[Clinicopathologic and prognosis features of Claudin-low breast cancers].

Objective: To investigate the clinicopathologic and prognostic features of Claudin-low breast cancers (CLBC). Methods: Tissue microarray sections were scored semiquantitatively for the immunohistochemical expression of claudin-1, -3, -4, -7 and -8 in 233 cases of invasive breast cancers collected from Qingdao Central Hospital from January 2010 to December 2011. Results: The expression rate of Claudin-3 (72/212, 33.9%) and -4 (56/212, 45.2%) was most similar, and Claudin-4 showed the highest expression. Twenty one cases (21/212, 9.0%) were diagnosed as CLBC, with triple-negative breast cancer (TNBC) accounted for the highest proportion (11/21, 52.4%). Among the CLBC cases, the invasive carcinoma no special type (66.7%, 14/21) and metaplastic carcinoma (14.3%, 3/21) were mostly seen, while metaplastic squamous carcinoma did not show Claudin-low pattern. Compared to the non CLBC in this cohort, CLBC had higher proportion of histologic grade 3 and tumors larger than 2 cm, and the proportions were slightly lower than TNBC. Patients with CLBC had lower 5 year disease-free(P>0.05) and overall survival rates(P=0.018). Conclusion: CLBC shows distinct clinicopathologic and prognostic features comparing to other subtypes, and is associated with poor prognosis.

Difference in resting-state fractional amplitude of low-frequency fluctuation between bipolar depression and unipolar depression patients.

OBJECTIVE: To investigate the difference in fractional amplitude of low-frequency fluctuation (fALFF) of localized brain activities in the resting-state between bipolar depression and unipolar depression patients and to find biological markers that differentiate the two groups of patients. PATIENTS AND METHODS: Thirteen patients with bipolar depression, 15 patients with unipolar depression, and 16 healthy control subjects that were matched in age and years of education were subjected to 3.0 T resting-state functional magnetic resonance scans. The values of whole brain fALFF were calculated and statistical analysis was performed. RESULTS: The fALFF-values of the right inferior temporal gyrus, left cerebellar posterior lobe, right middle temporal gyrus, left inferior frontal gyrus/insula, right inferior frontal gyrus/insula, left lingual gyrus and right middle temporal gyrus of the three groups showed significant differences (p < 0.05). Compared with the healthy control (HC) group, the fALFF-values of the unipolar depression (UD) patient group significantly increased in the right superior temporal gyrus, left insula, left inferior frontal gyrus, right inferior frontal gyrus, right supramarginal gyrus and right medial frontal gyrus but significantly decreased in the right medial occipital gyrus, left frontal lobe, right superior parietal lobule; the fALFF-values of the bipolar depression (BD) patient group significantly decreased in the left cerebellum posterior lobe, right lingual gyrus, left lingual gyrus, right middle temporal gyrus, left middle temporal gyrus, and left superior frontal gyrus and significantly increased in the right inferior frontal gyrus and left insula compared to those of the HC group; compared with those of the UD group, the fALFF-values of the BD group significantly decreased in the left middle occipital gyrus, right middle temporal gyrus, left middle frontal gyrus, and left medial frontal gyrus. CONCLUSIONS: The brain activities of BD and UD patients in the resting-state exhibit abnormalities, which differ between the two groups of patients.

Allopregnanolone enhances the neurogenesis of midbrain dopaminergic neurons in APPswe/PSEN1 mice.

An earlier study has demonstrated that exogenous allopregnanolone (APα) can reverse the reduction of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc) of 3-month-old male triple transgenic Alzheimer's disease mouse (3xTgAD). This paper is focused on further clarifying the origin of these new-born TH-positive neurons induced by exogenous APα treatment. We performed a deeper research in another AD mouse model, 4-month-old male APPswe/PSEN1 double transgenic AD mouse (2xTgAD) by measuring APα concentration and counting immunopositive neurons using enzyme-linked immunosorbent assay (ELISA) and unbiased stereology. It was found that endogenous APα level and the number of TH-positive neurons were reduced in the 2xTgAD mice, and these reductions were present prior to the appearance of ß-amyloid (Aß)-positive plaques. Furthermore, a single 20mg/kg of exogenous APα treatment prevented the decline of total neurons, TH-positive neurons and TH/bromodeoxyuridine (BrdU) double-positive neurons in the SNpc of 2xTgAD mice although the decreased intensity of TH-positive fibers was not rescued in the striatum. It was also noted that exogenous APα administration had an apparent increase in the doublecortin (DCX)-positive neurons and DCX/BrdU double-positive neurons of subventricular zone (SVZ), as well as in the percentage of neuronal nuclear antigen (NeuN)/BrdU double-positive neurons of the SNpc in the 2xTgAD mice. These findings indicate that a lower level of endogenous APα is implicated in the loss of midbrain dopaminergic neurons in the 2xTgAD mice, and exogenous APα-induced a significant increase in the new-born dopaminergic neurons might be derived from the proliferating and differentiation of neural stem niche of SVZ.

Echinosporins as new cell cycle inhibitors and apoptosis inducers from marine-derived Streptomyces albogriseolus.

Bioassay-guided fractionation of the ethyl acetate extract from the fermentation broth of marine-derived Streptomyces albogriseolus A2002 led to the isolation of echinosporin (1) and 7-deoxyechinosporin (2). Compound 1 inhibited the proliferation of tsFT210, K562 and HCT-15 cancer cells (IC(50) 91.5 microM, 25.1 microM and 247 microM respectively) and 2 showed the same effect on K562 cells (IC(50) 143 microM). Flow cytometric analysis suggested that 1 and 2 exert their anti-proliferative effects on those cells through inhibiting cell cycle at the G(2)/M phase and inducing apoptosis.

