Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Multifaceted properties of Andreev bound states: interplay of symmetry and topology.

Andreev bound states (ABSs) ubiquitously emerge as a consequence of non-trivial topological structures of the order parameter of superfluids and superconductors and significantly contribute to thermodynamics and low-energy quantum transport phenomena. We here share the current status of our knowledge on their multifaceted properties such as Majorana fermions and odd-frequency pairing. A unified concept behind ABSs originates from a soliton state in the one-dimensional Dirac equation with mass domain wall and interplay of ABSs with symmetry and topology enrich their physical characteristics. We make an overview of ABSs with a special focus on superfluid 3He. The quantum liquid confined to restricted geometries serves as a rich repository of noteworthy quantum phenomena, such as the mass acquisition of Majorana fermions driven by spontaneous symmetry breaking, topological quantum criticality, Weyl superfluidity and the anomalous magnetic response. The marriage of the superfluid 3He and nano-fabrication techniques will take one to a new horizon of topological quantum phenomena associated with ABSs.This article is part of the theme issue 'Andreev bound states'.

A novel in vivo model for predicting myelotoxicity of chemotherapeutic agents using IL-3/GM-CSF transgenic humanized mice.

Evaluating myelotoxicity is essential for ensuring the safety of novel drugs before they are approved for clinical applications. Although in vivo prediction of the maximum tolerated doses (MTDs) of anticancer drugs is usually performed in rodents, the results are not always applicable to clinical treatment because drugs may have different effects in human and rodent cells. Previously, we generated a human IL-3 and GM-CSF transgenic humanized mouse (hu-IL-3/GM Tg), in which human granulocytes effectively differentiated after hematopoietic stem cell transplantation. In this study, we established a novel in vivo preclinical evaluation model for predicting human myelotoxicity of anticancer drugs using these hu-IL-3/GM Tg mice. The myelotoxicity was investigated by kinetic flow cytometry of human or murine granulocytes and by colony-forming unit granulocyte/macrophage (CFU-GM) assays. In both in vivo and in vitro analyses, topotecan was more myelotoxic to human than murine granulocytes. In contrast, oxaliplatin was more myelotoxic to murine granulocytes. The level of myelotoxicity of paclitaxel treatment was comparable between human and mouse cells. These results demonstrate that our humanized mouse model can simultaneously evaluate myelotoxicity against human and mouse cells in vivo, and provides an effective preclinical tool for predicting appropriate doses of anticancer agents for clinical treatment.

Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3ß-Snail pathway.

Pancreatic cancer is one of the most difficult malignancies to treat owing to the rapid acquisition of resistance to chemotherapy. Gemcitabine, a first-line treatment for pancreatic cancer, prolongs patient survival by several months, and combination treatment with gemcitabine and other anti-cancer drugs in the clinic do not show any significant effects on overall survival. Thus, identification of a drug that resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine and a better understanding of the molecular mechanisms of gemcitabine resistance are critical to develop new therapeutic options for pancreatic cancer. Here, we report that zidovudine resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine as shown by screening a compound library, including clinical medicine, using gemcitabine-resistant cells. In analyzing the molecular mechanisms of zidovudine effects, we found that the epithelial-to-mesenchymal transition (EMT)-like phenotype and downregulation of human equilibrative nucleoside transporter 1 (hENT1) are essential for the acquisition of gemcitabine resistance, and zidovudine restored these changes. The chemical biology investigations also revealed that activation of the Akt-GSK3ß-Snail1 pathway in resistant cells is a key signaling event for gemcitabine resistance, and zidovudine resensitized resistant cells to gemcitabine by inhibiting this activated pathway. Moreover, our in vivo study demonstrated that co-administration of zidovudine and gemcitabine strongly suppressed the formation of tumors by gemcitabine-resistant pancreatic cancer and prevented gemcitabine-sensitive pancreatic tumors from acquiring gemcitabine-resistant properties, inducing an EMT-like phenotype and downregulating hENT1 expression. These results suggested that co-treatment with zidovudine and gemcitabine may become a novel therapeutic strategy for pancreatic cancer by inhibiting chemoresistance-specific signaling.

