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A lithium-rich layer-structured cathode material (Li1.2Ni0.2Mn0.6O2) is promising for lithium ion batteries due to its high practical capacity; however, it has several issues such as low rate performance, potential shift during cycling, and large irreversible capacity. Previously, our group reported that the change in the metal composition from Li1.2Ni0.2Mn0.6O2 to Li1.16Ni0.37Mn0.47O2 was effective in improving rate performance and suppressing potential shift; however, the large irreversible capacity could not be addressed by the composition change. In this study, Li2O extraction, which occurs during initial charging and causes irreversible capacity, progressed using (NH4)2SO4 before charging to reduce the irreversible capacity for Li1.16Ni0.37Mn0.47O2. The results obtained in the composition, morphology, specific surface area, and crystal structure analyses indicate that the (NH4)2SO4 treatment can extract Li2O from the particle surface without changing the crystal structure. The results obtained in the electrochemical measurements indicate that the irreversible capacity was reduced due to the chemical treatment. Moreover, the high rate and cycling performance for the Li1.16Ni0.37Mn0.47O2 was maintained after the treatment. The treatment with (NH4)2SO4 can reduce the irreversible capacity for Li1.16Ni0.37Mn0.47O2 without harming this material’s advantages such as high rate and cycling performance.

While the progress of chemotherapy and molecular targeted therapy has improved the outcome of colorectal cancer patients, the mortality of colon cancer remains high, indicating the need to develop novel therapeutic targets for improving the outcome of colon cancer. Heterogeneous ribonucleoprotein A1 (hnRNP A1) is highly expressed in colorectal cancer and its expression correlates with malignant transformation. In this study, we performed a microarray analysis with the RNA immunoprecipitation (RNA-IP) method and identified hnRNP A1-interacting miRs, including miR-26a and -584, in a colorectal cancer cell line, SW620. A SRB assay revealed the tumor suppressive effect of miR-26a and -584, and the tumor suppressive effect of these miRs was diminished by the downregulation of hnRNP A1. The combined method of a transcriptome analysis and RNA-IP revealed hnRNP A1-interacting mRNAs, including cyclin dependent kinase 6 (CDK6). A Western blot analysis revealed the downregulation of CDK6 in miR-26a and -584 overexpression cells, as well as hnRNP A1 knockdown cells. The binding assay indicated that the binding of hnRNP A1-CDK6 mRNA was reduced by transfection of miR-26a and -584. The expression of cleaved caspase-3 was induced in miR-26a and -584 overexpression cells. These data indicate that miR-26a and -584 inhibit the binding of hnRNP A1-CDK6 mRNA and induce colorectal cancer cell apoptosis.

Inflammatory bowel disease frequently causes intestinal obstruction because of extensive fibrosis. This study investigated whether polyphosphate (poly P), an active molecule derived from Lactobacillus brevis , could improve the fibrosis in a model of chronic colitis. In this study, dextran sodium sulfate (DSS)-induced chronic colitis models and trinitrobenzene sulfonic acid (TNBS)-induced colitis models were used as models of fibrosis. To clarify the mechanism responsible for the observed effects, Caco-2/brush border epithelial (BBE) and naive T helper lymphocyte (THP)-1 cells were treated with lipopolysaccharide (LPS) to induce inflammation. Non-cancer human colon fibroblast (CCD-18) cells were treated with transforming growth factor beta 1 (TGF-β1) to induce fibrosis. The expression levels of fibrosis- and inflammation-associated molecules were evaluated by both a Western blotting analysis and reverse transcriptase–polymerase chain reaction (RT-PCR). The histologic inflammation and fibrosis were significantly improved in the group administered poly P in both the DSS and TNBS colitis models. The levels of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were significantly decreased by poly P treatment. The expression levels of TGF-β1 and collagens in the colitis mice were decreased by poly P. The LPS-induced expressions of IL-1β and TGF-β1 in Caco-2/BBE cells and of TNF-α in THP-1 cells were reduced by poly P treatment. Poly P did not affect the expression of collagens and connective tissue growth factor in the CCD-18 cells. In conclusion, poly P suppresses intestinal inflammation and fibrosis by downregulating the expression of inflammation- and fibrosis-associated molecules in the intestinal epithelium. The administration of poly P is therefore a novel option to treat fibrosis because of chronic intestinal inflammation.

GAREM1 (Grb2-associated regulator of Erk/MAPK1) is an adaptor protein that is involved in the epidermal growth factor (EGF) pathway. The nuclear localization of GAREM1 depends on the nuclear localization sequence (NLS), which is located at the N-terminal CABIT (cysteine-containing, all in Themis) domain. Here, we identified 14-3-3ε as a GAREM-binding protein, and its binding site is closely located to the NLS. This 14-3-3 binding site was of the atypical type and independent of GAREM phosphorylation. Moreover, the binding of 14-3-3 had an effect on the nuclear localization of GAREM1. Unexpectedly, we observed that the CABIT domain had intramolecular association with the C-terminal SAM (sterile alpha motif) domain. This association might be inhibited by binding of 14-3-3 at the CABIT domain. Our results demonstrate that the mechanism underlying the nuclear localization of GAREM1 depends on its NLS in the CABIT domain, which is controlled by the binding of 14-3-3 and the C-terminal SAM domain. We suggest that the interplay between 14-3-3, SAM domain and CABIT domain might be responsible for the distribution of GAREM1 in mammalian cells.

The stability of charged Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 at elevated temperature was investigated by using thermal desorption spectrometry-mass spectrometry (TDS-MS), X-ray diffraction (XRD), and X-ray absorption fine structure (XAFS) measurements. The TDS-MS and XRD spectra indicated that the crystal structure of the delithiated Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 changed from layer to spinel, and oxygen was released at high temperature. However, the amount of oxygen released from Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 in a full-charge state was much less than that released from LiNi 0.8 Mn 0.1 Co 0.1 O 2 in a full-charge state. The XAFS spectra indicated that the high oxidation state of manganese was more stable than that of nickel and cobalt. The high stability of charged Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 at high temperature was, therefore, attributed to the high manganese content of the transition metal.

