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Internal exposure to actinides such as uranium and plutonium has been reduced using chelating agents for decorporation because of their potential to induce both radiological and chemical toxicities. This study measures uranium chemical forms in serum in the presence and absence of chelating agents based on X-ray absorption spectroscopy (XAS). The chelating agents used were 1-hydroxyethane 1,1-bisphosphonate (EHBP), inositol hexaphosphate (IP6), deferoxamine B (DFO), and diethylenetriaminepentaacetate (DTPA). Percentages of uranium–chelating agents and uranium–bioligands (bioligands: inorganic and organic ligands coordinating with uranium) dissolving in the serum were successfully evaluated based on principal component analysis of XAS spectra. The main ligands forming complexes with uranium in the serum were estimated as follows: IP6 > EHBP > bioligands > DFO >> DTPA when the concentration ratio of the chelating agent to uranium was 10. Measurements of uranium chemical forms and their concentrations in the serum would be useful for the appropriate treatment using chelating agents for the decorporation of uranium.

体内にアクチニドなどの放射性物質が取り込まれると、生体内配位子がアクチニドと化合物を生成し、体内滞留の原因となりうる。本研究では、アクチニドを体外に排出させるためのキレート剤の結合性評価を行うため、キレート剤と結合した元素の局所構造をX線吸収分光法によって解析し結合力を評価した。プルトニウム模擬元素としてジルコニウム (Zr)、キレート剤として、EHBP (1-hydroxyethylidene-1,1-diphosphonate) 及びDTPA (diethylenetriaminepentaacetate) を用いた。ZrはEHBPと八面体構造の錯体を形成するとともに、Zr-EHBP錯体はZr-DTPA錯体より強い結合を有することが分かった。これらの知見は、放射性元素による内部被ばく線量評価や、放射性元素を体外に取り除くための適切な除染方法の提案につながる。

腸管は経口で摂取し消化された食物を吸収する器官で、脂質や蛋白分解物、金属元素など様々な物質を体内に取り込む入口となる。福島第一原子力発電所事故では放射性核種が環境中に放出され、放射性核種を含む食物の摂取による内部被ばくに関心が寄せられた。我々は内部被ばく核種の腸管動態を理解するための基礎研究として、マイクロPIXE（荷電粒子励起X線）分析による腸管組織の元素分布解析手法を検討した。試料としてポリプロピレン薄膜（6 μm厚）に付着させたマウスの腸管の凍結切片（10 μm厚）を用いた。ヘマトキシリン－エオシン染色を施した測定試料の隣接切片で腸管組織構造把握をして、空腸（上・中・下部）、回腸および大腸の5領域の腸管横断面について腸管基底部から管腔側にかけてマイクロPIXE分析を行い、リン、イオウ、塩素、カリウムについての明瞭な元素分布を得た。さらに詳細な分析を行ったところ、中・下部空腸では、絨毛および粘膜層基底部においてカリウム局在が見出された。本手法は腸管組織微細構造と対応した元素分布解析に有効であると考えられた。

RNA interference-based gene silencing drugs are attracting attention for treating various diseases. Lipid nanoparticles (LNPs) are carriers that efficiently deliver small interfering RNA (siRNA) to the cytoplasm of target cells. Recently, we developed potent and well-tolerated biodegradable LNPs with asymmetric ionizable lipids. Here, we evaluated the effect of LNPs on immune cells in mice. After intravenous administration, LNPs were efficiently incorporated into several tissue-resident macrophages, including liver macrophages, through an apolipoprotein E (ApoE)-independent mechanism. Administration of LNP-encapsulated siRNA against Irf5, encoding the transcription factor critical for inflammatory responses, sharply reduced its expression in macrophages in vivo, and persisted for as long as 7 days. The therapeutic potential of Irf5 siRNA-loaded LNPs in inflammatory diseases was tested in a concanavalin A (Con A)-induced hepatitis model, whose pathogenic mechanisms are dependent on cytokine secretion from macrophages. We found that Con A-induced liver injury was significantly attenuated after LNP injection. Serum aspartate transaminase, alanine aminotransferase, and inflammatory cytokine levels were significantly reduced in mice injected with Irf5 siRNA-loaded LNPs compared to those injected with control siRNA-loaded LNPs. Our results suggest that administering biodegradable LNPs to deliver siRNA is a promising strategy for treating inflammatory disorders., Graphical abstract, Kawase et al. report that ionizable lipid-based biodegradable LNPs are effectively incorporated into macrophages in vivo. Administration of LNP-encapsulated siRNA against Irf5, encoding a transcription factor mediating inflammatory responses, resulted in long-term IRF5 downregulation in liver macrophages and prevented cytokine production and liver damage in a hepatitis model.

