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Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future.
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Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia Adoptiva , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Animales , Inmunoterapia Adoptiva/métodos , Ratones , Línea Celular Tumoral , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Cadena Pesada de la Proteína-1 Reguladora de Fusión/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Anticuerpos Monoclonales/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , FemeninoRESUMEN
Background: Although awake surgery is the gold standard for resecting brain tumors in eloquent regions, patients with hearing impairment require special consideration during intraoperative tasks. Case Description: We present a case of awake surgery using sign language in a 45-year-old right-handed native male patient with hearing impairment and a neoplastic lesion in the left frontal lobe, pars triangularis (suspected to be a low-grade glioma). The patient primarily communicated through sign language and writing but was able to speak at a sufficiently audible level through childhood training. Although the patient remained asymptomatic, the tumors gradually grew in size. Awake surgery was performed for tumors resection. After the craniotomy, the patient was awake, and brain function mapping was performed using tasks such as counting, picture naming, and reading. A sign language-proficient nurse facilitated communication using sign language and the patient vocally responded. Intraoperative tasks proceeded smoothly without speech arrest or verbal comprehension difficulties during electrical stimulation of the tumor-adjacent areas. Gross total tumor resection was achieved, and the patient exhibited no apparent complications. Pathological examination revealed a World Health Organization grade II oligodendroglioma with an isocitrate dehydrogenase one mutant and 1p 19q codeletion. Conclusion: Since the patient in this case had no dysphonia due to training from childhood, the task was presented in sign language, and the patient responded vocally, which enabled a safe operation. Regarding awake surgery in patients with hearing impairment, safe tumor resection can be achieved by performing intraoperative tasks depending on the degree of hearing impairment and dysphonia.
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Cerebral organoids (COs) are derived from human-induced pluripotent stem cells in vitro and mimic the features of the human fetal brain. The development of COs is largely dependent on "self-organization" mechanisms, in which differentiating cells committed to cortical cells autonomously organize into the cerebral cortex-like tissue. However, extrinsic manipulation of their morphology, including size and thickness, remains challenging. In this study, we discovered that silicate microfiber scaffolds could support the formation of cortical neuronal layers and successfully generated cortical neuronal layers, which are 9 times thicker than conventional COs, in 70 days. These cortical neurons in the silicate microfiber layer were differentiated in a fetal brain-like lamination pattern. While these cellular characteristics such as cortical neurons and neural stem/progenitor cells were like those of conventional COs, the cortical neuronal layers were greatly thickened in sheet-like configuration. Moreover, the cortical neurons in the scaffolds showed spontaneous electrical activity. We concluded that silicate microfiber scaffolds support the formation of the cortical neuronal layers of COs without disturbing self-organization-driven corticogenesis. The extrinsic manipulation of the formation of the cortical neuronal layers of COs may be useful for the research of developmental mechanisms or pathogenesis of the human cerebral cortex, particularly for the development of regenerative therapy and bioengineering.
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Células Madre Pluripotentes Inducidas , Células-Madre Neurales , Humanos , Neuronas , Corteza Cerebral/fisiología , Organoides , Diferenciación CelularRESUMEN
Background: New therapies for glioblastoma (GBM) are urgently needed because the disease prognosis is poor. Chimeric antigen receptor (CAR)-T cell therapy that targets GBM-specific cell surface antigens is a promising therapeutic strategy. However, extensive transcriptome analyses have uncovered few GBM-specific target antigens. Methods: We established a library of monoclonal antibodies (mAbs) against a tumor cell line derived from a patient with GBM. We identified mAbs that reacted with tumor cell lines from patients with GBM but not with nonmalignant human brain cells. We then detected the antigens they recognized using expression cloning. CAR-T cells derived from a candidate mAb were generated and tested in vitro and in vivo. Results: We detected 507 mAbs that bound to tumor cell lines from patients with GBM. Among them, E61 and A13 reacted with tumor cell lines from most patients with GBM, but not with nonmalignant human brain cells. We found that B7-H3 was the antigen recognized but E61. CAR-T cells were established using the antigen-recognition domain of E61-secreted cytokines and exerted cytotoxicity in co-culture with tumor cells from patients with GBM. Conclusions: Cancer-specific targets for CAR-T cells were identified using a mAb library raised against primary GBM tumor cells from a patient. We identified a GBM-specific mAb and its antigen. More mAbs against various GBM samples and novel target antigens are expected to be identified using this strategy.