To investigate the associations between psychosocial factors and the development of chronic disabling low back pain (LBP) in Japanese workers. A 1 yr prospective cohort of the Japan Epidemiological Research of Occupation-related Back Pain (JOB) study was used. The participants were office workers, nurses, sales/marketing personnel, and manufacturing engineers. Self-administered questionnaires were distributed twice: at baseline and 1 yr after baseline. The outcome of interest was the development of chronic disabling LBP during the 1 yr follow-up period. Incidence was calculated for the participants who experienced disabling LBP during the month prior to baseline. Logistic regression was used to assess risk factors for chronic disabling LBP. Of 5,310 participants responding at baseline (response rate: 86.5%), 3,811 completed the questionnaire at follow-up. Among 171 eligible participants who experienced disabling back pain during the month prior to baseline, 29 (17.0%) developed chronic disabling LBP during the follow-up period. Multivariate logistic regression analysis implied reward to work (not feeling rewarded, OR: 3.62, 95%CI: 1.17-11.19), anxiety (anxious, OR: 2.89, 95%CI: 0.97-8.57), and daily-life satisfaction (not satisfied, ORs: 4.14, 95%CI: 1.18-14.58) were significant. Psychosocial factors are key to the development of chronic disabling LBP in Japanese workers. Psychosocial interventions may reduce the impact of LBP in the workplace.

Living organisms take in essential molecules and get rid of wastes effectively through the selective transport of materials. Especially in the digestive tract, advanced transport systems are indispensable for the absorption of nutrients and elimination of waste products. These transport pathways control physiological functions by modulating the ionic environment inside and outside the cells. Moreover, recent studies have shown the importance of the expression of trafficking-related molecules and the population of gut microbiota. We found that the molecules secreted from microorganisms are imported into the cells via transporters or endocytosis and that they activate cell survival pathways of intestinal epithelial cells. These findings indicate that the interactions between the gut microbiota and host cells are mediated, at least partly, by the membrane transport systems. In addition, it is well known that the breakdown of transport systems induces various diseases. This review highlights the significance of the transport systems as the pathogenic molecules and therapeutic targets in gastrointestinal disorders. For example, abnormal expression of the genes encoding membrane transport-related molecules is frequently involved in digestive diseases, such as colorectal cancer and inflammatory bowel disease. We herein review the significance of these molecules as pathogenic and therapeutic targets for digestive diseases.

The effect of Li3PO4 coating was investigated for LiNi0.5Mn1.5O4 epitaxial thin film electrodes synthesized on SrTiO3 substrates by pulsed laser deposition (PLD). Amorphous Li3PO4 with a thickness of 1–4 nm was coated at room temperature onto 30 nm thick epitaxial LiNi0.5Mn1.5O4 thin films with (111), (110) and (100) lattice orientations. Electrodes with the surface coating exhibit high charge–discharge capacities and small capacity degradation during cycling experiments in the high voltage region. X-ray absorption near edge structure (XANES) and hard X-ray photoelectron spectroscopy (HAXPES) analyses indicate a higher manganese valence for the electrode surface of the Li3PO4 stacked LiNi0.5Mn1.5O4 film than that for the surface of a pristine LiNi0.5Mn1.5O4 film. Thus, surface coating affects the manganese valence near the electrode surface and improves the cycling characteristics.

Cardiolipin and phosphatidic acid-binding protein (CLPABP) controls the stability of the mRNA harboring an AU-rich element (ARE) in the 3' UTR with the help of the RNA stabilizer, human antigen R (HuR). Although CLPABP is localized on the mitochondrial surface as a large protein-RNA complex, its precise role is not yet known. Recently, CLPABP was identified as an N-myristoylated protein. Here, we demonstrate the effects of N-myristoylation on the functions of CLPABP. In the present study, compared to the wild-type protein that possessed the "MG" motif at the N-terminus for N-myristoylation, the mutant CLPABP protein that lacked N-myristoylation modification site was unstable. Furthermore, the expression of the G/A mutant of CLPABP, which lacked N-myristoylation site, induced morphological alterations in mitochondria. Because pleckstrin homology domain-deleted mutant, which was fused with the N-myristoylation site derived from intact CLPABP, could not colocalize with mitochondria, N-myristoylation of CLPABP was predicted to affect its stability onto the mitochondrial membrane rather than its subcellular localization.

We have demonstrated the use of scanning internal photoemission microscopy (SIPM) to characterize crystal defects in an AlGaN/GaN heterostructure grown on Si substrates. SIPM enabled the visualization of unusually grown regions owing to cracking of the Si substrates. In these regions, photocurrent was large, which was consistent with leaky current–voltage characteristics. We also found smaller photoyield regions, which may originate from the Al-rich AlGaN regions on hillocks. We confirmed the usefulness of SIPM for investigating the inhomogeneity of crystal quality and electrical characteristics from macroscopic viewpoints.

PR interval is the period from the onset of P wave to the start of the QRS complex on electrocardiograms. A recent genomewide association study (GWAS) suggested that GAREM1 was linked to the PR interval on electrocardiograms. This study was designed to validate this correlation using additional subjects and examined the function of Garem1 in a mouse model. We analyzed the association of rs17744182, a variant in the GAREM1 locus, with the PR interval in 5646 subjects who were recruited from 2 Korean replication sets, Yangpyeong (n = 2471) and Yonsei (n = 3175), and noted a significant genomewide association by meta-analysis (P = 2.39 × 10−8). To confirm the function of Garem1 in mice, Garem1 siRNA was injected into mouse tail veins to reduce the expression of Garem1. Garem1 transcript levels declined by 53% in the atrium of the heart (P = 0.029), and Garem1-siRNA injected mice experienced a significant decrease in PR interval (43.27 ms vs. 44.89 ms in control, P = 0.007). We analyzed the expression pattern of Garem1 in the heart by immunohistology and observed specific expression of Garem1 in intracardiac ganglia. Garem1 was expressed in most neurons of the ganglion, including cholinergic and adrenergic cells. We have provided evidence that GAREM1 is involved in the PR interval of ECGs. These findings increase our understanding of the regulatory signals of heart rhythm through intracardiac ganglia of the autonomic nervous system and can be used to guide the development of a therapeutic target for heart conditions, such as atrial fibrillation.

