Autonomous and intercellular chemokine signaling elicited from mesenchymal stem cells regulates migration of undifferentiated gastric cancer cells.

Accumulating evidence demonstrates that bone marrow (BM)-derived mesenchymal stem cells (MSCs) play critical roles in regulating progression of various types of cancer. We have previously shown that Wnt5a-Ror2 signaling in MSCs induces expression of CXCL16, and that CXCL16 secreted from MSCs then binds to its cognate receptor CXCR6 on the surface of an undifferentiated gastric cancer cell line MKN45 cells, eventually leading to proliferation and migration of MKN45 cells. However, it remains unclear about a possible involvement of another (other) cytokine(s) in regulating progression of gastric cancer. Here, we show that CXCL16-CXCR6 signaling is also activated in MSCs through cell-autonomous machinery, leading to upregulated expression of CCL5. We further show that CCR1 and CCR3, receptors of CCL5, are expressed on the surface of MKN45 cells, and that CCL5 secreted from MSCs promotes migration of MKN45 cells presumably via its binding to CCR1/CCR3. These data indicate that cell-autonomous CXCL16-CXCR6 signaling activated in MSCs upregulates expression of CCL5, and that subsequent activation of CCL5-CCR1/3 signaling in MKN45 cells through intercellular machinery can promote migration of MKN45 cells. Collectively, these findings postulate the presence of orchestrated chemokine signaling emanated from MSCs to regulate progression of undifferentiated gastric cancer cells.

[Surgical Dissection for an Abdominal Para-Aortic Lymph Node Recurrence after Curative Resection for Early Gastric Cancer - Report of a Case].

A 72-year-old man underwent endoscopic submucosal dissection for early gastric cancer at antrum in July 2015. The histopathological examination revealed an adenocarcinoma invading the deep submucosal layer(SM2)with lymphatic invasion, consistent with the diagnosis of non-curative resection. Additional surgery was recommended, and he underwent laparoscopic distal gastrectomy in August 2015. The histopathological examination of resected specimen revealed there were no lymph node metastases, and postoperative diagnosis was Stage I A. However, 8 months after the surgery, abdominal enhanced computed tomography(CT)revealed an enlargement of para-aortic lymph node. Positron emission tomography-CT showed high accumulation at the enlarged lymph node. A para-aortic lymph node metastasis was suspected, and laparoscopic lymph node dissection was performed in July 2016. The histopathological examination revealed lymph node metastasis of gastric cancer. He was given systematic chemotherapy using S-1 plus cisplatin after the surgery, and has been followed-up without recurrences for 21 months after the first operation. Although recurrence of the para-aortic lymph nodes was assumed as part of a systemic metastasis, some population certainly benefit from multidisciplinary treatment including surgical approach.

[A Case of Recurrent Colorectal Cancer with Bilateral Ovarian Metastases That Were Reduced with Regorafenib Therapy].

A 63-year-old woman had recurrences of metastatic rectal cancer in the lung, peritoneum, and ovary. Regorafenib was administered at 160mg/day as third-line chemotherapy. The patient developed Grade(Gr)3 hand-foot syndrome(HFS) and Gr 2 rash, but the abdominal distension and pain were relieved by the 1st course. Analgesics could be reduced and regorafenib was administrated at reduced dosage. The patient received keishi-bukuryo-gan(EK-25)and sai-rei-tou(TJ-114) for HFS. At the beginning of therapy, ovarian metastases were not reduced and showed poor contrast enhancement on CT. Serum levels of lactate dehydrogenase(LDH)and tumor markers were increased. During the 4th course of therapy, ovarian metastases tended to shrink and serum levels of LDH and tumor markers were decreased. Ovarian metastases showed a partial response(PR)after the 6th course. Lung metastases showed a progressive disease during the 2nd course, but a PR after the 3rd course, and were not apparent after the 6th course. Reduction of metastases was maintained at 16 months after the start of therapy, and HFS was assessed at Gr 2 or lower. Physical, laboratory, and imaging findings should be carefully evaluated prior to long-term administration of regorafenib.

Effects of Fe3O4 Magnetic Nanoparticles on A549 Cells.

