tumoral/genética , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Carcinoma Ductal/genética , Carcinoma Ductal/patologia , Carcinoma Ductal/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transcriptoma , Receptores CCR5RESUMO
Histologic evaluations revealed excessive accumulations of macrophages and absence of fibroblastic interstitial cells in explanted bioprosthetic valves. Comprehensive gene and protein expression analysis and histology unveiled an accumulation of fibrinogen and plasminogen, an activator of infiltrated macrophages, from degenerated valve surfaces in the interstitial spaces. These pathologies were completely reproduced in a goat model replaced with an autologous pericardium-derived aortic valve. Further preclinical animal experiments using goats demonstrated that preventing infiltration of macrophages and circulating proteins by increasing collagen density and leaflet strength is an effective treatment option.
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Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.
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Carcinoma Neuroendócrino , Carcinoma de Células de Transição , Neoplasias da Próstata , Neoplasias da Bexiga Urinária , Idoso , Humanos , Masculino , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Expressão Gênica , Perfilação da Expressão Gênica , Neoplasias da Próstata/complicações , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Microambiente TumoralRESUMO
The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/caspase-1/interleukin(IL)-1ß axis, also known as the inflammasome pathway, is indispensable for IL-1ß activation in response to various pathogens or own damages. Previously, we developed an NLRP3-inflammasome using a cell-free system and identified ASC targeting drugs; thus, examination of ASC-related histopathology in various diseases could help to provide indications for these drugs. Here, we generated mice deficient only in ASC-protein (ASC-deficient (AD) mice) using CRISPR/Cas9 technology, studied which tissues were most affected, and obtained histopathological images of lipopolysaccharide (LPS)-induced endotoxemia. C57BL/6 wild-type (WT) and (AD) mice were injected intraperitoneally with a lethal dose (50 µg/g) of LPS. Statistical analysis of the survival of C57BL/6 mice and AD mice was performed using the Kaplan-Meier method and the log-rank test. The histopathological findings of multiple tissues from these mice were compared. Acute inflammation (e.g., catarrhal inflammation), along with congestion was observed in the colon of WT mice but not in that of AD mice. Adhesion of neutrophils to capillaries, along with interstitial infiltration, were observed in multiple tissues from WT mice. In AD mice, neutrophil infiltration was less severe but remained evident in the stomach, small intestine, heart, liver, kidney, spleen, and brain. Notably, there was no difference between WT and AD mice with respect to alveolar neutrophil infiltration and interstitial edema. These findings suggest that even though ASC contributes to systemic inflammation, it is dependent on the tissue involved. Intestinal congestion and edema might be good candidates for anti-ASC-targeted therapy.
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Endotoxemia , Inflamassomos , Animais , Camundongos , Inflamassomos/metabolismo , Lipopolissacarídeos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Endotoxemia/induzido quimicamente , Camundongos Endogâmicos C57BL , Caspase 1/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , EdemaRESUMO
BACKGROUND: The role of surgery in primary central nervous system lymphoma (PCNSL) is to allow pathological diagnosis from tumor biopsy. However, PCNSL is often difficult to distinguish from other tumors, particularly glioblastoma multiforme (GBM). Quantitative evaluations to facilitate differentiation between PCNSL and GBM would be useful. Here, we investigated the best examinations for exact differentiation of PCNSL from GBM among preoperative examinations, including imaging studies and tumor markers. METHODS: Various examinations were performed for 68 patients with PCNSL , including serum soluble interleukin 2 receptor, ß2-microglobulin (MG) in cerebrospinal fluid (CSF), diffusion-weighted imaging, 11C-methionine-positron emission tomography (PET), and 18F-fluorodeoxyglucose (FDG)-PET. These results were compared with findings from 28 patients with consecutive GBM who underwent the same examinations to evaluate the utility and accuracy of different investigations. RESULTS: CSF ß2-MG ≥2.0 mg/L was relatively specific for PCNSL, offering 95.0% sensitivity and 85.7% specificity. Tumor-to-contralateral normal brain tissue ratio ≥2.4 on 18F-FDG-PET was also quite specific for PCNSL, offering 83.8% sensitivity and 95.2% specificity. No other examinations displayed any significant differences in quantitative differential markers between PCNSL and GBM. CONCLUSIONS: Both ß2-MG ≥2.0 mg/dL in CSF and tumor-to-contralateral normal brain tissue ratio ≥2.4 from 18F-FDG-PET allow quantitative differentiation of PCNSL from GBM, potentially representing clinically useful indicators. These findings could lead to innovative methods for differentiating PCNSL from GBM as well as new treatment strategies for other brain tumors.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioblastoma , Linfoma , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Fluordesoxiglucose F18 , Linfoma/diagnóstico por imagem , Linfoma/cirurgia , Diagnóstico Diferencial , Tomografia Computadorizada por Raios X , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/cirurgiaRESUMO
