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The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N -ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs. JmjC histone demethylases (KDMs) are cancer targets due to their links to cell proliferation, but selective inhibition remains a challenge. Here the authors identify potent inhibitors of KDM4A-C—via in vitro selection from a vast library of cyclic peptides—that show selectivity over other KDMs.

The Community Multiscale Air Quality Model (CMAQ) v5.0.2 was applied to PM2.5 simulation in Japan, which is strongly affected by long-range transport (LRT) from anthropogenic sources in the Asian Continent, for one year from April 2010 to March 2011. The model performance for LRT and local pollution (LP) of PM2.5 was evaluated to identify the model processes that need to be improved. CMAQ well simulated temporal and spatial variation patterns of PM2.5 but underestimated the concentration level by 15% on average. The contribution of LRT was estimated from the difference between the baseline simulation case and a zero-emission case for anthropogenic emissions in the continent. The estimated LRT contribution to PM2.5 was 50% on average and generally higher in the western areas of Japan (closer to the continent). Days that were dominantly affected by LRT or LP were determined based on the contribution of LRT to sulfate, which was fairly well simulated and strongly affected by LRT among major PM2.5 components. The underestimation of PM2.5 was larger in LP days (by 26% on average) than LRT days (by 10% on average). Therefore, it is essential to improve local emissions, formation, and loss processes of precursors and PM2.5 in Japan.

Purpose To prospectively clarify the effects of obstructive jaundice (OJ) on hepatic hemodynamics using contrast-enhanced ultrasonography (US). Methods Subjects comprised 14 patients admitted to our hospital for OJ between April 2013 and March 2014. Contrast-enhanced US was performed using the LOGIQ E9 ultrasound device during the jaundice phase, before biliary drainage, and again after improvement of jaundice. After injecting the Sonazoid contrast agent, contrast dynamics were recorded in the right kidney and liver segments 5 or 6. Prototype software was used to calculate mean arrival time (AT) of the contrast agent in the liver parenchyma. Statistical analysis was performed to compare the mean AT in the jaundice and improved jaundice phases. Results We were unable to follow up three of the 14 patients after biliary drainage; thus, we included 11 patients for further analysis. The mean AT of the contrast agent was 2.0 ± 1.8 and 6.1 ± 2.3 s in the jaundice and improved jaundice phases, respectively, showing significantly shorter AT in the jaundice phase ( p  = 0.0033). Conclusion Our findings indicate that OJ may influence the blood flow balance between the hepatic portal vein and hepatic artery.

The present study reports the case of a 68-year-old male patient who presented to Tokyo Rosai Hospital for the treatment of alcoholic liver disease. A high density was observed in liver segment S2, while a tumor, 30 mm in size, exhibiting a low density was observed in the delayed phase upon contrast-enhanced computed tomography (CT), which was performed prior to admission. The tumor appeared slightly poorly defined upon abdominal ultrasound and was observed as a 30 mm low-echoic nodule that was internally heterogeneous. A 5-mm thick contrast enhancement effect was observed in the tumor border in the vascular phase on Sonazoid contrast-enhanced ultrasonography, while a defect in the entire tumor was observed in the post-vascular phase. Dysphagia had commenced three months prior to presentation and a weight loss of ~3 kg was observed. Therefore, the patient was admitted to Tokyo Rosai Hospital due to the presence of a hepatic tumor, and to undergo a close inspection of the cause of the tumor. Upon close inspection, it was determined that the weight loss and aphagia were caused by progressive bulbar paralysis. A contrast-enhanced CT was performed on post-admission day 29 as a follow-up regarding the hepatic tumor. As a result, although no change in the tumor size was observed, the contrast enhancement in the tumor borderline had disappeared. Necrosis of the tumor was considered. However, as viable persistence of the malignant tumor could not be excluded, a hepatic left lobe excision was performed. The patient was diagnosed with hepatocellular carcinoma (HCC) based on the morphology of the cellular necrosis. In addition, occlusion due to thrombus was observed within the blood vessels passing inside the fibrous capsule. It was hypothesized that the formation of a thick fibrous capsule and occlusion due to thrombus in the feeding vessel were possibly involved as the cause of complete spontaneous necrosis. Written informed consent was obtained from the patient.

