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1.  Annexin A4 induces platinum resistance in a chloride-and calcium-dependent manner 
Oncotarget  2014;5(17):7776-7787.
Platinum resistance has long been a major issue in the treatment of various cancers. We previously reported that enhanced annexin A4 (ANXA4) expression, a Ca2+-regulated phospholipid-binding protein, induces chemoresistance to platinum-based drugs. In this study, we investigated the role of annexin repeats, a conserved structure of all the annexin family, responsible for platinum-resistance as well as the effect of knockdown of ANXA4. ANXA4 knockdown increased sensitivity to platinum-based drugs both in vitro and in vivo. To identify the domain responsible for chemoresistance, ANXA4 deletion mutants were constructed by deleting annexin repeats one by one from the C terminus. Platinum resistance was induced both in vitro and in vivo in cells expressing either full-length ANXA4 or the deletion mutants, containing at least one intact annexin repeat. However, cells expressing the mutant without any calcium-binding sites in the annexin repeated sequence, which is essential for ANXA4 translocation from the cytosol to plasma membrane, failed to acquire platinum resistance. After cisplatin treatment, the intracellular chloride ion concentration, whose channel is partly regulated by ANXA4, significantly increased in the platinum-resistant cells. These findings indicate that the calcium-binding site in the annexin repeat induces chemoresistance to the platinum-based drug by elevating the intracellular chloride concentration.
PMCID: PMC4202160  PMID: 25277200
Annexin A4; platinum resistance; annexin repeat; chloride ion
2.  Expression of insulin-like growth factor-II mRNA-binding protein-3 as a marker for predicting clinical outcome in patients with esophageal squamous cell carcinoma 
Oncology Letters  2014;8(5):2027-2031.
Insulin-like growth factor-II mRNA-binding protein-3 (IMP3) is an important factor in carcinogenesis, although its clinical significance in esophageal squamous cell carcinoma (ESCC) remains unknown. The present study investigated the associations between IMP3 expression and the clinicopathological parameters. IMP3 expression was assessed in 191 resected ESCC specimens, and the associations between IMP3 expression in ESCC, the clinicopathological parameters and patient prognosis were examined. Using immunohistochemistry, 113 (59.2%) tumors were identified as IMP3-positive. IMP3 positivity correlated significantly with high pathological (p)Stage, pT stage and pN stage. The IMP3-positive patients exhibited a poorer prognosis compared with the IMP3-negative patients. In univariate analyses, histology [hazard ratio (HR), 1.94; 95% confidence interval (CI), 1.18–3.49; P=0.0082], pT (HR, 2.34; 95% CI, 1.55–3.62; P<0.0001), pN (HR, 2.85; 95% CI, 1.81–4.69; P<0.0001), lymphatic invasion (HR, 2.08; 95% CI, 1.26–3.70; P=0.0036), venous invasion (HR, 1.79; 95% CI, 1.21–2.64; P=0.0039), neoadjuvant chemotherapy (NAC) (HR, 2.01; 95% CI, 1.35–3.00; P=0.0005) and IMP3 expression (HR, 2.12; 95% CI, 1.40–3.29; P=0.0003) were significantly associated with overall survival. Using multivariate analyses, histology (HR, 1.87; 95% CI, 1.13–3.29; P=0.014), pN (HR, 2.19; 95% CI, 1.36–3.66; P=0.0010), NAC (HR, 1.88; 95% CI, 1.24–2.86; P=0.0028) and IMP3 expression (HR, 1.84; 95% CI, 1.18–2.93; P=0.0064) were significant prognostic factors. IMP3 may therefore be a prognostic factor for patients with ESCC who have undergone a curative resection.
