VKH-Like Uveitis after Nivolumab and Ipilimumab Administration

Nivolumab and ipilimumab are widely used immune checkpoint inhibitors (ICPIs) for the treatment of metastatic melanoma. ICPIs cause an array of side effects called immune-related adverse events (IRAEs) due to activation of an immune response. ICPI-uveitis can cause irreversible vision loss if untreated. There are few reports of recurrent Vogt-Koyanagi-Harada (VKH) disease-like uveitis induced by nivolumab and ipilimumab. We report a case of VKH disease-like uveitis recurrence after resuming ICPIs. A 73-year-old man with advanced melanoma was referred to our clinic with visual loss 25 days after starting nivolumab/ipilimumab. His corrected visual acuity was 0.5 in the right eye and 0.02 in the left eye. Enhanced-depth imaging optical coherence tomography (EDI-OCT) showed marked choroid thickening. The patient was diagnosed with VKH disease-like uveitis due to IRAEs. Subtenon injection of triamcinolone acetonide was performed, and nivolumab/ipilimumab was suspended, but serous retinal detachment (SRD) markedly worsened and choroidal detachment appeared. With 2 courses of steroid pulse therapy and oral steroids, SRD disappeared, and corrected visual acuity recovered in both eyes. Five months after the first injection, exacerbation of melanoma was observed, and nivolumab and oral steroids were restarted. Six weeks later, an increase in choroidal thickness was observed with EDI-OCT and diagnosed as a recurrence of VKH disease-like uveitis. Monitoring for the recurrence of VKH disease-like uveitis during the administration of ICPIs, even after uveitis is treated, is essential. Assessment of choroidal thickness with EDI-OCT may be useful for detecting early signs of VKH disease-like uveitis

Constructing a digital museum with a large-scale archive for endangered languages

In this presentation we will propose a design for a digital museum for endangered languages. Just like a real museum, the digital museum proposed here consists of (1) a storage space, where items are archived, and (2) an exhibition space, where a selection of items from the storage are exhibited. Currently, in language documentation and conservation, the archives and the web pages are treated separately. Language archives are created mainly for the purpose of storing language data permanently for future reference. The web spaces for language conservation or exhibition are usually constructed without direct reference to the archived data. In our previous work presented at the first ICLDC, we proposed a basic design for a digital museum and demonstrated its prototype, featuring Nishihara village, where Ikema, a dialect of Miyako, one of the endangered languages of Ryukyuan, is spoken. It consisted of three layered digital spaces, the first layer is used for the exhibition, the second for the storage of past exhibits and the third for the raw data. The proposed digital museum has been implemented by an open source content management platform, providing a webpage easily updatable and extendable to other languages, making a step forward in the documentation and conservation of endangered languages. The museum was made public early this year (www.kikigengo.jp). As it is, however, the site has not been linked to the data archives, mostly due to technical reasons. With the recent development of cloud technologies and services, however, we are now able to construct a digital museum, in which the large-scale archive space is directly linked with an exhibition space. The archive is constructed in a large-scale cloud space from which files can be directly linked to the web exhibit space. We will use an open source video asset management platform on the private cloud service at our university, which manages audio-visual files and controls the security and privacy of the archives constructed on the cloud. The archive space can be compartmentalized into “publishers,” each of which can serve as a distinct password protected archive for a different language conservation project. The publishers can also be used for exchanging files with other members of the same project. The system enables us to construct a digital space for endangered languages linked to a large-scale archive at an individual level and at a manageable price, thereby providing us with a powerful tool for language documentation and conservation

クリゾチニブ ガ ソウコウ シタ Performance Status フリョウ anaplastic lymphoma kinase イデンシ テンザ ヨウセイ ハイセンガン ノ 1レイ

A ２７-year-old female was referred to our hospital for further examination of hoarseness, cough, and hemoptysis. Positron emission tomography-computed tomography revealed FDG accumulation in a huge mass in the left lower lobe, lymph nodes in the hilum, mediastinum and right cervical lesion left scapula and vertebral body. Further examination yielded the diagnosis of primary lung adenocarcinoma （cT２aN３M１b : Stage IV） harboring the anaplastic lymphoma kinase （ALK） fusion oncogene. Although her general condition was getting worse due to rapid increase of the pleural effusion, crizotinib promptly diminish the pleural effusion and ameliorated the patient’s condition. The adverse events of crizotinib, such as nausea, vomiting and visual disturbance, were generally mild and well tolerable during treatment. These findings suggest that crizotinib is a promising candidate for ALK-positive non-small cell lung cancer patients even with poor performances

Skipping of an alternative intron in the srsf1 3' untranslated region increases transcript stability

