Showing papers by "Hokkaido University published in 2018"

Long noncoding RNA MALAT1 suppresses breast cancer metastasis

Abstract: MALAT1 has previously been described as a metastasis-promoting long noncoding RNA (lncRNA). We show here, however, that targeted inactivation of the Malat1 gene in a transgenic mouse model of breast cancer, without altering the expression of its adjacent genes, promotes lung metastasis, and that this phenotype can be reversed by genetic add-back of Malat1. Similarly, knockout of MALAT1 in human breast cancer cells induces their metastatic ability, which is reversed by re-expression of Malat1. Conversely, overexpression of Malat1 suppresses breast cancer metastasis in transgenic, xenograft, and syngeneic models. Mechanistically, the MALAT1 lncRNA binds and inactivates the prometastatic transcription factor TEAD, preventing TEAD from associating with its co-activator YAP and target gene promoters. Moreover, MALAT1 levels inversely correlate with breast cancer progression and metastatic ability. These findings demonstrate that MALAT1 is a metastasis-suppressing lncRNA rather than a metastasis promoter in breast cancer, calling for rectification of the model for this highly abundant and conserved lncRNA.

Photoassisted Construction of Holey Defective g-C3N4 Photocatalysts for Efficient Visible-Light-Driven H2O2 Production

Abstract: Holey defective g-C3 N4 photocatalysts, which are easily prepared via a novel photoassisted heating process, are reported. The photoassisted treatment not only helps to create abundant holes, endowing g-C3 N4 with more exposed catalytic active sites and crossplane diffusion channels to shorten the diffusion distance of both reactants from the surface to bulk and charge carriers from the bulk to surface, but also introduces nitrogen vacancies in the tri-s-triazine repeating units of g-C3 N4 , inducing the narrowing of intrinsic bandgap and the formation of defect states within bandgap to extend the visible-light absorption range and suppress the radiative electron-hole recombination. As a result, the holey defective g-C3 N4 photocatalysts show much higher photocatalytic activity for H2 O2 production with optimized enhancement up to ten times higher than pristine bulk g-C3 N4 . The newly developed synthetic strategy adopted here enables the sufficient utilization of solar energy and shows rather promising for the modification of other materials for efficient energy-related applications.

Phantom: A smoothed particle hydrodynamics and magnetohydrodynamics code for astrophysics

Abstract: We present Phantom, a fast, parallel, modular, and low-memory smoothed particle hydrodynamics and magnetohydrodynamics code developed over the last decade for astrophysical applications in three dimensions. The code has been developed with a focus on stellar, galactic, planetary, and high energy astrophysics, and has already been used widely for studies of accretion discs and turbulence, from the birth of planets to how black holes accrete. Here we describe and test the core algorithms as well as modules for magnetohydrodynamics, self-gravity, sink particles, dust–gas mixtures, H2 chemistry, physical viscosity, external forces including numerous galactic potentials, Lense–Thirring precession, Poynting–Robertson drag, and stochastic turbulent driving. Phantom is hereby made publicly available.

Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives.

Abstract: Recent research has demonstrated that the non-coding genome plays a key role in genetic programming and gene regulation during development as well as in health and cardiovascular disease. About 99% of the human genome do not encode proteins, but are transcriptionally active representing a broad spectrum of non-coding RNAs (ncRNAs) with important regulatory and structural functions. Non-coding RNAs have been identified as critical novel regulators of cardiovascular risk factors and cell functions and are thus important candidates to improve diagnostics and prognosis assessment. Beyond this, ncRNAs are rapidly emgerging as fundamentally novel therapeutics. On a first level, ncRNAs provide novel therapeutic targets some of which are entering assessment in clinical trials. On a second level, new therapeutic tools were developed from endogenous ncRNAs serving as blueprints. Particularly advanced is the development of RNA interference (RNAi) drugs which use recently discovered pathways of endogenous short interfering RNAs and are becoming versatile tools for efficient silencing of protein expression. Pioneering clinical studies include RNAi drugs targeting liver synthesis of PCSK9 resulting in highly significant lowering of LDL cholesterol or targeting liver transthyretin (TTR) synthesis for treatment of cardiac TTR amyloidosis. Further novel drugs mimicking actions of endogenous ncRNAs may arise from exploitation of molecular interactions not accessible to conventional pharmacology. We provide an update on recent developments and perspectives for diagnostic and therapeutic use of ncRNAs in cardiovascular diseases, including atherosclerosis/coronary disease, post-myocardial infarction remodelling, and heart failure.

Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis

Abstract: To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.

Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer

Abstract: Background Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. Methods This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. Results Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse-free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare. Conclusion The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/).

