DOES PHYSICAL EXERCISE INCREASE BRAIN-DERIVED NEUROTROPHIC FACTOR IN MAJOR DEPRESSIVE DISORDER? A META-ANALYSIS

Background: Major depressive disorder (MDD) is one of the most common disorders in the world, but is generally refractory to antidepressant treatment. However, physical exercise has been demonstrated to improve MDD symptoms, though the mechanism through which this is achieved is not clear. This systematic review and meta-analysis aimed to clarify whether physical exercise increased brainderived neurotrophic factor (BDNF) in patients with MDD to either establish or rule out this effect as a possible mechanism. Subjects and methods: We searched five electronic databases (PubMed, PsycINFO, CHINAL, Cochran Library, and Japanese Central Review of Medicine) for interventional studies released prior to 24 October 2017, examining the effects of physical exercise on BDNF in patients with MDD that compared the experimental group with an MDD control group. Those studies meeting the inclusion criteria were subjected to a meta-analysis in which changes of BDNF from baseline to post-exercise were quantified, with a standard mean difference and random effect model. Results: Five studies were eligible and included 199 participants. All articles included subjects with severe symptoms; three articles studied inpatient populations. All articles introduced aerobic exercise. We found no significant effect of physical exercise on BDNF levels (Z=0.32, p=0.75), and no heterogeneity (I2=0%). The risk of bias was moderate. Conclusions: We conclude that physical exercise does not significantly increase BDNF in patients with MDD. Thus, while increased BDNF has been shown to be beneficial in patients with MDD, physical exercise likely produces its benefits through a different mechanism. However, the small number of included articles and lack of multiple reviewers increase the risk of the result being a false negative

Analysis of Clinical Outcome of Patients with Poorly Differentiated Thyroid Carcinoma

Background. We retrospectively analyzed whether poor differentiation is the independent prognostic factor for thyroid carcinoma or not. Methods. The subjects were 29 patients with PDTC who were treated between April 1996 and March 2006 to compare with those of well-differentiated papillary carcinoma patients (n = 227). Results. The relapse free (RFS), distant relapse-free survival and cause-specific survival, rates were significantly lower in patients with PDTC (P < .0001, P < .001, and P < .05). After classification into focal (<10%) and diffuse type (over 10%) of PDTC, there were no significant differences in RFS and cause-specific survival due to component type or proportion of poorly differentiated component. On multivariate analysis, poor differentiation (P < .0005, RR = 4.456, 95% CI; 1.953–10.167) and extrathyroidal infiltration (P < .05, RR = 2.898, 95% CI; 1.278–6.572) showed a significant impact on DFS, and poor differentiation (P < .05, RR = 9.343, 1.314–66.453) and age (P < .005, RR = 1.306, 1.103–1.547) significantly impacted cause-specific survival. Conclusion. Poor differentiation was an independent factor for survival. Distant relapse was significantly more common among PDTC patients, and systemic therapy might be warranted

Aberrantly methylated genes in human papillary thyroid cancer and their association with BRAF/RAS mutation

Cancer arises through accumulation of epigenetic and genetic alteration. Aberrant promoter methylation is a common epigenetic mechanism of gene silencing in cancer cells. We here performed genome-wide analysis of DNA methylation of promoter regions by Infinium HumanMethylation27 BeadChip, using 14 clinical papillary thyroid cancer samples and 10 normal thyroid samples. Among the 14 papillary cancer cases, 11 showed frequent aberrant methylation, but the other three cases showed no aberrant methylation at all. Distribution of the hypermethylation among cancer samples was non-random, which implied existence of a subset of preferentially methylated papillary thyroid cancer. Among 25 frequently methylated genes, methylation status of six genes (HIST1H3J, POU4F2, SHOX2, PHKG2, TLX3, HOXA7) was validated quantitatively by pyrosequencing. Epigenetic silencing of these genes in methylated papillary thyroid cancer cell lines was confirmed by gene re-expression following treatment with 5-aza-2′-deoxycytidine and trichostatin A, and detected by real-time RT-PCR. Methylation of these six genes was validated by analysis of additional 20 papillary thyroid cancer and 10 normal samples. Among the 34 cancer samples in total, 26 cancer samples with preferential methylation were significantly associated with mutation of BRAF/RAS oncogene (P = 0.04, Fisher's exact test). Thus, we identified new genes with frequent epigenetic hypermethylation in papillary thyroid cancer, two subsets of either preferentially methylated or hardly methylated papillary thyroid cancer, with a concomitant occurrence of oncogene mutation and gene methylation. These hypermethylated genes may constitute potential biomarkers for papillary thyroid cancer

Role of the expression of collagen prolyl-4-hydroxylase α subunits 1 and 2 in the development and prognosis of breast cancer