The srsf1 gene encodes serine/arginine-rich splicing factor 1 (SRSF1) that participates in both constitutive and alternative splicing reactions. This gene possesses two ultraconserved elements in the 3’ untranslated region (UTR). Skipping of an alternative intron between the two elements has no effect on the protein-coding sequence, but it generates a premature stop codon (PTC)-containing mRNA isoform, whose degradation is considered to depend on nonsense-mediated mRNA decay (NMD). However, several cell lines (HCT116, RKO, HeLa, and WI38 cells) constitutively expressed significant amounts of the srsf1 PTC variant. HCT116 cells expressed the PTC variant nearly equivalent to the major isoform that includes the alternative intron in the 3’ UTR. Inhibition of NMD by silencing a key effecter UPF1 or by treatment with cycloheximide failed to increase amounts of the PTC variant in HCT116 cells, and the PTC variant was rather more stable than the major isoform in the presence of actinomycin D. Our results suggest that the original stop codon may escape from the NMD surveillance even in skipping of the alternative intron. The srsf1 gene may produce an alternative splice variant having truncated 3’ UTR to relief the microRNA- and/or RNA-binding protein-mediated control of translation or degradation

Truncated serine/arginine-rich splicing factor 3 accelerates cell growth through up-regulating c-Jun expression

Serine/arginine-rich splicing factor 3 (SRSF3), a member of the SRSF family, plays a wide-ranging role in gene expression. The human SRSF3 gene generates a major mRNA isoform encoding a functional, full-length protein and a PTC-containing isoform (SRSF3-PTC). The latter is expected to be degraded through the nonsense-mediated mRNA decay system. However, it was reported that SRSF3-PTC mRNA was produced under stressful conditions and translated into a truncated SRSF3 protein (SRSF3-TR). To disclose unknown functions of SRSF3-TR, we established Flp-In-293 cells stably expressing SRSF3-TR. The SRSF3-TR-expressing cells increased mRNA and protein levels of positive regulators for G1 to S phase transition (cyclin D1, cyclin D3, CDC25A, and E2F1) and accelerated their growth. c-Jun is required for progression through the G1 phase, the mechanism by which involves transcriptional control of the cyclin D1 gene. We also found that the JUN promoter activity was significantly increased in the Flp-In-293 cells stably expressing SRSF3-TR, compared with mock-transfected control cells. The SRSF3-TR-expressing cells increased c-Jun and Sp-1 levels, which are important for the positive autoregulation and basal transcription of JUN, respectively. Our results suggest that stress-inducible SRSF3-TR may participate in the acceleration of cell growth through facilitating c-Jun-mediated G1 progression under stressful conditions

Flavor Neutrino Masses giving sin\theta_{13}=0

Among neutrino mixings, the reactor mixing angle, \theta_{13}, is observed to be almost vanishing and is consistent with \theta_{13}=0. We discuss how the condition of \theta_{13}=0 constrains models of neutrino mixings and show that, for flavor neutrino masses given by M_{ij} (i,j=e,\mu,\tau), two conditions of M_{e\tau}=-e^{2i\gamma}tan(\theta_{23})M_{e\mu} and M_{\tau\tau}=e^{4i\gamma}M_{\mu\mu}+e^{2i\gamma}[2/tan(2\theta_{23})]M_{\mu\tau} lead to \theta_{13}=0, where \theta_{23} is the atmospheric neutrino mixing angle and \gamma is its associated phase. The rephasing invariance can select two phases provided by \alpha=arg(M_{e\mu}) and \beta=arg(M_{e\tau}), giving \gamma=(\beta-\alpha)/2.Comment: 5 pages, typos corrected and references update

Truncated SRSF3 regulates IL-8 production

Serine/arginine-rich splicing factor 3 (SRSF3) is a member of the SR protein family and plays wide-ranging roles in gene expression. The human SRSF3 gene generates two alternative splice transcripts, a major mRNA isoform (SRSF3-FL) encoding functional full-length protein and a premature termination codon (PTC)-containing isoform (SRSF3-PTC). The latter is degraded through nonsense-mediated mRNA decay (NMD). Treatment of a human colon cancer cell line (HCT116) with 100 μM sodium arsenite increased SRSF3-PTC mRNA levels without changing SRSF3-FL mRNA levels. A chemiluminescence-based NMD reporter assay system demonstrated that arsenite treatment inhibited NMD activity and increased SRSF3-PTC mRNA levels in the cytoplasm, facilitating translation of a truncated SRSF3 protein (SRSF3-TR) from SRSF3-PTC mRNA. SRSF3-TR lacked two-thirds of Arg/Ser-rich (RS) domain whose phosphorylation state is known to be crucial for subcellular distribution. SRSF3-FL was localized in the nucleus, while overexpressed SRSF3-TR was diffusely distributed in the cytoplasm and the nucleus. A part of SRSF3-TR was also associated with stress granules in the cytoplasm. Interestingly, treatment of HCT116 cells with a small interference RNA specifically targeting SRSF3-PTC mRNA significantly attenuated arsenite-stimulated induction of c-JUN protein, its binding activity to the AP-1 binding site (-126 to 120 bp) in the interleukin (IL)-8 gene promoter, and AP-1 promoter activity, resulting in significant reduction of arsenite-stimulated IL-8 production. Our results suggest that SRSF3-TR may function as a positive regulator of oxidative stress-initiated inflammatory responses in colon cancer cells

