CD40 is expressed in the subsets of endothelial cells undergoing partial endothelial-mesenchymal transition in tumor microenvironment.

Tumor progression and metastasis are regulated by endothelial cells undergoing endothelial-mesenchymal transition (EndoMT), a cellular differentiation process in which endothelial cells lose their properties and differentiate into mesenchymal cells. The cells undergoing EndoMT differentiate through a spectrum of intermediate phases, suggesting that some cells remain in a partial EndoMT state and exhibit an endothelial/mesenchymal phenotype. However, detailed analysis of partial EndoMT has been hampered by the lack of specific markers. Transforming growth factor-ß (TGF-ß) plays a central role in the induction of EndoMT. Here, we showed that inhibition of TGF-ß signaling suppressed EndoMT in a human oral cancer cell xenograft mouse model. By using genetic labeling of endothelial cell lineage, we also established a novel EndoMT reporter cell system, the EndoMT reporter endothelial cells (EMRECs), which allow visualization of sequential changes during TGF-ß-induced EndoMT. Using EMRECs, we characterized the gene profiles of multiple EndoMT stages and identified CD40 as a novel partial EndoMT-specific marker. CD40 expression was upregulated in the cells undergoing partial EndoMT, but decreased in the full EndoMT cells. Furthermore, single-cell RNA sequencing analysis of human tumors revealed that CD40 expression was enriched in the population of cells expressing both endothelial and mesenchymal cell markers. Moreover, decreased expression of CD40 in EMRECs enhanced TGF-ß-induced EndoMT, suggesting that CD40 expressed during partial EndoMT inhibits transition to full EndoMT. The present findings provide a better understanding of the mechanisms underlying TGF-ß-induced EndoMT and will facilitate the development of novel therapeutic strategies targeting EndoMT-driven cancer progression and metastasis.

Acute bilateral hypotropia and esotropia complex as first manifestation of multiple sclerosis: a case report.

A 21-year-old Japanese woman presented with sudden eye movement disorders. An ophthalmic examination revealed bilateral hypotropia and esotropia complex. Brain magnetic resonance imaging revealed abnormal signals in the posterior and medial part of the lower pontine tegmentum (including periventricular and subcortical white matter) that were suggestive of demyelination. A cerebrospinal fluid test was positive for oligoclonal bands. She was subsequently diagnosed with multiple sclerosis and was administered intravenous methylprednisolone and oral dimethyl fumarate, with complete recovery from hypotropia and esotropia after two months. Bilateral hypotropia and esotropia are important clinical signs for the accurate diagnosis of multiple sclerosis.

Prefrontal activation during simulated driving in people with schizophrenia: A functional near-infrared spectroscopy study.

People with schizophrenia (PWS) could be at risk when driving, yet this remains to be confirmed. In this study, we used functional near-infrared spectroscopy (fNIRS) and a driving simulator to assess potential driving skill difficulties as reflected by brain activity in PWS and compared them with those of healthy controls (HCs). Twenty PWS and 20 HCs were evaluated. Four tasks were performed: 50-kph and 100-kph sudden braking and 50-kph left and right curve tasks. The hemodynamic activity and driving performance of the two groups were compared. No significant differences were found in the performance of the four tasks. However, significant differences in hemodynamic activity were observed in the left and right dorsolateral prefrontal cortex (DLPFC) during the 100-kph sudden braking task. In addition, a significant negative correlation was found between brake reaction time and brain activity in the left DLPFC during the 100-kph sudden braking task in both groups. The brain mechanisms involved in processing the mental load associated with driving a car are possibly similar in PWS and HCs. Our results suggest that PWS may be able to drive their vehicles safely in the community.

Two cases of NMOSD with MRI findings mimicking CADASIL.