A 60-year-old man presented with postoperative recurrence of intrahepatic cholangiocarcinoma with right portal vein tumor thrombosis (PVTT). After failure of standard chemotherapy, a liver biopsy showed that his microsatellite instability (MSI) status was high. Treatment with the immune checkpoint inhibitor (ICI) pembrolizumab was commenced, which resulted in a partial response and resolution of the PVTT. There were no significant immune-related adverse events. According to recently published reports, the frequency of MSI-high biliary tract cancer (BTC) is about 0%-2.1%, which is extremely rare. However, ICIs may be effective in patients with MSI-high BTC, such as the present patient.

Highlights • Novel coronavirus (SARS-Coronavirus-2:SARS-CoV-2) which emerged in Wuhan, China, has spread to multiple countries rapidly. • This is the first case of meningitis associated with SARS-CoV-2 who was brought in by ambulance. • The specific SARS-CoV-2 RNA was not detected in the nasopharyngeal swab but was detected in a CSF. • This case warns the physicians of patients who have CNS symptoms., Novel coronavirus (SARS-Coronavirus-2:SARS-CoV-2) which emerged in Wuhan, China, has spread to multiple countries rapidly. We report the first case of meningitis associated with SARS-CoV-2 who was brought in by ambulance due to a convulsion accompanied by unconsciousness. He had never been to any foreign countries. He felt generalized fatigue and fever (day 1). He saw doctors nearby twice (day 2 and 5) and was prescribed Laninamivir and antipyretic agents, His family visited his home and found that he was unconsciousness and lying on the floor in his vomit. He was immediately transported to this hospital by ambulance (day 9). Under emergency transport, he had transient generalized seizures that lasted about a minute. He had obvious neck stiffness. The specific SARS-CoV-2 RNA was not detected in the nasopharyngeal swab but was detected in a CSF. Anti- HSV 1 and varicella-zoster IgM antibodies were not detected in serum samples. A brain MRI showed hyperintensity along the wall of right lateral ventricle and hyperintense signal changes in the right mesial temporal lobe and hippocampus, suggesting the possibility of SARS-CoV-2 meningitis. This case warns the physicians of patients who have CNS symptoms.

MicroRNAs (miRNAs) are endogenous small noncoding RNAs that negatively regulate gene expression by interfering with the translation or stability of target transcripts. Some tumor-suppressive miRNAs can concurrently target multiple cancer-promoting genes and may be useful as therapeutic anticancer agents. However, the development of drug delivery systems is critical for the implementation of miRNA-based therapeutics. We have previously demonstrated that the enforced expression of miR-634 effectively induces apoptosis by concurrently and directly targeting genes associated with mitochondrial homeostasis, antiapoptosis signaling, antioxidant ability, and autophagy in cancer cells. In the current study, we validated the therapeutic potential of lipid nanoparticle (LNP)-mediated delivery of miR-634 for cancer therapy. We confirmed the ability of enforced expression of miR-634 to induce apoptosis in various cancer cell lines, including pancreatic cancer cells. Intravenous administration of LNPs harboring miR-634 significantly reduced the xenograft tumor growth of BxPC-3 pancreatic cancer cells in mice. These findings suggest that LNP-mediated delivery of miR-634 can potentially be used for cancer therapy.

