A useful approach to total analysis of RISC-associated RNA

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Engineering a BCR-ABL–Activated Caspase for the Selective Elimination of Leukemic Cells

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations

The epigenetic function of androgen receptor in prostate cancer progression

Androgen and androgen deprivation (castration) therapies, including androgen receptor antagonists, are clinically used to treat patients with prostate cancer. However, most hormone-dependent prostate cancer patients progress into a malignant state with loss of hormone-dependency, known as castration (drug)-resistant prostate cancer (CRPC), after prolong androgen-based treatments. Even in the CRPC state with irreversible malignancy, androgen receptor (AR) expression is detectable. An epigenetic transition to CRPC induced by the action of AR-mediated androgen could be speculated in the patients with prostate cancer. Androgen receptors belongs to the nuclear receptor superfamily with 48 members in humans, and acts as a ligand-dependent transcriptional factor, leading to local chromatin reorganization for ligand-dependent gene regulation. In this review, we discussed the transcriptional/epigenetic regulatory functions of AR, with emphasis on the clinical applications of AR ligands, AR protein co-regulators, and AR RNA coregulator (enhancer RNA), especially in chromatin reorganization, in patients with prostate cancer

2-dimensional FDTD simulations of estimating spatial structure of Es layer by wave propagation characteristics with different frequencies

第3回極域科学シンポジウム/第36回極域宙空圏シンポジウム 11月26日（月）、27日（火） 国立極地研究所 2階ラウン

Lap-Protector and Circular Stapler Are Useful in Cystogastrostomy for Large Pancreatic Pseudocyst with Severe Infection

Lap-Protector, which is an abdominal wall sealing device, is usually used for wound protection from implantation of malignant cells or pyogenic fluid. A circular stapler is a common easy-to-use device for anastomosis of the digestive tract. We report the case of an infected pancreatic pseudocyst which was treated by surgical procedure using these useful devices. A 69-year-old man was followed up in our hospital after severe acute pancreatitis. He had undergone drainage surgeries twice for intractable pancreatic abscess followed by severe acute pancreatitis. He was admitted to our hospital complaining of loss of appetite, hiccups, and high fever. Computed tomography of the abdomen revealed an infected pancreatic pseudocyst which compressed the gastric wall. Internal drainage into the stomach was performed using Lap-Protector and circular stapler. The patient recovered uneventfully. Recently many endoscopic or laparoscopic procedures in cystogastrostomy are reported; however, a conventional open surgical approach is also important. This easy method may be useful for operative cystogastrostomy

Debiasing Graph Transfer Learning via Item Semantic Clustering for Cross-Domain Recommendations

Deep learning-based recommender systems may lead to over-fitting when lacking training interaction data. This over-fitting significantly degrades recommendation performances. To address this data sparsity problem, cross-domain recommender systems (CDRSs) exploit the data from an auxiliary source domain to facilitate the recommendation on the sparse target domain. Most existing CDRSs rely on overlapping users or items to connect domains and transfer knowledge. However, matching users is an arduous task and may involve privacy issues when data comes from different companies, resulting in a limited application for the above CDRSs. Some studies develop CDRSs that require no overlapping users and items by transferring learned user interaction patterns. However, they ignore the bias in user interaction patterns between domains and hence suffer from an inferior performance compared with single-domain recommender systems. In this paper, based on the above findings, we propose a novel CDRS, namely semantic clustering enhanced debiasing graph neural recommender system (SCDGN), that requires no overlapping users and items and can handle the domain bias. More precisely, SCDGN semantically clusters items from both domains and constructs a cross-domain bipartite graph generated from item clusters and users. Then, the knowledge is transferred via this cross-domain user-cluster graph from the source to the target. Furthermore, we design a debiasing graph convolutional layer for SCDGN to extract unbiased structural knowledge from the cross-domain user-cluster graph. Our Experimental results on three public datasets and a pair of proprietary datasets verify the effectiveness of SCDGN over state-of-the-art models in terms of cross-domain recommendations.Comment: 11 pages, 4 figure

Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers

BACKGROUND: Nectin-2 is a Ca(2+)-independent cell-cell adhesion molecule that is one of the plasma membrane components of adherens junctions. However, little has been reported about the involvement of Nectin-2 in cancer. METHODS: To determine the expression of Nectin-2 in cancer tissues and cancer cell lines, we performed gene expression profile analysis, immunohistochemistry studies, and flow cytometry analysis. We also investigated the potential of this molecule as a target for antibody therapeutics to treat cancers by generating and characterizing an anti-Nectin-2 rabbit polyclonal antibody (poAb) and 256 fully human anti-Nectin-2 monoclonal antibodies (mAbs). In addition, we tested anti-Nectin-2 mAbs in several in vivo tumor growth inhibition models to investigate the primary mechanisms of action of the mAbs. RESULTS: In the present study, we found that Nectin-2 was over-expressed in clinical breast and ovarian cancer tissues by using gene expression profile analysis and immunohistochemistry studies. Nectin-2 was over-expressed in various cancer cell lines as well. Furthermore, the polyclonal antibody specific to Nectin-2 suppressed the in vitro proliferation of OV-90 ovarian cancer cells, which express endogenous Nectin-2 on the cell surface. The anti-Nectin-2 mAbs we generated were classified into 7 epitope bins. The anti-Nectin-2 mAbs demonstrated antibody-dependent cellular cytotoxicity (ADCC) and epitope bin-dependent features such as the inhibition of Nectin-2-Nectin-2 interaction, Nectin-2-Nectin-3 interaction, and in vitro cancer cell proliferation. A representative anti-Nectin-2 mAb in epitope bin VII, Y-443, showed anti-tumor effects against OV-90 cells and MDA-MB-231 breast cancer cells in mouse therapeutic models, and its main mechanism of action appeared to be ADCC. CONCLUSIONS: We observed the over-expression of Nectin-2 in breast and ovarian cancers and anti-tumor activity of anti-Nectin-2 mAbs via strong ADCC. These findings suggest that Nectin-2 is a potential target for antibody therapy against breast and ovarian cancers