A 66-year-old male with unbearable pruritus and jaundice was admitted for detailed examination. Blood tests on admission showed increased bilirubin with a dominant direct fraction. Ultrasonography and computed tomography performed subsequent to admission showed no narrowing or distension of the bile ducts. As the jaundice symptoms were not improved by the oral administration of ursodeoxycholic acid (300 mg/day) that had been started immediately after admission, endoscopic retrograde cholangiopancreatography (ERCP) was performed on hospital day 14. This also showed no abnormalities of the bile ducts. After considerating its potential effects for improving jaundice, endoscopic nasobiliary drainage (ENBD) was performed on the same day and was followed by immediate improvements in pruritus and jaundice. Detailed examinations were performed to identify the cause of the jaundice, which was suspected to be viral hepatitis, autoimmune hepatitis or drug-induced liver injury, however, there were no findings suggestive of any of these conditions. Following a further increase in bilirubin levels, confirmed by additional blood tests, a liver biopsy was performed. Histological findings were consistent with the histological features of benign recurrent intrahepatic cholestasis (BRIC). Although ursodeoxycholic acid is used as a first-line treatment in most cases of BRIC, ENBD should also be considered for patients not responding to this treatment.

A 63-year-old woman was admitted to hospital with pain in the right lower quadrant. Abdominal computed tomography (CT) revealed a 60-mm cystic mass at a site corresponding to the appendix. The mass wall on the appendicular ostium was thickened and enhanced by contrast, while calcification was observed in the mass wall on the appendicular tip. No projection was observed in the mass cavity. On abdominal ultrasonography (US), the mass wall on the appendicular ostium was thickened and projections were observed at two sites in the mass cavity. On contrast-enhanced US (CEUS), only one of these projections was enhanced. Based on the thickened and contrast-enhanced wall of the mass on the appendicular ostium on CT and US, as well as the contrast enhancement of a projection on US, the mass was diagnosed as mucinous cystadenocarcinoma of the appendix. Ileocecal resection was subsequently performed on day 10. A detailed examination of the surgical specimen revealed carcinoma cells in the mass wall on the appendicular ostium. The contrast-enhanced projection was identified as granulation tissue that had grown to come into contact with the tumor, while the non-contrast-enhanced projection was identified as solidified mucus. US enabled successful visualization of projections in the mass cavity that were not visible on abdominal CT. CEUS also proved useful for assessing blood flow in these projections.

An 85-year-old woman was an outpatient treated at Tokyo Rosai Hospital for cirrhosis caused by hepatitis B. She had previously been diagnosed as having common bile duct stones, for which she underwent endoscopic retrograde cholangiopancreatography (ERCP). However, as stone removal was unsuccessful, a plastic stent was placed after endoscopic sphincterotomy. In October 2012, the stent was replaced endoscopically because she developed cholangitis due to stent occlusion. Seven days later, we performed ERCP to treat recurring cholangitis. During the procedure, the stone was successfully removed by a balloon catheter when cleaning the common bile duct. The next day, the patient developed abdominal pain, abdominal distension, and nausea and was diagnosed as having gallstone ileus based on abdominal computed tomography (CT) and abdominal ultrasonography findings of an incarcerated stone in the terminal ileum. Although colonoscopy was performed after inserting an ileus tube, no stone was visible. Subsequent CT imaging verified the disappearance of the incarcerated stone from the ileum, suggesting that the stone had been evacuated naturally via the transanal route. Although it is extremely rare for gallstone ileus to develop as a complication of ERCP, physicians should be aware of gallstone ileus and follow patients carefully, especially after removing huge stones.

