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In animal cells, vacuoles are absent, but can be induced by diseases and drugs. While phosphoinositides are critical for membrane trafficking, their role in the formation of these vacuoles remains unclear. The immunosuppressive KRP203/Mocravimod, which antagonizes sphingosine-1-phosphate receptors, has been identified as having novel multimodal activity against phosphoinositide kinases. However, the impact of this novel KRP203 activity is unknown. Here, we show that KRP203 disrupts the spatial organization of phosphoinositides and induces extensive vacuolization in tumor cells and immortalized fibroblasts. The KRP203-induced vacuoles are primarily from endosomes, and augmented by inhibition of PIKFYVE and VPS34. Conversely, overexpression of PTEN decreased KRP203-induced vacuole formation. Furthermore, V-ATPase inhibition completely blunted KRP203-induced vacuolization, pointing to a critical requirement of the endosomal maturation process. Importantly, nearly a half of KRP203-induced vacuoles are significantly decorated with PI4P, a phosphoinositide typically enriched at the plasma membrane and Golgi. These results suggest a model that noncanonical spatial reorganization of phosphoinositides by KRP203 alters the endosomal maturation process, leading to vacuolization. Taken together, this study reveals a previously unrecognized bioactivity of KRP203 as a vacuole-inducing agent and its unique mechanism of phosphoinositide modulation, providing a new insight of phosphoinositide regulation into vacuolization-associated diseases and their molecular pathologies.
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Endosomas , Fosfohidrolasa PTEN , Fosfatidilinositoles , Vacuolas , Vacuolas/metabolismo , Vacuolas/efectos de los fármacos , Endosomas/metabolismo , Endosomas/efectos de los fármacos , Humanos , Fosfatidilinositoles/metabolismo , Animales , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Fosfatidilinositol 3-Quinasas Clase III/genética , Ratones , Morfolinas/farmacología , ATPasas de Translocación de Protón Vacuolares/metabolismo , ATPasas de Translocación de Protón Vacuolares/antagonistas & inhibidores , ATPasas de Translocación de Protón Vacuolares/genética , Citoplasma/metabolismo , Células HeLa , Aminopiridinas , Compuestos Heterocíclicos con 3 AnillosRESUMEN
While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4Kß, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kß preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kß is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kß is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kß. The critical role of the GTP-sensing activity of PI5P4Kß in cancer signifies this lipid kinase as a cancer therapeutic target.
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Carcinogénesis/metabolismo , Carcinogénesis/patología , Guanosina Trifosfato/metabolismo , Espacio Intracelular/enzimología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Animales , Proliferación Celular , Cristalografía por Rayos X , Células HEK293 , Humanos , Hidrólisis , Cinética , Ratones , Datos de Secuencia Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Unión Proteica , Proteómica , Transducción de SeñalRESUMEN
OBJECTIVES: Distal anterior cerebral artery (DACA) aneurysms account for 1%-9% of all intracranial aneurysms. Microsurgical treatment is generally preferred for DACA aneurysms; however, it presents challenges owing to the anatomical complexities. Advances in neuro-interventional techniques have yielded promising results. This study aims to compare the clinical outcomes of DACA aneurysms treated with microsurgery and endovascular treatment (EVT) to elucidate the efficacy of EVT. MATERIALS AND METHODS: A multicenter observational registry comprising 16 stroke centers was utilized for this study. Data was retrospectively and prospectively analyzed from 166 patients with DACA aneurysms in our database, which included 4,552 consecutive patients with ruptured or unruptured intracranial aneurysms who underwent microsurgical or endovascular treatment between January 2013 and December 2021. RESULTS: Surgical clipping was performed in 115 patients, and 51 underwent coil embolization. The median follow-up duration was 15.3 months. No significant differences were observed in patient characteristics between the two treatment modalities. There were no differences in complication-related morbidity between the microsurgical treatment and EVT groups in either unruptured (10.5% vs. 9.1%, p=1.00) or ruptured aneurysms (5.2% vs. 6.9%, p=0.66). Coil embolization resulted in higher recurrence and retreatment rates than surgical clipping did, especially for ruptured aneurysms (2.6% vs. 27.6%, p<0.01). CONCLUSIONS: Endovascular treatment is an alternative to microsurgery for DACA aneurysms especially in unruptured cases or the patients who have difficulty undergoing craniotomy due to their general condition, albeit with considerations for higher recurrence and retreatment rates, particularly in ruptured cases. Close follow-up is crucial for the effective management of these challenges. Further studies are needed to refine the treatment strategies for DACA aneurysms.