The echinoderm microtubule‐associated protein‐like 4 (EML4)–anaplastic lymphoma kinase (ALK) fusion gene, a driver mutation in lung carcinoma, is fairly common in lung adenocarcinoma but rare in large cell neuroendocrine carcinoma (LCNEC). Here we report a case of stage IV LCNEC positive for this fusion gene in a patient with a poor performance status (PS) who was effectively treated with alectinib. The patient was a 72‐year‐old non‐smoking man diagnosed as LCNEC with multiple metastases. Because of his poor PS, cytotoxic chemotherapy was not indicated, but he was later found to be positive for the ALK fusion gene and treated with alectinib as first‐line therapy. One month later, the tumour had shrunk remarkably, and the therapeutic effect was rated as a partial response. The PS also improved from 4 to 1. Investigating actionable driver mutations seems worth doing for advanced LCNEC, especially if the patient's PS is poor., We report a patient with LCNEC harbouring ALK rearrangement with a poor performance status, who showed a good response to alectinib as first‐line treatment. The patient's PS also improved, made him eligible for further chemotherapy when alectinib had failed.

Background and study aims A white opaque substance (WOS) has been observed in the epithelia of gastric, duodenal, and colorectal epithelial adenomas and carcinomas, using magnifying endoscopy (ME). The WOS has been reported to be derived from a dense accumulation of minute lipid droplets in the epithelium. This study aimed to investigate whether the WOS in colorectal hyperplastic polyps was derived from lipid droplets accumulated in the epithelium, as observed in the case of gastric, duodenal, and colorectal epithelial neoplasms. Patients and methods We analyzed 30 consecutive patients who were positive for the WOS, as visualized in colorectal hyperplastic polyps by ME with narrow-band imaging and 30 consecutive patients who were negative for the WOS. Biopsy specimens obtained from the polyps were immunostained with anti-adipophilin antibody to determine the correlation between the presence of the WOS and that of lipid droplets in the epithelium. Results In all patients, the epithelial cells were histologically positive for adipophilin. However, the area of adipophilin-positive epithelial cells in the WOS-positive group was significantly larger than that in the WOS-negative group (P Conclusions This study reveals that the WOS visualized in the superficial layers of colorectal hyperplastic polyps is produced by a dense accumulation of minute lipid droplets in the epithelia of the polyps.

A 72‒year‒old man with hepatocellular carcinoma(HCC)was treated with transarterial chemoembolization(TACE)and radiofrequency ablation(RFA). Six months after RFA, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid(Gd‒ EOB‒DTPA)‒enhanced magnetic resonance imaging(MRI)revealed multiple metastatic recurrences in the liver. TACE was performed for the recurrent HCC. However, the treatment response on the Gd‒EOB‒DTPA‒enhanced MRI showed that the lesions had advanced and that the liver metastatic nodules had ring‒shaped contrast effects. We suspected metastatic liver cancer based on the MRI findings and performed colonoscopy. Finally, we diagnosed the patient with multiple hepatic metastases of sigmoid colon cancer based on the results of the endoscopic colon biopsy and percutaneous liver tumor biopsy. In conclusion, we had a teachable case of the treatment of HCC.

Pulmonary pleomorphic carcinoma (PPC) is a poorly differentiated non‐small cell lung cancer. Because of its rarity, no standard therapy has been established for advanced disease. We herein report on a 62‐year‐old man with recurrent post‐operative PPC, for whom durvalumab after chemoradiotherapy was effective. He was referred to our hospital because of an abnormal shadow in the right upper lung on chest X‐ray. After surgical resection was performed, the imaging and histopathological findings revealed PPC (T4N0M0, stage IIIA) with elevated expression of programmed cell death‐ligand 1 (PD‐L1). A metastasis was found in the left hemithorax 22 months later, and chemoradiotherapy consisting of 60 Gy of radiation and cisplatin plus tegafur/gimeracil/oteracil potassium was administered. Durvalumab was then begun as consolidation therapy. The efficacy of the treatments has continued for longer than 10 months. This case suggests that multidisciplinary treatment with chemoradiotherapy and consolidation immunotherapy may improve the prognosis of locally advanced PPC., Pulmonary pleomorphic carcinoma (PPC) is a poorly differentiated non‐small cell lung cancer. No standard therapy has been established for advanced disease. We herein report on a 62‐year‐old man with recurrent post‐operative PPC, for whom durvalumab after chemoradiotherapy was effective.

