Local Control of Squamous Cell Carcinoma of the Cervix Treated with CT-based Three-dimensional Image-Guided Brachytherapy with or without Central Shielding

The purposes of this retrospective study were to analyze local control of squamous cell carcinoma of the cervix treated with computed tomography (CT)-based image-guided brachytherapy (IGBT), as well as the factors affecting local control. A total of 39 patients were analyzed. The prescribed dose to the pelvis was 45-50 Gy with or without central shielding (CS). IGBT was delivered in 1-5 fractions. The total dose for high-risk clinical target volume (HR-CTV) was calculated as the biologically equivalent dose in 2-Gy fractions. The median follow-up period was 29.3 months. The 2-year overall survival and local control rates were 97% and 91%, respectively. In univariate analysis, the dose covering 90% of the HR-CTV (D90) and tumor size were found to be significant factors for local control. The cutoff values of tumor size and D90 for local control were 4.3 cm (area under the curve [AUC] 0.75) and 67.7 Gy (AUC 0.84) in the CS group and 5.3 cm (AUC 0.75) and 73.7 Gy (AUC 0.78) in the group without CS, respectively. However, though the local control of CT-based IGBT was favorable, the results suggested that the dose required for tumor control may differ depending on the presence of CS

Correction: Suppression of class I compensated cell enlargement by xs2 mutation is mediated by salicylic acid signaling.

[This corrects the article DOI: 10.1371/journal.pgen.1008873.]

Evaluation of the Effects of the Japanese Herbal Medicine “Goreisan” on Traumatic Cerebral Edema in Rats and Identification of Active Ingredients in Cultured Astrocytes

Purpose: Traumatic brain injury is associated with a high mortality rate, and the ensuing cerebral edema further raises the fatality rate. Goreisan（Oryeongsan）, a traditional Japanese herbal Kampo medicine, has been recently shown to be effective against chronic subdural hematoma and cerebral edema associated with tumors or ischemia. However, no study has reported these effects of Goreisan. Thus, we investigated the effect of Goreisan on cerebral edema occurring as a sequela of traumatic brain injury and explored the possible mechanism underlying its activity. Methods: Goreisan was administered to rats after the induction of traumatic brain injury via the open-skull controlled cortical impact method, and brain water content was measured. In astrocyte cultured cells, cellular edema was measured after exposure to Goreisan, Sojutsu（a crude constituent of Goreisan）, and β-eudesmol（an ingredient of Sojutsu）. Results: Seven days after traumatic brain injury surgery, the brain water content of rats treated with Goreisan was significantly lower than that of rats treated with saline（P = 0.0035）. Swelling was significantly suppressed in the Goreisan-, Sojutsu-, and β-eudesmol-exposed groups（P = 0.013, 0.0383, and 0.0010, respectively）. Conclusion: Goreisan appears to be effective in suppressing traumatic cerebral edema, and the effect may be mediated by its components, Sojutsu and β-eudesmol.departmental bulletin pape

Utility of Ki67 labeling index, cyclin D1 expression, and ER-activity level in postmenopausal ER-positive and HER2-negative breast cancer with neoadjuvant chemo-endocrine therapy.

In this study, we investigated the relationships of pathological response after neoadjuvant chemo-endocrine therapy with alterations in the Ki67 labeling index (LI), expression of cyclin D1 (CCND1) and progesterone receptor (PgR), and estrogen receptor (ER) activity in breast cancer. A total of 43 Japanese post-menopausal ER-positive and human epidermal growth factor receptor 2-negative invasive breast cancer patients with tumors >2 cm or positive lymph nodes were enrolled. Exemestane alone was administered for 2 months. Neoadjuvant chemo-endocrine therapy included four cycles of doxorubicin plus paclitaxel followed by weekly paclitaxel. The immunohistochemical expression of Ki67 LI, CCND1, and PgR, and ER activity were evaluated using core needle biopsy samples at the pretreatment and post-exemestane alone stages. ER activity was evaluated through transfection of an adenovirus vector carrying an estrogen-response element-green fluorescent protein gene. In current study, marked pathological responses (including 4.7% with pathological complete response) were obtained in 34.9% of patients. Ki67 LI and PgR expression were significantly decreased after treatment. High Ki67 LI at pretreatment was a significant predictive factor of marked pathological response. At the stage of post-exemestane alone, Ki67 LI was not significantly associated with pathological response; however, high CCND1 expression was significantly correlated with high Ki67 LI. Moreover, low-level ER activity at the post-exemestane alone stage was significantly associated with marked pathological response. In conclusions, pretreatment Ki67 LI was a predictor of response to neoadjuvant chemo-endocrine therapy. CCND1 expression and ER activity at the post-endocrine therapy alone stage may be useful in determining further treatments