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a key mediator of inflammation and plays an important role in the pathogenesis of atherosclerosis. Conversely, LOX-1 deficiency has been shown to decrease inflammation and atherosclerosis, both of which have been proposed to contribute to abdominal aortic aneurysm (AAA) pathogenesis. However, the role of LOX-1 in AAA pathogenesis remains unknown. Here, we investigated the effects of Olr1 (which encodes LOX-1) deletion on angiotensin II (Ang II)-induced AAA in apolipoprotein E knockout (ApoE KO) mice to determine whether LOX-1 deficiency mitigates AAA development. To accomplish this, we used serial, non-invasive ultrasound assessment, which revealed that the incidence and expansion rate of AAA were similar regardless of Olr1 deletion. However, Olr1 deletion significantly increased severe AAAs, including ruptured AAAs resulting in death. Oil Red O staining of the harvested aortas showed that the extent of atheroma burden localized in aneurysmal lesions did not differ between LOX-1-deficient and control mice, suggesting that Olr1 deletion did not decrease atheroma burden in the aneurysmal wall. Further histopathological analysis revealed that aneurysmal lesions in LOX-1-deficient mice had fewer fibroblasts and myofibroblasts, as well as thinner adventitial collagen, although the degree of elastin fragmentation or disruption was similar between LOX-1-deficient and control mice. An in vitro study confirmed that the proliferation of adventitial fibroblasts collected from LOX-1-deficient mice was significantly attenuated despite Ang II stimulation. In conclusion, Olr1 deletion may not mitigate aneurysm development but rather increases the vulnerability of rupture by suppressing adventitial fibroblast proliferation and collagen synthesis.
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Aneurisma da Aorta Abdominal , Aterosclerose , Placa Aterosclerótica , Animais , Camundongos , Angiotensina II/farmacologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/patologia , Aterosclerose/complicações , Colágeno , Modelos Animais de Doenças , Inflamação/complicações , Camundongos Endogâmicos C57BL , Receptores Depuradores Classe E/genética , Camundongos Knockout para ApoERESUMO
Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Humanos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , ConsensoRESUMO
In the treatment of primary central nervous system lymphoma (PCNSL), intraoperative rapid pathological diagnosis can dramatically change the surgical strategy, and more accurate diagnostic methods are required. In April 2020, we adopted intraoperative rapid immunohistochemistry (IHC) in addition to conventional rapid intraoperative diagnosis based on morphological assessment, mainly for patients with PCNSL. Here, we investigate the usefulness and significance of intraoperative rapid IHC based on our initial experience. We performed intraoperative rapid IHC using antibodies for cluster of differentiation (CD)20, CD3, leukocyte common antigen (LCA) and glial fibrillary acidic protein (GFAP) using enzyme-labeled antibody methods in 25 patients, including PCNSL patients, from April 2020 to July 2022. We examined the utility of this approach in determining treatment strategies for brain tumors. Postoperative final pathological diagnoses from paraffin-embedded sections were as follows: diffuse large B-cell lymphoma, 16 cases; glioblastoma, six cases; pilocytic astrocytoma, one case; adenocarcinoma, one case; and inflammatory disorder, one case. The entire process took 32 min and staining for CD20, CD3, LCA, and GFAP was comparable to that using paraffin-embedded sections. In all cases, the results of intraoperative rapid IHC were consistent with final pathological diagnoses from paraffin-embedded sections. In addition, in two cases, the results of conventional intraoperative rapid pathological diagnosis based on morphological assessments using frozen sections were drastically changed by adding intraoperative rapid IHC. Intraoperative rapid IHC contributes to deciding appropriate treatment strategies and facilitating early initiation of chemotherapy for PCNSL. This may allow new therapeutic strategies not only for PCNSL but also for other brain tumors.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Linfoma Difuso de Grandes Células B , Humanos , Imuno-Histoquímica , Neoplasias Encefálicas/patologia , Glioblastoma/diagnóstico , Astrocitoma/patologiaRESUMO
Proinsulinoma is a subtype of insulinoma that is surgically curable, but localization can be difficult as these tumors are typically too small to be visualized by imaging. We report the case of a 53-year-old woman referred to our hospital with dizziness and headache. Her blood glucose level was 46 mg/dl and Whipple's triad was present. Although her immunoreactive insulin level during hypoglycemia was in the normal range (5.0 µU/ml), the proinsulin level was elevated (408 pmol/l). Imaging examinations showed no evidence of pancreatic tumor. A preoperative selective arterial calcium injection (SACI) test showed excessive insulin secretion in the splenic artery region, which localized the proinsulinoma to the body or tail of the pancreas, and laparoscopic spleen-preserving distal pancreatectomy was performed. Intraoperative SACI test performed after tumor removal did not show excessive insulin secretion. The intraoperative SACI test appears to be useful for localization and for confirming complete resection of proinsulinoma.