The layered complex cathode has attracted much interest recently due to its high capacity, which exceeds 250 mAhg−1. On the other hand, it also shows large voltage hysteresis which causes energy loss when applied as a practical battery material. It has been reported that the hysteresis is an intrinsic bulk property, and the phenomenological model due to the migration of transition metal has been also proposed. Then, it is considered that to study the hysteresis for various compositions of transition metal is valuable to clarify the phenomenon. In this work, the layered complex cathode of 0.5Li2MnO3-0.5LiNi1/3Co1/3Mn1/3O2 was investigated. The results are discussed in comparison with the previous reports for 0.5Li2MnO3-0.5LiMn0.5Ni0.5O2. Investigating dQ/dV profilesrevealed that redox peaks at around 3.75 V showed small dependency on composition of transition metal, while it seemed that a reduction peak at 3.26 V was independent on the composition. Precise measurement of open circuit potential vs. capacity characteristics demonstrated that the energy dissipation during a cycle was abut 26 kJmol−1.

High-Ni-content layer-structured cathode materials for lithium-ion secondary batteries have high capacity but they suffer from poor thermal stability. We studied the mechanism responsible for their thermal stability to make them more stable. We used X-ray absorption fine structure (XAFS) spectra to clarify the changes in the oxidation states and the local structures for each transition metal in Li 0.2 Ni x Mn (1− x )/2 Co (1− x )/2 O 2 ( x = 1/3, 0.6, and 0.8) at high temperature. The X-ray absorption near edge structure (XANES) spectra indicated that the oxidation state of Ni and Co changed due to heating. Although, pre-edge of XANES spectra indicated that the occupation sites of Co ions changed from octahedral to tetrahedral, Mn ions remained in the octahedral sites at high temperature. The extended X-ray absorption fine structure (EXAFS) results supported the change in the occupation sites of Co and Mn ions due to heating. It can be concluded that Co and Mn affected thermal stability of those Ni-based cathode materials differently. The Co ions migrated from octahedral to tetrahedral sites, and they stably occupy tetrahedral sites. Hence, so the structural change from spinel to rock-salt is suppressed. The oxidation state of Mn is stable and remains unchanged in layer structure at high temperature.

Grb2-associated regulator of Erk/MAPK (GAREM), is an adaptor protein related to the several cell growth factor receptor-signaling. The GAREM family has two subtypes, GAREM1 and GAREM2, both encoded in the human and mouse genome. Recent genome-wide research identified GAREM2 as a candidate of neurodegenerative diseases. Here, we use knockout (KO) mice to show the role of GAREM2, that is highly expressed in the brain. According to the comprehensive behavioral battery, they exhibited less anxiety both in elevated plus maze and open field tests, mildly increased social approaching behavior in the reciprocal social interaction test, and longer latency to immobility in the tail suspension test as compared to wild-type (WT). Additionally, the extension of neurites in the primary cultured neurons was suppressed in ones derived from GAREM2 KO mice. Furthermore, we also identified Intersectin, as a binding partner of GAREM2 in this study. Intersectin is also a multi-domain adaptor protein that regulates endocytosis and cell signaling, which can potentially alter the subcellular localization of GAREM2. The important molecules, such as the neurotrophin receptor and Erk family, that are involved in the signaling pathway of the neural cell growth in the mouse brain, have been reported to participate in emotional behavior. As GAREM plays a role in the cellular growth factor receptor signaling pathway, GAREM2 may have a common role related to the transduction of Erk signaling in the higher brain functions.

Lithium-ion batteries (LIBs) are now used in the variety of fields including vehicles, and industrial and portable uses. Since the current LIBs use volatile and flammable electrolyte liquid, they have a risk on safety, e.g. explosion owing to an unexpected short. For ensuring the LIB safety, the cooling and safety mechanisms need to be installed in battery packs used for large scale applications, i.e. electric vehicles (EVs), and they compromise battery energy density and cost competitiveness. To overcome the issue related to the LIB safety, we recently developed a novel electrolyte having the lower vapor pressure than the conventional organic liquid electrolyte, and incorporated it into LIB. High energy density of over 300 Wh/kg and high output power of over 1,600 W/kg were successfully demonstrated. In the presention, the concept of our less volatile electrolyte, and evaluated results on performance of our highly safe, high energy density and high power LIB will be reported. This work was supported by Innovative Science and Technology Initiative for Security, ATLA, Japan.

Improving thermal stability is one of the most serious issues concerning Ni-based cathode materials for Li ion batteries. To increase the capacity for maintaining good thermal stability, we substitute Mo for Mn. We apply differential scanning calorimetry (DSC), thermal desorption spectrometry-mass spectrometry (TDS-MS), and X-ray diffraction (XRD) to elucidate the effect of Mo substitution. The application of DSC indicates that Mo substitution effectively reduces the exothermic reaction between the cathode and electrolyte. The applications of TDS-MS and XRD indicate that Mo substitution suppresses crystal structure change and reduces the oxygen release that accompanies heating below 350 °C. However, the discharge capacities of Mo-substituted samples are lower than that of sample without Mo substitution. We optimize the Li/transition metal ratio and obtain Li1.10Ni0.8Mn0.06Co0.1Mo0.04O2+δ, which satisfy both high capacity and high thermal stability requirements.

Background The precise role of microRNAs in inflammatory disease is not clear. The present study investigated the effect of microRNA (miR-146b) with respect to improving intestinal inflammation. Methods The microRNA profile in interleukin-10 deficient mice was examined using microRNA arrays and miR-146b was selected for the subsequent experiments. The expression vectors containing either the whole sequence of miR-146b or small interfering RNA for miR-146b were intraperitoneally administered to the dextran sodium sulfate (DSS)-induced colitis mouse. The expression levels of inflammation-related mediators were examined by the reverse transcriptase-polymerase chain reaction and western blotting analysis. Intestinal barrier function was evaluated by an ex vivo mannitol flux study. Results The overexpression of miR-146b activated the NF-κB pathway, improved epithelial barrier function, relieved intestinal inflammation in the DSS-induced colitis mice, and improved the survival rate of mice with lethal colitis. Furthermore, this amelioration of intestinal inflammation by miR-146b was negated by the inhibitor for the NF-κB pathway. The overexpression of miR-146b decreased the expression of siah2, which has a target sequence for miR-146b, and promoted the ubiquitination of TRAF proteins. This suggests that the up-regulation of NF-κB by miR-146b was mediated by inhibition of the ubiquitination of TRAF proteins upstream of NF-κB. Conclusions miR-146b improves intestinal inflammation by up-regulating NF-κB as a result of the decreased expression of siah2, which ubiquitinates TRAF proteins. Modulation of the miR-146b expression is a potentially useful therapy for the treatment of intestinal inflammation via activation of the NF-κB pathway. Copyright © 2013 John Wiley & Sons, Ltd.

