Background/Aim: Thymic epithelial tumors (TETs) mainly consist of thymoma and thymic carcinoma. Complete surgical resection is vital for the successful management of these TETs, and adjuvant therapy ...such as systematic chemotherapy and/or radiotherapy plays important roles in the management of recurrent or metastasized disease. However, there is still a lack of a standard treatment after the failure of these adjuvant therapies. There is thus a need to develop molecular targeted therapies for advanced malignant TETs. In the present study, we evaluated the biological significance of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling for TETs. Materials and Methods: The expression of TrkB in 48 formalin-fixed, paraffin-embedded TET specimens (43 thymoma and 5 thymic carcinoma) collected by surgical resection was evaluated immunohistochemically. A thymic carcinoma cell line was evaluated for the role of BDNF/TrkB signaling pathway in an in vitro assay. Results: High TrkB expression was related to significantly poor prognosis in patients with TETs. In vitro experiments showed that BDNF/TrkB signaling was involved in the proliferation of Ty-82 cells, but not their invasion and migration. Conclusion: TrkB expression is a biomarker of the prognosis for TETs and the BDNF/TrkB signaling pathway is potentially a new therapeutic target for mTETs.
An arrival time of an elastic wave is the important parameter to visualize the locations of the failures and/or elastic wave velocity distributions in the field of non-destructive testing (NDT). The ...arrival time detection is conducted generally using automatic picking algorithms in a measured time-history waveform. According to automatic picking algorithms, it is expected that the detected arrival time from low S/N signals has low accuracy if low S/N signals are measured in elastic wave measurements. Thus, in order to accurately detect the arrival time for NDT, the classification of measured elastic waves is required. However, the classification of elastic waves based on algorithms has not been extensively conducted. In this study, a classification method based on self-organizing maps (SOMs) is applied to classify the measured waves. SOMs visualize relation of measured data wherein the number of classes is unknown. Therefore, using SOM selects high and low S/N signals adequately from the measured waves. SOM is validated on model tests using the pencil lead breaks (PLBs), and it was confirmed that SOM successfully visualize the classes consisted of high S/N signal. Moreover, classified high S/N signals were applied to the source localization and it was noteworthy that localized sources were more accurate in comparison with using all of the measured waves.
A 41-year-old woman was diagnosed with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome based on polyneuropathy, hepatosplenomegaly, sclerotic bone lesions, ...IgA-λ M-protein, and an elevated level of serum vascular endothelial growth factor. One month after the initiation of lenalidomide-dexamethasone with prophylactic aspirin, she developed facial paralysis, dysarthria, and left hemiplegia. Multiple cerebral infarctions and internal carotid artery stenosis were detected. Five months after switching to pomalidomide-dexamethasone, she again developed cerebral infarction. Progressed stenotic lesions in the bilateral internal carotid artery terminal portions were detected, showing a moyamoya disease-like appearance. Quasi-moyamoya disease can be an important phenotype of systemic vasculopathies of POEMS syndrome.
The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their ...roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.
•Human antibodies recognize GA or GP RAN proteins with high affinity and selectivity•Human antibodies cross the blood-brain barrier and engage RAN protein targets in vivo•α-GA1 antibody reduces GA, GP, and GR levels in C9 models•α-GA1 improves behavior and survival and decreases neurodegeneration in C9-BAC mice
Nguyen et al. show that targeting polyGA proteins with a human antibody reduces GA aggregates and improves survival, behavior, and neurodegeneration in C9-BAC mice. These data demonstrate that RAN proteins drive disease and describe a novel therapeutic strategy for C9orf72 ALS/FTD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Swallowing function is both directly and indirectly related to postures, such as head and cervical angle and body position. However, the effects of different sitting postures on oropharyngeal ...swallowing have not been investigated. This study aimed to investigate whether the change in thoracolumbar alignment affected the oropharyngeal swallowing. A total of 58 healthy adult women (mean age 22.2 ± 1.67 years) without dysphagia were enrolled in this cross-sectional study. Participants were positioned in three sitting postures: comfortable sitting (CS), thoracic upright sitting (TUS), and slump sitting (SS). In each sitting posture, the kyphosis index (using a flexicurve), head and cervical angles (using a digital camera), swallowing speed (100-ml water swallowing test), and oral and articulatory function by maximum tongue pressure (MTP) and oral diadochokinesis (ODK) were evaluated. SS showed the largest kyphosis index and was associated with a greater anterior translation of the head. Swallowing speed was significantly decreased in SS compared with CS (
p
= 0.002) and TUS (
p
= 0.020) and ODK was significantly decreased in SS compared with other postures, for both /ta/ (
p
= 0.004) and /ka/ (
p
< 0.001) syllables. Further, MTP tended to decrease in SS compared with TUS (
p
= 0.064). Our results suggest that changes in sitting posture with different thoracolumbar alignments affect swallowing speed and oral and articulatory function. Consequently, adjustments to reduce sitting postural kyphosis may improve swallowing speed and oral and articulatory function.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We encountered a 37-year-old Japanese man with KIF1A-associated neurological disorder (KAND) who exhibited motor developmental delay, intellectual disability, and slowly progressive cerebellar ...ataxia, hypotonia, and optic neuropathy. Pyramidal tract signs were evident late in this case. At 30 years old, the patient developed a neurogenic bladder. A molecular diagnosis revealed a uniallelic missense de novo variant (p.L278P) of KIF1A. Serial neuroradiological studies revealed atrophy of the cerebellum at an early age, and cerebral hemisphere atrophy progressed slowly over a 22-year observation period. Our study suggests that the primary etiology of KAND may be acquired, long-standing neurodegeneration rather than congenital hypoplasia.