The intraductal papillary neoplasm of the bile duct (IPNB) is a novel disease concept that was recently classified as a biliary cystic tumor by the revised World Health Organization classification. This is the case report of a 70-year-old female patient who experienced repeated episodes of obstructive jaundice and cholangitis since 2000, attributed to a mucus-producing hepatic tumor. Surgery was advised due to the repeated episodes; however, the patient refused. In May, 2011, the patient developed jaundice and fever and was treated with antibiotics. Since there was no improvement, the patient was admitted to the Tokyo Rosai Hospital. Abdominal computed tomography (CT) revealed a 50-mm cystic mass with an internal septum in the left hepatic lobe. Although the tumor size had remained almost unchanged compared to the initial CT scan performed in 2000, intra- and extra-hepatic bile duct dilation was more prominent on the second CT scan. Following admission, endoscopic retrograde cholangiopancreatography was performed and revealed an expanded papilla of Vater due to a mucous plug. A balloon catheter was inserted into the bile duct to remove the mucous plug, resulting in the drainage of copious amounts of mucus and infected bile. The patient finally consented to surgery and left hepatic lobectomy was performed. Consequently, the diagnosis of low-grade IPNB was made. Branch duct type IPNB, which is characterized by imaging appearance of a cystic mass and slow progression, is attracting increasing attention. In the present case, a cystic mass was identified in the left hepatic lobe, with no significant change in size after 11 years of follow-up, leading to the diagnosis of branch duct type IPNB. Considering the fact that IPNB is usually treated surgically at the time of diagnosis, the present case, due to the long-term follow-up, provides valuable insight into the natural history of the tumor.

The Community Multiscale Air Quality Model (CMAQ) v5.0.2 was applied to PM 2.5 simulation in Japan, which is strongly affected by long-range transport (LRT) from anthropogenic sources in the Asian Continent, for one year from April 2010 to March 2011. The model performance for LRT and local pollution (LP) of PM 2.5 was evaluated to identify the model processes that need to be improved. CMAQ well simulated temporal and spatial variation patterns of PM 2.5 but underestimated the concentration level by 15% on average. The contribution of LRT was estimated from the difference between the baseline simulation case and a zero-emission case for anthropogenic emissions in the continent. The estimated LRT contribution to PM 2.5 was 50% on average and generally higher in the western areas of Japan (closer to the continent). Days that were dominantly affected by LRT or LP were determined based on the contribution of LRT to sulfate, which was fairly well simulated and strongly affected by LRT among major PM 2.5 components. The underestimation of PM 2.5 was larger in LP days (by 26% on average) than LRT days (by 10% on average). Therefore, it is essential to improve local emissions, formation, and loss processes of precursors and PM 2.5 in Japan.

The Community Multiscale Air Quality Model (CMAQ) v5.0.2 was applied to [PM.sub.2.5] simulation in Japan, which is strongly affected by long-range transport (LRT) from anthropogenic sources in the Asian Continent, for one year from April 2010 to March 2011. The model performance for LRT and local pollution (LP) of [PM.sub.2.5] was evaluated to identify the model processes that need to be improved. CMAQ well simulated temporal and spatial variation patterns of [PM.sub.2.5] but underestimated the concentration level by 15% on average. The contribution of LRT was estimated from the difference between the baseline simulation case and a zeroemission case for anthropogenic emissions in the continent. The estimated LRT contribution to [PM.sub.2.5] was 50% on average and generally higher in the western areas of Japan (closer to the continent). Days that were dominantly affected by LRT or LP were determined based on the contribution of LRT to sulfate, which was fairly well simulated and strongly affected by LRT among major [PM.sub.2.5] components. The underestimation of [PM.sub.2.5] was larger in LP days (by 26% on average) than LRT days (by 10% on average). Therefore, it is essential to improve local emissions, formation, and loss processes of precursors and [PM.sub.2.5] in Japan.