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The adaptor protein GAREM has two subtypes. Each is involved in Erk activation signaling downstream of the cell growth factor receptor in cultured cells. Regarding their role in individual animals, we have previously reported that mice deficient in GAREM2, which is highly expressed in the brain, exhibit emotional changes. In this paper, we report an amino acid substitution mutation (K291R) in GAREM1, in a patient with idiopathic short stature, which indicates that the mutant exhibits dominant-negative properties. The GAREM K291R mutant did not promote Erk activation in EGF-stimulated cultured cells. Similar features were also observed in cells in which GAREM1 expression was suppressed by genome editing; along with Erk, phosphorylation of S6 kinase and 4EBP1, whose activation is necessary for cell proliferation and biological growth, were inhibited Furthermore, we generated mice deficient in GAREM1 and showed that the mutant mice are lighter in weight. Overall, the results of this paper suggest that GAREM1 is required for normal growth and for maintaing average body size in humans and mice.

Mutations in GNAS drive pancreatic tumorigenesis and frequently occur in intraductal papillary mucinous neoplasm (IPMN); however, their value as a therapeutic target is yet to be determined. This study aimed at evaluating the involvement of mutant GNAS in tumor aggressiveness in established pancreatic cancer.CRISPR/Cas9-mediated GNAS R201H silencing was performed using human primary IPMN-associated pancreatic cancer cells. The role of oncogenic GNAS in tumor maintenance was evaluated by conducting cell culture and xenograft experiments, and western blotting and transcriptome analyses were performed to uncover GNAS-driven signatures.Xenografts of GNAS wild-type cells were characterized by a higher Ki-67 labeling index relative to GNAS-mutant cells. Phenotypic alterations in the GNAS wild-type tumors resulted in a significant reduction in mucin production accompanied by solid with massive stromal components. Transcriptional profiling suggested an apparent conflict of mutant GNAS with KRAS signaling. A significantly higher Notch intercellular domain (NICD) was observed in the nuclear fraction of GNAS wild-type cells. Meanwhile, inhibition of protein kinase A (PKA) induced NICD in GNAS-mutant IPMN cells, suggesting that NOTCH signaling is negatively regulated by the GNAS-PKA pathway. GNAS wild-type cells were characterized by a significant invasive property relative to GNAS-mutant cells, which was mediated through the NOTCH regulatory pathway.Oncogenic GNAS induces mucin production, not only via MUC2 but also via MUC5AC/B, which may enlarge cystic lesions in the pancreas. The mutation may also limit tumor aggressiveness by attenuating NOTCH signaling; therefore, such tumor-suppressing effects must be considered when therapeutically inhibiting the GNAS pathway.

Cellular compartmentalization plays an essential role in organizing the complex and multiple biochemical reactions in the cell. An artificial compartment would provide powerful strategies to develop new biochemical tools for material production and diagnosis, but it is still a great challenge to synthesize the compartments that encapsulate materials of interest while controlling their accurate locations, numbers, and stoichiometry. In this study, we evaluated chemical characteristics of a liposome-encapsulated compartment, which has great potential to locate various materials of interest with precise control of their locations and numbers in the compartment. A nanoliposome was constructed inside a ring-shaped DNA origami skeleton according to the method of Yang et al., and further equipped with a double-stranded DNA platform to assemble molecules of interest in the nanoliposome. Upon formation of the nanoliposome, a pH-sensitive fluorophore on the bridged platform showed little or no response to the pH change of the outer buffer, ensuring that the molecules assembled on the platform are effectively shielded from the outer environment. The ring-shaped DNA skeleton equipped with a double-stranded DNA platform allows spatial assembly of several functional molecules inside the nanoliposome to isolate them from the outer environment.

Hepatocellular carcinoma (HCC) activates platelets through the action of adjacent sinusoidal cells. Activated platelets bind to tumor-associated endothelial cells and release growth factors that promote tumor progression. We hypothesized that platelets encapsulated with tumor inhibitors would function as drug carriers for tumor therapy. We propose a therapeutic strategy for HCC using autologous platelets encapsulating multiple tyrosine kinase inhibitors in a rat chemically induced HCC model. Sorafenib or lenvatinib was encapsulated in platelets isolated from tumor-bearing rats in vitro. The rats were divided into groups that received repeated intravenous injections (twice a week for 10 weeks) of the following materials: placebo, sorafenib (SOR), lenvatinib (LEN), autologous platelets, autologous platelets encapsulating sorafenib (SOR-PLT) and autologous platelets encapsulating lenvatinib (LEN-PLT). The therapeutic effect was then analyzed by ultrasonography (US) and histopathological analysis. Histopathological and US analysis demonstrated extensive tumor necrosis in the tumor tissue of SOR-PLT or LEN-PLT, but not in other experimental groups. By liquid chromatography-mass spectrometry, more abundant sorafenib was detected in tumor tissues after SOR-PLT administration than in surrounding normal tissues, but no such difference in sorafenib level was observed with SOR administration. Therefore, the use of autologous platelets encapsulating drugs might be a novel therapeutic strategy for HCC.

An attempt to use combination therapy with anti-tumor necrosis factor α (TNFα) antibodies and tacrolimus (TAC) has been tried to induce remission in ulcerative colitis (UC). However, the optimal dose of TAC in combination therapy with anti-TNFα antibodies (TAC + anti-TNFα therapy) remains unclear. We examined the efficacy of various doses of TAC + anti-TNFα therapy in a mouse colitis model. Dextran sulfate sodium induced colitis model mice were divided into an anti-TNFα antibody monotherapy group and the groups that received various doses of TAC + anti-TNFα therapy. The nuclear factor expression of activated T-cells, cytoplasmic 1 (NFATc1) in the nuclei and the mRNA expression of inflammatory cytokines were assessed by immunohistochemistry and RT-PCR, respectively. The serum anti-TNFα antibody concentration was measured with an enzyme-linked immunosorbent assay. The colon length and histological severity were significantly improved in the groups that received any dose of TAC + anti-TNFα therapy. The nuclear expression of NFATc1 was inversely proportional to the administered doses of TAC. The expression levels of inflammatory cytokines tended to decrease in proportion to the dose of TAC. The serum concentration of anti-TNFα antibodies in the high-dose TAC + anti-TNFα therapy was significantly higher than those in the other groups. Low-dose TAC exerted its immunosuppressive effect on T-cells, and additionally, high-dose TAC maintained the serum anti-TNFα antibody concentration. When administered in combination with anti-TNFα antibodies, the dose of TAC should be adjusted according to the disease severity.

