Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation

The abundance of the cyclin-dependent kinase (CDK) inhibitor p57Kip2, an important regulator of cell cycle progression, is thought to be controlled by the ubiquitin-proteasome pathway. The Skp1/Cul1/F-box (SCF)-type E3 ubiquitin ligase complex SCFSkp2 has now been shown to be responsible for regulating the cellular level of p57Kip2 by targeting it for ubiquitylation and proteolysis. The elimination of p57Kip2 was impaired in Skp2-/- cells, resulting in abnormal accumulation of the protein. Coimmunoprecipitation analysis also revealed that Skp2 interacts with p57Kip2 in vivo. Overexpression of WT Skp2 promoted degradation of p57Kip2, whereas expression of a dominant negative mutant of Skp2 prolonged the half-life of p57Kip2. Mutation of the threonine residue (Thr-310) of human p57Kip2 that is conserved between the COOH-terminal QT domains of p57Kip2 and p27Kip1 prevented the effect of Skp2 on the stability of p57Kip2, suggesting that phosphorylation at this site is required for SCFSkp2-mediated ubiquitylation. Finally, the purified recombinant SCFSkp2 complex mediated p57Kip2 ubiquitylation in vitro in a manner dependent on the presence of the cyclin E-CDK2 complex. These observations thus demonstrate that the SCFSkp2 complex plays an important role in cell-cycle progression by determining the abundance of p57Kip2 and that of the related CDK inhibitor p27Kip1.     

Mediastinal Malignant Melanoma Markedly Shrinking in Response to Nivolumab

Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.     

Recent progress in the use of diaziridine-based sweetener derivatives to elucidate the chemoreception mechanism of the sweet taste receptor

All sweeteners are recognized by the sweet taste receptor (T1R2–T1R3). The elucidation of the chemoreception mechanism of receptor–ligand interactions is an attractive topic for researchers. Molecular biology and computational biology techniques can reveal the proposed mechanisms for this topic. Other approaches, including chemical biology (bioorganic chemistry), have helped to identify mechanisms on the basis of molecular structure. In this mini-review, we have summarized the recent progress in the synthesis of sweetener derivatives, which includes the use of photoaffinity labeling of diazirine-based derivatives to elucidate the chemoreception of sweeteners.

The review summarized recent progress for the elucidation of the chemoreception mechanism of sweet taste receptor–sweetener interactions with photoaffinity labeling.     

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in ApcMin/+ mice

Hepatocyte growth factor activator inhibitor‐1 (HAI‐1), encoded by the SPINT1 gene, is a membrane‐bound protease inhibitor expressed on the surface of epithelial cells. Hepatocyte growth factor activator inhibitor‐1 regulates type II transmembrane serine proteases that activate protease‐activated receptor‐2 (PAR‐2). We previously reported that deletion of Spint1 in Apc^Min/+ mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor‐κB signaling. In this study, we examined the role of PAR‐2 in accelerating tumor formation in the Apc^Min/+ model in the presence or absence of Spint1. We observed that knockout of the F2rl1 gene, encoding PAR‐2, not only eliminated the enhanced formation of intestinal tumors caused by Spint1 deletion, but also reduced tumor formation in the presence of Spint1. Exacerbation of anemia and weight loss associated with HAI‐1 deficiency was also normalized by compound deficiency of PAR‐2. Mechanistically, signaling triggered by deregulated protease activities increased nuclear translocation of RelA/p65, vascular endothelial growth factor expression, and vascular density in Apc^Min/+‐induced intestinal tumors. These results suggest that serine proteases promote intestinal carcinogenesis through activation of PAR‐2, and that HAI‐1 plays a critical tumor suppressor role as an inhibitor of matriptase, kallikreins, and other PAR‐2 activating proteases.     