Although SPE-39 is a binding protein to Vps33B that is one of the subunit in the mammalian HOPS complex, the elements of SPE-39 function remain unknown. Here, we show that tyrosine phosphorylation of SPE-39 following EGF stimulation plays a role in the stability of SPE-39 itself. Ubiquitination of the C-terminal region of SPE-39 was also elevated in response to EGF stimulation, and this process was regulated by the phosphorylation of Tyr-11 in SPE-39. However, association of Vps33B with SPE-39 inhibited the elevation of ubiquitination of SPE-39 following EGF stimulation, which might be responsible for the stabilization of SPE-39. Furthermore, an opposing functional relationship between SPE-39 and Vps33B on the downregulation of the EGF receptor was observed in EGF-stimulated COS-7 cells.Structured summary of protein interactionsVps33B and EGFR colocalize by fluorescence microscopy (View interaction)Vps33B and SPE-39 physically interact by anti bait coimmunoprecipitation (View interaction)Vps33B and SPE-39 physically interact by anti tag coimmunoprecipitation (View interaction)Vps33B and SPE-39 colocalize by fluorescence microscopy (View interaction)

SummaryBackground and purposeThere have been no large-scale studies on the impact of diabetes mellitus (DM) on outcomes in Japanese patients undergoing coronary artery bypass grafting (CABG).Methods and subjectsA multi-institutional retrospective cohort study was conducted in 14 Japanese centers. All adult patients who underwent isolated CABG from 2007 to 2008 were included (n=1522, mean age: 68.5years). The definitions of DM were all patients admitted with diagnosis of DM and preoperative glycated hemoglobin (Hb) A1c≥6.5%. Univariate and multivariate analyses were performed to identify the risk of morbidity and mortality.ResultsThere were 849 DM and 572 non-DM patients. Preoperative mean HbA1c were 7.1% in the DM group and 5.7% in the non-DM group (p

A 47-year-old female with a history of untreated hypertension and diabetes mellitus was referred because of a left ventricular echocardiographic mass with congestive heart failure. At the time of admission, she had already had a cardio-embolic stroke with loss of recent memory and slight paralysis of the right upper arm. It was difficult to distinguish between thrombus and tumor. However, her clinical condition required surgical resection as soon as possible. We performed cardiac CT to evaluate the coronary arteries and to scan the mass at the left ventricular apex. This CT evaluation revealed another mass at the left atrial appendage. Thus, these two masses were highly suggestive of thrombi. Subemergency surgical resection of the two masses and a part of the myocardium at the left ventricular apex was successfully performed. The pathological results showed that both the mass in the left ventricular apex and the mass in the left atrial appendage were thrombi, and the myocardial disarray confirmed the echocardiographic diagnosis as hypertrophic cardiomyopathy.

In order to develop safe lithium-ion batteries using Ni-based cathode active materials, such as LiNixMn(1−x)/2Co(1−x)/2O2, thermal stability is one of the most important requirements. We used XRD and TDS-MS in the first step of our study to elucidate the thermal stability and to improve it under anomalous high temperature conditions. We investigated the relationship between the thermal stability and cathode composition, especially for that of the nickel and lithium content. The XRD indicated that the crystal structure of electrochemically delithiated materials changed from a layered into a spinel structure followed by a rock-salt structure as the temperature rose. The TDS-MS indicated that these changes coincided with the release of oxygen from the cathode materials. We found that decreasing the lithium content and increasing the nickel content made the temperature of the crystal structure change and oxygen release lower, and thus, influenced the cathode composition.

ESCRT-I, which mediates the sorting of ubiquitinated cargo protein from the plasma membrane to the endosomal vesicle, comprises a heterotetramer of TSG101 (Vps23), Vps28, Vps37 and MVB12 protein. In humans, the structurally similar subtypes MVB12A and MVB12B are subunits of ESCRT-I. However, no functional description of these proteins has been described. Here we show the differing effects of tyrosine phosphorylation and ubiquitination of both MVB12 proteins on their respective functions. As noted in our previous study, Tyr204 phosphorylation of MVB12A in response to epidermal growth factor (EGF) stimulation affects binding to CD2AP, which regulates the amounts of EGF receptor bound to ESCRT-I. Strikingly, ubiquitination of Lys264 and Lys290 of MVB12B was induced and led to the instability and inclusion of MVB12B in COS-7 cells. These ubiquitinations increased upon EGF stimulation, which was regulated by the phosphorylations of Tyr241 and Tyr243 of MVB12B. Furthermore, MVB12A was also involved in the aggregation-prone proteins of MVB12B. These results suggest that the expression of MVB12B may be normally suppressed through the ubiquitin-proteasome pathway that simultaneously regulates the fate of MVB12A and the functions of ESCRT-I.

Enhancing battery energy density is of particular importance for distributing electric vehicles and stationary uses. For EV uses, high energy density battery allows for longer driving distance per a charge, and cycle life, while it leads to an enlarged risk on safety. Hence, it exists a trade-off relationship between energy density and safety for battery packs developed for EVs. Safety failure in the current lithium ion battery is often related to an explosion of a volatile and flammable electrolyte liquid. Once internal short takes place irregularly, joule heat generation takes place and thereby it leads to the explosion of volatile and flammable electrolyte as this called thermal runaway. In addition, fields of the battery used is limited, namely, the battery use in the enclosed space is likely to be prohibited to prevent the leakage of toxic and volatile electrolyte liquid into the space. To overcome the issues related to the battery safety, we recently developed a novel electrolyte having a lower vapor pressure electrolyte than the conventional organic liquid electrolyte, and applied the electrolyte to lithium ion battery with a high energy density. A repeated operation of the battery was successfully demonstrated. In this presentation, the concept our electrolyte, and evaluated results on electrolyte volatility and charge-discharge property of the battery will be reported.