Background In mammals, there are two subtypes of Grb2-associated regulator of Erk/MAPK (GAREM), an adaptor protein that functions downstream of the cell growth factor receptor. GAREM1 is ubiquitously expressed, whereas GAREM2 is mainly expressed in the brain. However, the precise mechanism of the translocation of each GAREM subtype in growth factor-stimulated cells is still unclear. Methods In this study, immunofluorescence staining with specific antibodies against each GAREM subtype and time-lapse analysis using GFP fusion proteins were used to analyze the subcellular localization of each GAREM subtype in a cell growth stimulus-dependent manner. We also biochemically analyzed the correlation between its subcellular localization and tyrosine phosphorylation of GAREM2. Results We found that endogenously and exogenously expressed GAREM2 specifically aggregated and formed granules in NGF-stimulated PC-12 cells and in EGF-stimulated COS-7 cells. Based on the observed subcellular localizations of chimeric GAREM1 and GAREM2 proteins, a glycine-rich region, which is present only in GAREM2, is required for the observed granule formation. This region also regulates the degree of EGF-stimulation-dependent tyrosine phosphorylation of GAREM2. Conclusions Our results, showing that aggregation of GAREM2 in response to EGF stimulation is dependent on a glycine-rich region, suggest that GAREM2 aggregation may be involved in neurodegenerative diseases.

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in regulating cell growth, survival, and metastasis. STAT3 signaling is constitutively activated in various types of hematologic or solid malignancies. YHO-1701 has been developed as an orally available STAT3 inhibitor. Herein, YHO-1701 in combination with molecular-targeted agents was evaluated. Additive or synergistic effects were observed in a broad spectrum of “combination treatment + cell line” pairs. Of particular interest was the synergistic effect observed when YHO-1701 was combined with imatinib or dasatinib [breakpoint cluster region-abelson (BCR-ABL) inhibitors], osimertinib [epidermal growth factor receptor (EGFR) inhibitor], crizotinib, alectinib, or ceritinib [anaplastic lymphoma kinase (ALK) inhibitors]. The results further showed a close relationship between these synergistic effects and the cellular levels of the key molecules involved in the target pathways for YHO-1701 and each combination drug. The combination of YHO-1701 with alectinib resulted in a significantly greater antitumor activity without exhibiting body weight loss in an NCI-H2228 [echinoderm microtubule–associated protein-like 4 (EML4)-ALK fusion] xenograft mouse model. Our results strongly suggest that the logical strategy in combination with the novel STAT3 inhibitor YHO-1701 and other mechanistically different targeted agents could be a promising approach in the clinical setting.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of cancer found in children. Although the overall survival rates are now >80%, 15%-20% of pediatric patients relapse, with survival rates subsequently dropping to 5%-10%. Cmpd10357, 3-amino-5-arylamino-6-chloro-N- (diaminomethylene) pyrazine-2-carboximide, is a highly potent, cell-permeant compound recently shown to have cytotoxic effects on solid tumors, including human breast cancer and high-grade gliomas, independent of their proliferative status. Cmpd10357 demonstrated concentration-dependent cytotoxicity in two human B-ALL cell lines, JM1 and Reh, at half-maximal inhibitory concentrations (IC50) of 3.2 and 3.3 μM, respectively. Cmpd10357, at a dose of 5 mg/kg, significantly prolonged survival in our B-ALL xenograft mouse model, with a median survival time of 49.0 days compared with 45.5 days in the control group (p < 0.05). The cytotoxicity of Cmpd10357 demonstrated caspase-independent, nonapoptotic cancer cell demise associated with the nuclear translocation of apoptosis-inducing factor (AIF). The cytotoxicity of Cmpd10357 in B-ALL cells was inhibited by Necrostatin-1 but not by Necrosulfonamide. These studies suggest that an AIF-mediated, caspase-independent necrosis mechanism of Cmpd10357 in B-ALL could be used in combination with traditional apoptotic chemotherapeutic agents.

We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear. We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse. Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected. The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group. Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.

Background Hypothermia triggers coagulation, which can lead to the development of a life-threatening condition. We previously reported that hypothermia induces platelet activation in the spleen, resulting in microthrombosis after rewarming. However, the changes in whole blood clotting properties that occur remain unclear. Using thromboelastography, we investigated blood clotting activity and the effects of rewarming in a murine model of hypothermia. Methods C57Bl/6 mice were exposed to an ambient temperature of −20 °C under general anesthesia until their rectal temperature decreased to 15 °C. One group of mice was kept at 4 °C for 2 h and then euthanized. Another group was rewarmed, kept in normal conditions for 24 h, and then euthanized. Tissue and citrated whole blood samples were obtained from the mice for histopathological analysis, flow cytometry, and thromboelastography. Results Hypothermia induced the activation of platelets in the spleen; however, rewarming significantly reduced the number of activated platelets in the spleen while their numbers significantly increased in peripheral blood. In hypothermic mice not subjected to rewarming, no increase in activated platelets was observed in peripheral blood. Thromboelastography analysis showed that whole blood samples from the rewarmed mice displayed an enhanced clotting strength. Conclusions Rewarming from hypothermia enhances whole blood coagulation activity accompanied by an increase in the number of active platelets in peripheral blood. This phenomenon may lead to formation of microthrombi and thrombotic disorders.