Background/aim Sorafenib is standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a notorious side-effect of this therapy. This study evaluated prophylactic benefits of an oral nutritional supplement (ONS) on sorafenib-associated HFSR in advanced HCC. Patients and methods This was a prospective, single-center, open-label trial arm using combined ONS and sorafenib in patients with unresectable HCC from August 2014 to February 2018. Control patients received sorafenib without ONS from 2011 to 2014. From September 2014, prophylactic ONS containing β-hydroxy-β-methylbutyrate (HMB), L-arginine, and L-glutamine was given. Sorafenib dosage was 400 mg/day for both groups. Results Each group comprised 22 men and three women. Age, sex, Child-Pugh score, and clinical stage excluding IV-B did not significantly differ between the groups. HFSR occurred after 2 weeks: 15/25 patients in the control group (60%; HFSR grade 1: 6, grade 2: 7, grade 3: 2) vs. 8/25 in the ONS group (32%; HFSR grade 1: 4, grade 2: 4, grade 3: 0; p=0.047, Pearson's Chi-square test). Conclusion Prophylactic HMB, L-arginine and L-glutamine supplementation effectively prevented sorafenib-associated HFSR in patients with advanced HCC.

Nephrotoxicity is the primary health effect of uranium exposure. However, the renal transport and intracellular behavior of uranium remains to be clearly elucidated. In the present study, the intracellular uranium distribution was examined with the cell lines derived from the S3 segment of mouse renal proximal tubules, which is a toxic target site of uranium, using microbeam-based elemental analysis. Uranium exposure at 100 μM for 24 h (non-toxic phase) was performed in S3 cells. Two types of measurement specimens, including those that are adhesive cell specimens and cryosection specimens, were examined for the positional relationship of the intracellular localization of uranium. Based on the combined results of single-cell imaging from the two types of cell specimens, uranium was distributed inside the cell and localized in the cytoplasm near the cell nucleus. In some cells, uranium was colocalized with phosphorus and potassium. The amount of uranium accumulated in S3 cells was estimated using thin section-standards. The mean uranium content of three adhesive cells was hundreds of femtogram per cell. Thus, we believe that single-cell imaging would be useful for studies on renal uranium transportation and cellular behavior.

Simple methods for the determination of elements in biological fluids have been developed. It is important to quantify the accidental incorporation of radionuclides during the decommissioning work at nuclear power plants. Herein, we proposed the simple preparations and determination methods of uranium concentrations in urine for microbeam scanning particle induced X-ray emission (µ-PIXE) analysis in a rat model. A droplet (1 µL) of mixed solution of urine treated with a five-fold amount of concentrated nitric acid was placed on polypropylene film coated with perfluoroalkoxy alkanes (PFA) and dried at room temperature. The µ-PIXE imaging analysis revealed that successful condensation with homogeneous distribution of uranium in the specimen was achieved using by PFA coating. Uranium concentrations in the urine collected from uranium-injected rats were quantified. The obtained results were consistent with those determined by inductively coupled plasma mass spectrometry.

Actinoids are transition metallic radionuclides and the most of them are stable in the oxidation state at trivalent and tetravalent. When they penetrate into animal body, they coordinate with endogenous ligand in interstitial (extracellular) fluid, and stagnate in the infiltrated tissue. After the ligand substituted with migrative serum proteins that possess affinity with multivalent metal cation such as transferrin, they are translocated to circulation and dispersed whole body. A chelating agent, diethylenetriaminepentaacetate (DTPA) is used for internal decorporation therapy. The first process of the action mechanism of the chelating agent is that the injected DTPA molecule captures multivalent metal cation from bioorganic ligand. Subsequently, resulted stable chelate coordinated with metal translocates urinary excretion system. However, the practical chelate action is far complicated because the interstitial fluid in the body contains various bioorganic ligands which react with multivalent metal cation and chelate, and the coordination compounds affect on the bind-dissociation reaction each other. The biochemical data on reaction velocity using the interstitial fluid are necessary or more accurate estimation of the effect of chelate treatment on the committed effective dose in organ following internal exposure of tri-/tetravalent radionuclide. We studied metal substitution from serum proteins to chelate using Fe(III) model. 59Fe-bound serum prepared from mouse was treated in physiological condition with DTPA, ethylenediaminetetraacetate, or deferoxamine. The substitution velocity, obtained by the measurement of the amounts of chelate-59Fe and protein-59Fe after the separation by isoelectric focusing electrophoresis, were consistent with decorporation experiments in mice., 日本放射線影響学会第63回大会