Introduction Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. Methods and analysis The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m 2 /day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). Ethics and dissemination The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. Trial registration number UMIN000018752.

We identified a new protein containing the pleckstrin homology (PH) domain through tyrosine phosphoproteomics using epidermal growth factor-stimulated cells. The tandem PH domains of this protein can bind to mitochondria-specific phospholipid, cardiolipin or its dehydro product, phosphatidic acid; therefore, we have designated this protein as cardiolipin and phosphatidic acid-binding protein (CLPABP). In this study, we show that CLPABP is localized on the tubulin network and the mitochondrial surface in the granular form along with other proteins and RNA. The affinity of CLPABP to mitochondria is elevated depending on the extent of tyrosine phosphorylation. The CLPABP complex contains various proteins related to cytoplasmic mRNA metabolism. The unique subcellular localization of CLPABP requires its PH domains and a multifunctional protein, SF2p32, as its binding protein. The CLPABP granule also contains the cytochrome c transcript, which may be mediated by the RNA-binding protein HuR. Immunofluorescence staining reveals that the CLPABP granule is colocalized with cytochrome c and various ribosomal proteins that are present in the CLPABP complex. Therefore, the CLPABP RNA–protein complex may play a role in transporting cytochrome c mRNA and its translated product to the mitochondria.

Objective: In this retrospective study, all free-flap transfers done at the Kanagawa Dental College, Kanagawa, Japan, for reconstruction following ablation of head and neck tumours were analysed. The 5 patients who developed complications following reconstructive surgery and the course of recovery were examined. Patients and Methods: Thirty four microvascular free-flap transfer operations were performed, which included patients with cutaneous radial forearm (17; 50%), myocutaneous rectus abdominis (13; 38%), osteocutaneous scapula composite (2; 6%), osteocutaneous scapula composite with forearm chimera (1; 3%), and myocutaneous rectus abdominis with forearm chimera (1; 3%). Results: Complications were seen in the forearm (n = 2), osteocutaneous scapula composite (n = 2), and chimeric (scapula composite + forearm) [n = 1] microvascular free flaps. The facial artery showed the most complications when used as a recipient artery, presenting 2 complications in 4 inosculation cases; only 2 complications (7%) were observed for the superior thyroid artery (n = 28). The most frequently used recipient vein, the internal jugular vein (n = 27), showed 3 complications (11%). The presenting complications were first observed at 0.5, 4, 36, and 58 hours (mean ± standard deviation, 19.8 ± 26.1 hours) in the 5 patients with complication. Thrombosis was related to the cause of all complications, including bending of the anastomosis (n = 1), distorted pedicle (n = 1), oppression of the pedicle (n = 1), oppression due to coagulation in the surrounding scar (n = 1), and unknown factors (n = 1). Complete recovery was achieved in all patients. Conclusion: Early detection of complications, with diligent and meticulous postsurgical follow-up, is key to achieving complete recovery rates following free-flap transfer surgeries.

Using an organelle proteomics approach, we previously studied the rat peroxisome in order to characterize the proteins participating in its biogenesis. A peroxisome-specific isoform of Lon (pLon) protein was accordingly identified. However, the precise role of pLon in peroxisomes remains to be elucidated. Here, we demonstrate that pLon plays a role in processing and activating a specific regulatory protein belonging to the peroxisome targeting signal (PTS) 1-containing proteins. Proteomic analysis of proteins co-immunoprecipitated with Lon suggested that Lon interacts with PMP70 and several enzymes involved in beta-oxidation, including acyl-CoA oxidase (AOX). The processing of AOX for its activation in peroxisomes was strongly inhibited in cells expressing a dominant negative form of pLon. Furthermore, a catalase possessing a modified PTS1 sequence was misdistributed in this cell line. pLon exhibits little, if any, in vitro AOX processing activity, and does not process PTS2-containing 3-ketoacyl-coenzyme A thiolase (PTL). Therefore, pLon may specifically control, sort and process PTS1 proteins. Based on the relationship between pLon and the beta-oxidation enzymes that regulate peroxisomal morphology, the observation of enlarged peroxisomes in cells expressing recombinant pLon suggests that pLon is a critical factor determining peroxisome morphology.

Extranodal NK/T cell lymphoma, nasal type, rarely arises in the oral cavity. We report the case of a 52-year-old man in whom the lesion originated in the left lower gingiva. The patient had slight pain and swelling at the left lower third molar region. Under a diagnosis of pericoronitis, the left lower third molar was extracted at a dental clinic. Because of a poor postoperative course, he was referred to our clinic. Intraoral examination revealed an ulcer and necrotic mucosa around the socket of the extracted third molar. CT scanning showed no bone resorption in the region around the extraction socket. Although the clinical findings suggested necrotizing ulcerative gingivitis, a biopsy revealed accumulation of atypical lymphocytes around the blood vessels. The biopsy specimen was positive for cytoplasmic CD3e, Epstein-Barr virus encoded small RNA 1 in situ hybridization (EBER 1/ISH), and granzyme B, and negative for CD56 and CD20. Genetic screening of the frozen specimen was negative for T cell receptor gene rearrangement (TCR). On the basis of these findings, a definite diagnosis of extranodal NK/Tcell lymphoma, nasal type, was confirmed. The patient was treated with 50 Gy of radiation and 3 courses of DeVIC (CBDCA, VP-16, IFO, DEX) chemotherapy. His general condition remarkably improved, and there were no signs of recurrence after treatment. Because of the poor prognosis for patients with this type of tumor, prompt diagnosis and treatment are very important.