Three-dimensional (3D) representation of a tumor with respect to its size, shape, location, and boundaries is still a challenge in photoacoustic (PA) imaging using artificial contrast agents as probes. We carried out PA imaging of tumors in mice using 800RS-PMPC, which was obtained by coupling of 800RS, a near-infrared cyanine dye, with PMPC, a highly selective tumor-targeting methacrylate polymer having phosphorylcholine side chains, as a probe. The conjugate 800RS-PMPC forms compact nanoparticles (dDLS = 14.3 nm), retains the biocompatibility of the parent polymer (PMPC) and exhibits unprecedented PA performance. When applied to mice bearing a 6 × 3 × 3 mm3 tumor buried 6 mm beneath the skin, the probe 800RS-PMPC selectively accumulates in the tumor and emits PA signals that are strong enough to be unambiguously distinguished from noise signals of endogenous blood/hemoglobin. The PA image thus obtained under high-threshold conditions allows 3D characterization of the tumor in terms of its size, shape, location, and boundaries.

Pancreatic cancer is associated with a poor prognosis due to challenges in early detection, severe progression of the primary tumor, metastatic lesions, and resistance to antitumor agents. However, previous studies have indicated a relationship between the microbiome and pancreatic cancer outcomes. Our previous study demonstrated that ferrichrome derived from Lactobacillus casei, a probiotic bacteria, exhibited tumor‑suppressive effects in colorectal and gastric cancer, and that the suppressive effects were stronger than conventional antitumor agents, such as 5‑fluorouracil (5‑FU) and cisplatin, suggesting that certain probiotics exert antitumorigenic effects. However, whether or not probiotic‑derived molecules, including ferrichrome, exert a tumor‑suppressive effect in other gastrointestinal tumors, such as pancreatic cancer, remains unclear. In the present study, it was demonstrated that probiotic‑derived ferrichrome inhibited the growth of pancreatic cancer cells, and its tumor‑suppressive effects were further revealed in 5‑FU‑resistant pancreatic cancer cells in vitro and in vivo in a mouse xenograft model. Ferrichrome inhibited the progression of cancer cells via dysregulation of the cell cycle by activating p53. DNA fragmentation and cleavage of poly (ADP‑ribose) polymerase were induced by ferrichrome treatment, suggesting that ferrichrome induced apoptosis in pancreatic cancer cells. A transcriptome analysis revealed that the expression p53‑associated mRNAs was significantly altered by ferrichrome treatment. Thus, the tumor‑suppressive effects of probiotics may mediated by probiotic‑derived molecules, such as ferrichrome, which may have applications as an antitumor drug, even in refractory and 5‑FU‑resistant pancreatic cancer.

RNA regulation mediating RNA-binding proteins (RBPs) have been shown to be related to the maintenance of homeostasis as well as cancer progression. However, the tumor-associated functions as well as the detailed mechanisms underlying the anti-tumor effects of most RBPs have yet to be explored. We herein report that the phosphorylated heterogeneous ribonucleoprotein (hnRNP) A0 promotes mitosis through the RAS-associated protein 3 GTPase-activating protein catalytic subunit 1 (RAB3GAP1)-Zeste white 10 interactor (ZWINT1) cascade. The downregulation assay of 20 representative hnRNPs, a major family of RNA-binding proteins, in colorectal cancer cells revealed that hnRNPA0 is a strong regulator of cancer cell growth. The tumor promotive function of hnRNPA0 was confirmed in gastrointestinal cancer cells, including pancreatic, esophageal, and gastric cancer cells, but not in non-cancerous cells. Flow cytometry and Western blotting analyses revealed that hnRNPA0 inhibited the apoptosis through the maintenance of G2/M phase promotion in colorectal cancer cells. A comprehensive analysis of mRNAs regulated by hnRNP A0 and immunostaining revealed that mitotic events were regulated by the hnRNPA0-RAB3GAP1 mRNA-mediated ZWINT-1 stabilization in colorectal cancer cells, but not in non-tumorous cells. The interaction of hnRNP A0 with mRNAs was dramatically changed by the deactivation of its phosphorylation site in cancer cells, but not in non-tumorous cells. Therefore, the tumor-specific biological functions characterized by the abnormal phosphorylation of RBPs are considered to be an attractive target for tumor treatment.

Introduction When surgery is performed for osteoporotic vertebral fractures, the extent to which kyphosis can be corrected by the intraoperative position of the body is often determined by preoperative radiography in the extension position. However, patients have difficulty adopting an adequate extension position due to the pain associated with their vertebral fracture. We place a pillow beneath the fractured vertebral body before surgery and take radiographs in the supine position to evaluate the extent to which the kyphosis can be corrected. This study aimed to examine the usefulness of this imaging method by comparing postoperative radiographs with preoperative radiographs taken with a pillow placed beneath the fractured vertebral body. Methods Lateral preoperative radiographs were taken of the patients in seated flexion and extension positions and the supine position. Lateral radiographs (rollback) were also taken 5 min after placing a firm pillow 20 cm in diameter beneath the fractured vertebral body. The kyphotic angle was compared between preoperative lateral radiographs of patients in the flexion, extension, and supine positions, rollback, and postoperative lateral radiographs in the supine position. Results The mean kyphotic angle was 33.3° in the flexion position, 28.3° in the extension position, 14.8° in the supine position, and 5.6° in rollback preoperatively and 6.4° postoperatively. The preoperative kyphotic angle differed from the postoperative kyphotic angle by ≥11° in 91% and 83% of participants in the flexion and extension positions, respectively; the difference was ≤ 5° in 30% and 61% of participants in the supine position and rollback, respectively. Differences in the postoperative angle were small in the order of rollback, supine position, extension position, and flexion position. Conclusions Compared with radiographs taken in the flexion, extension, and supine positions, rollback showed little difference from postoperative radiographs, which showed almost the same angle as the intraoperative kyphotic angle.