Theracurmin inhibits intestinal polyp development in Apc‐mutant mice by inhibiting inflammation‐related factors

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Therefore, it is important to establish useful methods for preventing CRC. One prevention strategy involves the use of cancer chemopreventive agents, including functional foods. We focused on the well‐known cancer chemopreventive agent curcumin, which is derived from turmeric. However, curcumin has the disadvantage of being poorly soluble in water due to its high hydrophobicity. To overcome this problem, the formation of submicron particles with surface controlled technology has been applied to curcumin to give it remarkably improved water solubility, and this derived compound is named Theracurmin. To date, the preventive effects of Theracurmin on hereditary intestinal carcinogenesis have not been elucidated. Thus, we used Apc‐mutant mice, a model of familial adenomatous polyposis, to evaluate the effects of Theracurmin. First, we showed that treatment with 10‐20 µM Theracurmin for 24 hours reduced nuclear factor‐κB (NF‐κB) transcriptional activity in human colon cancer DLD‐1 and HCT116 cells. However, treatment with curcumin mixed in water did not change the NF‐κB promoter transcriptional activity. As NF‐κB is a regulator of inflammation‐related factors, we next investigated the downstream targets of NF‐κB: monocyte chemoattractant protein‐1 (MCP‐1) and interleukin (IL)‐6. We found that treatment with 500 ppm Theracurmin for 8 weeks inhibited intestinal polyp development and suppressed MCP‐1 and IL‐6 mRNA expression levels in the parts of the intestine with polyps. This report provides a proof of concept for the ongoing Theracurmin human trial (J‐CAP‐C study)

Opposing role of condensin hinge against replication protein A in mitosis and interphase through promoting DNA annealing

Condensin is required for chromosome dynamics and diverse DNA metabolism. How condensin works, however, is not well understood. Condensin contains two structural maintenance of chromosomes (SMC) subunits with the terminal globular domains connected to coiled-coil that is interrupted by the central hinge. Heterotrimeric non-SMC subunits regulate SMC. We identified a novel fission yeast SMC hinge mutant, cut14-Y1, which displayed defects in DNA damage repair and chromosome segregation. It contains an amino acid substitution at a conserved hinge residue of Cut14/SMC2, resulting in diminished DNA binding and annealing. A replication protein A mutant, ssb1-418, greatly alleviated the repair and mitotic defects of cut14-Y1. Ssb1 protein formed nucleolar foci in cut14-Y1 cells, but the number of foci was diminished in cut14-Y1 ssb1-418 double mutants. Consistent with the above results, Ssb1 protein bound to single-strand DNA was removed by condensin or the SMC dimer through DNA reannealing in vitro. Similarly, RNA hybridized to DNA may be removed by the SMC dimer. Thus, condensin may wind up DNA strands to unload chromosomal components after DNA repair and prior to mitosis. We show that 16 suppressor mutations of cut14-Y1 were all mapped within the hinge domain, which surrounded the original L543 mutation site

Association between COVID-19 incidence and postponement or cancellation of elective surgeries in Japan until September 2020: a cross-sectional, web-based survey

Objectives This study aimed to examine whether and how the COVID-19 pandemic has affected the postponement or cancellation of elective surgeries in Japan.Design and setting A cross-sectional, web-based, self-administered survey was conducted nationwide from August 25 to September 30 2020. We used data from the Japan ‘COVID-19 and Society’ Internet Survey collected by a large internet research agency, Rakuten Insight, which had approximately 2.2 million qualified panellists in 2019.Participants From a volunteer sample of 28 000 participants, we extracted data from 3678 participants with planned elective surgeries on any postponement or cancellation of elective surgeries.Outcome measures The main outcome measure was any postponement or cancelltion of elective surgeries. In addition, for all respondents, we extracted data on sociodemographic, health-relatedcharacteristics, psychological characteristics and prefectural-level residential areas. We used weighted logistic regression approaches to fulfil the study objectives, minimising potential bias relating to web-based surveys.Results Of the 3678 participants, 431 (11.72%) reported experiencing postponement or cancellation of their elective surgeries. Notably, the participants living in prefectures where the declaration of the state of emergency was made on 7 April 2020 were significantly more likely to experience postponement or cancellation of elective surgeries than those residing in prefectures with the stateof emergency beginning on 16 April 2020 (174 (26.02%) vs 153 (12.15%)).Conclusions The proportion of patients whose elective surgery had been postponed was limited during Japan’s first wave of the COVID-19 pandemic, although the declaration of a state of emergency increased the likelihood of postponement. It is imperative to increase awareness of the secondary health effects related to policy intervention in pandemics and other health crises and to use appropriate countermeasures such as standard infectious control measures and triage of surgical patients