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Increased phosphoinositide signaling is commonly associated with cancers. While "one-drug one-target" has been a major drug discovery strategy for cancer therapy, a "one-drug multi-targets" approach for phosphoinositide enzymes has the potential to offer a new therapeutic approach. In this study, we sought a new way to target phosphoinositides metabolism. Using a high-throughput phosphatidylinositol 5-phosphate 4-kinase-alpha (PI5P4Kα) assay, we have identified that the immunosuppressor KRP203/Mocravimod induces a significant perturbation in phosphoinositide metabolism in U87MG glioblastoma cells. Despite high sequence similarity of PI5P4K and PI4K isozymes, in vitro kinase assays showed that KRP203 activates some (e.g., PI5P4Kα, PI4KIIß) while inhibiting other phosphoinositide kinases (e.g., PI5P4Kß, γ, PI4KIIα, class I PI3K-p110α, δ, γ). Furthermore, KRP203 enhances PI3P5K/PIKFYVE's substrate selectivity for phosphatidylinositol (PI) while preserving its selectivity for PI(3)P. At cellular levels, 3 h of KRP203 treatment induces a prominent increase of PI(3)P and moderate increase of PI(5)P, PI(3,5)P2, and PI(3,4,5)P3 levels in U87MG cells. Collectively, the finding of multimodal activity of KRP203 towards multi-phosphoinositide kinases may open a novel basis to modulate cellular processes, potentially leading to more effective treatments for diseases associated with phosphoinositide signaling pathways.
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The twisting phenomenon of the flow diverter stents rarely occurs, but it recently became relatively well-recognized. There have been few reports on single-layer flow diverters only. The Flow Redirection Endoluminal Device (FRED) (MicroVention, Tustin, California) has a unique design characterized by a braided dual-layer self-expanding stent. There have been no reports on the twisting phenomenon of FRED. This study reports two cases of acute in-stent blood flow disturbances after the deployment of FRED in a patient with intracranial aneurysms associated with "ghost twisting." In this phenomenon, the inner layer does not expand with the coning deformation, even though the outer layer is fully open. This was confirmed through high-resolution cone-beam computed tomography, but not conventional angiography. The two cases were successfully treated using balloon angioplasty and showed favorable outcomes. The structural issue of "ghost twisting" was a possible underlying factor for the ischemic complications associated with FRED deployment.
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BACKGROUND AND PURPOSE: To investigate the associations of perioperative P2Y12 reaction units (PRU) measured using VerifyNow with ischemic and bleeding events, and to determine the PRU threshold in the setting of elective neuro-endovascular treatment (EVT) for intracranial/extracranial vascular disease in patients taking aspirin and clopidogrel. METHODS: Of the patients undergoing elective neuro-EVT while taking aspirin and clopidogrel, those taking both antiplatelet agents for 7 days or more and whose PRU and aspirin reaction units (ARU) were measured were included. The primary and safety outcomes were defined as symptomatic ischemic and major bleeding events within 30 days after EVT. RESULTS: A total of 197 patients were available for the analyses. Higher PRU was associated with symptomatic ischemic events on multivariable logistic analysis (odds ratio per 10 increase 1.14 [95% confidence interval 1.03-1.27], p=0.011). Receiver operating characteristic curve analysis showed that PRU ≥212 was the threshold to predict symptomatic ischemic events (area under the curve=0.73; sensitivity, 62.5%; specificity, 82.0%). Lower PRU was also associated with major bleeding events (odds ratio per 10 increase 0.87 [0.78-0.96], p=0.004), and the threshold to predict major bleeding events was PRU ≤46 (area under the curve=0.76; sensitivity, 70.0%; specificity, 87.2%) CONCLUSIONS: The PRU value was associated with symptomatic ischemic and major bleeding events after elective neuro-EVT in patients taking aspirin and clopidogrel. PRU ≥212 and PRU ≤46 appeared to be the threshold values to predict symptomatic ischemic and major bleeding events, respectively.