PURPOSE: The purpose of this study is to increase awareness of the importance of considering neuromyelitis optica spectrum disorder (NMOSD) as a differential diagnosis for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: We report two NMOSD patients demonstrating magnetic resonance imaging (MRI) abnormalities resembling those of CADASIL. RESULTS: Brain MRIs of both patients showed symmetrical hyperintense signals in the temporal poles and cerebral hemispheres on T2 weighted images. One case also involved the bilateral external capsule. The chief complaint of both patients was loss of visual acuity, and neurologic examination showed no other apparent neurological signs or symptoms. Anti-aquaporin-4 antibodies were detected on serological examination, and NMOSD was subsequently diagnosed. Visual acuity improved following intravenous methylprednisolone therapy. One patient refused further immunological treatment. Although she remained clinically stable, gradual radiographic deterioration was observed. This deterioration then stabilized after the patient commenced oral prednisolone therapy. The other patient was treated with prednisolone and azathioprine. She is clinically stable, but we have observed gradual radiographic deterioration over the past 5 years. CONCLUSION: MRI findings in patients with NMOSD may resemble those of CADASIL, namely symmetrical hyperintensities in the temporal poles, external capsules and cerebral hemispheres. NMOSD is a differential diagnosis for CADASIL, and testing for anti-AQP4 antibodies should be considered.

TGF-beta and TNF-alpha cooperatively induce mesenchymal transition of lymphatic endothelial cells via activation of Activin signals.

Lymphatic systems play important roles in the maintenance of fluid homeostasis and undergo anatomical and physiological changes during inflammation and aging. While lymphatic endothelial cells (LECs) undergo mesenchymal transition in response to transforming growth factor-ß (TGF-ß), the molecular mechanisms underlying endothelial-to-mesenchymal transition (EndMT) of LECs remain largely unknown. In this study, we examined the effect of TGF-ß2 and tumor necrosis factor-α (TNF-α), an inflammatory cytokine, on EndMT using human skin-derived lymphatic endothelial cells (HDLECs). TGF-ß2-treated HDLECs showed increased expression of SM22α, a mesenchymal cell marker accompanied by increased cell motility and vascular permeability, suggesting HDLECs to undergo EndMT. Our data also revealed that TNF-α could enhance TGF-ß2-induced EndMT of HDLECs. Furthermore, both cytokines induced the production of Activin A while decreasing the expression of its inhibitory molecule Follistatin, and thus enhancing EndMT. Finally, we demonstrated that human dermal lymphatic vessels underwent EndMT during aging, characterized by double immunostaining for LYVE1 and SM22α. These results suggest that both TGF-ß and TNF-α signals play a central role in EndMT of LECs and could be potential targets for senile edema.

[A case of Alexander disease with dropped head syndrome].

A 51-year-old woman presented with progressive weakness of the neck extensor muscles and gait disturbances since the past 6 years. In addition, she presented with symptoms such as dysarthria, dysphagia, bladder, and rectal disturbances. Bilateral plantar reflex was positive. Her gait was short-stepped-spastic. Brain and cervical MRI showed atrophy of the medulla and spinal cord. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. We identified a heterozygous c.368T>C missense mutation of the GFAP gene in the patient. This was the first case of the mutation in Japanese patients, and subsequently, she was diagnosed with AxD type 2. There are a few studies which reported that patients with AxD complained of dropped head syndrome. Dropped head syndrome can be the initial manifestation of AxD.

Antioxidant effects of water-soluble fullerene derivatives against ultraviolet ray or peroxylipid through their action of scavenging the reactive oxygen species in human skin keratinocytes.

Chemically generated hydroxyl radicals were scavenged by PEG-modified fullerene, hydroxy-fullerene and isostearate-mixed fullerene as efficiently as ascorbic acid (Asc) or its 2-O-phosphorylated derivative (A2P) as shown by the DMPO-spin trap/ESR method. Enzymatically generated superoxide anion radicals were also scavenged by PEG-modified or PVP-entrapped fullerene similarly as done by Asc or A2P. Some reactive oxygen species (ROS) such as hydroperoxides and hydrogen peroxides were generated preferably in the nuclei of UVB-irradiated human skin keratinocytes HaCaT, and repressed by PVP- or gamma-cyclodextrin-fullerene. In contrast, the cytoplasm in the keratinocytes accumulated the ROS that were generated by the peroxylipid model compound t-BuOOH, and underwent the ROS repression by PVP-fullerene more markedly than by A2P. Thus several fullerene derivatives, especially PVP-fullerene, were shown to diminish the ROS amounts in terms of the molecular and cellular levels against either UVB or t-BuOOH, suggesting the expectation for development as rejuvenation cosmetics.