We have previously reported that the levels of DNA damage-induced mRNA and lncRNA in blood cells from mouse irradiated with 10mGy class of low-dose ionizing radiation can be used as biodosimetric quantitative indicators of DNA damage, based on conventional molecular biological technique. The principle of the quantification is the measurement of cellular intermediate RNA products which are generated by known and unknown mechanism triggered by various type of DNA damage. The method is suitable for analysis after single and multiple irradiation in relatively short-time. However, method is not suitable for comparison of damage level followed by hours of continuous irradiation, by the low-dose rate effect. We aimed to establish alternative general method to quantitate DNA damage based on different principles that is applicable for low-dose rate irradiation in heterogenous cell population. Several histochemical procedures were compared using a mouse osteoclastoma cell line, RAW264.7. Among them, the quantitative indicator suitable for low dose irradiation was only gamma H2ax, double-strand break-indicator, and we established the universal methodology to quantify damages in the cell population. Several metallic organic compounds have been known to induced DNA damage. However, quantitative study to compare toxicity level between the compounds and ionizing radiation has not well-investigated. We simultaneously quantitated DNA damage-induced RNAs and gamma-H2ax levels in RAW 264.7 cells after treatment with irradiation or metal compounds. The difference in DNA-damage mechanism between radiation and metal compounds reflects the quantitative values of these indicators., 日本放射線影響学会第63回大会

Immune checkpoint inhibition is associated with a broad spectrum of immune toxicities referred to as immune‐related adverse events (irAEs). Myositis is known to be a potentially fatal irAE. Here, we report a case of immune‐related myositis after the administration of durvalumab. A 60‐year‐old man with stage IIIA lung adenocarcinoma was treated with durvalumab after concurrent chemoradiation therapy. After the third dose of durvalumab, his serum CK level was elevated, and soon thereafter myalgia of the proximal muscles and blepharoptosis were observed. We diagnosed immune‐related myositis based on the results of pathological examination and initiated systemic corticosteroid therapy. His symptoms then improved and the serum CK level immediately dropped to within a normal range. Clinicians should be aware of possible myositis during the early phase of durvalumab therapy., We report a case of immune‐related myositis after administration of durvalumab in patient with non‐small cell lung cancer (NSCLC).

PEGylation-modification with polyethylene glycol (PEG)-is useful for stabilizing lipid nanoparticles (LNPs). However, such PEGylation can prevent small interfering RNA (siRNA) encapsulated in LNPs from exerting its gene-silencing effects by disrupting the interaction of LNPs with target cells and by inducing the accelerated blood clearance phenomenon via anti-PEG IgM. PEG-lipids with short acyl chains can be used to address these issues because they are quickly shed from LNPs after administration; however, there are few reports on the relationships among PEG shedding rate, anti-PEG IgM production, and the gene-silencing activity of siRNA upon repeated LNP administration. Here, in mice, we found that LNPs conjugated to a fast-shedding PEG-lipid (short acyl chain) induced less anti-PEG IgM compared with LNPs conjugated to a slow-shedding PEG-lipid (long acyl chain). Moreover, pretreatment of mice with LNPs conjugated to the slow-shedding PEG-lipid caused loss of RNA interference activity after subsequent LNP administration because the payload siRNA was delivered primarily to Kupffer cells rather than to hepatocytes. Together, these findings imply that manipulating PEG shedding rate and anti-PEG antibody production is enormously important in the development of RNA interference-based therapeutics utilizing LNP technology.