doi:10.3892/ol.2014.2465
PMCID: PMC4186614  PMID: 25295085
insulin-like growth factor-II mRNA-binding protein-3; esophageal squamous cell carcinoma; immunohistochemistry
3.  Superior mediastinal paraganglioma associated with von Hippel-Lindau syndrome: report of a case 
Extra-adrenal pheochromocytomas are termed paragangliomas. Paragangliomas in the mediastinum, especially the superior mediastinum, are extremely rare. It is known that paragangliomas or pheochromocytomas occur in combination with von Hippel-Lindau syndrome. We present the case of a non-functional superior mediastinal paraganglioma in a patient with von Hippel-Lindau syndrome, without a familial history suggestive of the condition. This case highlights that we should be aware of possible sporadic von Hippel-Lindau syndrome in patients with a mediastinal paraganglioma.
doi:10.1186/1477-7819-12-74
PMCID: PMC3977687  PMID: 24678933
Mediastinal paraganglioma; Pheochromocytoma; von Hippel-Lindau syndrome; VHL gene
4.  Mitral valve repair in patient with absent right superior vena cava in visceroatrial situs solitus 
We report on a 74-year-old woman with an absence of right superior vena cava in visceroatrial situs solitus who underwent mitral valve plasty for severe mitral regurgitation. Preoperative three-dimensional computed tomography revealed an absent right and persistent left superior vena cava that drained into the right atrium by way of the coronary sinus. Perioperaively, placement of pulmonary artery catheter, site of venous cannulation, and management of associated rhythm abnormalities were great concern. Obtaining the information about this central venous malformation preoperatively, we performed mitral valve plasty without any difficulties related to this anomaly.
doi:10.1186/1749-8090-8-9
PMCID: PMC3560078  PMID: 23317475
Absent right superior vena cava; Persistent left superior vena cava; Visceroatrial situs solitus; Mitral valve plasty
5.  Spermatic Cord Lymphoma: A Case Report and Literature Review 
Case Reports in Medicine  2012;2012:513707.
Spermatic cord lymphoma is a rare lethal disease. It has a poor prognosis even in stage I or II disease when treated locally, therefore, multidisciplinary treatment for early stage is recommended. On the other hand, the treatment of choice for stage III or IV spermatic cord lymphoma remains to be determined. It is said that spermatic cord lymphoma is clinicopathologically similar to primary testicular lymphoma, therefore the treatment of spermatic cord lymphoma has often been determined by reference to the recommended treatment for primary testicular lymphoma. Here we report a new case of spermatic cord lymphoma, which was found in stage IV disease. We also review thirty-three cases which have been reported as spermatic cord lymphoma to date, and discuss treatment options.
doi:10.1155/2012/513707
PMCID: PMC3295330  PMID: 22431934
6.  β-Galactosylceramide Alters Invariant Natural Killer T Cell Function and is Effective Treatment for Lupus 
Clinical immunology (Orlando, Fla.)  2009;132(3):321-333.
NZB/W female mice spontaneously develop systemic lupus, an autoantibody mediated disease associated with immune complex glomerulonephritis. Natural Killer (NK) T cells augment anti-dsDNA antibody secretion by NZB/W B cells in vitro, and blocking NKT cell activation in vivo with anti-CD1 mAb ameliorates lupus disease activity. In the current study, we show that β-galactosylceramide reduces the in vivo induction of serum IFN-γ and/or IL-4 by the potent NKT cell agonist α-galactosylceramide and reduces NKT cell helper activity for IgG secretion. Treatment of NZB/W mice with the β-galactosylceramide ameliorated lupus disease activity as judged by improvement in proteinuria, renal histopathology, IgG anti-dsDNA antibody formation, and survival. In conclusion, β-galactosylceramide, a glycolipid that reduces the cytokine secretion induced by a potent NK T cell agonist ameliorates lupus in NZB/W mice.
doi:10.1016/j.clim.2009.05.018
PMCID: PMC2720447  PMID: 19564135
Innate Immunity; NK T Cells; T Cells; Systemic Lupus Erythematosus
7.  Natural killer T cells and innate immune B cells from lupus-prone NZB/W mice interact to generate IgM and IgG autoantibodies 
European journal of immunology  2008;38(1):156-165.