Rotaxanes as Mechanochromic Fluorescent Force Transducers in Polymers

Abstract: The integration of mechanophores, motifs that transduce mechanical forces into chemical reactions, allows creating materials with stress-dependent properties. Typical mechanophores are activated by cleaving weak covalent bonds, but these reactions can also be triggered by other stimuli, and this renders the behavior unspecific. Here we show that this problem can be overcome by extending the molecular-shuttle function of rotaxanes to mechanical activation. A mechanically interlocked mechanophore composed of a fluorophore-carrying macrocycle and a dumbbell-shaped molecule containing a matching quencher was integrated into a polyurethane elastomer. Deformation of this polymer causes a fluorescence turn-on, due to the spatial separation of fluorophore and quencher. This process is specific, efficient, instantly reversible, and elicits an easily detectable optical signal that correlates with the applied force.

A Facile Method to Fabricate Anisotropic Hydrogels with Perfectly Aligned Hierarchical Fibrous Structures

Abstract: Natural structural materials (such as tendons and ligaments) are comprised of multiscale hierarchical architectures, with dimensions ranging from nano- to macroscale, which are difficult to mimic synthetically. Here a bioinspired, facile method to fabricate anisotropic hydrogels with perfectly aligned multiscale hierarchical fibrous structures similar to those of tendons and ligaments is reported. The method includes drying a diluted physical hydrogel in air by confining its length direction. During this process, sufficiently high tensile stress is built along the length direction to align the polymer chains and multiscale fibrous structures (from nano- to submicro- to microscale) are spontaneously formed in the bulk material, which are well-retained in the reswollen gel. The method is useful for relatively rigid polymers (such as alginate and cellulose), which are susceptible to mechanical signal. By controlling the drying with or without prestretching, the degree of alignment, size of superstructures, and the strength of supramolecular interactions can be tuned, which sensitively influence the strength and toughness of the hydrogels. The mechanical properties are comparable with those of natural ligaments. This study provides a general strategy for designing hydrogels with highly ordered hierarchical structures, which opens routes for the development of many functional biomimetic materials for biomedical applications.

Punishment diminishes the benefits of network reciprocity in social dilemma experiments.

Abstract: Network reciprocity has been widely advertised in theoretical studies as one of the basic cooperation-promoting mechanisms, but experimental evidence favoring this type of reciprocity was published only recently. When organized in an unchanging network of social contacts, human subjects cooperate provided the following strict condition is satisfied: The benefit of cooperation must outweigh the total cost of cooperating with all neighbors. In an attempt to relax this condition, we perform social dilemma experiments wherein network reciprocity is aided with another theoretically hypothesized cooperation-promoting mechanism—costly punishment. The results reveal how networks promote and stabilize cooperation. This stabilizing effect is stronger in a smaller-size neighborhood, as expected from theory and experiments. Contrary to expectations, punishment diminishes the benefits of network reciprocity by lowering assortment, payoff per round, and award for cooperative behavior. This diminishing effect is stronger in a larger-size neighborhood. An immediate implication is that the psychological effects of enduring punishment override the rational response anticipated in quantitative models of cooperation in networks.

Phylogenomics and the evolution of hemipteroid insects.

Abstract: Hemipteroid insects (Paraneoptera), with over 10% of all known insect diversity, are a major component of terrestrial and aquatic ecosystems. Previous phylogenetic analyses have not consistently resolved the relationships among major hemipteroid lineages. We provide maximum likelihood-based phylogenomic analyses of a taxonomically comprehensive dataset comprising sequences of 2,395 single-copy, protein-coding genes for 193 samples of hemipteroid insects and outgroups. These analyses yield a well-supported phylogeny for hemipteroid insects. Monophyly of each of the three hemipteroid orders (Psocodea, Thysanoptera, and Hemiptera) is strongly supported, as are most relationships among suborders and families. Thysanoptera (thrips) is strongly supported as sister to Hemiptera. However, as in a recent large-scale analysis sampling all insect orders, trees from our data matrices support Psocodea (bark lice and parasitic lice) as the sister group to the holometabolous insects (those with complete metamorphosis). In contrast, four-cluster likelihood mapping of these data does not support this result. A molecular dating analysis using 23 fossil calibration points suggests hemipteroid insects began diversifying before the Carboniferous, over 365 million years ago. We also explore implications for understanding the timing of diversification, the evolution of morphological traits, and the evolution of mitochondrial genome organization. These results provide a phylogenetic framework for future studies of the group.

Restorative effects of human neural stem cell grafts on the primate spinal cord

Abstract: We grafted human spinal cord-derived neural progenitor cells (NPCs) into sites of cervical spinal cord injury in rhesus monkeys (Macaca mulatta). Under three-drug immunosuppression, grafts survived at least 9 months postinjury and expressed both neuronal and glial markers. Monkey axons regenerated into grafts and formed synapses. Hundreds of thousands of human axons extended out from grafts through monkey white matter and synapsed in distal gray matter. Grafts gradually matured over 9 months and improved forelimb function beginning several months after grafting. These findings in a 'preclinical trial' support translation of NPC graft therapy to humans with the objective of reconstituting both a neuronal and glial milieu in the site of spinal cord injury.

Neural basis of major depressive disorder: Beyond monoamine hypothesis.