Background/Aims Colonic diverticular hemorrhage (DH) was a rare disease until the 1990s, and its incidence has increased rapidly since 2000 in Japan. In recent years, colonic DH has been the most frequent cause of lower gastrointestinal bleeding (LGIB). Nearly all cases of DH are mild, with the bleeding often stopping spontaneously. Some cases, however, require surgery or arterial embolization. In this study, using a cohort at Fukuoka University Chikushi Hospital, we investigated factors associated with severe colonic DH. Methods Among patients with LGIB who underwent colonoscopy at our hospital between 1995 and 2013, DH was identified in 273 patients. Among them, 62 patients (22.7%) were defined as having severe colonic DH according to recurrence of bleeding in a short period, and/or the necessity of transfusion, arterial embolization, or surgery. We then evaluated risk factors for severe DH among DH patients in this retrospective cohort. Results Among the 273 patients with DH, use of non-steroidal anti-inflammatory drugs (NSAIDs) (odds ratio [OR], 2.801; 95% confidence interval [CI], 1.164-6.742), Charlson Risk Index (CRI) ≥2 (OR, 3.336; 95% CI, 1.154-7.353), right-sided colonic DH (OR, 3.873; 95% CI, 1.554-9.653), and symptoms of cerebral hypoperfusion (such as light-headedness, dizziness, or syncope) (OR, 2.926; 95% CI, 1.310-6.535) showed an increased risk of severe DH even after controlling for other factors. Conclusions Severe DH occurred in 23% of DH patients, and NSAID use, CRI ≥2, right-sided colonic DH, and symptoms of cerebral hypoperfusion are suggested to be predictors of severe DH.

Background and study aims The non-extension sign relates to a localized increase in thickness and rigidity due to deep submucosal invasive (SM-d: depth of 1000 μm or more) cancer. The present study aimed to evaluate the efficacy of the non-extension sign in assessing the optical diagnosis of colorectal SM-d cancer. Patients and methods We retrospectively analyzed 309 patients with 315 early colorectal cancers that had been endoscopically or surgically resected. The non-extension sign was judged from chromoendoscopy (CE) using conventional white-light imaging with indigo carmine, and is taken to be positive when any one of the findings of rigidity of a circular arc, trapezoid elevation, or converging mucosal folds are seen. We assessed comparing the accuracy of CE, magnifying chromoendoscopy (M-CE), and magnifying narrow-band imaging (M-NBI) for the optical diagnosis of colorectal SM-d cancer. Results Sensitivity, specificity, and accuracy for the diagnosis of SM-d cancer were 66.0 %, 95.8 %, and 86.3 % for CE; 80 %, 90.7 %, and 87.3 % for M-CE; and 65.0 %, 94.4 %, and 85.1 % for M-NBI, respectively. The specificity of CE was significantly higher than that of M-CE (P = 0.034). The sensitivity of M-CE was significantly higher than that of CE (P = 0.026). In a comparison of positive and negative groups for the non-extension sign in SM-d cancer, SM invasion was significantly deeper in the positive group than in the negative group (3012.5 μm vs 2002.4 μm, respectively; P Conclusions The non-extension sign offers high diagnostic specificity for SM-d cancer, and surgery should be considered in patients with a positive non-extension sign.

Nucleic acid therapeutics are developing into precise medicines that can manipulate specific genes. However, the development of safe and effective delivery system for the target cells has remained a challenge. Lipid nanoparticles (LNPs) have provided a revolutionary delivery system that can ensure multiple clinical translation of RNA-based candidates. In 2018, Patisiran (Onpattro) was first approved as an LNP-based siRNA drug. In 2020, during the coronavirus disease 2019 (COVID-19) outbreak, LNPs have enabled the development of two SARS-CoV-2 mRNA vaccines, Tozinameran (Comirnaty or Pfizer-BioNTech COVID-19 vaccine) and Elasomeran (Spikevax or COVID-19 vaccine Moderna) for conditional approval. Here, we reviewed the state-of-the-art LNP technology employed in three approved drugs (one siRNA-based and two mRNA-based drugs) and discussed the differences in their mode of action, formulation design, and biodistribution.