Drug-tolerant cells are mediators of acquired resistance. BIM-intron2 deletion polymorphism (BIM-del) is one of the mechanisms underlying the resistance to epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI)-mediated apoptosis that induces drug tolerance. Here, we investigated whether resminostat, a histone deacetylase inhibitor, circumvents BIM-del-associated apoptosis resistance. The human EGFR-mutated non-small cell lung cancer (NSCLC) cell line PC-9 and its homozygous BIM-del-positive variant (PC-9 BIMi2- / -), established by editing with zinc finger nuclease, were used. In comparison with PC-9 cells, PC-9 BIMi2- / - cells were less sensitive to apoptosis mediated by EGFR-TKIs such as gefitinib and osimertinib. The combined use of resminostat and an EGFR-TKI preferentially induced the expression of the pro-apoptotic BIM transcript containing exon 4 rather than that containing exon 3, increased the level of pro-apoptotic BIM protein (BIMEL), and stimulated apoptosis in vitro. In a subcutaneous tumor model derived from PC-9 BIMi2- / - cells, gefitinib monotherapy decreased tumor size but retained residual lesions, indicative of the presence of tolerant cells in tumors. The combined use of resminostat and gefitinib increased BIMEL protein level and induced apoptosis, subsequently leading to the remarkable shrinkage of tumor. These findings suggest the potential of resminostat to circumvent tolerance to EGFR-TKIs associated with BIM deletion polymorphism. J. Med. Invest. 67 : 343-350, August, 2020.

In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (pin vivo, showing leukemia initiating capacity. Our study provides insight into the biologic mechanisms of B-ALL initiation and survival.

Background Several microorganisms inhabit the mammalian gastrointestinal tract and are associated with the pathogenesis of various diseases, including cancer. Recent studies have indicated that several probiotics produce antitumor molecules and inhibit host tumor progression. We demonstrated that heptelidic acid (HA), a sesquiterpene lactone derived from the probiotic Aspergillus oryzae, exerts antitumor effects against pancreatic cancer in vitro and in vivo. In this study, the antitumor effects of HA against extraintestinal melanoma were assessed in vitro and in vivo. Results Sulforhodamine B (SRB) assay revealed that the growth of B16F10 cells was significantly inhibited by HA in a concentration-dependent manner. The enzymatic activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) decreased in proportion with the growth inhibition effect of HA. Moreover, oral HA administration significantly suppressed the growth of transplanted B16F10 tumors without any significant changes in biochemical test values. Moreover, GAPDH activity in the transplanted tumor tissues in the HA group significantly decreased compared with that in the PBS group. Conclusion This study suggests that orally administered HA was absorbed in the gastrointestinal tract, reached the cancer cells transplanted in the skin, and inhibited GAPDH activity, thereby inhibiting the growth of extraintestinal melanoma cells. Thus, this study proposes a novel system for extraintestinal tumor regulation via gut bacteria-derived bioactive mediators.

Frostbite occurs when the skin is exposed to localized low temperatures. The main causes of frostbite are thought to be direct cell injury due to freezing of cells and tissue ischemia due to abnormal blood circulation. However, the molecular mechanism of frostbite has not been elucidated. This study aims to explain the molecular dynamics of frostbite using a mouse frostbite model and keratinocyte cell culture. Comprehensive gene expression analysis performed on mouse skin samples revealed that β-catenin signaling is activated by frostbite. Immunohistochemistry showed nuclear translocation of β-catenin in the skin of frostbite model mice that was not observed in mice subjected to a mechanical skin damage model induced by tape stripping. Tissue hypoxia, as detected by pimonidazole staining, coexisted with nuclear expression of β-catenin. In keratinocyte cell cultures, nuclear translocation of β-catenin was induced by hypoxia, but not by low temperature. Hypoxia induced epithelial-mesenchymal transition - an important biological event in the healing process of skin - and in vitro wound-healing activity, both of which were suppressed by β-catenin inhibition. Our results suggest that during frostbite, impaired blood flow causes hypoxia, which in turn activates β-catenin that promotes keratinocyte motility and tissue repair.

Background Accidental hypothermia (AH) sometimes leads to coagulation disorder, especially in severe AH. We previously demonstrated that intrasplenic platelet activation caused aberrant hemostasis and thrombus formation after rewarming in a murine AH model. However, no study has focused on the appropriate management of platelets causing coagulation activation after rewarming of AH. We investigated whether or not recombinant soluble thrombomodulin (rTM) can suppress thrombosis formation after rewarming using a rat AH model. Methods Wistar rats were exposed to an ambient temperature of −20 °C under general anesthesia until their rectal temperature decreased to 26 °C. The Hypo group rats (n = 5) were immediately euthanized, while the Hypo/Re group (n = 5) and rTM group rats (n = 5), which were administered rTM (1 mg/kg) via the tail vein, were rewarmed until the rectal temperature returned to 34 °C and then euthanized 6 h later. Tissue and blood samples were collected from all rats for histopathological and coagulation analyses at euthanasia. Results There was no significant change in the D-dimer level in the Hypo group rats, while the D-dimer level was significantly elevated at 6 h after rewarming in the Hypo/Re group rats (P = 0.015), and histopathology detected both fibrin and platelets in the renal glomerulus. However, the rTM group rats did not show any elevation of the D-dimer levels at 6 h after rewarming, and no fibrin was noted on histopathology. Conclusions rTM may be useful as an appropriate anticoagulant in cases of aberrant hemostasis after rewarming of AH.