Abstract: The monoamine hypothesis has been accepted as the most common hypothesis of major depressive disorder (MDD) for a long period because of its simplicity and understandability. Actually, most currently used antidepressants have been considered to act based on the monoamine hypothesis. However, an important problem of the monoamine hypothesis has been pointed out as follows: it fails to explain the latency of response to antidepressants. In addition, many patients with MDD have remained refractory to currently used antidepressants. Therefore, monoamine-alternate hypotheses are required to explain the latency of response to antidepressants. Such hypotheses have been expected to contribute to identifying hopeful new therapeutic targets for MDD. Past studies have revealed that the volume of the hippocampus is decreased in patients with MDD, which is likely caused by the failure of the hypothalamic-pituitary-adrenal axis and following elevation of glucocorticoids. Two hypotheses have been proposed to explain the volume of the hippocampus: (i) the neuroplasticity hypothesis; and (ii) the neurogenesis hypothesis. The neuroplasticity hypothesis explains how the hippocampal volume is decreased by the morphological changes of hippocampal neurons, such as the shortening length of dendrites and the decreased number and density of spines. The neurogenesis hypothesis explains how the hippocampal volume is decreased by the decrease of neurogenesis in the hippocampal dentate gyrus. These hypotheses are able to explain the latency of response to antidepressants. In this review, we first overview how the neuroplasticity and neurogenesis hypotheses have been developed. We then describe the details of these hypotheses.

Diagnosis and management of pemphigus: Recommendations of an international panel of experts

Abstract: Background Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. Objective We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. Methods A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. Results The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. Limitations Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. Conclusions We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.

Tough Hydrogels with Fast, Strong, and Reversible Underwater Adhesion Based on a Multiscale Design.

Abstract: Hydrogels have promising applications in diverse areas, especially wet environments including tissue engineering, wound dressing, biomedical devices, and underwater soft robotics. Despite strong demands in such applications and great progress in irreversible bonding of robust hydrogels to diverse synthetic and biological surfaces, tough hydrogels with fast, strong, and reversible underwater adhesion are still not available. Herein, a strategy to develop hydrogels demonstrating such characteristics by combining macroscale surface engineering and nanoscale dynamic bonds is proposed. Based on this strategy, excellent underwater adhesion performance of tough hydrogels with dynamic ionic and hydrogen bonds, on diverse substrates, including hard glasses, soft hydrogels, and biological tissues is obtained. The proposed strategy can be generalized to develop other soft materials with underwater adhesion.

Neutrino mixing from finite modular groups

Abstract: We study the lepton flavor models, whose flavor symmetries are finite subgroups of the modular group such as ${S}_{3}$ and ${A}_{4}$. In our models, couplings are also nontrivial representations of these groups and modular functions of the modulus. We study the possibilities that these models realize realistic values of neutrino masses and lepton mixing angles.

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

Abstract: Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML. Sorafenib-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+ AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+ T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

The immunoproteasome and thymoproteasome: functions, evolution and human disease.

Abstract: The basic principle of adaptive immunity is to strictly discriminate between self and non-self, and a central challenge to overcome is the enormous variety of pathogens that might be encountered. In cell-mediated immunity, immunological discernment takes place at a molecular or cellular level. Central to both mechanisms of discernment is the generation of antigenic peptides associated with MHC class I molecules, which is achieved by a proteolytic complex called the proteasome. To adequately accomplish the discrimination between self and non-self that is essential for adaptive immunity and self-tolerance, two proteasome subtypes have evolved via gene duplication: the immunoproteasome and the thymoproteasome. In this Review, we describe various aspects of these immunity-dedicated proteasomes, from their discovery to recent findings.

Tumor-Intrinsic PD-L1 Signaling in Cancer Initiation, Development and Treatment: Beyond Immune Evasion.

Abstract: Although the role of PD-L1 in suppressing the anti-tumor immune response is extensively documented, recent discoveries indicate a distinct tumor-intrinsic role for PD-L1 in modulating epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC)-like phenotype, metastasis and resistance to therapy In this review, we will focus on the newly discovered functions of PD-L1 in the regulation of cancer development, describe underlying molecular mechanisms responsible for PD-L1 upregulation and discuss current insights into novel components of PD-L1 signaling Furthermore, we summarize our current understanding of the link between PD-L1 signaling and the EMT program as well as the CSC state Tumor cell-intrinsic PD-L1 clearly contributes to cancer stemness, EMT, tumor invasion and chemoresistance in multiple tumor types Conversely, activation of OCT4 signaling and upregulation of EMT inducer ZEB1 induce PD-L1 expression in cancer cells, thereby suggesting a possible immune evasion mechanism employed by cancer stem cells during metastasis Our meta-analysis demonstrated that PD-L1 is co-amplified along with MYC, SOX2, N-cadherin and SNAI1 in the TCGA endometrial and ovarian cancer datasets Further identification of immune-independent PD-L1 functions and characterization of crucial signaling events upstream or downstream of PD-L1 in diverse cancer types and specific cancer subtypes, would provide additional targets and new therapeutic approaches