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1.  3'-Ethynylcytidine, an RNA polymerase inhibitor, combined with cisplatin exhibits a potent synergistic growth-inhibitory effect via Vaults dysfunction 
BMC Cancer  2014;14(1):562.
We previously reported that 3'-ethynylcytidine (ECyd, TAS-106), an RNA polymerases inhibitor, enhances the anti-tumor efficacy of platinum in several tumor types in both in vitro and in vivo tumor models. However, the molecular mechanisms underlying the ECyd-induced enhancement remain elusive.
Cisplatin (CDDP)-resistant head and neck cancer KB cells were established by stepwise dose escalation with CDDP. The combination effect of ECyd and CDDP were assessed using isobologram analysis. The transcriptional and post-translational statuses of several molecules were detected using real-time PCR, immunoblot analysis and immunocytochemistry. Xenograft assays were used to confirm the mechanisms underlying the ECyd induced enhancement of CDDP anti-tumor efficacy in vivo.
ECyd sensitized KB to CDDP by inhibiting the drug transporter Vault complex (Vaults). First, we showed that Vaults were overexpressed in CDDP-resistant KB cells. The suppression of major vault protein (MVP) by RNA interference restored the sensitivity to CDDP. Next, we showed that ECyd significantly sensitized the resistant cells to CDDP, compared with the parental paired cell line. A molecular analysis revealed that ECyd inhibited the synthesis of vRNAs as well as the induction of MVP, both of which are critical components of Vaults as a drug transporter. Furthermore, we found that the synergistic effect of ECyd and CDDP was correlated with the MVP expression level when the effect was analyzed in additional cancer cell lines. Finally, we demonstrated that ECyd decreased the vRNAs expression level in xenograft tumor.
Our data indicated the ability of ECyd to cancel the resistance of cancer cells to CDDP by inhibiting the Vaults function and the decrease of Vaults expression itself, and the ability of the combination therapy with CDDP and ECyd to offer a new strategy for overcoming platinum resistance. Moreover, the study results suggest that Vaults could be a biomarker for stratifying patients who may benefit from the combination therapy with ECyd and platinum.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-562) contains supplementary material, which is available to authorized users.
PMCID: PMC4131025  PMID: 25087851
ECyd; Vaults; Cisplatin; Biomarker; Resistance
2.  Sex Differences Between cT4b and pT4b Rectal Cancers 
International Surgery  2013;98(3):200-204.
We retrospectively evaluated rectal cancer surgery cases in which resection had been performed for invasion of other organs in terms of pathologic findings from the viewpoint of sex differences. We enrolled 61 consecutive patients with rectal cancer who had undergone curative surgery with resection of invaded adjacent organs. We investigated invasion of adjacent organs in terms of pathologic findings according to sex differences. Among males, 4 cases (13.8%) had received combined radical resections of more than 2 organs, while the number of such female cases was 15 (46.9%). The difference between males and females was statistically significant (P = 0.006). Among male cases, histopathologic invasion was present in 4 (13.8%), while 9 female cases (28.1%) showed this feature. Nevertheless, there was not a statistically significant difference between males and females (P = 0.08); the rate in females was roughly twice that in males. No significant difference was recognized in the overall survival rates between males and females, but more females than males experienced local recurrence. In cases with rectal cancer invading neighboring organs, the effect of the invasion must be carefully determined, and the most appropriate operative approach selected accordingly.