Town-Watching Workshop Using Disaster Information Tweeting and Mapping System

Self- and mutual-help by citizens are important as well as social-help from the local governments, for disaster prevention and mitigation. Then, town watching and disaster prevention map-making workshops are held to review the town and promote self- and mutual-help by citizens. On the other hand, the use of social media for information sharing during and after disasters has been gaining attention. To facilitate information sharing in disasters, we developed a web system, Disaster Information Tweeting and Mapping System (DITS/DIMS). From the above background, we organized a town-watching workshop using DITS/DIMS in October 2018 in Minami Ward, Sapporo City, Hokkaido, Japan; affected area of the Hokkaido Eastern Iburi Earthquake in September 2018. In this paper, we explain the workshop procedure, outcome, questionnaire survey results, and post-meeting. The questionnaire survey result shows that the workshop educated the participants about posting useful information on social media during a disaster. In addition, at the post-meeting, the participants recognized that they had reviewed the town only from the perspective of “daily life” convenience before the earthquake, and they had not evaluated the “emergency viewpoint.” Therefore, the workshop was a meaningful opportunity for the participants to review the town in terms of disaster prevention and mitigation

Proposal for a new method for sustainable and advanced utilization of oil palm trunk waste

Abstract A method to more easily separate vascular bundles and parenchyma was investigated for the purpose of proposing a sustainable and advanced utilization of oil palm trunk (OPT). In addition, particleboard made from vascular bundles was produced as one of the effective ways to utilize the obtained vascular bundles. The following results were obtained. A Zephyr rolling equipment was used for separation, and it was found that the vascular bundles could be easily separated with the veneer in a dry state. SEM observations showed that the vascular bundles could be separated while maintaining the tissue structure. However, some parenchyma remained on the surface of the vascular bundles. The presence of starch was also confirmed within the parenchyma. Particleboard was produced using the separated vascular bundles. The MOR and MOE of the three-layered particleboards with long vascular bundles obtained by Zephyr treatment were about 74.2 MPa and 7.3 GPa, respectively, which are much higher than those of previous wood materials made from OPTs. These results may be the result of extracting the potential of vascular bundles. Graphical Abstrac

HP1γ as a novel target for HIPK2

Homeodomain-interacting protein kinase 2 (HIPK2) is a potential tumor suppressor that plays a crucial role in the DNA damage response (DDR) by regulating cell cycle checkpoint activation and apoptosis. However, it is unclear whether HIPK2 exerts distinct roles in DNA damage repair. The aim of this study was to identify novel target molecule(s) of HIPK2, which mediates HIPK2-dependent DNA damage repair. HIPK2-knockdown human colon cancer cells (HCT116) or hipk1/hipk2 double-deficient mouse embryonic fibroblasts could not remove histone H2A.X phosphorylated at Ser139 (γH2A.X) after irradiation with a sublethal dose (10 J/m2) of ultraviolet (UV)-C, resulting in apoptosis. Knockdown of HIPK2 in p53-null HCT116 cells similarly promoted the UV-C-induced γH2A.X accumulation and apoptosis. Proteomic analysis of HIPK2-associated proteins using liquid chromatography-tandem mass spectrometry identified heterochromatin protein 1γ (HP1γ) as a novel target for HIPK2. Immunoprecipitation experiments with HCT116 cells expressing FLAG-tagged HIPK2 and one of the HA-tagged HP1 family members demonstrated that HIPK2 specifically associated with HP1γ, but not with HP1α or HP1β, through its chromo-shadow domain. Mutation of the HP1box motif (883-PTVSV-887) within HIPK2 abolished the association. HP1γ knockdown also enhanced accumulation of γH2A.X and apoptosis after sublethal UV-C irradiation. In vitro kinase assay demonstrated an HP1γ-phosphorylating activity of HIPK2. Sublethal UV-C irradiation phosphorylated HP1γ. This phosphorylation was absent in endogenous HIPK2-silenced cells with HIPK2 3’UTR siRNA. Overexpression of FLAG-HIPK2, but not the HP1box-mutated or kinase-dead HIPK2 mutant, in the HIPK2-silenced cells increased HP1γ binding to trimethylated (Lys9) histone H3 (H3K9me3), rescued the UV-C-induced phosphorylation of HP1γ, triggered release of HP1γ from histone H3K9me3, and suppressed γH2A.X accumulation. Our results suggest that HIPK2-dependent phosphorylation of HP1γ may participate in the regulation of dynamic interaction between HP1γ and histone H3K9me3 to promote DNA damage repair. This HIPK2/HP1γ pathway may uncover a new functional aspect of HIPK2 as a tumor suppressor