Structure changes of LiNi 0.5 Mn 0.5 O 2 were detected at the electrode/electrolyte interface of lithium cell using synchrotron X-ray scattering and two-dimensional model electrodes. The electrodes were constructed by an epitaxial film of LiNi 0.5 Mn 0.5 O 2 synthesized by pulsed laser deposition (PLD) method. The orientation of the film depends on the substrate plane; the 2D layer of LiNi 0.5 Mn 0.5 O 2 is parallel to the SrTiO 3 (1 1 0) substrate ((1 1 0) LiNi 0.5 Mn 0.5 O 2 //(1 1 0) SrTiO 3 ), while the 2D layer is perpendicular to the SrTiO 3 (1 1 1) substrate ((0 0 3) LiNi 0.5 Mn 0.5 O 2 //(1 1 1) SrTiO 3 ). The in situ X-ray diffraction of LiNi 0.5 Mn 0.5 O 2 (0 0 3) confirmed three-dimensional lithium diffusion through the two-dimensional transition meal layers. The intercalation reaction of LiNi 0.5 Mn 0.5 O 2 will be discussed.

The CLOCK-interacting protein, Circadian (CIPC), has been identified as an additional negative-feedback regulator of the circadian clock. However, recent study on CIPC knockout mice has shown that CIPC is not critically required for basic circadian clock function, suggesting other unknown biological roles for CIPC. In this study, we focused on the cell cycle dependent nuclear-cytoplasmic shuttling function of CIPC and on identifying its binding proteins. Lys186 and 187 were identified as the essential amino acid residues within the nuclear localization signal (NLS) of CIPC. We identified CIPC-binding proteins such as the multifunctional enzyme CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase), which is a key enzyme for de novo pyrimidine synthesis. Compared to control cells, HEK293 cells overexpressing wild-type CIPC showed suppressed cell proliferation and retardation of cell cycle. We also found that PMA-induced Erk activation was inhibited with expression of wild-type CIPC. In contrast, the NLS mutant of CIPC, which reduced the ability of CIPC to translocate into the nucleus, did not exhibit these biological effects. Since CAD and Erk have significant roles in cell proliferation and cell cycle, CIPC may work as a cell cycle regulator by interacting with these binding proteins.

Probiotics exhibit beneficial functions for host homeostasis maintenance. We herein investigated the mechanism by which Lactobacillus brevis-derived poly P exhibited a beneficial function. Immunostaining indicated that poly P was captured in the plasma membrane via integrin β1 in Caco2/bbe cells. The uptake of poly P was reduced by the inhibition of integrin β1 as well as caveolin-1, a major component of lipid rafts. The function of poly P, including the induction of HSP27 and enhancement of the intestinal barrier function, was suppressed by the inhibition of caveolin-1, illustrating that the function of poly P was mediated by the endocytic pathway. High-throughput sequencing revealed that poly P induced tumor necrosis factor alpha-induced protein 3, which contributes to cytoprotection, including upregulation of the intestinal barrier function. The present study demonstrates a novel host-probiotic interaction through the uptake of bacterial substance into host cells, which is distinct from pattern recognition receptor pathways.

Background The role of hnRNP A1 in the onset of intestinal inflammation remains unclear. This study investigated the function of hnRNP A1 in mice enteritis models. Methods C57Bl6/J mice were intraperitoneally injected with anti-CD3 antibodies to develop enteritis. In the DSS-induced colitis group, the mice were allowed free access to 3% DSS solution in their drinking water for 5 days. 3H-mannitol flux and complementary DNA array tests were used to assess the intestinal barrier function and messenger RNA (mRNA) expression, respectively. Real-time PCR was performed after immunoprecipitation with anti-hnRNP antibodies to determine the specific mRNA binding of hnRNP A1. Results The hnRNP A1 expression was increased in the intestine of the mouse at 24 hours after treatment with anti-CD3 antibodies and 5 days after starting DSS administration. Small interfering RNA (siRNA) against hnRNP A1 exacerbated the intestinal injuries in both models. According to the microarray analysis, trefoil factor 2 (TFF2) was identified as a candidate molecule targeted by hnRNP A1 in the anti-CD3 antibody-induced enteritis group. Moreover, the binding between hnRNP A1 and TFF2 mRNA significantly increased in the enteritis mice, and the administration of siRNA against either hnRNP A1 or TFF2 exacerbated the degree of intestinal injury. In the DSS-induced colitis group, treatment with the siRNA of hnRNP A1 worsened the intestinal injury, while the expression of TFF3 did not change. Conclusions hnRNP A1 improves intestinal injury in anti-CD3 antibody-induced enteritis mice through the upregulation of TFF2, which regulates apoptosis and enhances epithelial restoration, whereas this molecule ameliorates DSS-induced colitis through a different pathway.

The ligand-mediated down-regulation of the growth factor receptors is preceded by the involvement of various other factors. In particular, a ubiquitin ligase, Cbl, plays a central role in this event. Several candidates that have potential effects on the negative control of the epidermal growth factor (EGF) receptor have now been identified by our recent studies in phospho-proteomics. Among these molecules, we focus on characterizing a novel protein, Ymer, which is a tyrosine-phosphorylated and ubiquitinated protein. Ymer is found to be phosphorylated at tyrosine 145 and 146 upon EGF stimulation, and lysine 129 of Ymer has been identified as a ubiquitination site. Ymer has two motifs interacting with the ubiquitin (MIU) domains that might function as a binding site for the ubiquitinated EGF receptor. Although Ymer and EGF receptors are associated in an EGF-dependent manner, their interaction is required not only for MIU domains but also for the tyrosine phosphorylation of Ymer. Phosphorylated Ymer is mainly located at the plasma membrane with EGF receptor and functions in its endocytosis and degradation. Furthermore, EGF-mediated secondary modifications of an activated-EGF receptor are inhibited by overexpressing Ymer in COS7 cells. Therefore, Ymer may have competitive effects on the activation of the EGF receptor. Our findings suggest that Ymer functions as a novel inhibitor for the down-regulation of the EGF receptor and plays a crucial role for regulating the amount of the EGF receptor on the cell surface membrane.