Tumour-suppressive function of SIRT4 in human colorectal cancer.

BACKGROUND: SIRT4, which is localised in the mitochondria, is one of the least characterised members of the sirtuin family of nicotinamide adenine dinucleotide-dependent enzymes that play key roles in multiple cellular processes such as metabolism, stress response and longevity. There are only a few studies that have characterised its function and assessed its clinical significance in human cancers. METHODS: We established colorectal cancer cell lines (SW480, HCT116, and HT29) overexpressing SIRT4 and investigated their effects on proliferation, migration and invasion, as well as E-cadherin expression, that negatively regulates tumour invasion and metastases. The associations between SIRT4 expression in colorectal cancer specimens and clinicopathological features including prognosis were assessed by immunohistochemistry. RESULTS: SIRT4 upregulated E-cadherin expression and suppressed proliferation, migration and invasion through inhibition of glutamine metabolism in colorectal cancer cells. Moreover, SIRT4 expression in colorectal cancer decreased with the progression of invasion and metastasis, and a low expression level of SIRT4 was correlated with a worse prognosis. CONCLUSIONS: SIRT4 has a tumour-suppressive function and may serve as a novel therapeutic target in colorectal cancer.

Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

eNOS plays an important role in the regulation of colonic inflammation: a novel therapeutic target and a predictive marker for the prognosis of ulcerative colitis.

BACKGROUND: We reported that deficiency of the eNOS protein exacerbates colitis induced by dextran sodium sulfate (DSS-induced colitis). However, the role of eNOS in colitis remains controversial. Therefore, we studied how over-expression of eNOS affected this inflammatory condition, using vascular endothelial cells and mice as in vitro and in vivo models, respectively. Furthermore, we investigated the influence of a polymorphism in the eNOS gene on the clinical features of ulcerative colitis (UC). METHODS: We examined the effect of eNOS overexpression on the expression of adhesion molecules in the endothelium and assessed the degree of DSS-induced colitis in eNOS transgenic (eNOS-Tg) mice. We also investigated the relationship between a polymorphism in the eNOS gene and clinical features of patients with UC. RESULTS: The expression of adhesion molecules, under inflammatory conditions, was attenuated in eNOS gene-transfected vascular endothelial cells, as measured by western blot analysis. Symptoms of DSS-induced colitis were likewise attenuated in eNOS-Tg mice, which exhibited lower weight loss, mortality, histological damage (by inflammation score and crypt damage score), and colonic myeloperoxidase activity, tumor necrosis factor-α expression, and MAdCAM-1 expression than in wild-type mice. Furthermore, there was a significant relationship between intractable cases of UC and a polymorphism in the eNOS gene promoter (c.-786 T > C) that decreases eNOS expression. CONCLUSION: The eNOS gene plays an important role in the regulation of colonic inflammation. The level of eNOS expression may be a predictive marker for prognosis of UC, and eNOS expression may be a novel therapeutic target.

Acid inhibits TRPV4-mediated Ca²âº influx in mouse esophageal epithelial cells.