Fe3O4 magnetic nanoparticles (MgNPs-Fe3O4) are widely used in medical applications, including magnetic resonance imaging, drug delivery, and in hyperthermia. However, the same properties that aid their utility in the clinic may potentially induce toxicity. Therefore, the purpose of this study was to investigate the cytotoxicity and genotoxicity of MgNPs-Fe3O4 in A549 human lung epithelial cells. MgNPs-Fe3O4 caused cell membrane damage, as assessed by the release of lactate dehydrogenase (LDH), only at a high concentration (100 µg/mL); a lower concentration (10 µg/mL) increased the production of reactive oxygen species, increased oxidative damage to DNA, and decreased the level of reduced glutathione. MgNPs-Fe3O4 caused a dose-dependent increase in the CD44+ fraction of A549 cells. MgNPs-Fe3O4 induced the expression of heme oxygenase-1 at a concentration of 1 µg/mL, and in a dose-dependent manner. Despite these effects, MgNPs-Fe3O4 had minimal effect on cell viability and elicited only a small increase in the number of cells undergoing apoptosis. Together, these data suggest that MgNPs-Fe3O4 exert little or no cytotoxicity until a high exposure level (100 µg/mL) is reached. This dissociation between elevated indices of cell damage and a small effect on cell viability warrants further study.

Depressive states in healthy subjects lead to biased processing in frontal-parietal ERPs during emotional stimuli.

Subthreshold depressive (sD) states and major depression are considered to occur on a continuum, and there are only quantitative and not qualitative differences between depressive states in healthy individuals and patients with depression. sD is showing a progressively increasing prevalence and has a lifelong impact, and the social and clinical impacts of sD are no less than those of major depressive disorder (MDD). Because depression leads to biased cognition, patients with depression and healthy individuals show different visual processing properties. However, it remains unclear whether there are significant differences in visual information recognition among healthy individuals with various depressive states. In this study, we investigated the event-related potentials (ERPs) and event-related spectrum perturbation (ERSP) of healthy individuals with various depressive states during the perception of emotional visual stimulation. We show that different neural activities can be detected even among healthy individuals. We divided healthy participants into high, middle, and low depressive state groups and found that participants in a high depressive state had a lower P300 amplitude and significant differences in fast and slow neural responses in the frontal and parietal lobes. We anticipate our study to provide useful parameters for assessing the evaluation of depressive states in healthy individuals.

Apical functionalization of chiral heterohelicenes.

We describe a synthetic protocol to selectively functionalize chiral bridged triarylamines at the apical position using regioselective copper-catalyzed amination reaction. This protocol allows the coupling of diphenylamines with a sterically hindered but electronically activated aryl-Br bond in the presence of a sterically unhindered but electronically unactivated aryl-Br bond. The unactivated aryl-Br bond was utilized further to synthesize a chiral heterohelicene homodimer using Stille coupling.

Risk Factors for Complications Following Lateral Pelvic Lymph Node Dissection for Rectal Cancer.

BACKGROUND: Lateral pelvic lymph node metastasis impairs the oncological outcomes of patients with rectal cancer. Although lateral pelvic lymph node dissection (LLND) might be an effective procedure for such patients, the associated risk factors for postoperative complications are unknown. PATIENTS AND METHODS: The operative outcomes of 21 patients undergoing unilateral LLND and 26 patients undergoing bilateral LLND for rectal cancer were compared. The risk factors for complications were evaluated using a logistic regression model. RESULTS: Univariate and multivariate analyses revealed that a longer operative time (≥480 min) was the most important risk factor for grade II or more postoperative complications according to the Clavien-Dindo classification (odds ratio=6.58; 95% confidence interval=1.35-32.1; p=0.020). A bilateral procedure was not a significant risk factor for postoperative complications. CONCLUSION: Surgeons should make efforts to shorten the operative time to reduce the risk of postoperative complications.

Smad4 regulates the nuclear translocation of Nkx2-5 in cardiac differentiation.