Summary
Lupus-prone NZB/W F1 mice develop glomerulonephritis after T helper cell dependent isotype switching of autoantibody secretion from IgM to IgG at about six months of age. We compared innate immune natural killer (NK) T cells and conventional T cells for their capacity to help spontaneous in vitro immunoglobulin and autoantibody secretion of innate immune (B-1 and marginal zone) and conventional (follicular) B cell subsets from NZB/W F1 mice. We found that purified NKT cells not only increased spontaneous secretion of IgM and IgM anti-dsDNA antibodies by B-1 and marginal zone B cells, but also facilitated secretion of IgG anti-dsDNA antibodies predominantly by B-1 B cells. Little IgM or IgG anti-dsDNA antibodies was secreted by follicular B cells, and conventional T cells failed to provide potent helper activity to any B cell subset. All combinations of T and B cell subsets from normal C57BL/6 mice failed to generate vigorous IgM and IgG secretion. NZB/W NKT cell helper activity was blocked by anti-CD1 and anti-CD40L mAbs. In conclusion, direct interactions between innate immune T and B cells form a pathway for the development of IgM and IgG lupus autoantibody secretion in NZB/W mice.
doi:10.1002/eji.200737656
PMCID: PMC2915938  PMID: 18050273
B cells; T cells; Systemic lupus erythematosus; Autoantibodies
8.  LOCALIZATION OF THE SITES AND CHARACTERIZATION OF THE MECHANISMS BY WHICH ANTI-LIGHT CHAIN ANTIBODIES NEUTRALIZE THE ACTIONS OF THE BOTULINUM HOLOTOXIN 
Vaccine  2009;27(19):2616-2624.
The recombinant, catalytically active light chain of botulinum toxin type A was evaluated as a potential vaccine candidate. Previous studies have shown that the light chain can elicit protective immunity in vivo. [5], but the underlying basis for this observation was not determined. In the present study, antibodies directed against the light chain were shown to act at three different sites in the body to produce neutralization. Firstly, these antibodies acted to block toxin absorption into the body. This was demonstrated in vitro, in studies on binding and transport of toxin across epithelial monolayers, and in vivo, in studies on inhalation poisoning. Secondly, anti-light chain antibodies acted to promote clearance of toxin from the general circulation. This was demonstrated in vivo in studies on toxin levels in blood and in parallel studies on toxin accumulation in liver and spleen. Finally, anti-light chain antibodies acted to protect cholinergic nerves from botulinum toxin action. This was demonstrated in two types of in vitro assays: rate of paralysis of murine phrenic nerve-hemidiaphragm preparations and extent of binding to Neuro-2a cells. When taken together, these data show that anti-light chain antibodies can evoke three layers of protection against botulinum toxin.
doi:10.1016/j.vaccine.2009.02.051
PMCID: PMC2709450  PMID: 19428868
Botulinum toxin; Botulism vaccine; Neutralization
9.  Comparison of temporal changes in psychological distress after hematopoietic stem cell transplantation among the underlying diseases of Japanese adult patients 
Background
Although hematopoietic stem cell transplantation (HSCT) can potentially cure some hematological malignancies, patients who undergo HSCT experience psychological distress. However, there have been few studies on the short-term influence of HSCT on psychological distress.
Methods
The subjects were 71 patients with hematological malignancies who underwent HSCT: 33 with acute leukemia, 19 with chronic leukemia, nine with myelodysplastic syndrome, and 10 with malignant lymphoma. Psychological distress was assessed prior to HSCT and on the seventh day after HSCT using the Profile of Mood States (POMS).
Results
With regard to Anger-Hostility, the interaction of time (pre- and post-HSCT) and group (the four groups) was significant in male patients (p = 0.04), but not in female patients. With regard to the other subscales of POMS, there was no significant main effect or interaction in male or female patients.
