RESUMEN
Meningioma is the most common primary intracranial tumor in adults, with up to 10% manifesting as multiple tumors. Data on the genomic and molecular changes in sporadic multiple meningiomas are scarce, leading to ongoing debates regarding their evolutionary processes. A comprehensive genetic analysis of a large number of lesions, including precursor lesions, is necessary to explore these two possible origins: clonal and independent. In the present study, we performed whole-exome sequencing and analyzed somatic single-nucleotide variants (SNVs), insertions/deletions (INDELs), and copy number alterations (CNAs) in a patient with sporadic multiple meningiomas. These meningiomas included two mass-forming lesions of different histological subtypes (transitional and chordoid) and two small meningothelial nests. Genetic analysis revealed CNAs on chromosomes 22q and Y as common abnormalities in the two largest tumors. Furthermore, we identified SNV/INDELs unique to each focus, with NF2 mutation prevalent in the transitional meningioma and CREBBP mutation in the chordoid meningioma. Loss of chromosome 22 was detected in two small meningothelial nests. Overall, we elucidated the clonal origin and subtype-specific evolution of multiple meningiomas in this case. CNAs may serve as the initial driving event in meningioma development.
RESUMEN
Approximately 60% of hemangioblastomas (HBs) have peritumoral cysts adjacent to the tumor, which can cause neurological deficits due to the mass effect, and the management of cyst formation is a clinical challenge. Vascular mural cells surrounding endothelial cells consist of vascular smooth muscle cells (vSMCs) and pericytes, which are essential elements that support blood vessels and regulate permeability. This study investigated the involvement of mural cells in cyst formation. We analyzed the expression of α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-beta (PDGFRB), and CD31 in 39 consecutive human cerebellar HBs, 20 of cystic and 19 of solid type. Solid type HBs showed stronger diffuse expression of α-SMA in precapillary arterioles and capillaries within the tumor than cystic type HBs (p = 0.001), whereas there was no difference in PDGFRB and CD31 expression. Detailed observation with immunofluorescence demonstrated that α-SMA was expressed in vascular mural cells surrounding capillaries in the solid rather than in the cystic type. Multivariate analysis including various clinical and pathological factors showed that lower α-SMA expression was significantly correlated with cyst formation (p < 0.001). Our data suggested that vascular mural cells from precapillary arterioles to capillaries expressing α-SMA may be pericytes and play a crucial role in HB cystogenesis.
Asunto(s)
Quistes , Hemangioblastoma , Humanos , Actinas/metabolismo , Hemangioblastoma/genética , Hemangioblastoma/metabolismo , Células Endoteliales/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Pericitos/metabolismo , Quistes/metabolismoRESUMEN
OBJECTIVE: An extracellular matrix such as collagen is an essential component of the tumor microenvironment. Collagen alpha-2(I) chain (COL1A2) is a chain of type I collagen whose triple helix comprises two alpha-1 chains and one alpha-2 chain. The authors' proteomics data showed that COL1A2 is significantly higher in the blood of patients with glioblastoma (GBM) compared with healthy controls. COL1A2 has many different functions in various types of cancers. However, the functions of COL1A2 in GBM are poorly understood. In this study, the authors analyzed the functions of COL1A2 and its signaling pathways in GBM. METHODS: Surgical specimens and GBM cell lines (T98, U87, and U251) were used. The expression level of COL1A2 was examined using GBM tissues and normal brain tissues by quantitative real-time polymerase chain reaction. The clinical significance of these levels was evaluated using Kaplan-Meier analysis. Small interfering RNA (siRNA) and small hairpin RNA of COL1A2 were transfected into GBM cell lines to investigate the function of COL1A2 in vitro and in vivo. Flow cytometry was introduced to analyze the alteration of cell cycles. Western blot and immunohistochemistry were performed to analyze the underlying mechanisms. RESULTS: The expression level of COL1A2 was upregulated in GBM compared with normal brain tissues. A higher expression of COL1A2 was correlated with poor progression-free survival and overall survival. COL1A2 inhibition significantly suppressed cell proliferation in vitro and in vivo, likely due to G1 arrest. The invasion ability was notably deteriorated by inhibiting COL1A2. Cyclin D1, cyclin-dependent kinase 1, and cyclin-dependent kinase 4, which are involved in the cell cycle, were all downregulated after blockade of COL1A2 in vitro and in vivo. Phosphoinositide 3-kinase inhibitor reduced the expression of COL1A2. Although downregulation of COL1A2 decreased the protein kinase B (Akt) phosphorylation, Akt activator can phosphorylate Akt in siRNA-treated cells. This finding suggests that Akt phosphorylation is partially dependent on COL1A2. CONCLUSIONS: COL1A2 plays an important role in driving GBM progression. COL1A2 inhibition attenuated GBM proliferation by promoting cell cycle arrest, indicating that COL1A2 could be a promising therapeutic target for GBM treatment.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Colágeno Tipo I , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular , ARN Interferente Pequeño/uso terapéutico , Microambiente TumoralRESUMEN
SMARCB1 (INI1) is one of the switch/sucrose nonfermentable (SWI/SNF) complexes whose loss is associated with several tumors. SMARCB1 (INI1)-deficient intrathoracic neoplasms are extremely rare and known to be highly malignant and lethal. This report presents the case of a patient diagnosed with SMARCB1 (INI1)-deficient intrathoracic neoplasm during chemotherapy for plasma cell myeloma. A 77-year-old male patient complained of cough, bloody sputum, and fever with an enlarged right lung mass and pleural effusion. His cytological examination revealed undifferentiated epithelioid and rhabdoid/plasmacytoid cells with bi- or multinucleation, vacuolization, mitosis, and pleomorphism. However, it was difficult to distinguish the relapse of plasma cell myeloma as atypical plasmacytoid cells were detected. Immunohistochemically, the neoplastic cells showed a loss of SMARCB1 (INI1) expression in the cell block of pleural fluid and in the right lung of the autopsy specimen. Further, the patient was diagnosed with SMARCB1 (INI1)-deficient intrathoracic neoplasm of the right lung based on histological and autopsy findings. To the best of our knowledge, this is the first report of cytomorphology in a SMARCB1 (INI1)-deficient intrathoracic neoplasm.