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BACKGROUND: The incidence of brain metastasis of pancreatic cancer has been reported to be approximately 0.3%. The blood-brain barrier of the central nervous system restricts the transfer of substances, including chemotherapeutic agents, from the bloodstream. It is hypothesized that brain metastasis may occur despite successful chemotherapy for the primary tumor. Herein, we report a case of brain metastases of pancreatic cancer that occurred after chemotherapy and discuss relevant literature. CASE PRESENTATION: A 64-year-old man underwent distal pancreatectomy with D2 lymph node dissection for resectable pancreatic tail cancer. Invasive ductal carcinoma of pancreas, pT3N2M0 pStageIII (TNM Classification of Malignant Tumors, UICC 8th edition) was diagnosed. S-1 adjuvant chemotherapy was initiated. Three months postoperatively, CA19-9 had increased to 619 U/mL. Additionally, contrast-enhanced computed tomography (CT) and fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT revealed local recurrence in the para-aortic lymph nodes. Chemotherapy was revised to a combined regimen of gemcitabine and nab-paclitaxel. After 4 cycles, tumor markers were normalized. After 5 cycles, recurrence could not be identified on contrast-enhanced CT; therefore, the patient was adjudged to be in complete remission. However, after 29 cycles of chemotherapy, the patient had symptoms of raised intracranial pressure. Magnetic resonance imaging showed two metastatic lesions of 20 mm and 32 mm in the left frontal lobe and cerebellum, respectively. Quasi-emergency resection of the metastatic brain tumors was performed. Pathological examination revealed that the resected specimens originated from primary pancreatic cancer. The patient was discharged on postoperative day 12, without any complications. Postoperatively, a total of 53 Gy of local brain radiation therapy was added. On postoperative day 30, blood carcinoembryonic antigen level had decreased to 5.4 ng/dl and all other tumor markers were negative. Additionally, tumor markers of the cerebrospinal fluid were markedly reduced and the cytology was negative for tumor cells. These results suggested complete resection of the metastatic brain tumors. CONCLUSIONS: Aggressive resection and salvage stereotactic radiotherapy for metastatic brain tumors may lead to complete cure and a good long-term prognosis.
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INTRODUCTION: Dialysis-related amyloidosis (DRA) caused by ß2-microgloblin (B2M) fibrils is a serious complication for patients with kidney failure on long-term dialysis. Deposition of B2M amyloid fibrils is thought to be due not only to serum extracellular B2M but also to infiltrating inflammatory cells, which may have an important role in B2M amyloid deposition in osteoarticular tissues in patients with DRA. Here, we asked whether B2M amyloid fibrils activate the inflammasome and contribute to formation and deposition of amyloid fibrils in cells. METHODS: Amyloid formation was confirmed by a thioflavin T (ThT) spectroscopic assay and scanning electron microscopy (SEM). Activation of inflammasomes was assessed by detecting interleukin (IL)-1ß in culture supernatants from human embryonic kidney (HEK) 293T cells ectopically expressing inflammasome components. IL-1ß secretion was measured by enzyme-linked immunosorbent assay. Expression and co-localization were analyzed by immunohistochemistry and dual immunofluorescence microscopy. RESULTS: B2M amyloid fibrils interacted directly with NLRP3/Pyrin and to activate the NLRP3/Pyrin inflammasomes, resulting in IL-1ß secretion. When HEK293T cells were transfected with inflammasome components NLRP3 or Pyrin, along with ASC, pro-caspase-1, pro-IL-1ß, and B2M, ThT fluorescence intensity increased. This was accompanied by IL-1ß secretion, which increased in line with the amount of transfected B2M. In this case, morphological glowing of amyloid fibrils was observed by SEM. In the absence of ASC, there was no increase in ThT fluorescence intensity or IL-1ß secretion, or any morphological glowing of amyloid fibrils. NLRP3 or Pyrin and B2M were co-localized in a "speck" in HEK293T cells, and co-expressed in infiltrated monocytes/macrophages in the osteoarticular synovial tissues in a patient with DRA. CONCLUSION: Taken together, these data suggest that inflammasome assembly is required for the subsequent triggering of intracellular formation of B2M amyloid fibrils, which may contribute to osteoarticular deposition of B2M amyloid fibrils and inflammation in patients with DRA.