BACKGROUND: The transient receptor potential vanilloid 4 (TRPV4), a thermo-sensitive stretch-activated cation channel, is expressed in the skin stratified squamous epithelium, contributing to the acquisition of barrier function. Similarly, functional TRPV4 may be located in the stratified squamous epithelial lining of the esophagus, being involved in the pathogenesis of gastroesophageal reflux disease (GERD). Here we investigated the expression of TRPV4 in the mouse esophageal epithelium. METHODS: TRPV4 expression at the mRNA and protein levels was examined by reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. A calcium imaging technique and ATP assay were used to evaluate the functionality of TRPV4 in freshly isolated esophageal epithelial cells. KEY RESULTS: Transcripts and proteins encoding TRPV4 were colocalized in the basal and intermediate layers of the esophageal epithelium. Both 4α-phorbol 12,13- didecanoate (4α-PDD), a selective agonist for TRPV4, and hypo-osmolar solution (160 mOsm) elevated the intracellular calcium concentration ([Ca(2+) ](i) ) in a subset of the isolated cells (70%). These [Ca(2+) ](i) increases were potently inhibited by ruthenium red (RuR), a TRPV4 channel antagonist, and were suppressed by extracellular protons (pH 5.0). Finally, application of 4α-PDD evoked ATP release in primary esophageal epithelial cells. CONCLUSIONS & INFERENCES: Acid-sensitive TRPV4 channels were mainly expressed in the esophageal epithelial cells of the basal and intermediate layers. Direct exposure of TRPV4-expressing cells to gastric acid, as would occur in cases of GERD, could influence their cellular functions, possibly aggravating the disease state.

Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis.

Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is a serious clinical concern and myofibroblasts have been suggested to have a major role, with it recently being revealed that some of these myofibroblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (EMT). In this study, we examined the EMT-inducing abilities of drugs known to induce ILD clinically. EMT-like phenotypes were induced by A771726, an active metabolite of leflunomide having an inhibitory effect on dihydroorotate dehydrogenase (DHODH). Smad-interacting protein 1 (a transcription factor regulating EMT) and the Notch-signaling pathway but not transforming growth factor-ß was shown to be involved in A771726-induced EMT-like phenotypes. When the cultures were supplemented with exogenous uridine, the A771726-induced EMT-like phenotypes and activation of the Notch-signaling pathway disappeared. Similarly, an A771726 analog without inhibitory activity on DHODH produced no induction, suggesting that this process is mediated through the inhibition of DHODH. In vivo, administration of leflunomide stimulated bleomycin-induced EMT-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fibrosis, both of which were suppressed by coadministration of uridine. Taken together, these findings suggest that leflunomide-dependent exacerbation of bleomycin-induced pulmonary fibrosis is mediated by stimulation of EMT of lung epithelial cells, providing the first evidence that drug-induced pulmonary fibrosis involves EMT of these cells.

BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers.

BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF (C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RT-PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression.

Role of the Majorana fermion and the edge mode in chiral superfluidity near a p-wave Feshbach resonance.

The visualization of chiral p-wave superfluidity in Fermi gases near p-wave Feshbach resonances is theoretically examined. It is proposed that the superfluidity becomes detectable in the entire BCS-BEC regimes through (i) vortex visualization by the density depletion inside the vortex core and (ii) intrinsic angular momentum in vortex-free states. It is revealed that both (i) and (ii) are closely connected with the Majorana zero energy mode of the vortex core and the edge mode, which survive until the strong coupling BCS regime is approached from the weak coupling limit and vanish in the Bose-Einstein condensation regime.

Majorana bound state in rotating superfluid 3He-A between parallel plates.

A concrete and experimentally feasible example for testing the putative Majorana zero-energy state bound in a vortex is theoretically proposed for a parallel plate geometry of superfluid 3He-A phase. We examine the experimental setup in connection with ongoing rotating cryostat experiments. The theoretical analysis is based on the well-established Ginzburg-Landau functional, supplemented by microscopic calculations of the Bogoliubov-de Gennes equation, both of which allow the precise location of the parameter regions of the Majorana state to be found in realistic situations.

Kelvin waves of quantized vortex lines in trapped Bose-Einstein condensates.

We have theoretically investigated Kelvin waves of quantized vortex lines in trapped Bose-Einstein condensates. Counterrotating perturbation induces an elliptical instability to the initially straight vortex line, driven by a parametric resonance between a quadrupole mode and a pair of Kelvin modes of opposite momenta. Subsequently, Kelvin waves rapidly decay to longer wavelengths emitting sound waves in the process. We present a modified Kelvin wave dispersion relation for trapped superfluids and propose a simple method to excite Kelvin waves of specific wave number.