Background Colchicine binds to intracellular tubulin and prevents mitosis. Colchicine is also used as an anti-inflammatory drug. Meanwhile, excess administration of medication or accidental ingestion of colchicine-containing plants can cause acute colchicine poisoning, which initially results in gastrointestinal effects that may be followed by multiorgan dysfunction. However, the mechanism of colchicine poisoning remains unclear, and there are no standard therapeutic strategies. Aims We focused on intestinal barrier function and attempted to reveal the underlying mechanism of colchicine poisoning using an animal model. Methods Colchicine was orally administered to C57Bl/6 mice. Then, we performed histopathological analysis, serum endotoxin assays, and intestinal permeability testing. Additionally, the LPS-TLR4 signaling inhibitor TAK-242 was intraperitoneally injected after colchicine administration to analyze the therapeutic effect. Results We observed villus height reduction and increased numbers of apoptotic cells in the gastrointestinal epithelium of colchicine-treated mice. Both intestinal permeability and serum endotoxin levels were higher in colchicine-treated mice than in control mice. Although colchicine-poisoned mice died within 25 h, those that also received TAK-242 treatment survived for more than 48 h. Conclusion Colchicine disrupted intestinal barrier function and caused endotoxin shock. Therapeutic inhibition of LPS-TLR4 signaling might be beneficial for treating acute colchicine poisoning.

Lead fluoride (PbF₂) is a promising electrode material for fluoride shuttle batteries (FSBs) owing to its high theoretical capacity (219 mAh g⁻¹). In this study, the discharge and charge capacities of a PbF₂ electrode were measured using a bis[2‐(2‐methoxyethoxy)ethyl] ether containing cesium fluoride and triphenylborane as an electrolyte. A high specific capacity was maintained during both the discharge and charge processes in the first cycle, but the capacity decreased from the first charge process to the following discharge process. To clarify the electrochemical reaction mechanism, the dissolution and change in the electronic state of Pb at the PbF2 electrode during the discharge and charge processes were evaluated via atomic absorption spectrometry (AAS) and X‐ray photoelectron spectroscopy (XPS). The results obtained from AAS and XPS indicated that Pb was formed during the discharge process. Conversely, the formation of PbF₂ and dissolution of Pb coexisted within the wide range of charge process. The PbF₂ could react in the following cycle, but the dissolved Pb was unable to contribute to the following discharge/charge reaction. Therefore, after the initial charge process, the capacity decreased., This article also appears in: Electro, Physical & Theoretical Chemistry

Fluoride shuttle battery (FSB) is a promising next-generation battery candidate. In the FSB, metal fluoride and organic solvent containing supporting electrolyte salt and anion acceptor were used as active material and electrolyte. In this study, using bis[2-(2-methoxyethoxy)ethyl] ether (tetraglyme: G4) containing cesium fluoride (CsF; 0.45 mol dm⁻³ or saturated) and triphenylboroxine (TPhBX; 0.50 mol dm⁻³) as electrolyte (CsF(0.45)–TPhBX(0.50)–G4 and CsF(sat.)–TPhBX(0.50)–G4), the electrochemical performance of bismuth fluoride (BiF₃) was assessed. Although the discharge and charge reactions of BiF₃ electrode proceeded in both electrolytes, the cycling performance of BiF₃ electrode in CsF(0.45)–TPhBX(0.50)–G4 was poorer than that in CsF(sat.)–TPhBX(0.50)–G4. The cause of differences in the electrochemical properties was investigated using atomic absorption spectrometry (AAS), X-ray photoelectron spectroscopy (XPS), and cross-sectional scanning electron microscopy (SEM)/energy dispersive X-ray spectroscopy (EDX). The AAS results indicate that the poor cycling performance with CsF(0.45)–TPhBX(0.50)–G4 was due to the dissolution of active material during charging. The XPS and cross-sectional SEM/EDX results indicate that the formation state of Bi, and the progress of electrolyte decomposition during discharging were affected by the CsF/TPhBX ratio in the electrolyte.

Bismuth fluoride (BiF3) is a promising positive electrode material for fluoride shuttle batteries (FSBs) owing to its high theoretical specific capacity (302 mA h g−1). However, it exhibits low practical capacity. The methods for preparing the electrode are known to have significant effects on battery performance. The mixture between BiF3 and carbon, BiF3/C, prepared by high energy ball milling method has been already approved in lithium ion batteries. With this method, a significant improvement over the discharge and charge capacities of the BiF3/C electrode has been achieved. In this work, for the first time, BiF3/C electrode has been used for FSB. Using BiF3/C electrode significantly increased the discharge and charge capacities. To confirm the progress of the discharge and charge reactions of BiF3/C electrode, the crystal structure of active materials and oxidation state of Bi for the BiF3/C electrode during discharging and charging has been investigated by X-ray diffraction and X-ray absorption fine structure. The results reveal that, with higher capacity values, discharge and charge reactions related to BiF3/C have been realized.

In fluoride shuttle batteries (FSBs), the addition of an anion acceptor (AA) is required to dissolve the supporting electrolyte salt in an organic solvent. Based on theoretical calculations and practical experiments, the effectiveness of triphenylboroxine (TPhBX) as an AA for FSB was verified. Using an electrolyte with TPhBX as an AA, the specific capacities of the following two types of lead fluoride (PbF2) electrodes were evaluated: (i) PbF2 pulverized using a ball mill, (ii) pulverized PbF2 mixed with carbon using a ball mill. The experimental results indicate that mixing PbF2 with carbon using a ball mill increases the specific capacity of PbF2 electrode.

Objectives: To evaluate the ‘One Stretch’ exercise’s effect on improvements in low back pain (LBP), psychological factors, and fear avoidance in a large number of nurses.Methods: Between July 2015 ...