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Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Amiloide , Células HEK293 , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , PirinaAssuntos
Osteoma , Neoplasias da Medula Espinal , Dura-Máter , Humanos , Imageamento por Ressonância Magnética , Osteoma/diagnóstico por imagem , Osteoma/cirurgia , Pia-Máter , Medula Espinal/diagnóstico por imagem , Medula Espinal/cirurgia , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/cirurgia , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgiaRESUMO
The characterization of aortic valve interstitial cells (VICs) cultured under optimal conditions is essential for understanding the molecular mechanisms underlying aortic valve stenosis. Here, we propose 2% hypoxia as an optimum VIC culture condition. Leaflets harvested from patients with aortic valve regurgitation were digested using collagenase and VICs were cultured under the 2% hypoxic condition. A significant increase in VIC growth was observed in 2% hypoxia (hypo-VICs), compared to normoxia (normo-VICs). RNA-sequencing revealed that downregulation of oxidative stress-marker genes (such as superoxide dismutase) and upregulation of cell cycle accelerators (such as cyclins) occurred in hypo-VICs. Accumulation of reactive oxygen species was observed in normo-VICs, indicating that low oxygen tension can avoid oxidative stress with cell-cycle arrest. Further mRNA quantifications revealed significant upregulation of several mesenchymal and hematopoietic progenitor markers, including CD34, in hypo-VICs. The stemness of hypo-VICs was confirmed using osteoblast differentiation assays, indicating that hypoxic culture is beneficial for maintaining growth and stemness, as well as for avoiding senescence via oxidative stress. The availability of hypoxic culture was also demonstrated in the molecular screening using proteomics. Therefore, hypoxic culture can be helpful for the identification of therapeutic targets and the evaluation of VIC molecular functions in vitro.
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Antígenos CD34/biossíntese , Insuficiência da Valva Aórtica/metabolismo , Valva Aórtica/metabolismo , Técnicas de Cultura de Células , Regulação da Expressão Gênica , Células-Tronco/metabolismo , Valva Aórtica/patologia , Insuficiência da Valva Aórtica/patologia , Hipóxia Celular , Feminino , Humanos , Masculino , RNA Mensageiro/biossíntese , Células-Tronco/patologiaRESUMO
The long battle between humans and various physical, chemical, and biological insults that cause cell injury (e.g., products of tissue damage, metabolites, and/or infections) have led to the evolution of various adaptive responses. These responses are triggered by recognition of damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs), usually by cells of the innate immune system. DAMPs and PAMPs are recognized by pattern recognition receptors (PRRs) expressed by innate immune cells; this recognition triggers inflammation. Autoinflammatory diseases are strongly associated with dysregulation of PRR interactomes, which include inflammasomes, NF-κB-activating signalosomes, type I interferon-inducing signalosomes, and immuno-proteasome; disruptions of regulation of these interactomes leads to inflammasomopathies, relopathies, interferonopathies, and proteasome-associated autoinflammatory syndromes, respectively. In this review, we discuss the currently accepted molecular mechanisms underlying several autoinflammatory diseases.
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BACKGROUND: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. METHODS: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium (CM) derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the CM. We assessed angiogenic activities by treatment of HUVECs with LNCaP-derived CM using a tube formation assay that mimics angiogenesis. RESULTS: Immunohistochemistry of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in 4 of 33 prostate cancer patients (12.1%). We also found that the 10,000g pellet fraction of the LNCaP-derived CM containing PSMA-positive membranes, such as microvesicles transformed HUVECs "PSMA-negative" into "PSMA-positive." Furthermore, treatment of HUVECs with the 10,000g pellet fraction of the LNCaP-derived CM significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. CONCLUSIONS: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues.
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Antígenos de Superfície/metabolismo , Células Endoteliais/patologia , Glutamato Carboxipeptidase II/metabolismo , Neovascularização Patológica/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Idoso , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Meios de Cultivo Condicionados , Perfilação da Expressão Gênica/métodos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imuno-Histoquímica , Masculino , Gradação de Tumores , Próstata , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/cirurgia , Células Tumorais CultivadasRESUMO
We report a case of rupture of a synchronous metastatic liver tumor secondary to a thymoma. A 56-year-old woman was referred to our hospital with acute abdomen. Computed tomography (CT) revealed a 10 cm diameter tumor in the left lateral segment of the liver, together with ascites, which was suggestive of intra-abdominal bleeding. She was in stable condition and hemostasis was confirmed by angiography. CT also revealed a mass in the anterior mediastinum. Elective laparoscopic left lateral segmentectomy was performed to make a pathological diagnosis and for radical resection. No peritoneal dissemination was observed and the liver tumor was curatively resected. The patient subsequently underwent thymectomy. The pathological diagnoses were thymoma with the liver metastasis. Currently, at 30 months post-treatment, she has had no tumor recurrence. Rupture of a metastatic liver tumor secondary to a thymoma is a rare condition; careful preoperative management and aggressive treatment might improve the patient's prognosis.