PMCID: PMC3756839  PMID: 23971770
Rectal cancer; Invasion of other organs; Sex differences
3.  Intraoperative Near-infrared Fluorescence Imaging with Novel Indocyanine Green-Loaded Nanocarrier for Spinal Metastasis: A Preliminary Animal Study 
Marginal resection during resection of a spinal metastasis is frequently difficult because of the presence of important tissues such as the aorta, vena cava, and dura mater, including the spinal cord adjacent to the vertebral body. Thus, there is an urgent need for novel intraoperative imaging modalities with the ability to clearly identify bone metastasis. We have proposed a novel nanocarrier loaded with indocyanine green (ICG) (ICG-lactosome) with tumor selectivity attributable to its enhanced permeation and retention (EPR) effect. We studied its feasibility in intraoperative near-infrared (NIR) fluorescence diagnosis with ICG-lactosome for imaging spinal metastasis. A rat model of subcutaneous mammary tumor and a rat model of spinal metastasis of breast cancer were used. Fluorescence emitted by the subcutaneous tumors and the spinal metastasis were clearly detected for at least 24 h. Moreover, imaging of the dissected spine revealed clear fluorescence emitted by the metastatic lesion in the L6 vertebra while the normal bone lacked fluorescence. This study was the first report on NIR fluorescence imaging of spinal metastasis in vivo. NIR fluorescence imaging with ICG-lactosome could be an effective intraoperative imaging modality for detecting spinal metastasis.
PMCID: PMC3391655  PMID: 22787518
Animal study; indocyanine green; intraoperative imaging modality; nanocarrier; near-infrared fluorescence imaging; spinal metastasis.
4.  Crystallization and heavy-atom derivatization of StHsp14.0, a small heat-shock protein from Sulfolobus tokodaii  
A variant of StHsp14.0, a small heat-shock protein from S. tokodaii, has been crystallized. Heavy-atom derivative crystals could be prepared by the cocrystallization method.
Small heat-shock proteins (sHsps) bind and stabilize proteins denatured by heat or other stresses in order to prevent unfavourable protein aggregation. StHsp14.0 is an sHsp found in the acidothermophilic archaeon Sulfolobus tokodaii. A variant of StHsp14.0 was crystallized by the sitting-drop vapour-diffusion method. The crystals diffracted X-rays to 1.85 Å resolution and belonged to space group P21212, with unit-cell parameters a = 40.4, b = 61.1, c = 96.1 Å. The V M value was estimated to be 2.1 Å3 Da−1, assuming the presence of two molecules in the asymmetric unit. Heavy-atom derivative crystals were prepared successfully by the cocrystallization method and are isomorphic to native crystals.
PMCID: PMC2765887  PMID: 19851008
cocrystallization; heavy-atom derivatization; IXI/V motif; small heat-shock proteins; StHsp14.0
5.  Psychological characteristics of Japanese patients with chronic pain assessed by the Rorschach test 
The increasing number of patients with chronic pain in Japan has become a major issue in terms of the patient's quality of life, medical costs, and related social problems. Pain is a multi-dimensional experience with physiological, affective, cognitive, behavioral and social components, and recommended to be managed via a combination of bio-psycho-social aspects. However, a biomedical approach is still the dominant method of pain treatment in Japan. The current study aimed to evaluate comprehensive psychological functions and processes in Japanese chronic pain patients.
The Rorschach Comprehensive System was administered to 49 in-patients with non-malignant chronic pain. Major variables and frequencies from the test were then compared to normative data from non-patient Japanese adults by way of the t-test and chi-square test.
Patients exhibited high levels of emotional distress with a sense of helplessness with regard to situational stress, confusion, and ambivalent feelings. These emotions were managed by the patients in an inappropriate manner. Cognitive functions resulted in moderate dysfunction in all stages. Information processing tended to focus upon minute features in an inflexible manner. Mediational dysfunction was likely to occur with unstable affective conditions. Ideation was marked by pessimistic and less effective thinking. Since patients exhibited negative self-perception, their interpersonal relationship skills tended to be ineffective. Originally, our patients displayed average psychological resources for control, stress tolerance, and social skills for interpersonal relationships. However, patient coping styles were either situation- or emotion-dependent, and patients were more likely to exhibit emotional instability influenced by external stimuli, resulting in increased vulnerability to pain.
Data gathered from the Rorschach test suggested psychological approaches to support chronic pain patients that are likely to be highly beneficial, and we thus recommend their incorporation into the course of current pain treatments.
PMCID: PMC3016376  PMID: 21110860

Results 1-5 (5)