Conclusion
It may be important to provide psychological support to patients throughout the period of HSCT in consideration of differences in mood changes associated with the underlying disease and patient sex in order to provide efficient psychiatric intervention for both better psychiatric and survival outcomes.
doi:10.1186/1751-0759-2-24
PMCID: PMC2603014  PMID: 19025589
10.  Neutralization of Botulinum Neurotoxin by a Human Monoclonal Antibody Specific for the Catalytic Light Chain 
PLoS ONE  2008;3(8):e3023.
Background
Botulinum neurotoxins (BoNT) are a family of category A select bioterror agents and the most potent biological toxins known. Cloned antibody therapeutics hold considerable promise as BoNT therapeutics, but the therapeutic utility of antibodies that bind the BoNT light chain domain (LC), a metalloprotease that functions in the cytosol of cholinergic neurons, has not been thoroughly explored.
Methods and Findings
We used an optimized hybridoma method to clone a fully human antibody specific for the LC of serotype A BoNT (BoNT/A). The 4LCA antibody demonstrated potent in vivo neutralization when administered alone and collaborated with an antibody specific for the HC. In Neuro-2a neuroblastoma cells, the 4LCA antibody prevented the cleavage of the BoNT/A proteolytic target, SNAP-25. Unlike an antibody specific for the HC, the 4LCA antibody did not block entry of BoNT/A into cultured cells. Instead, it was taken up into synaptic vesicles along with BoNT/A. The 4LCA antibody also directly inhibited BoNT/A catalytic activity in vitro.
Conclusions
An antibody specific for the BoNT/A LC can potently inhibit BoNT/A in vivo and in vitro, using mechanisms not previously associated with BoNT-neutralizing antibodies. Antibodies specific for BoNT LC may be valuable components of an antibody antidote for BoNT exposure.
doi:10.1371/journal.pone.0003023
PMCID: PMC2515629  PMID: 18714390
11.  Isolation of a Human Monoclonal Antibody with Strong Neutralizing Activity against Diphtheria Toxin  
Infection and Immunity  2006;74(6):3682-3683.
We isolated a human monoclonal antibody against diphtheria toxin (DT). It bound to fragment B with a binding activity (Kd) of 3.01 nM. The neutralizing activity assayed by the rabbit skin test was estimated to be 73,600 IU/g. This could be used as a therapeutic drug against DT in place of the traditional equine sera.
doi:10.1128/IAI.01731-05
PMCID: PMC1479265  PMID: 16714603
12.  Ligand-independent Dimer Formation of Epidermal Growth Factor Receptor (EGFR) Is a Step Separable from Ligand-induced EGFR Signaling 
Molecular Biology of the Cell  2002;13(7):2547-2557.
Dimerization and phosphorylation of the epidermal growth factor (EGF) receptor (EGFR) are the initial and essential events of EGF-induced signal transduction. However, the mechanism by which EGFR ligands induce dimerization and phosphorylation is not fully understood. Here, we demonstrate that EGFRs can form dimers on the cell surface independent of ligand binding. However, a chimeric receptor, comprising the extracellular and transmembrane domains of EGFR and the cytoplasmic domain of the erythropoietin receptor (EpoR), did not form a dimer in the absence of ligands, suggesting that the cytoplasmic domain of EGFR is important for predimer formation. Analysis of deletion mutants of EGFR showed that the region between 835Ala and 918Asp of the EGFR cytoplasmic domain is required for EGFR predimer formation. In contrast to wild-type EGFR ligands, a mutant form of heparin-binding EGF-like growth factor (HB2) did not induce dimerization of the EGFR-EpoR chimeric receptor and therefore failed to activate the chimeric receptor. However, when the dimerization was induced by a monoclonal antibody to EGFR, HB2 could activate the chimeric receptor. These results indicate that EGFR can form a ligand-independent inactive dimer and that receptor dimerization and activation are mechanistically distinct and separable events.
doi:10.1091/mbc.01-08-0411
PMCID: PMC117333  PMID: 12134089

Results 1-12 (12)