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Procedimientos Endovasculares , Antagonistas del Receptor Purinérgico P2Y , Ticlopidina , Aspirina/efectos adversos , Clopidogrel/efectos adversos , Hemorragia/inducido químicamente , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Pruebas de Función Plaquetaria , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Ticlopidina/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Postoperative cerebral embolic stroke is a serious complication of pulmonary lobectomy, occurring in 1.1% of patients undergoing lobectomy through video-assisted thoracoscopic surgery (VATS). The mechanism of this complication is thought to be embolic stroke caused by thrombus formed due to stagnation in the pulmonary vein stump after VATS lobectomy. There have been few reports demonstrating the utility of endovascular treatment (EVT) for cerebral embolic stroke after VATS lobectomy. CASE DESCRIPTION: In our case series, cerebral embolic stroke occurred after VATS pulmonary lobectomy for lung cancer, including the left upper lobe in three cases and the right lobe in one. The median duration of ischemic stroke after VATS was 4.5 days (interquartile range, 2-9 days). The median time from stroke onset to puncture was 130 min. Successful recanalization was achieved in all cases, and two patients achieved favorable clinical outcomes (modified Rankin scale, 0-2). CONCLUSION: We report a case series of four patients who underwent EVT for acute embolic stroke after VATS lobectomy for lung cancer. EVT is considered a reasonable and feasible therapeutic option for this condition.
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Accidente Cerebrovascular Embólico , Accidente Cerebrovascular Isquémico , Neoplasias Pulmonares , Accidente Cerebrovascular , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Neumonectomía/efectos adversos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/terapia , Cirugía Torácica Asistida por Video/efectos adversosRESUMEN
OBJECTIVES: Collateral status (CS) is considered a predictor of clinical outcome after reperfusion therapy (RT) in patients with acute ischemic stroke (AIS). We proposed a quantitative assessment of CS using cerebral blood volume (CBV) measured by computed tomography perfusion (CTP) imaging. MATERIALS AND METHODS: This retrospective study was approved by the Institutional Review Board. Between February 2019 and September 2020, 60 patients with anterior circulation large-vessel occlusion who presented to our institution within 8 h after stroke onset were included. The ratio of the average CBV values in the affected middle cerebral artery (MCA) territories to the unaffected side was defined as the CBV ratio. CS was assessed by scores from previously reported qualitative scoring systems (Tan & regional leptomeningeal collateral (rLMC) scores). RESULTS: The CBV ratio was an independent factor contributing to a good functional outcome (P<0.01) and was significantly correlated with the Tan score (ρ=0.73, P<0.01) and the rLMC score (ρ=0.77, P<0.01). Among the patients with recanalization, the CBV ratio was a useful parameter that predicted both a good functional outcome (area under the receiver operating characteristic curve (AUC-ROC), 0.76; 95% CI, 0.55-0.89) and a good radiological outcome (AUC-ROC, 0.90; 95% CI, 0.72-0.97), and it was an independent predictor for good radiological outcome (OR: 4.38; 95% CI:1.29-14.82; P<0.01) in multivariate models. CONCLUSIONS: The CBV ratio is a suitable parameter for evaluating CS quantitatively for patients with AIS that can predict patient response to recanalization.
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Volumen Sanguíneo , Circulación Cerebrovascular , Circulación Colateral , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Arteria Cerebral Media/diagnóstico por imagen , Tomografía Computarizada Multidetector , Imagen de Perfusión , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Accidente Cerebrovascular Isquémico/fisiopatología , Accidente Cerebrovascular Isquémico/terapia , Masculino , Arteria Cerebral Media/fisiopatología , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Trombectomía , Terapia Trombolítica , Resultado del TratamientoRESUMEN
BACKGROUND: Diffuse midline glioma, H3K27M mutant is a glioma located in the thalamus, brainstem, or spine with the H3K27M mutation, which is a new entity in the 2016 revised WHO classification. The treatment of thalamic glioma(TG)and brainstem glioma(BSG), which includes diffuse midline gliomas, the H3K27M mutant is challenging, and there are no standard therapeutic strategies. It is important to determine the characteristics of these brain tumors. Here, we retrospectively reviewed 31 consecutive patients with TG and BSG who were treated at our institute between January 1994 and May 2018, including methionine-positron emission tomography(MET-PET)data. RESULTS: Fourteen patients had TG, while 17 patients had BSG. Six patients were children, and 25 were adults. Nine patients with TGs and seven with BSG were enhanced by gadolinium. Twenty-seven patients were treated with radiotherapy, and 20 patients were treated with chemotherapy. All 21 tumors that underwent surgery showed wild-type IDH. The H3K27M mutation was present in four TG and two BSG. There was no statistically significant association between methionine uptake and gadolinium contrast enhancement and tumor grade. The median overall survival period(OS)of all cases was 16.9 months, whereas those of TG and BSG were 22.8 and 10.0 months, respectively. CONCLUSION: Because TG and BSG still have poor prognoses, it is necessary to elucidate the pathology of the disease and establish its standard therapy.