Spinor dipolar bose-einstein condensates: classical spin approach.

Bose-Einstein condensates which are dominated by magnetic dipole-dipole interaction are discussed under spinful situations. We treat the spin degrees of freedom as a classical spin vector, approaching from the large spin limit to obtain an effective minimal Hamiltonian. This is a version extended from a nonlinear sigma model. By solving the Gross-Pitaevskii equation, we find several novel spin textures where the mass density and spin density are strongly coupled, depending upon trap geometries due to the long-range and anisotropic natures of the dipole-dipole interaction.

Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis.

A limited number of therapeutic strategies are currently available for patients with inflammatory bowel disease (IBD). In particular, the maintenance therapy after remission in Crohn's disease (CD) is not satisfactory and new approaches are needed. Interleukin-10 gene-deficient (IL-10-/-) mice, a well-characterized experimental model of CD, develop severe chronic colitis due to an aberrant Th1 immune response. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), a new immunosuppressive reagent, has been used successfully in animal models for heart, liver, lung and kidney transplantation. In the present study, we examined the efficacy of everolimus in the treatment of chronic colitis in an IL-10-/- mouse model. Everolimus was administered orally for a period of 4 weeks to IL-10-/- mice with clinical signs of colitis. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. The 4-week administration of everolimus resulted in a significant decrease in the severity of colitis, together with a significant reduction in the number of CD4+ T cells in the colonic lamina propria as well as IFN-gamma production in colonic lymphocytes. Everolimus treatment of established colitis in IL-10-/- mice ameliorated the colitis, probably as a result of decreasing the number of CD4+ T cells in the colonic mucosa and an associated reduction in IFN-gamma production.

Various stress proteins protect gastric mucosal cells against non-steroidal anti-inflammatory drugs.

Gastric mucosal cell death induced by non-steroidal anti-inflammatory drugs (NSAIDs) is suggested to be involved in NSAID-induced gastric lesions. Therefore, cellular factors that suppress this cell death are important for protection of the gastric mucosa from NSAIDs. When cells are exposed to various stressors, including NSAIDs, they induce a number of proteins, so-called stress proteins, in order to protect themselves against such stressors. Stress proteins contain cytosolic molecular chaperons (such as heat shock proteins), endoplasmic reticulum molecular chaperons (such as glucose-regulated proteins) and heme oxygenase-1. We recently showed that (i) these stress proteins are up-regulated by NSAIDs both in vitro and in vivo; (ii) these up-regulation make gastric mucosal cells resistant to NSAIDs in vitro; (iii) these up-regulation protects the gastric mucosa from NSAID-induced gastric lesions in vivo. In this review, I summarize these results and propose that non-toxic inducers of these stress proteins are therapeutically beneficial as anti-ulcer drugs.

Vortex-core structure in neutral fermion superfluids with population imbalance.

Quantized vortex-core structure is theoretically investigated in fermion superfluids with population imbalance for two atom species of neutral atom clouds near a Feshbach resonance. In contrast with the vortex core in balance case where the quantum depletion makes a vortex visible through the density profile measurement, the vortex core is filled in and becomes less visible because the quantized discrete bound states are occupied exclusively by the majority species. Yet it is shown that the core can be visible through the minority density profile experiment using phase contrast imaging, revealing an interesting opportunity to examine low-lying fermionic core bound states unexplored so far.

Generic phase diagram of Fermion superfluids with population imbalance.

It is shown by microscopic calculations for trapped imbalanced Fermi superfluids that the gap function always has sign changes, i.e., the Fulde-Ferrell-Larkin-Ovchinnikov (FFLO)-like state, up to a critical imbalance P(c), beyond which normal state becomes stable, at temperature T=0. A temperature-versus-pressure phase diagram is constructed, where the BCS state without sign change is stable only at T not equal to 0. We reproduce the observed bimodality in the density profile to identify its origin and evaluate P(c) as functions of T and the coupling strength. These dependencies match with the recent experiments.