HCC2998 is a highly differentiated human colon carcinoma cell line, which has been shown to be converted to a poorly differentiated one after expression of a constitutively active phosphatidylinositol 3-kinase (PI3' kinase). These cells express aberrant sizes of a regulatory subunit of PI3' kinase, p85alpha, with molecular weights of 50 and 76 kDa at a very low level. To elucidate how these cells express these proteins, we analyzed mutations within the p85alpha gene. DNA sequencing analysis revealed that these mutant proteins were generated by independent point mutations in the two alleles of the p85alpha gene: one in the coding sequence, and the other in the acceptor sequence for splicing. Introduction of wild-type p85alpha into HCC2998 cells induced slight rounding of the cells and enhancement of mucin secretion. At the same time, a membrane receptor, ErbB3, was phosphorylated on tyrosine, which in turn, binds to PI3' kinase. Since ErbB3 is upstream of PI3' kinase, it is likely that there is an autocrine loop in which PI3' kinase is activated by ErbB3, which may contribute to dedifferentiation of the cells.

At Jichi Medical School Hospital, three types of mechanical prosthetic valves (CarboMedics, Omnicarbon, Bicarbon) were used without randomization from 1991 to 2000. A retrospective study of valve replacements done between June 1991 and November 2000 utilizing 180 CarboMedics valves in 145 patients who had not previously undergone prosthetic valve replacement or aortic root and/or arch replacement was conducted to evaluate midterm patient outcomes to assess the future continuous use of CarboMedics valves. Women made up 47.6% of the patients and the mean age was 57.5 years (range 12-80 years). Preoperative New York Heart Association functional class was III or IV in 92.4% (134/145) of patients. Mean follow-up of 4.5 years (range 0-10.0 years) was 95.9% complete, with a total of 628 patient-years (PY). Early (within 30 postoperative days) mortality was 5.5% (8 of 145): 3 from hemorrhage, 3 from nonvalve-related heart failure, 1 from infection, and 1 from arrhythmia. There were 16 late deaths (2.54%/PY): 1 from hemorrhage, 4 from unknown causes/sudden death, 4 from nonvalve-related heart failure, and 7 from other noncardiac causes. A total of 121 patients (83.0%) were alive at the last follow-up, done in November 2000. The linearized death rate was 3.82%/year (including 1.11%/year for valve-related deaths). Linearized death rates from various causes were: bleeding, 0.96%/year; thromboembolism, 1.11%/year; thrombosis, 0.39%/year; perivalvular leak, 0.96%/year; endocarditis, 0%/year; hemolysis, 0%/year; and reoperation, 0.63%/year. No structural valve failure was observed. Comparative early mortality rates of valve replacement without aortic root replacement or arch replacement, excluding repeat valve replacement operations, in our institute, were 3.5% (12/307) for all valve types used contemporaneously, 2.6% (2/76) for Omnicarbon valves, and 2.3% (2/86) for Bicarbon valves. Although the CarboMedics valve had a rather high mortality rate of 5.5% (8/145) compared with the total early mortality rate of 3.5%, the low incidence of valve-related complications might support the continued use of the CarboMedics valve for valve replacement.

This study was designed to evaluate the long-term clinical results of the Omniscience tilting disc valve. Omniscience valves were implanted in 51 patients (mean age, 50 +/- 10 years); 18 had aortic valve, 24 had mitral valve, and 9 had both aortic and mitral valve replacements. Oral warfarin potassium and dipyridamole were prescribed as our anticoagulant therapy. Preoperatively, 42 patients were in New York Heart Association class III or IV, and 23 of 25 surviving patients were in class I or II after operation. There were 2 (3.9%) early deaths and 23 late deaths (3.5 +/- 0.7% per patient-year). Cardiac related mortality including congestive heart failure, sudden death, and thromboembolism, and hemorrhagic complications were seen in 16 patients. Overall survival at 10, 15, and 20 years was 77 +/- 6%, 62 +/- 7%, and 46 +/- 7%, respectively. Thromboembolic complications were seen in 5 patients, for a rate of 0.8 +/- 0.3% per patient-year; similarly, hemorrhagic complications were also seen in 5 patients. Nonstructural prosthetic valve dysfunction was seen in 4 patients, for a rate of 0.6 +/- 0.3% per patient-year, and sudden death was seen in 2, a rate of 0.3 +/- 0.2% per patient-year. The Omniscience prosthesis demonstrated excellent postoperative clinical status with low rates of valve related complications.

Dialysis-related spondyloarthropathy (DRS) is a severe complication of long-term hemodialysis that ultimately leads to functional disability of the upper and lower extremities. Although the cause of this disease is still unknown, it is thought that amyloid deposits are involved. beta2-Microglobulin (beta2M) is a major component of amyloid fibrils, some of which are modified with the advanced glycation end-product (AGE). To clarify the pathophysiology of DRS we histologically examined the ligamentum flavum of the cervical spine in 15 patients with DRS. The mean duration of hemodialysis was 20 years (12-27 years). In addition to the congo red stain for amyloid, beta2M and AGE were detected by immunohistochemical methods. Macrophages were stained with CD68 antibody. Amyloid deposits were found in tissues, although the extent of the stained area differed among the patients. Part of the amyloid deposit area was positively immunostained for beta2M and AGE. In 10 cases macrophages positive for CD68 infiltrated around the amyloid deposits. Comparing these histological findings with the dialysis duration, more positive staining areas for beta2M and AGE were found in the tissue from patients with long-term dialysis. These findings suggest that both beta2M and AGE play roles in the pathogenesis of DRS.

Signet-ring cell carcinoma is classified in poorly differentiated adenocarcinoma with an aggressive nature and a poor prognosis. We have shown that the activation of PI 3-kinase in highly differentiated adenocarcinomas induces loss of cell-cell contact and formation of vacuoles, giving phenotypes similar to those of signet-ring cell lines. SB203580, a potent p38 MAP kinase inhibitor, blocked this transition, and expression of an active form of MKK6 (MKK6DA), an activator of p38 MAP kinase, gave effects similar to those induced by expression of the active form of PI 3-kinase (BD110), although formation of large vacuoles was not induced. Activation of MKK3, another activator of p38 MAP kinase, was activated in native signet-ring carcinoma cell lines. Anchorage-independent growth of signet-ring cell lines was inhibited by LY294002 or SB203580. These results suggest that p38 MAP kinase is functioning downstream of PI 3-kinase in signaling of the malignant phenotype. Secretion of mucins was enhanced in BD110-expressing cells, but not in MKK6DA-expressing cells, suggesting that secretion of mucins is independent of the MKK6-p38 MAP kinase cascade. Thus, there may be at least two pathways, p38 MAP kinase-dependent and -independent, which are involved in regulation of cell-cell contact and the protein secretion system, respectively.