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Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Tronco Encefálico , Niño , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/terapia , Histonas/genética , Humanos , Mutación , Estudios Retrospectivos , Tálamo/diagnóstico por imagenRESUMEN
Chordomas are uncommon tumors occurring from remnants of the notochord. They are mainly localized in the sacrococcygium, the spine and the central skull base. Here we report a rare case of clivus chordoma presenting with cerebrospinal fluid(CSF)rhinorrhea. A 41-year-old man with a 11-year history of recurrent CSF rhinorrhea was found to have a clival lesion. Bone image CT revealed lytic bone destruction at the clivus. MRI showed a cystic mass with a membrane enhanced by gadolinium protruding into the sphenoid sinus thorough the bone defect. However, there was no solid component observed. The membrane was partially resected and the CSF fistula was repaired via endoscopic endonasal approach. The pathological diagnosis was chordoma, and there has been no recurrence for three years after the surgery. It is necessary for chordoma to be considered as a differential diagnosis for cystic lesions of the clivus when the cyst membrane is enhanced by gadolinium.
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Rinorrea de Líquido Cefalorraquídeo , Cordoma , Neoplasias de la Base del Cráneo , Adulto , Fosa Craneal Posterior , Humanos , Masculino , Recurrencia Local de NeoplasiaRESUMEN
Primary cerebellar glioblastoma is a rare disease that accounts for 0.4-3.4% of glioblastoma multiforme(GBM)cases. The clinicopathological characteristics and prognosis of primary cerebellar GBM are not well understood due to its rarity and the lack of an established treatment strategy. To elucidate the prognostic factors and dissemination pattern, we retrospectively assessed four cases of cerebellar GBM that we treated between 2003 and 2013. All cases involved men, and the age range was 53 to 76 years(median 69.5 years);each patient underwent surgical removal and received adjuvant chemotherapy or radiotherapy. Every cerebellar GBM patient developed intrathecal dissemination at every stage of cerebellar GBM. Two patients had spinal metastases with tumor recurrence, and no patient had brain stem invasion. IDH1 mutation and MGMT expression were both negative in three cases. The median overall survival of cerebellar GBM patients was 13.8 years, and the median progression-free survival was 5.5 years, which is similar to that reported in previous reports-and similar in terms of results-for supratentorial GBM treated at the same time at our institution. In conclusion, the prognosis of cerebellar GBM appears to be similar to that of supratentorial GBM;however, the pattern of tumor progression, such as intrathecal dissemination, is different. Craniospinal irradiation on cerebellar GBM should be carefully considered with frequent follow-up by whole spine survey using MRI.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Glioblastoma , Anciano , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Estudios RetrospectivosRESUMEN
Distal anterior cerebral artery(DACA)aneurysms are relatively rare. The detection of the surgical trajectory of DACA aneurysmal clipping is difficult because DACA aneurysms are located at various sites in the ACA. The purpose of this study was to evaluate the effectiveness of intraoperative use of color Doppler ultrasonography for the surgery of DACA aneurysms. DACA aneurysms of ten patients(three men, seven women;64.5 years old on median)were examined using intraoperative color Doppler imaging(CDI), which was performed before microscopic procedures, to detect the location of the aneurysms. Among them, six patients had ruptured aneurysms with diameters ranging from 2.5 to 10.8mm, and four of them had intracerebral hematomas. All the aneurysms and surrounding arteries were clearly detected using CDI. Moreover, in larger aneurysms, blood flow dynamics inside the aneurysm were also observed using CDI. As a result, we concluded that the intraoperative use of color Doppler ultrasonography was effective of detecting the trajectory for the DACA aneurysms without causing any damage to the brain by redundant dissections.