Effects of two antiprogestins on early pregnancy in the long-tailed macaque (Macaca fascicularis).

The abortifacient effects of mifepristone and HRP 2000 were compared in gravid long-tailed macaques. Thirty-six animals were studied with treatment administered either by the oral (0.5 or 5.0 mg/kg; N = 5 per antiprogestin per dose) or intramuscular (i.m.) routes (0.5 mg/kg; N = 5 per antiprogestin) on gestational days (GD) 23-26; six vehicle controls were included. Blood samples were collected for assay of progesterone (P4) and each of the antiprogestins (pre-treatment, daily GD 23-28, every other day GD 30-40), and animals were monitored sonographically throughout gestation. Results of these studies indicated high rates of abortion with i.m. administration (3/5 mifepristone, 4/5 HRP 2000) and 5.0 mg/kg oral route (4/5, 2/5, respectively), with less effects noted at oral doses of 0.5 mg/kg (2/5, 0/5, respectively). No early abortions were observed in the control groups. Following daily i.m. treatment, peak levels of 8-16 ng/ml mifepristone were detected whereas 6-10 ng/ ml of HRP 2000 were noted (GD 26-27). No serum levels of mifepristone were detected following either of the oral doses whereas serum levels of 2-6 ng/ml HRP 2000 were noted with high dose oral administratation. Results of these studies suggest: (1) both antiprogestins are roughly comparable in terminating early pregnancy although HRP 2000 may be more efficacious when administered i.m. whereas mifepristone may be more effective when administered orally; (2) similar levels of biological activity are seen with the i.m. and high dose oral dosing regimens, with little or no activity with the oral low dose; and (3) infants resulting from surviving pregnancies were not affected by early gestation exposure.

PIP: The primary objective was to compare the relative potencies of mifepristone and another newly synthesized antiprogestin, HRP 2000 (17-alpha-acetoxy-11-beta-[4-N,N-dimethylaminophenyl]-pregna-4,9- diene-3,20-dione) in terminating early pregnancy in gravid long-tailed macaques. 36 animals were studied with treatment administered either by the oral (0.5 or 5.0 ng/kg; N = 5 per antiprogestin per dose) or intramuscular (im) routes (0.5 ng/kg; N = 5 per antiprogestin) on gestational days (GD) 23-26; 6 vehicle controls were included. Blood samples were collected for assay of progesterone (P4) and each of the antiprogestins (pre-treatment, daily GD 23-28, every other day GD 30-40), and the animals were monitored sonographically throughout gestation. Results of these studies indicated high rates of abortion with im administration (3/5 mifepristone, 4/5 HRP 2000) and the 5.0 mg/kg oral route (4/5, 2/5, respectively), with less effects noted at oral doses of 0.5 mg/kg (2/5, 0/5, respectively). No early abortions were observed in the control groups. Following daily im treatment, peak levels of 8-16 ng/ml mifepristone were detected, whereas 6-10 ng/ml of HRP 2000 were noted (GD 26-27). No serum levels of mifepristone were detected following either of the oral doses, whereas serum levels of 2-6 ng/ml HRP 2000 were noted with high-dose oral administration. Results of these studies suggest: 1) both antiprogestins are roughly comparable in terminating early pregnancy, although HRP 2000 may be more efficacious when administered im, whereas mifepristone may be more effective when administered orally; 2) similar levels of biological activity are seen with the im and high-dose oral dosing regimens, with little or no activity with the oral low dose; and 3) infants resulting from surviving pregnancies were not affected by early gestation exposure.

Tamoxifen as an antifertility agent in the long-tailed macaque (Macaca fascicularis).

The potential use of tamoxifen, a nonsteroidal antiestrogen, as an antifertility agent was studied in the long-tailed macaque (Macaca fascicularis). Twenty-six cycling females were bred, then treated with a single oral dose of tamoxifen (5 mg/kg) (N = 13) or vehicle (N = 13) on day 4 post-ovulation. Serum progesterone (P4) and tamoxifen concentrations were evaluated on post-ovulation days 4, 8, 12, 16, and 18. No effects of treatment were observed on P4 concentrations or on the fertility rate--pregnancy was achieved in 4/13 controls (31%) and 6/13 treated females (46%). Analysis for serum tamoxifen concentrations in samples collected during the fertility and a supplemental pharmacokinetic study (N = 3; single oral dose of 10 mg/kg; urine and serum evaluated) failed to reveal any detectable tamoxifen levels. It was concluded that (1) absorption of tamoxifen may be negligible under the described treatment regimens or (2) tamoxifen metabolism/clearance occurs at a rapid rate.

(2R), (1'R) and (2R), (1'S)-2-amino-3-(1,2-dicarboxyethylthio)propanoic acids from Amanita pantherina. Antagonists of N-methyl-D-aspartic acid (NMDA) receptors.

An antagonist of NMDA-sensitive glutamate receptors in rat brain membrane and rat spinal motoneurones was isolated from Amanita pantherina and identified as a diastereoisomeric mixture of 2-amino-3-(1,2-dicarboxyethylthio)propanoic acids. The mixture was separated and the absolute configurations of the components were determined as (2R), (1'R) and (2R), (1'S), by analysis of the optical properties.