As a cathode material, Li1.2Ni0.2Mn0.6O2 delivers high discharge capacity at low C-rate but low discharge capacity at high C-rate. Furthermore, a large potential hysteresis occurs during charge and discharge, and the charge-discharge curves change shape during the charge-discharge cycling. Increasing nickel/manganese (Ni/Mn) ratio in Li1.2NiyMn0.8−yO2 improves discharge capacity at high C-rate, but it decreases discharge capacity at low C-rate. To accomplish high discharge capacity at both high and low C-rates, lithium/transition-metal (Li/TM) ratio in high-nickel-content material, namely, Li1.2Ni0.35Mn0.45O2, was adjusted. Cathode materials with varied lithium/transition-metal ratio (x), namely, Li1.2−xNi0.35+(0.35/0.8)xMn0.45+(0.45/0.8)xO2 (x = 0, 0.02, 0.04, 0.06, or 0.08), were prepared, and their electrochemical performances were evaluated. It was found that as x was decreased, discharge capacity first increased then decreased, and Li1.2−xNi0.35+(0.35/0.8)xMn0.45+(0.45/0.8)xO2 (x = 0.04), which can be described as Li1.16Ni0.37Mn0.47O2, was found to exhibit the highest discharge capacity. Accordingly, the electrochemical properties of Li1.16Ni0.37Mn0.47O2 were compared with those of a conventional lithium-rich layer-structured cathode material, namely, Li1.2Ni0.2Mn0.6O2. The rate performance of Li1.16Ni0.37Mn0.47O2 was higher than that of Li1.2Ni0.2Mn0.6O2. Furthermore, potential hysteresis and shape change of the charge-discharge curves for Li1.16Ni0.37Mn0.47O2 were smaller than those for Li1.2Ni0.2Mn0.6O2. It is thus concluded that changing the composition of the cathode material from Li1.2Ni0.2Mn0.6O2 to Li1.16Ni0.37Mn0.47O2 alleviates the drawbacks of lithium-rich layer-structured cathode material, namely, low rate performance, potential hysteresis, and shape change of charge-discharge curves.

Intake of probiotics or fermented food produced by some probiotic bacteria is believed to exert anti-tumor functions in various cancers, including pancreatic cancer, because several studies have demonstrated the anti-tumor effects of probiotic bacteria in vitro and in vivo in animal carcinogenesis models. However, the mechanisms underlying the anticancer effects of probiotics on pancreatic cancer have not been clarified. In this study, we assessed the anti-tumor effects of probiotic bacteria against pancreatic cancer cells. Among the known probiotic bacteria, Aspergillus oryzae exhibited a strong pancreatic tumor suppression effect. The culture supernatant of A. oryzae was separated by HPLC. Heptelidic acid was identified as an anti-tumor molecule derived from A. oryzae by LC–MS and NMR analysis. The anti-tumor effect of heptelidic acid was exhibited in vitro and in vivo in a xenograft model of pancreatic cancer cells. The anti-tumor effect of heptelidic acid was exerted by the p38 MAPK signaling pathway. Heptelidic acid traverses the intestinal mucosa and exerts anti-tumor effects on pancreatic cancer cells. This is a novel anti-tumor mechanism induced by beneficial bacteria against pancreatic cancer in which bacterial molecules pass through the intestinal tract, reach the extra-intestinal organs, and then induce apoptosis via an inducible signaling pathway.

An asymptomatic 75-year-old woman was identified with a 40-mm-sized, round-shaped lesion beside the pulmonary artery on computed tomography (CT). Coronary angiography showed a coronary artery fistula (CAF) with an aneurysm branching from the left anterior descending artery toward the pulmonary artery. The CAF aneurysm (CAFA) was resected and coronary artery bypass graft surgery using the left internal thoracic artery was performed successfully. Pathological analysis revealed that medial depletion similar to segmental arterial mediolysis (SAM) may contribute to aneurysm formation.

Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD), is an intractable intestinal inflammation associated with the disruption of the intestinal mucosa. We previously demonstrated that Lactobacillus brevis-derived long-chain polyphosphate (poly P) improved the intestinal barrier function by the upregulation of cell adhesion and relieved intestinal inflammation, thereby exerting a curing effect on colitis in vitro, in vivo, and in an investigator-initiated clinical study of UC. However, how poly P improves mucosal defects induced by intestinal inflammation has not been elucidated. In this study, we detected the accumulation of platelets in inflamed tissues induced by poly P in a dextran sulfate sodium- (DSS-) induced colitis mouse model. A light transmission aggregometry analysis and scanning electron microscopy showed that poly P promoted the platelet aggregation. An SRB assay and ki-67 staining showed that the supernatant of poly P-treated platelet-rich plasma (PRP) increased intestinal epithelial cell growth. A wound healing assay showed that the supernatant of poly P-treated PRP, but not poly P itself, accelerated wound healing. A Western blotting analysis indicated that mitogen-activated protein kinase activation was induced by the supernatant of poly P-treated human PRP in the epithelial cells and its wound healing effect was significantly decreased by the inhibition of ERK signaling. These data suggested that platelet-derived mediators induced by poly P improved intestinal inflammation through the promotion of epithelial cell growth by the activation of the ERK signaling pathway. The mechanism is a novel host-microbe interaction through mammalian platelet-derived mediators induced by bacterial molecules.

Background Colorectal cancers develop through several pathways, including the adenoma–carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. Methods SRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo. Results Ferrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway. Conclusions Ferrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population., Koda et al. present the results of a randomized phase 3 trial comparing granulocyte colony-stimulating factor versus placebo in patients with acute spinal cord injury. While the primary endpoint was not met, a sub-analysis revealed a trend towards superior efficacy of G-CSF versus placebo in an elderly population.

The oncogenic properties of heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) have been reported, although the tumor-promoting mechanism remains unclear. We herein report the mechanism underlying colorectal cancer cell progression mediated by hnRNP H1. The growth of colorectal cancer cells was suppressed by hnRNP H1 downregulation. A terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed the anti-apoptotic effect of hnRNP H1 in colorectal cancer cells. An RNA immunoprecipitation assay revealed that hnRNP H1 bound to sphingosine-1-phosphate lyase 1 (SGPL1). Reverse transcription-polymerase chain reaction revealed the high expression of hnRNP H1 mRNA in colorectal cancer cells and Spearman&rsquo, s rank correlation coefficient showed a strong positive correlation between hnRNP H1 mRNA and SGPL1 mRNA. An siRNA of hnRNP H1 decreased SGPL1 mRNA expression in colorectal cancer cells, but not in non-tumorous cells. These findings suggested that hnRNP H1 increased SGPL1 mRNA expression specifically in cancer cells through direct binding. Targeted knockdown of hnRNP H1 or SGPL1 with siRNAs upregulated p53 phosphorylation and p53-associated molecules, resulting in cell growth inhibition, while hnRNP H1 upregulated the mRNA of SGPL1 and inhibited p53 activation, thereby promoting tumor cell growth. This is a novel mechanism underlying colorectal cancer cell progression mediated by hnRNP H1&ndash, SGPL1 mRNA stabilization.