Bigeminal pulmonary vein ectopy suppressed by pulmonary vein isolation

A 58-year-old man with atrial fibrillation underwent pulmonary vein (PV) isolation (PVI). Bigeminal atrial premature beats persisted from the beginning of the PVI. The cardiac recordings from a basket catheter (BC) revealed the PV ectopic origin in the distal right superior PV. Successful PVI with the guidance of BC was confirmed by the appearance of concealed ectopy. Surprisingly, the PV ectopy completely disappeared immediately after the successful PVI. The findings suggest that the generation of PV trigger is sometimes dependent on left atrial input and that the underlying mechanism of the PV trigger may have been triggered activity or reentry.     

Lipid profile is associated with the incidence of cognitive dysfunction in viral cirrhotic patients: A data‐mining analysis

Aim: Cognitive dysfunction (CD) is frequently observed in cirrhotic patients. However, the biochemical profiles associated with CD remain unclear. We investigated the biochemical profiles associated with the incidence of CD in cirrhotic patients by using multivariate analyses, including a decision‐tree algorithm. Methods: In this study, 27 viral cirrhotic patients were enrolled. All subjects underwent neuropsychiatric tests; two or more abnormal results were defined as CD. A logistic regression model was used for multivariate stepwise analysis. A decision‐tree algorithm was constructed, and the categorical differences based on the decision‐tree model were analyzed by χ²‐tests. Results: Multivariate stepwise analysis showed the levels of total bilirubin, triglycerides and free fatty acids (FFA) as independent bioparameters associated with the incidence of CD in cirrhotic patients. The decision‐tree algorithm showed that among patients with FFA of 514 mEq/L or more, 77.8% had CD. Meanwhile, among patients with FFA of less than 514 mEq/L and triglycerides of 106 mg/dL or more, 20.0% had CD. The sensitivity, specificity and accuracy for the incidence of CD using the lipid profile (FFA >514 mEq/L or triglycerides <106 mg/dL) were 85.7% (12/14), 61.5% (8/13) and 74.1% (20/27), respectively. Conclusion: The levels of total bilirubin, FFA and triglycerides are independently associated with the incidence of CD in cirrhotic patients. In addition, a decision‐tree algorithm revealed that FFA of more than 514 mEq/L or triglycerides of less than 106 mg/dL is a profile associated with the incidence of CD. Thus, this lipid profile could be a possible screening bioparameter for CD in cirrhotic patients.     

Long-Term follow-up of the circadian rhythm of heart rate and heart rate variability in healthy elderly patients.

BACKGROUND: The long-term age-related changes in circadian rhythm of heart rate variability (HRV), that is, autonomic nervous activity, remain unknown in elderly people. METHODS AND RESULTS: Holter monitoring was conducted twice at an interval of 15 years in 15 healthy elderly patients (age: 70.0 +/- 4.1 years, at first monitoring, female: 10) and assessed the age-related changes in 24-h mean and hourly mean normal sinus R-R interval (mean NN), HRV (high frequency (HF) component, low frequency (LF) component and LF/HF) and the circadian rhythms. As a result, 24-h mean mean NN (0.976 +/- 0.115 vs 0.903 +/- 0.117 (s), p = 0.0019), LF/HF (1.681 +/- 0.731 vs 0.962 +/- 0.442, p = 0.0022), and LF (278.88 +/- 176.43 vs 179.19 +/- 132.33 (ms2), p = 0.0039) significantly decreased 15 years later, although 24-h mean HF (221.20+/-138.89 vs 310.78+/-296.73 (ms2), p = 0.1102) increased slightly. The hourly mean NN closely correlated with hourly HF and LF/HF throughout circadian rhythms both at first and second monitoring. In the morning hours, amplitude rates of all HRV indices increased significantly 15 years later. CONCLUSION: In elderly people, age-related changes in the 24-h mean heart rate (HR) were conversely dissociated from those of the 24-h mean HRV. However, the close correlation between hourly HR and HRV was preserved, even in very elderly patients. Additionally, the amplitude rates in HRV in the morning increased with age. These age-related changes of HR and HRV might be characteristic of elderly people.