The tropomyosin-related kinase (Trk) family consists of TrkA, TrkB, and TrkC, which play essential roles in tumor progression and/or suppression in various cancers. Little is known about the ...biological significance of the Trk family in human lung squamous cell carcinoma (SCC). Here we investigated the clinical significance of the protein expression of Trk family members in samples from 99 SCC patients, and we explored the relationship between invasion/proliferation activities and Trk expression using lung SCC cell lines to clarify the biological significance of the Trk family in lung SCC. Immunohistochemical high expression of TrkB was significantly correlated with vascular invasion (P=0.004), lymph node metastasis (P<0.001), and advanced stage (P=0.0015). The overall survival of the patients with TrkB-high expression was significantly shorter than those with TrkB-low expression (P=0.0110). TrkA/TrkC expressions were not predictors of poor prognosis. An in vitro assay demonstrated that the inhibition of brain-derived neurotrophic factor (BDNF) (a TrkB ligand) and TrkB by K252a (a Trk inhibitor) or siRNA (BDNF-siRNA, TrkB-siRNA) suppressed the invasion, migration, and proliferative activities of lung SCC cells. The administration of recombinant human BDNF (rhBDNF) enhanced the invasion, migration, and proliferation activities, which were abrogated by K252a. TrkB-siRNA transfection increased the protein expression of E-cadherin and decreased vimentin expressions in lung SCC cells. Matrix metalloproteinase-2 (MMP-2)-mediated gelatin degradations were decreased in lung SCC cells transfected with TrkB-siRNA. Thus, TrkB-high expression is an indicator of poor prognosis in lung SCC, probably due to invasion/proliferation activities promoted by the BDNF/TrkB signaling pathway, which could become a therapeutic target for lung SCC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acoustic emission (AE) source localization has been used to visualize progress failures generated in a wide variety of materials. In the conventional approaches, AE source localization algorithms ...assume that the AE signal is propagated as a straight line. However, it is supposed that progress failures form heterogeneity of elastic wave velocity distributions. Hence, with the conventional source localization, it is expected that the localization accuracy is reduced in heterogeneous materials since diffraction and refraction waves are generated. Thus, if the straight propagation waves are classified, conventional source localizations are performed in the heterogeneous materials. The self-organizing map (SOM) is one of the unsupervised learning methods, and the SOM has potential to classify straight propagation waves for the source localizations. However, the application of classified AE signals in source localization is not popular. If classified AE signals are applied to the time difference of arrival (TDOA) method, which is the popular localization method, it is expected that number of visualized sources are decreased because the algorithm does not consider the selection of the propagated wave. Although ray tracing has potential to localize a larger number of sources than the TDOA method, it is expected that the localized sources are less accurate in comparison with results of the TDOA method. In this study, classified waves were applied to two of the source localizations, and model tests based on pencil-lead breaks (PLBs) generating artificial AE sources were conducted to validate the performance of the source localizations with classified waves. The results of the validation confirmed that the maximum error in the TDOA method is larger in comparison with ray tracing conducted with 20 mm intervals of source candidates. Moreover, ray tracing localizes the same number of sources as the number of PLB tests. Therefore, ray tracing is expected to more practically localize AE sources than the TDOA method if classified waves are applied.
This study developed a novel acoustic emission (AE) tomography algorithm for non-destructive testing (NDT) based on Lasso regression (LASSO). The conventional AE tomography method takes considerable ...measurement data to obtain the elastic velocity distribution for structure evaluation. However, the new algorithm in which the LASSO algorithm is applied to AE tomography eliminates these deficiencies and reconstructs equivalent velocity distribution with fewer event data to describe the defected range. Three numerical simulation models were studied to reveal the capacity of the proposed method, and the functional performance was verified by three different types of classical concrete damage numerical simulation models and compared to that of the conventional SIRT algorithm in the experiment. Finally, this study demonstrates that the LASSO algorithm can be applied in AE tomography, and the shadow parts are eliminated in resultant elastic velocity distributions with fewer measurement paths.
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