Receptor-based fluorescent sensors are the representative tool for quantitative detection of target ligands. The high substrate-selectivity originated from biomacromolecule receptor is one of the advantages of this tool, but a laborious trial and error is usually required to construct sensors showing satisfactory fluorescence intensity changes without diminishing the function of parent receptor. Ribonucleopeptide (RNP) provides a scaffold of fluorescent sensors to improve such issues. RNP receptors for the ligand of interest are constructed by applying in vitro selection for RNA-derived RNP library. Simple modification of the N-terminal of peptide in RNP by an appropriate fluorophore converts the RNP receptor into the fluorescent sensor with retaining the affinity and selectivity for the substrate. In this chapter, we introduce the protocols for construction of fluorescent RNP sensors through selection from a library of fluorophore-modified RNP complex or by a structure-based modular design. Furthermore, we describe the application of covalently linked RNP sensors for simultaneous detection of multiple ligands.

For liquid-based fluoride shuttle batteries, electrolyte composed of organic solvent and supporting electrolyte salt is developed. To increase the solubility of supporting electrolyte salt in organic solvent, anion acceptors (triphenylboroxine or triphenylborane) are added. The addition of anion acceptor greatly increases the solubility of supporting electrolyte salt, and discharge-charge reaction of BiF₃ electrode is confirmed in the prepared electrolytes. A supporting electrolyte salt (Cesium fluoride (CsF)) dissolves sparingly in an organic solvent (bis[2-(2-methoxyethoxy)ethyl]ether (tetraglyme: G4)); however, the solubility of the CsF in the G4 is greatly increased by addition of an anion acceptor (triphenylboroxine or triphenylborane). Using the developed electrolyte for fluoride shuttle battery, discharge and charge reactions of a metal fluoride electrode can be progressed.

Recently, the reversible discharge and charge reaction of BiF3 electrode for fluoride shuttle battery (FSB) that can be used as a promising candidate for next-generation battery are observed using a liquid-based electrolyte. In this study, we investigate the electrochemical performance of PbF2 as an active material for the FSB. To increase the electronic conductivity, the PbF2 was mixed with carbon, and the composite material between PbF2 and carbon, PbF2/C, is formed. High discharge and charge capacities are obtained for PbF2/C during the first cycle. Although the discharge and charge capacities gradually decreased, the discharge and charge reactions occurred in the second and third cycles. To confirm the progress of the discharge and charge reactions, the crystal structure change of the active material during discharging and charging in the first and second cycles is evaluated using X-ray diffraction (XRD). From the XRD results, the formation of Pb and PbF2 during discharging and charging can be confirmed, indicating that the discharge (PbF2 + 2e− → Pb + 2F−) and charge (Pb + 2F− → PbF2 + 2e−) reactions progress in both the first and second cycles.

We have developed a fluoride shuttle battery (FSB) which is a promising candidate for the next-generation high-energy-density secondary batteries. Using the bis [2-(2-methoxyethoxy) ethyl] ether (tetraglyme: G4) solvent containing 0.45 mol dm−3 cesium fluoride (CsF) and 0.5 mol dm−3 fluorobis (2,4,6-trimethylphenyl) borane (FBTMPhB) as an electrolyte for FSB, we have successfully conducted the discharge (BiF3 + 3e− → Bi + 3F−) and charge (Bi + 3F− → BiF3 + 3e−) reactions for a BiF3 electrode; however, the discharge and charge capacities significantly decreased during cycling. Atomic absorption spectrometry results indicated that, in addition to the formation of BiF3, dissolution of Bi (Bi → Bi3+ + 3e−) occurred during the charge process. The dissolution of Bi indicated that the active material was lost from the electrode, which decreased the capacity during cycling. An increased CsF/FBTMPhB ratio in the electrolyte was found to suppress the dissolution of Bi during the charge process and, therefore, improve the cycling performance.

The potential in each state of charge (SOC) during charging of Li1.2Ni0.13Mn0.54Co0.13O2 is higher than that during discharging. In other words, the potential hysteresis occurs between charging and discharging. Furthermore, the potential in each SOC changes according to the charge-discharge operating conditions, indicating that the charge-discharge reaction mechanism is also affected. To clarify the effect of charge-discharge operating conditions on the electrochemical reaction, Li1.2Ni0.13Mn0.54Co0.13O2 was charged and discharged under various charge-discharge operating ranges, and open-circuit potential (OCP), crystal structure, and oxidation states of the transition metals were evaluated by electrochemical measurement, X-ray diffraction (XRD), and X-ray absorption fine structure (XAFS). These results indicate that OCP, lattice parameters, and oxidation states of the transition metals of Li1.2Ni0.13Mn0.54Co0.13O2 in each SOC are not constant. The XRD results indicate that two phases, namely, LiNi0.33Mn0.33Co0.33O2-like and Li2MnO3-like, exist in Li1.2Ni0.13Mn0.54Co0.13O2. For the LiNi0.33Mn0.33Co0.33O2-like phase, the relationship between OCP, lattice parameters, and oxidation states of the transition metals in each SOC is not affected by the charge-discharge operating conditions, indicating that extraction and insertion of lithium ions for the LiNi0.33Mn0.33Co0.33O2-like phase progresses at almost the same potential. Although the extraction and insertion of lithium ions for the Li2MnO3-like phase progresses at almost the same potential in the low-SOC region, the OCP and lattice parameter in each SOC in the high-SOC region are not constant. Therefore, the extraction of lithium ions from the Li2MnO3-like phase in the high-SOC region causes the potential hysteresis of Li1.2Ni0.13Mn0.54Co0.13O2.