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Arteria Cerebral Anterior , Aneurisma Intracraneal , Anciano , Angiografía Cerebral , Femenino , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/cirugía , Masculino , Resultado del Tratamiento , Ultrasonografía Doppler en ColorRESUMEN
BACKGROUND: The aim of this study was to identify the unique morphological arterial features in patients with moyamoya disease on 3-dimensional rotational digital subtraction angiography. MATERIALS AND METHODS: One hundred seven hemispheres of 58 consecutive patients with moyamoya disease that were analyzed with fused 3-dimensional images of internal carotid angiograms and vertebral angiograms that were marked with different colors were reviewed. Angiographic findings in the posterior watershed area were classified, and the utility of the classification was analyzed by comparing it with clinical presentations and quantitative hemodynamic parameters obtained with positron emission tomography. RESULTS: Two unique angiographic appearances were identified. A vacant vessel appearance (no arterial inflow despite absence of cortical infarction) was observed mostly in transient ischemic attack hemispheres. In hemispheres with a vacant vessel appearance, cerebral blood flow was decreased, cerebral blood volume was increased, and mean transit time was prolonged significantly (P = .00017, P = .0061, and P = .00026, respectively). A cocktail vessel appearance (mixture of carotid and vertebral arterial flow) was most commonly observed in asymptomatic cases, as well as in ischemic hemispheres. Cerebral blood volume increased and mean transit time was prolonged significantly (P = .036 and P = .014, respectively) in hemispheres with a cocktail vessel appearance. The trend of progression in hemodynamic severity in the order of normal appearance, cocktail vessel appearance, and vacant vessel appearance in the watershed area was statistically significant. CONCLUSION: Fused 3-dimensional digital subtraction angiography demonstrated unique angiographic features in the watershed area, and this represented the degree of cerebral hemodynamic impairment in moyamoya disease.
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Angiografía de Substracción Digital , Angiografía Cerebral , Hemodinámica , Imagenología Tridimensional , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/fisiopatología , Adolescente , Adulto , Anciano , Angiografía de Substracción Digital/métodos , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Isquemia Encefálica/complicaciones , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/fisiopatología , Angiografía Cerebral/métodos , Circulación Cerebrovascular , Niño , Preescolar , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Enfermedad de Moyamoya/complicaciones , Radioisótopos de Oxígeno , Tomografía de Emisión de Positrones , Radiofármacos , Estudios Retrospectivos , Adulto JovenRESUMEN
We describe the case of a 75-year-old man with pharyngeal hemorrhage caused by a pseudoaneurysm of the lingual artery after accidentally swallowing his dentures. He developed sudden oral and nasal hemorrhage and was transported to a hospital near his residence. The doctors at the hospital diagnosed the case as epistaxis and treated the symptom with nasal packing. However, the bleeding did not stop and his blood pressure decreased. He was then transported to our hospital. We assumed that the bleeding was caused by epistaxis from branches of the internal maxillary artery, and tried to stop bleeding with the endovascular treatment using coils or liquid embolus materials. Angiography showed a pseudoaneurysm of the lingual artery. Coil embolization against the artery was effective in controlling bleeding. Correct diagnosis and appropriate treatments based on the correct diagnosis are essential in this case of swallowed dentures and bleeding of pseudoaneurysm of the lingual artery.
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Aneurisma Falso , Embolización Terapéutica , Epistaxis , Anciano , Aneurisma Falso/complicaciones , Angiografía , Arterias , Epistaxis/etiología , Epistaxis/terapia , Humanos , MasculinoRESUMEN
We describe an adult case of radiation-induced meningioma(RIM)that was identified within a short interval from the initial treatment for brain tumor. A 45-year-old woman, who had tumor resection followed by radiation therapy for right frontal oligodendroglioma, showed a small enhanced lesion on the right frontal region 3 years and 6 months after the initial radiation therapy. The pathological diagnosis was meningioma(World Health Organization(WHO)grade I)and the Ki-67 labeling index was 3.2%. Most RIMs occur after a long period of time(18.7-24.0 years on average)following radiation therapy. Several studies have suggested that the period before the occurrence of RIM is correlated with both the age of a patient and the radiation dose at the time of radiation therapy. A patient that receives a higher dose of radiation at a younger age has a higher risk of RIM occurrence. In this case, the patient was middle aged;however, she was exposed to a high dose of radiation(54 Gy). High-dose radiation might induce the early onset of RIM. Recently, treatments for glioma have been developed, thus resulting in an increased long-term survival rate among patients. Physicians must pay attention not only to the recurrence of gliomas but also to the occurrence of RIMs.