Bmp plays an important role in cardiomyocyte differentiation, but the function of Smad4 in Bmp signaling remains elusive. Here, we show that disruption of the Smad4 gene in cardiac progenitors expressing Sfrp5 led to embryonic lethality with hypoplastic heart formation. Although the expression of Nkx2-5 is regulated by Bmp signaling, expression of Nkx2-5 was weakly detected in the mutant heart. However, the nuclear translocation of Nkx2-5 was impaired. Expression of CK2 or PP1, which could alter the phosphorylation status of the NLS of Nkx2-5, was not affected, but Nkx2-5 was found to bind to Smad4 by co-immunoprecipitation experiments. Introduction of Smad4 into cells derived from Smad4 conditional knockout embryonic hearts restored the nuclear localization of Nkx2-5, and exogenous Nkx2-5 failed to translocate into the nucleus of Smad4-depleted fibroblasts. These results suggest that Smad4 plays an essential role in cardiomyocyte differentiation by controlling not only transcription but also the nuclear localization of Nkx2-5.

New Proximal Femoral Compaction Blade Provides Strong Antirotation Stability of the Femoral Head.

This study investigated the mechanical properties of a new rectangular compaction blade and compared this blade with other types of nail. Three types of nail were tested: the Magnum lag screw (Robert Reid Inc, Tokyo, Japan), proximal femoral nail, and Magnum Fid blade (Robert Reid Inc). The nails were inserted into solid rigid polyurethane foam, and the torsional moments were loaded with an Instron testing machine (Instron, Kanagawa, Japan). The force curve was recorded, and the average maximum torque was calculated from this curve. A simulation study was performed with finite element models to determine the mechanism underlying differences in rotational stability. Mechanical testing showed that the new compaction blade had stronger resistance against rotational force than the helical blade and lag screw implants. Finite element analysis also showed that the new compaction blade had stronger resistance to migration of the polyurethane foam cylinder than the other implant types. In addition, the new compaction blade had strong rotational stability. This implant should be useful for the treatment of unstable trochanteric fracture in patients with osteoporosis. [Orthopedics. 2017; 40(3):e491-e494.].

Hybridization of polyvinylpyrrolidone to a binary composite of curcumin/α-glucosyl stevia improves both oral absorption and photochemical stability of curcumin.

The tri-component system curcumin/α-glucosyl stevia (Stevia-G)/polyvinylpyrrolidone (PVP) was developed to improve the oral bioavailability and physicochemical properties of curcumin (CUR). The tri-component CUR formulation with Stevia-G and PVP was prepared with freeze-drying. The tri-component CUR system exhibited 13,000-fold higher solubility of CUR than the equilibrium solubility of CUR for 24h, indicating a stable tri-composite structure involving CUR. CUR could be converted into an amorphous form in the presence of Stevia-G and PVP by freeze-drying. The photo-degradation of CUR in the tri-component system was negligible even under an amorphous state of CUR. After oral administration in rats, the oral absorption of the tri-component CUR formulation (20mgCUR/kg) was 6.7-fold higher than that of crystalline CUR. The tri-component CUR formulation would therefore be a promising option to improve physicochemical properties and oral absorption of CUR.

Magnetic nanoparticles of Fe3O4 enhance docetaxel-induced prostate cancer cell death.

Docetaxel (DTX) is one of the most important anticancer drugs; however, the severity of its adverse effects detracts from its practical use in the clinic. Magnetic nanoparticles of Fe3O4 (MgNPs-Fe3O4) can enhance the delivery and efficacy of anticancer drugs. We investigated the effects of MgNPs-Fe3O4 or DTX alone, and in combination with prostate cancer cell growth in vitro, as well as with the mechanism underlying the cytotoxic effects. MgNPs-Fe3O4 caused dose-dependent increases in reactive oxygen species levels in DU145, PC-3, and LNCaP cells; 8-hydroxydeoxyguanosine levels were also elevated. MgNPs-Fe3O4 alone reduced the viability of LNCaP and PC-3 cells; however, MgNPs-Fe3O4 enhanced the cytotoxic effect of a low dose of DTX in all three cell lines. MgNPs-Fe3O4 also augmented the percentage of DU145 cells undergoing apoptosis following treatment with low dose DTX. Expression of nuclear transcription factor κB in DU145 was not affected by MgNPs-Fe3O4 or DTX alone; however, combined treatment suppressed nuclear transcription factor κB expression. These findings offer the possibility that MgNPs-Fe3O4-low dose DTX combination therapy may be effective in treating prostate cancer with limited adverse effects.