We analyzed midterm results using the Bicarbon valve in a single center. Forty-four patients had aortic valve replacement (AVR), 48 had mitral valve replacement (MVR), and 13 had both aortic and mitral valve replacement (DVR). The mean age of the 105 patients was 61.2 +/- 11.3 years. The mean follow-up was 1.8 +/- 1.1 years with a cumulative follow-up of 188 patient-years. There were 5 early deaths (4.7%: 4 in the AVR group and 1 in the MVR group) and 5 late deaths (2.7% per patient-year: 3 malignancy, 1 cerebral hemorrhage, 1 myocardial infarction). Survival at 3 years was 91 +/- 4% in the AVR group, 92 +/- 5% in the MVR group, and 66 +/- 23% in the DVR group. The linearized incidence of thromboembolic complications, hemorrhagic complications, and paravalvular leaks in all patients was 1.06 +/- 2.34%, 1.60 +/- 2.53%, and 0.53 +/- 2.22% per patient-year, respectively. No other complications were observed. In conclusion, the Bicarbon prosthetic heart valve has shown excellent clinical results associated with a low incidence of valve-related complications.

We discuss the usefulness of the Cosgrove-Edwards ring from our early clinical results from 25 rings in 24 patients who underwent mitral annuloplasty (MAP) or tricuspid annuloplasty (TAP) between June 1999 and December 2000. In the MAP group, the posterior mitral annulus between the anterior and posterior fibrous trigones was reinforced with the prosthetic ring. In the TAP group, the annuli of the anterior and posterior leaflets were splinted with the ring. The prosthetic ring was attached by pledgeted U-sutures. Cardiologists performed echocardiography pre- and postoperatively. Thirteen of the 14 in the MAP group showed mitral valve regurgitation of grade 0 or I. Six of the 11 in the TAP group showed tricuspid regurgitation of grade 0 or I, and 5 patients with regurgitation equal to or greater than grade II who remained in atrial fibrillation postoperatively recovered without further clinical symptoms. No patient has required reoperation during a follow-up period of up to 2 years. Cosgrove-Edwards ring-related complications, such as valve stenosis, ring detachment, and arrhythmia, have been not recognized in these patients. In conclusion, for mitral and tricuspid annuloplasty, the Cosgrove-Edwards prosthetic ring showed excellent early clinical results, particularly in patients maintained in sinus rhythm.

This study has been carried out on solidification of a model cream using palm oil as a sole fat source. It was found that the addition of 1-palmitoylglycerol to palm oil promoted the solidification of the model cream while the addition of 1-oleoylglycerol had no such effect. Solid fat content of palm oil in the cream with 1-palmitoylglycerol was found to be lower than those of palm oil and palm oil with 1-oleoylglycerol after cooling from 60 to 5 °C. Crystallization behaviors of bulk palm oil and mixture of 1,3-dipalmitoyl-2-oleoyl-glycerol (POP) and 1-palmitoyl-2,3-dioleoyl-glycerol (POO) were then studied in the presence of monoacylglycerols. Formation of granular crystals was observed for palm oil and POP/POO mixture in the presence of 1-palmitoylglycerol. HPLC of the granular crystals revealed that agglomeration of higher melting point triacylglycerols (TAGs) around 1-palmitolyglycerol took place, which promoted the formation of granular crystals. It was suggested that the agglomeration of higher melting point TAGs around 1 -palmitoylglycerol which was preferentially adsorbed at the oil-water interface of oil droplets in the model cream led to destabilization of oil-in-water emulsion and the solidification of the model cream. At the same time, it was suggested that the fatty acid moiety of emulsifiers played an important role in the agglomeration of TAGs and stabilization of o/w emulsions. La creme fouettee est un exemple d'emulsion huile dans l'eau. Dans cette etude, une creme modelisee en utilisant de l'huile de palme comme source de matiere grasse est produite avec des monoacylglycerols comme additifs. La solification de la preparation est observee en presence de 1-palmitoylglycerol. Le comportement de cristallisation de l'huile de palme et d'un melange de 1-dipalmitoyl-2-oleoyl-glycerol et de 2,3-dioleoyl-glycerol est etudie en presence de monoacylglycerols pour determiner les mecanismes de solidification de la creme.

Microendosopic discectomy (MED) is a minimally-invasive operative therapy for lumbar disc herniation. The purpose of this study is to review our clinical results and the problems of MED. We have obtained good cosmetic results by this method and reduced pain in early postoperative days. Patients are usually very satisfied with the results of MED because it dose not cause severe complications in short and mid-clinical term. However there is still room for improving our skills and the MED system to expand indications and obtain a good field of vision. Despite certain limits of indications, it way be possible to switch the operative method safely for lumbar disc herniation from conventional LOVE method to MED in certain cases.

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/), Ferrichrome is known to be a siderophore, but it was recently identified as a tumor-suppressive molecule derived from Lactobacillus casei ATCC334 ( L. casei). In the present study, we investigated the effects of ferrichrome in gastric cancer cells. Cell lines and xenograft models treated with ferrichrome demonstrated growth suppression. The expression levels of cleaved poly (adenosine diphosphate-ribose) polymerase, and cleaved caspase-9 were increased by ferrichrome treatment. Although the tumor-suppressive effects of ferrichrome were almost completely diminished by the iron chelation, the reduction in the intracellular iron by ferrichrome did not correlate with its tumor-suppressive effects. An exhaustive docking simulation indicated that iron-free ferrichrome can make stable conformations with various mammalian molecules, including transporters and receptors. In conclusion, probiotic-derived ferrichrome induced apoptosis in gastric cancer cells. The iron binding site of ferrichrome is the structure responsible for its tumor suppressive function.