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Neoplasias Meníngeas , Meningioma , Neoplasias Inducidas por Radiación , Neoplasias Encefálicas/radioterapia , Femenino , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/etiología , Meningioma/diagnóstico , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Inducidas por Radiación/diagnóstico , Oligodendroglioma/radioterapiaRESUMEN
Lysosome-associated protein transmembrane-4 beta (LAPTM4B)-35, a newly identified cancer-associated gene, is overexpressed in a wide variety of malignant tumors. However, studies of its expression and role in glioma have not yet been reported. This study aimed to investigate the expression and the role of LAPTM4B-35 in glioma and to assess its value as a prognostic factor. Seventy-seven glioma cases (Grade II in 18 patients, Grade III in 16 and Grade IV in 43) were immunohistochemically examined for LAPTM4B-35, pAkt, factor VIII and Ki-67 expressions. The LAPTM4B-35 expression score of Grade II gliomas was lower than those of Grade III-IV gliomas (p < 0.05), while the difference between Grade III and IV gliomas was not statistically significant. Of the 43 patients with glioblastoma (GBM), 27 (62.8%) had high LAPTM4B-35 expression, which was associated with high tumor micro-vessel density and pAkt activation. The median progression-free survival (PFS) of GBM patients with high LAPTM4B-35 expression was 5.13 months, significantly shorter than that of those with low LAPTM4B-35 expression (12.0 months, p < 0.0001). The median overall survival (OS) of GBM patients with high LAPTM4B-35 expression was 12.5 months, again significantly shorter than that of those with low LAPTM4B-35 expression (29.6 months, p < 0.0001). Multivariate analysis indicated LAPTM4B-35 to be an independent prognostic factor for PFS and OS of GBM patients. Our findings show LAPTM4B-35 to be strongly associated with tumor proliferation, tumor angiogenesis and poor outcomes of GBM patients, suggesting LAPTM4B-35 to potentially be applicable as a novel prognostic marker and even to possibly play a role in improving GBM treatment.
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Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas de la Membrana/metabolismo , Adulto , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/mortalidad , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Supervivencia sin Enfermedad , Femenino , Glioblastoma/complicaciones , Glioblastoma/mortalidad , Humanos , Antígeno Ki-67/metabolismo , Masculino , Metilación , Persona de Mediana Edad , Análisis Multivariante , Neovascularización Patológica/etiología , Proteína Oncogénica v-akt/metabolismo , Estudios Retrospectivos , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The etiology of Moyamoya disease (MMD) is still largely unclear, despite identification of RNF213 as the most significant susceptibility gene in East Asian patients. Following up our previous study confirming genetic heterogeneity in Japanese patients with MMD, we extensively surveyed novel candidate genes for a new perspective on the etiology of this disease. Two characteristic pedigrees without susceptibility variants in RNF213 were selected for whole-exome sequencing; 1 harbored 3 affected members, and the other included discordant monozygotic twins. In the former pedigree, 12 rare mutations in 12 genes were co-segregated with MMD. One of the most deleterious amino acid changes among these was p.T76_G80delinsPS in CCER2, which was also mutated in the latter pedigree (p.E242K), although the unaffected twin sister shared the same mutation reflecting reduced penetrance. These CCER2 mutations were predicted to promote aggregation or oligomerization of their protein product, using in silico functional analysis. Subsequent CCER2 re-sequencing in an additional 135 MMD probands identified 1 recurrent and an additional 2 in-frame insertion-deletion mutations, recurrent p.T76_G80delinsPS, p.H218_H220del, and p.E299del. Although CCER2 molecular function is not well characterized, it is a secretory protein expressed in the brain; therefore, it constitutes a potential biomarker of MMD.