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PURPOSE: This study aimed to compare the characteristics of triple-negative breast cancer (TNBC) with non-TNBC on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and synthetic MRI. METHOD: This retrospective study included 79 patients with histopathologically proven breast cancer (TNBC: 16, non-TNBC: 63) who underwent synthetic MRI. Using synthetic MR images, we obtained T1 and T2 relaxation times in breast lesions before (Pre-T1, Pre-T2, Pre-PD) and after (Gd-T1, Gd-T2, Gd-PD) contrast agent injection. Subsequently, we calculated the ΔT1 (Pre-T1 - Gd-T1), ΔT2 (Pre-T2 - Gd-T2), Pre-T1/T2, and Gd-T1/T2. We compared the aforementioned quantitative values, as well as several morphologic features between TNBCs and non-TNBCs that were identified on DCE-MRI. RESULTS: The multivariate analyses revealed that the Pre-T2 (P = 0.037) and the presence of rim enhancement (P-RIM) (P = 0.034) were significant and independent predictors of TNBC. The area under the receiver operating characteristics curve for all breast cancers was greater when a combination of Pre-T2 and P-RIM (Pre-T2ï¼P-RIM; Method 3, AUC (area under the curve) = 0.858) was used to distinguish between TNBCs and non-TNBCs versus the use of either Pre-T2 alone (Method 1, AUC = 0.786) or P-RIM alone (Method 2, AUC = 0.747). CONCLUSIONS: Pre-T2 obtained using synthetic MRI and P-RIM identified on DCE-MRI allowed the differentiation between TNBCs and non-TNBCs. However, these results are preliminary and need to be verified by further studies.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Mama , Neoplasias da Mama/diagnóstico por imagem , Meios de Contraste , Feminino , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/diagnóstico por imagemRESUMO
The management of systemic artery aneurysms secondary to Kawasaki disease (KD) in adults remains a therapeutic challenge. KD guidelines recommend the use of anticoagulation therapy with warfarin in addition to antiplatelet therapy when a giant coronary aneurysm or a history of thrombosis is documented. However, long-term use of warfarin presents several concerns. This case reports acute thrombotic occlusion due to the giant arterial aneurysm in an adult KD. A surgical resection of the aneurysm was performed because of recurrent thrombotic events, despite anticoagulant therapy with warfarin. Pathological examinations revealed a layered thrombus with inflammation in the aneurysm and Factor Xa expression mainly in newly formed thrombus. This study provides an insight into the anticoagulation therapy for cardiovascular sequelae after KD.
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BACKGROUND: The progression of chronic kidney disease (CKD) depends on the extent of fibrosis in the kidneys; however, a renal biopsy is necessary to evaluate the severity of renal fibrosis. Real-time tissue elastography (RTE), which measures heartbeat-induced tissue displacement, can assess the elasticity of organs. Here, we aimed to investigate the correlation between renal elasticity and the extent of fibrosis in renal biopsy samples. METHODS: We investigated 29 consecutive patients who underwent a renal biopsy at Ehime University Hospital from February 2018 to August 2019. Renal fibrosis was categorized into three grades, mild (< 25%), moderate (25-50%), and severe (> 50%), based on the total affected area within the biopsy sample. The association between renal elasticity assessed by RTE and the grade of renal fibrosis was evaluated, and a receiver operating characteristic curve was used to distinguish the severity of renal fibrosis. RESULTS: The mean age and estimated glomerular filtration rate (eGFR) were 58.8 years and 55.2 mL/min/1.73 m2, respectively. The median urine protein-to-creatinine ratio was 1.24 g/gCr. The mean renal elasticity of mild, moderate, and severe renal fibrosis was 3.40, 3.98, and 4.77, respectively. Renal elasticity of native kidneys was significantly positively correlated with the grade of renal fibrosis (ρ = 0.529, P = 0.003). At the cutoff point of 3.81, the area under the curve, sensitivity, and specificity were 0.778, 68.4%, and 81.8%, respectively. CONCLUSION: Real-time tissue elastography is a promising, non-invasive method for assessing renal fibrosis in patients with CKD.