Suppression of class I compensated cell enlargement by xs2 mutation is mediated by salicylic acid signaling

The regulation of leaf size has been studied for decades. Enhancement of post-mitotic cell expansion triggered by impaired cell proliferation in Arabidopsis is an important process for leaf size regulation, and is known as compensation. This suggests a key interaction between cell proliferation and cell expansion during leaf development. Several studies have highlighted the impact of this integration mechanism on leaf size determination; however, the molecular basis of compensation remains largely unknown. Previously, we identified extra-small sisters (xs) mutants which can suppress compensated cell enlargement (CCE) via a specific defect in cell expansion within the compensation-exhibiting mutant, angustifolia3 (an3). Here we revealed that one of the xs mutants, namely xs2, can suppress CCE not only in an3 but also in other compensation-exhibiting mutants erecta (er) and fugu2. Molecular cloning of XS2 identified a deleterious mutation in CATION CALCIUM EXCHANGER 4 (CCX4). Phytohormone measurement and expression analysis revealed that xs2 shows hyper activation of the salicylic acid (SA) response pathway, where activation of SA response can suppress CCE in compensation mutants. All together, these results highlight the regulatory connection which coordinates compensation and SA response

Contribution of Estrone Sulfate to Cell Proliferation in Aromatase Inhibitor (AI) -Resistant, Hormone Receptor-Positive Breast Cancer

<div><p>Aromatase inhibitors (AIs) effectively treat hormone receptor-positive postmenopausal breast cancer, but some patients do not respond to treatment or experience recurrence. Mechanisms of AI resistance include ligand-independent activation of the estrogen receptor (ER) and signaling via other growth factor receptors; however, these do not account for all forms of resistance. Here we present an alternative mechanism of AI resistance. We ectopically expressed aromatase in MCF-7 cells expressing green fluorescent protein as an index of ER activity. Aromatase-overexpressing MCF-7 cells were cultured in estrogen-depleted medium supplemented with testosterone and the AI, letrozole, to establish letrozole-resistant (LR) cell lines. Compared with parental cells, LR cells had higher mRNA levels of steroid sulfatase (STS), which converts estrone sulfate (E1S) to estrone, and the organic anion transporter peptides (OATPs), which mediate the uptake of E1S into cells. LR cells proliferated more in E1S-supplemented medium than did parental cells, and LR proliferation was effectively inhibited by an STS inhibitor in combination with letrozole and by ER-targeting drugs. Analysis of ER-positive primary breast cancer tissues showed a significant correlation between the increases in the mRNA levels of STS and the OATPs in the LR cell lines, which supports the validity of this AI-resistant model. This is the first study to demonstrate the contribution of STS and OATPs in E1S metabolism to the proliferation of AI-resistant breast cancer cells. We suggest that E1S metabolism represents a new target in AI-resistant breast cancer treatment.</p></div

Effects of a steroid sulfatase (STS) inhibitor and estrogen receptor (ER) inhibitors on ER activity and proliferation in letrozole (Let)-resistant (LR) cell lines.

<p><b>A)</b> Relative ER activity in LR cell lines and parental cells treated with or without the STS inhibitor STX64. <b>B)</b> The relative proliferation of LR and parental cells treated with testosterone (TS) in the presence or absence of Let, STX64 or both. <b>C)</b> Relative cell proliferation with or without 4-OH tamoxifen (tam) and fulvestrant (ful). Error bars show standard deviation. * p < 0.05. ** p < 0.01.</p