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Adenosina Trifosfatasas/genética , Predisposición Genética a la Enfermedad , Enfermedad de Moyamoya/genética , Ubiquitina-Proteína Ligasas/genética , Edad de Inicio , Anciano , Análisis de Varianza , Análisis Mutacional de ADN , Exoma/genética , Salud de la Familia , Femenino , Humanos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
Mammalian cells encode three closely related Ras proteins, H-Ras, N-Ras, and K-Ras. Oncogenic K-Ras mutations frequently occur in human cancers, which lead to dysregulated cell proliferation and genomic instability. However, mechanistic role of the Ras isoform regulation have remained largely unknown. Furthermore, the dynamics and function of negative regulation of GTP-loaded K-Ras have not been fully investigated. Here, we demonstrate RasG, the Dictyostelium orthologue of K-Ras, is targeted for degradation by polyubiquitination. Both ubiquitination and degradation of RasG were strictly associated with RasG activity. High resolution tandem mass spectrometry (LC-MS/MS) analysis indicated that RasG ubiquitination occurs at C-terminal lysines equivalent to lysines found in human K-Ras but not in H-Ras and N-Ras homologues. Substitution of these lysine residues with arginines (4KR-RasG) diminished RasG ubiquitination and increased RasG protein stability. Cells expressing 4KR-RasG failed to undergo proper cytokinesis and resulted in multinucleated cells. Ectopically expressed human K-Ras undergoes polyubiquitin-mediated degradation in Dictyostelium, whereas human H-Ras and a Dictyostelium H-Ras homologue (RasC) are refractory to ubiquitination. Our results indicate the existence of GTP-loaded K-Ras orthologue-specific degradation system in Dictyostelium, and further identification of the responsible E3-ligase may provide a novel therapeutic approach against K-Ras-mutated cancers.
Asunto(s)
Citocinesis/fisiología , Dictyostelium/enzimología , Proteolisis , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Protozoarias/metabolismo , Ubiquitinación/fisiología , Proteínas ras/metabolismo , Dictyostelium/genética , Guanosina Trifosfato/genética , Guanosina Trifosfato/metabolismo , Humanos , Lisina/genética , Lisina/metabolismo , Estabilidad Proteica , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas Protozoarias/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas ras/genéticaRESUMEN
Ras GTPases are signaling switches that control critical cellular processes including gene expression, differentiation, and apoptosis. The major Ras isoforms (K, H, and N) contain a conserved core GTPase domain, but have distinct biological functions. Among the three Ras isoforms there are clear differences in post-translational regulation, which contribute to differences in localization and signaling output. Modification by ubiquitination was recently reported to activate Ras signaling in cells, but the mechanisms of activation are not well understood. Here, we show that H-Ras is activated by monoubiquitination and that ubiquitination at Lys-117 accelerates intrinsic nucleotide exchange, thereby promoting GTP loading. This mechanism of Ras activation is distinct from K-Ras monoubiquitination at Lys-147, which leads to impaired regulator-mediated GTP hydrolysis. These findings reveal that different Ras isoforms are monoubiquitinated at distinct sites, with distinct mechanisms of action, but with a common ability to chronically activate the protein in the absence of a receptor signal or oncogenic mutation.
Asunto(s)
Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal/fisiología , Ubiquitinación/fisiología , Proteínas ras/metabolismo , Activación Enzimática/fisiología , Guanosina Trifosfato/genética , Guanosina Trifosfato/metabolismo , Células HEK293 , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas ras/genéticaRESUMEN
We present a unique case of a 45-year-old male with cerebral palsy, who experienced walking difficulties and altered consciousness. The initial MRI revealed an intraventricular mass that rapidly enlarged over a month, consisting of two distinct components with different characteristics on CT and MRI, and was associated with agenesis of the corpus callosum. Despite initial treatment, surgical intervention was necessary, where preoperative imaging suggested an exophytically growing glioblastoma. However, postsurgical pathological examination identified the mass as pleomorphic xanthoastrocytoma (PXA), World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) grade 3. This study is notable for its rarity and complexity, challenging standard diagnostic approaches. PXA is an uncommon astrocytic tumor, and its occurrence intraventricularly is extremely rare. This study highlights its unique imaging features and the critical role of MRI in preoperative assessment, underlining the tumor's unusual intraventricular location, and its relationship with corpus callosum agenesis. Our comprehensive review of PXA's history and imaging spectrum offers valuable insights for neuroradiologists and neurosurgeons, emphasizing the diagnostic challenges of such rare tumor locations and the importance of meticulous MRI analysis for accurate diagnosis.