Asunto(s)
Mieloma Múltiple , Tumor Rabdoide , Masculino , Humanos , Anciano , Recurrencia Local de Neoplasia , Proteína SMARCB1/genética , Biomarcadores de Tumor/metabolismo , Tumor Rabdoide/patologíaRESUMEN
The purpose was to assess whether consecutive monitoring of oxygenation by photoacoustic imaging (PAI) can objectively predict intestinal viability during surgery for acute mesenteric ischemia (AMI). PAI uses laser light to detect relative amounts of oxygenated and deoxygenated hemoglobin in intestinal tissue. In 30 rats, AMI was induced by clamping the mesenteric and marginal vessels of the ileum for 0 min in the control group, 30 min in the mild group, and 180 min in the severe group (10 rats per group). After 60 min of reperfusion, intestinal damage was evaluated pathologically. Oxygenation of the intestine was monitored throughout the procedure in real time by a commercially available PAI system and compared among the groups. All rats showed irreversible (i.e. transmucosal or transmural infarction) damage in the severe group. After reperfusion, the oxygenation in the mild group recovered immediately and was significantly higher than in the severe group at 1, 5, 10, 30, and 60 min (P = .011, 002, < .001, 001, and 001, respectively). Oxygenation showed a significant strong negative correlation with pathological severity (rs = - 0.7783, - 0.7806, - 0.7422, - 0.7728, and - 0.7704, respectively). In conclusion, PAI could objectively predict irreversible ischemic damage immediately after reperfusion, which potentially prevents inadequate surgery.
Asunto(s)
Diagnóstico por Imagen/métodos , Intestinos/irrigación sanguínea , Intestinos/metabolismo , Isquemia Mesentérica/diagnóstico , Isquemia Mesentérica/metabolismo , Oxígeno/metabolismo , Técnicas Fotoacústicas , Reperfusión , Animales , Biomarcadores , Modelos Animales de Enfermedad , Íleon/irrigación sanguínea , Ácido Láctico/metabolismo , Isquemia Mesentérica/etiología , Ratas , Reperfusión/métodos , Factores de TiempoRESUMEN
Rhabdomyosarcoma is the most common soft-tissue sarcoma affecting children and adolescents. It is defined as a malignant neoplasm characterized by morphologic, immunohistochemical, ultrastructural, or molecular genetic evidence of primary skeletal muscle differentiation, usually in the absence of any other pattern of differentiation. Primary intracranial rhabdomyosarcoma (PIRMS) is an extremely rare neoplasm, with only 60 cases reported in the literature, and generally has poor prognosis with an overall survival of only 9.1 months. The DICER1 gene encodes an RNA endoribonuclease that plays a key role in gene expression regulation through the production of small RNAs. Herein, we report two cases of PIRMS with somatic DICER1 mutation showing morphological and immunohistochemical evidence of primary skeletal muscle differentiation; the two cases share common clinical features, including young age, supratentorial tumor, and onset of intratumoral bleeding. Although methylation profiling was not performed, both cases shared clinical and pathological characteristics in common with recently proposed methylation entity "spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant (SCS-RMSlike-DICER1)''. Our cases provide further evidence of the link between primary intracranial sarcoma and DICER1 mutation which may form a distinct entity.
Asunto(s)
ARN Helicasas DEAD-box/genética , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Ribonucleasa III/genética , Adulto , Biomarcadores de Tumor/genética , Niño , ARN Helicasas DEAD-box/metabolismo , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Mutación , Ribonucleasa III/metabolismoRESUMEN
Accumulation of ß amyloid (Aß) peptides to nerve cells should be associated with the onset of Alzheimer's disease (AD). We prepared hybrid liposomes (HL) composed of 90 mol% phospholipids having various charged head groups (cationic L-α-dimyristoyltrimethyl ammonium propane (DMTAP), anionic L-α-dimyristoylphosphatidylserine (DMPS) or zwitterionic L-α-dimyristoylphosphatidylcholine (DMPC)) and 10 mol% polyoxyethylene(23) dodecyl ether (C(12)(EO)(23))), and investigated the inhibitory effects of HL on the accumulation of Aß(1-40) peptides into human neuroblastoma (SH-SY5Y) cells in vitro. It is noteworthy that remarkable inhibitory effects on the accumulation of Aß(1-40) peptides were observed for SH-SY5Y cells treated with anionic HL-DMPS, though the accumulation was not inhibited by cationic HL-DMTAP. On the other hand, the immediate fusion of HL-DMTAP into SH-SY5Y cells was confirmed using a confocal laser microscope. Interestingly, the specific interactions between anionic HL-DMPS and Aß(1-40) peptides were observed using the thioflavin T (ThT) assay. In addition, the cytotoxicity of Aß(1-42) peptides on the SH-SY5Y cells decreased after the treatment with HL-DMPS. These results suggest that anionic HL-DMPS could be used as a novel medicine for AD in the future.