　Background: The expression of prolyl-4-hydroxylase (P4H), an enzyme involved in collagen biosynthesis, is significantly upregulated during breast cancer development and progression. However, the molecular mechanisms by which P4H expression in cancer cells induces progression have not been elucidated. Thus, we aimed to determine the significance of the expression of isoforms 1 and 2 of P4H in breast cancer.　Methods: We performed immunohistochemical analysis for P4HA1 and P4HA2 on the tumor samples obtained from 182 patients with breast cancer and examined the correlation between clinicopathological factors and markers related to epithelial-mesenchymal transition and ischemia. Protein expression levels were investigated using western blotting. In addition, breast cancer cell cultures were used to characterize the expression.　Results: Expression of both P4HA1 and P4HA2 was upregulated in cancer cells compared with that in normal mammary glands; the high-P4H expression group tended to have a poorer prognosis than the low-P4H expression group. In particular, P4HA2 was strongly associated with tumor grade; P4HA2 expression showed a weak negative correlation with HIF-2α expression. In cultured breast cancer cells, the immunohistological expression of P4H and HIF increased tovarious degrees under hypoxia, while P4H protein levels increased in a time-dependent manner. 　Conclusion: P4HA2 can be used as a marker of breast cancer grade and a prognostic factor. Differential expression of P4HA1 and P4HA2 was observed in an ischemic environment,suggesting that each may be affected by the type of collagen involved

Preferential antitumor effect of the Src inhibitor dasatinib associated with a decreased proportion of aldehyde dehydrogenase 1-positive cells in breast cancer cells of the basal B subtype

<p>Abstract</p> <p>Background</p> <p>Recent studies have suggested that the Src inhibitor dasatinib preferentially inhibits the growth of breast cancer cells of the basal-like subtype. To clarify this finding and further investigate combined antitumor effects of dasatinib with cytotoxic agents, a panel of breast cancer cell lines of various subtypes was treated with dasatinib and/or chemotherapeutic agents.</p> <p>Methods</p> <p>Seven human breast cancer cell lines were treated with dasatinib and/or seven chemotherapeutic agents. Effects of the treatments on c-Src activation, cell growth, cell cycle, apoptosis and the proportion of aldehyde dehydrogenase (ALDH) 1-positive cells were examined.</p> <p>Results</p> <p>The 50%-growth inhibitory concentrations (IC₅₀s) of dasatinib were much lower in two basal B cell lines than those in the other cell lines. The IC₅₀s of chemotherapeutic agents were not substantially different among the cell lines. Dasatinib enhanced antitumor activity of etoposide in the basal B cell lines. Dasatinib induced a G1-S blockade with a slight apoptosis, and a combined treatment of dasatinib with etoposide also induced a G1-S blockade in the basal B cell lines. Dasatinib decreased the expression levels of phosphorylated Src in all cell lines. Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines.</p> <p>Conclusions</p> <p>The present study indicates that dasatinib preferentially inhibits the growth of breast cancer cells of the basal B subtype associated with a significant loss of putative cancer stem cell population. A combined use of dasatinib with etoposide additively inhibits their growth. Further studies targeting breast cancers of the basal B subtype using dasatinib with cytotoxic agents are warranted.</p

Anti-cancer stem cell activity of the Src inhibitor dasatinib in thyroid cancer cells

Although the prognosis of differentiated thyroid cancer (DTC) is good, those of poorly-differentiated and undifferentiated thyroid cancers (PDTC and UDTC) are poor. Recent preclinical studies have suggested that the Src inhibitor dasatinib is active in thyroid cancer cell lines. We conducted the present study in an attempt to clarify the antitumor activity of dasatinib in PDTC and UDTC. The expression levels of c-Src, phosphorylated Srcs (p-SrcY416 and p-SrcY527), focal adhesion kinase (FAK), and phosphorylated FAK (p-FAKY861) were immunohistochemically investigated in a case-control series (15 cases of PDTC or UDTC vs. 29 control cases of DTC). The PDTC cell line KTC-1 and UDTC cell line KTC-2 were used to investigate the anticell growth and anti-cancer stem cell (CSC) activities of dasatinib. The combined effects of dasatinib and the taxane paclitaxel on anti-cell growth and anti-CSC activities were also tested. c-Src and p-FAKY861 expression levels were significantly higher, while those of p-SrcY416 were slightly higher in PDTC and UDTC than in DTC. Dasatinib inhibited cell growth in association with G1-S cell cycle retardation and increased apoptosis in both cell lines. Dasatinib significantly decreased the proportion of CSCs and more than additively enhanced the anti-cell growth activity of paclitaxel. The results of this study suggest that the Src signaling pathway is activated more in PDTC and UDTC than in DTC. The Src inhibitor dasatinib exhibited anti-cell growth and anti-CSC activities. Furthermore, it more than additively enhanced the anti-cell growth activity of paclitaxel

Technetium-99m Methoxyisobutyl Isonitrile Scintigraphy of Bone Metastasis in Three Patients with Differentiated Thyroid Cancer

We studied the usefulness of ^Tc-methoxyisobutyl isonitrile (MIBI) scintigraphy in the detection of bone metastases and in evaluation of therapeutical response to ^I-Na in three patients with differentiated thyroid cancer. On ^Tc-MIBI scintigraphy, increased accumulations were observed in all bone metastatic lesions (14 lesions), whereas on bone scintigraphy using ^Tc-hydroxymethylene diphosphonate (^Tc-HMDP) both increased (eight lesions, 57%) and decreased (six lesions, 43%) accumulations were observed. Within two months after ^I-Na treatment, all 14 lesions were unchanged on bone scintigraphy. However, on ^Tc-MIJBI scintigraphy, disappearance of uptake (six lesions, 43%) and decreased uptake (seven lesions, 50%) were observed in 13/14 lesions (93%). Therefore, ^Tc-MIBI scintigraphy was useful not only in the detection of bone metastatic lesions but also in evaluation of the therapeutical response to ^I-Na in differentiated thyroid cancer