Background The JOA (Japan Orthopaedic Association) score has been a standard outcome measure to evaluate cervical myelopathy in Japan. Despite its reliability and convenience, there can be a rating bias in the JOA score. The current study was conducted to delineate the rater's bias of the JOA score by comparing it with a new objective outcome measure. Methods Two hundred and thirty four operative candidates with cervical myelopathy were included in the study. The patients were divided into four groups according to the surgeon (92 patients in group A, 60 patients in group B, 38 patients in group C and 44 patients in group D). Each patient's preoperative JOA score was exclusively recorded by the surgeon himself, while JOACMEQ (Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire) was recorded by each patient. Disease severity, the most important prognostic factor, was equalized between patient groups by a special statistical method called inverse-probability weighting (IPW). To define similarity of the two groups, Cohen's d was used. Results After the adjustment, the differences of the JOA score were only 0.1 between groups A and D and 0 between groups B and C. The values of Cohen's d were also very small both between groups A and D (3%), and between groups B and C (0.3%). The averaged JOA scores of groups A and D were higher by 0.4–0.8 than those of groups B and C, while the averaged JOA scores were almost the same both between groups A and D, and between groups B and C. Surgeons A and D had the same tendency to give higher JOA scores than surgeons B and C did. Conclusions The current study confirmed there is a definite rater's bias in the JOA score. JOACMEQ is to be applied as a more reliable outcome measure to evaluate myelopathy patients.

Two electrochemical reactions are possible in regard to Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 (0.5Li 2 MnO 3 −0.5LiNi 0.33 Mn 0.33 Co 0.33 O 2 ), viz, Li 2 MnO 3 -like and LiNi 0.33 Mn 0.33 Co 0.33 O 2 -like reactions. The open circuit potential (OCP) and changes in crystal structure during the charge-discharge process of Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 were investigated to clarify the mechanism responsible for the two reactions. Li 2 MnO 3 and LiNi 0.33 Mn 0.33 Co 0.33 O 2 were separately prepared for the investigation, and the OCPs and crystal structures in these cathodes were measured and then compared with those for Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 . The results obtained using X-ray diffraction (XRD) indicated that two phases existed in Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 . The changes in crystal structure of the two phases during the charge-discharge process were similar to those in Li 2 MnO 3 and LiNi 0.33 Mn 0.33 Co 0.33 O 2 . This indicated that two phases, viz, Li 2 MnO 3 -like and LiNi 0.33 Mn 0.33 Co 0.33 O 2 -like, existed in Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 . Li 2 MnO 3 -like, LiNi 0.33 Mn 0.33 Co 0.33 O 2 -like, and Li 2 MnO 3 -like phases were found to contribute mainly to electrochemical reactions in the low, middle, and high state of charge (SOC) ranges during the charge process from the results obtained using XRD and electrochemical measurements carried out on Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 . In contrast, the Li 2 MnO 3 -like and LiNi 0.33 Mn 0.33 Co 0.33 O 2 -like phases mainly contributed to electrochemical reactions in the low and high SOC ranges during the discharge process. Furthermore, the high polarization and potential decay during the charge-discharge cycling of Li 1.2 Ni 0.13 Mn 0.54 Co 0.13 O 2 were mainly attributed to the Li 2 MnO 3 -like phase.

The effect of chemical treatment using (NH4)2SO4 on the electrochemical properties of Li1.2Ni0.2Mn0.6O2 and Li1.2Ni0.25Mn0.55O2 was investigated. The treatment was effective in improving the Coulombic efficiency and discharge capacity of a Li1.2Ni0.2Mn0.6O2 cathode, but treatment with too much (NH4)2SO4 degraded the cathode's electrochemical performance. The effect of (NH4)2SO4 treatment on the charge-discharge reaction mechanism of Li1.2Ni0.2Mn0.6O2 was investigated by evaluating reaction potential, particle configuration, and oxidation state of transition metal. The experimental results indicated that the changes in the electrochemical performance of the treated cathodes were attributed to the changes in the surface state and of the element contributing to the redox reaction. Treatment with an appropriate amount of (NH4)2SO4 also improved the electrochemical performance of the high-nickel-content lithium-rich layer-structured cathode material Li1.2Ni0.25Mn0.55O2.

Background Pancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers. Methods The ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls; n = 22) were enriched using ExoQuick-TC™. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction. Results The expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p

The conversion-based BiF3 is a promising cathode material for lithium-ion batteries due to its high theoretical capacity (302 mAh g−1). Nanocomposites of BiF3 and carbon (BiF3/C) are known to improve the electrochemical performance by increasing the electronic conductivity of the electrode. Here we investigate the electrochemical performance of BiF3/C at high C-rates. In particular, we newly investigate the difference of high C-rate performance between discharge and charge reactions. The discharge and charge capacities in the first cycle were almost the same at 0.1 C. In contrast, the discharge capacity was higher than charge capacity at 10 C. Further, during cycling at 10 C, the charge capacity drastically decreased, but the discharge capacity remained high. The rate performance of the discharge reaction was higher than that of the charge reaction, especially after cycling.

MicroRNAs (miRNAs) are single-stranded short-chain RNAs that are endogenously expressed in vertebrates; they are considered the fine-tuners of cellular protein expression that act by modifying mRNA translation. miRNAs control tissue development and differentiation, cell growth, and apoptosis in cancer and non-cancer cells. Aberrant regulation of miRNAs is involved in the pathogenesis of various diseases including cancer. Numerous investigations have shown that the changes in cellular miRNA expression in cancerous tissues and extracellular miRNAs enclosed in exosomes are correlated with cancer prognosis. Therefore, miRNAs can be used as cancer biomarkers and therapeutic targets for cancer in clinical applications. In the previous decade, miRNAs have been shown to regulate cellular functions by directly binding to proteins and mRNAs, thereby controlling cancer progression. This regulatory system implies that cancer-associated miRNAs can be applied as molecular-targeted therapy. This review discusses the roles of miRNA–protein systems in cancer progression and its future applications in cancer treatment.