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Objective: The efficacy of endovascular treatment for middle cerebral artery (MCA) aneurysms remains controversial. However, recent studies have reported the safety of endovascular treatment for MCA aneurysms. In this study, we studied the efficacy and clinical outcomes of endovascular treatment for MCA aneurysms in our hospital and the morphology and anatomy of MCA aneurysms that were suitable for endovascular treatment. Methods: We retrospectively analyzed 26 cases of MCA aneurysms which had undergone endovascular treatment at our institution between January 2015 and October 2018. We studied sizes and shapes of the aneurysms, clinical and angiographical outcomes one year after the treatment, and complications in these 26 patients. We also compared the differences in these parameters of the 26 patients with those of 61 other patients who were treated with clipping during the same period. Results: The median aneurysm size was 6.1 mm (1.8-29.9 mm), with the shapes of the aneurysms irregular in 8, and round in the other 18 cases. Four cases (15.4%) had ruptured aneurysms. All aneurysms were treated with assist techniques; 8 (30.8%) were treated by stent-assisted technique and 18 (69.2%) were treated by balloon-assisted technique and endovascular treatment was successfully performed in all (100%) cases. While the aneurysms were completely obliterated in 22 of them (84.6%), the remaining 4 cases (15.4%) had neck remnants. We observed periprocedural complications in 5 of the 26 (19.2%) aneurysms, all of which were transient and completely recovered during the follow-up period. The efficacy and complication rates were not different from the MCA aneurysms treated with clipping. All MCA aneurysms arising from the M1 trunk were treated with endovascular treatment, and those with a round shape with the axis not deviating from M1 were also treated with endovascular treatment. Conclusion: Endovascular treatment for MCA aneurysms is safe and effective together with adjunctive techniques such as balloon-assisted technique or stent-assisted technique. Thus, M1 trunk aneurysms and MCA bifurcation aneurysms with a round shape along the same axis of MCA may be good indications for endovascular treatment. However, long-term clinical and angiographical outcomes remain unknown. Thus, further studies are needed to address the existing limitations.
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Extramammary Paget's disease (EMPD) is a rare form of neoplasm. Metastasis of EMPD to locations other than lymph nodes and intra-epithelial regions is rare; there are a limited number of case reports of metastases to the liver, lung, bone, and brain. We present a rare case of EMPD that metastasized to the brain and was treated with surgical resection. A 66-year-old man presented with a small palpable mass in the scrotum. After 5 years of observation, he was diagnosed with EMPD that metastasized to the lymph nodes and lung. Tumor resection and postoperative chemotherapy were performed. Six months after the last chemotherapy treatment, he presented with a right temporal lobe tumor and underwent surgical resection. Histopathological analysis revealed brain metastasis of EMPD. Three months after surgery, magnetic resonance imaging (MRI) showed local tumor recurrence, and intensity modulated radiation therapy (IMRT) (45 Gy/15 Fr) was performed. Although the metastatic brain tumor was well controlled, the primary tumor progressed. He was provided best supportive care and died 5 months after brain tumor resection. In this report, we present a rare case of brain metastasis of EMPD, treated with surgical resection, and histopathologically confirmed to be metastatic EMPD.
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OBJECTIVE: We produced a Japanese version of the Eating Disorder Inventory-2 (EDI-2) and investigated its reliability and validity. METHODS: EDI-2 Japanese version was administered to 246 patients with eating disorders and 100 control subjects. The internal consistency as well as discriminant validity were examined. RESULTS: The alpha reliability coefficients were high (0.71 to 0.92) in all subscales except the asceticism subscale which was rated 0.61. The anorexia nervosa binge-purging type and bulimia nervosa showed significantly higher scores in all the EDI-2 subscales when compared to the controls, and also significantly higher scores in seven EDI-2 subscales compared to anorexia nervosa restricting type (AN-R). AN-R showed significantly lower scores in the body dissatisfaction subscale. Lower scores in Japanese than Western patients for drive for thinness as well as marked difference in perfectionism and maturity fears suggested cross-cultural issues between Japan and western countries. CONCLUSION: Japanese version of EDI-2 is a measure instrument that can be expected to have a satisfactory level of internal consistency except the asceticism subscale as well as high validity as a tool for the evaluation of the psychopathology of eating disorder.
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Anorexia Nerviosa/diagnóstico , Bulimia Nerviosa/diagnóstico , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Escalas de Valoración Psiquiátrica , Anorexia Nerviosa/psicología , Anorexia Nerviosa/terapia , Bulimia Nerviosa/psicología , Bulimia Nerviosa/terapia , Estudios de Casos y Controles , Comparación Transcultural , Femenino , Humanos , Japón , Lenguaje , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Psicometría/estadística & datos numéricos , Psicoterapia , Encuestas y CuestionariosRESUMEN
OBJECTIVE: We evaluated the significance of purging behavior in the diagnosis of eating disorders through an objective assessment of eating disorder psychopathology including personality disorders. METHODS: Subjects were 42 consecutive outpatients with eating disorders who visited the Outpatient Psychiatric Clinic at Tokai University Hospital (Kanagawa, Japan). Diagnosis of eating and personality disorders was established using the modified Structured Clinical Interviews for DSM-III-R and DSM-III-R-Axis II. Eating disorder symptoms and psychopathology were assessed with the Eating Disorder Examination, Eating Disorder Inventory 2, Beck Depression Inventory, and Leyton Obsessional Inventory Results were compared between purgers and non-purgers. RESULTS: Purgers had severe borderline or avoidant personality disorder, mixed personality disorder, eating attitude, depressive symptoms, and obsessive symptoms. CONCLUSION: Purging behavior in eating disorder patients is associated with personality disorders, depression, and obsessive symptoms. Assessment of this behavior is critical in the diagnosis and treatment of eating disorders.