Effects of Intake of Maternal Dietary Elaidic Acids during Pregnancy and Lactation on the Fatty Acid Composition of Plasma, Erythrocyte Membrane, and Brain in Rat Pups

To investigate the effects of a dam’s dietary elaidic acid (EA) intake during pregnancy and lactation on the fatty acid composition of plasma, erythrocyte membrane, and brain in rat pups, we fed two groups of dams either a soybean oil diet (SOD) or a shortening diet (SHD) containing soybean oil (10%) or shortening (10%), respectively. Although EA was not detected in the SOD, EA accounted for 25.3% of all fatty acid content in the SHD. On day 8 after birth, the EA levels in the stomach, plasma, and erythrocyte membrane of pups nursed by the dams fed the SHD were %, %, and %, respectively. Although on day 8 after birth the EA level of the brains of pups nursed by SHD-fed dams was %, EA was not detected on day 21 or day 82 after birth. These results suggest that EA intake during pregnancy and lactation supplies EA to plasma, remains in the erythrocyte membrane of pups, and moves into the brain in early infancy

SIX1 maintains tumor basal cells via transforming growth factor-β pathway and associates with poor prognosis in esophageal cancer

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Although improvement in both surgical techniques and neoadjuvant chemotherapy has been achieved, the 5-year survival rate of locally advanced tumors was, at best, still 55%. Therefore, elucidation of mechanisms of the malignancy is eagerly awaited. Epithelial-mesenchymal transition (EMT) by transforming growth factor-β (TGF-β) has been reported to have critical biological roles for cancer cell stemness, whereas little is known about it in ESCC. In the current study, a transcriptional factor SIX1 was found to be aberrantly expressed in ESCCs. SIX1 cDNA transfection induced overexpression of transforming growth factors (TGFB1 and TGFB2) and its receptor (TGFBR2). Cell invasion was reduced by SIX1 knockdown and was increased in stable SIX1-transfectants. Furthermore, the SIX1-transfectants highly expressed tumor basal cell markers such as NGFR, SOX2, ALDH1A1, and PDPN. Although mock-transfectants had only a 20% PDPN-high population, SIX1-transfectants had 60?70%. In two sets of 42 and 85 ESCC patients receiving surgery alone or neoadjuvant chemoradiotherapy followed by surgery, the cases with high SIX1 mRNA and protein expression level significantly showed a poor prognosis compared with those with low levels. These SIX1 high cases also expressed the above basal cell markers, but suppressed the differentiation markers. Finally, TGF-β signaling blockade suppressed ESCC cell growth in association with the reduction of PDPN-positive tumor basal cell population. The present results suggest that SIX1 accelerates self-renewal of tumor basal cells, resulting in a poor prognosis for ESCC patients

Multiple roles of single-minded 2 in esophageal squamous cell carcinoma and its clinical implications

Degree of histological differentiation is an important characteristic of cancers and may be associated with malignant potential. However, in squamous cell carcinomas, a key transcriptional factor regulating tumor differentiation is largely unknown. Chemoradiotherapy (CRT) is a standard treatment for locally advanced esophageal squamous cell carcinoma; however, the survival rate is still below 40%. From microarray data, single‐minded 2 (SIM2) was overexpressed in the epithelial subtype. Here, we investigated the correlation between SIM2 expression and its clinical implication, and in vitro and in vivo functions of SIM2 in tumor differentiation and in CRT sensitivity. Although SIM2 was suppressed in cancerous tissues, SIM2‐high ESCC showed a favorable prognosis in CRT. Transient SIM2 expression followed by 3D culture induced expression of differentiation markers and suppressed epithelial‐mesenchymal transition‐ and basal‐cell markers. Levels of PDPN‐high tumor basal cells and of expression of genes for DNA repair and antioxidant enzymes were reduced in stable transfectants, and they showed high CDDP and H2O2 sensitivities, and their xenografts showed a well‐differentiated histology. Reduction of tumor basal cells was restored by knockdown of aryl hydrocarbon receptor nuclear translocator (ARNT) that interacted with SIM2. Together, SIM2 increases CRT sensitivity through tumor differentiation by cooperation with ARNT

Risk factors for the onset of dependence and chronic psychosis due to cannabis use: Survey of patients with cannabis-related psychiatric disorders.

AIM: The objective of the current study was to identify risk factors that affect the onset of dependence and chronic psychosis due to cannabis use. METHODS: We examined clinical genetic factors, psychiatric disorders prior to cannabis use, starting age of cannabis use, duration and frequency of cannabis use, types of cannabis products used, combined use of other psychoactive substances, and the psychiatric diagnosis of 71 patients with cannabis-related psychiatric disorders who underwent treatment at nine mental health hospitals in Japan. Information was collected from cross-sectional interview surveys conducted by each patient's attending psychiatrist. RESULTS: For the diagnosis of dependence syndrome due to the use of cannabis, we found associations with the number of years of cannabis use and the use of cannabis products with a high Δ9-tetrahydrocannabinol (THC) content. However, we found no association between diagnosis of residual and late-onset psychotic disorders and clinical genetic factors, presence of preceding psychiatric disorders, duration and frequency of cannabis use, starting age of cannabis use, or combined use of other psychoactive substances; an association was found only for the absence of use of cannabis products other than dried cannabis. CONCLUSION: The onset of cannabis dependence was related to long-term cannabis use and the use of cannabis products with a high THC content. However, chronic psychosis was not associated with total THC intake or psychiatric vulnerability. Thus, unknown factors appear to be involved in the onset of chronic psychosis

Discovery of a good responder subtype of esophageal squamous cell carcinoma with cytotoxic T-lymphocyte signatures activated by chemoradiotherapy

Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-Term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre-and post-Treatment biopsy specimens of 30 ESCC patients and 121 pre-Treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-Activation associated genes such as IFNG, PRF1, and GZMB, were found in post-Treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune-Activated cases, designating them as I-Type, from other cases. However, despite the better CR rate in the I-Type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-Type was significantly better than that of the CDH2-positive cases in the I-Type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested tocooperatively enhance the effect of CRT in the CDH2-negative I-Type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics

Identification and Characterization of CXCR4-Positive Gastric Cancer Stem Cells

<div><p>Diffuse-type solid tumors are often composed of a high proportion of rarely proliferating (i.e., dormant) cancer cells, strongly indicating the involvement of cancer stem cells (CSCs) Although diffuse-type gastric cancer (GC) patients have a poor prognosis due to high-frequent development of peritoneal dissemination (PD), it is limited knowledge that the PD-associated CSCs and efficacy of CSC-targeting therapy in diffuse-type GC. In this study, we established highly metastatic GC cell lines by <i>in vivo</i> selection designed for the enrichment of PD-associated GC cells. By microarray analysis, we found C-X-C chemokine receptor type 4 (CXCR4) can be a novel marker for highly metastatic CSCs, since CXCR4-positive cells can grow anchorage-independently, initiate tumors in mice, be resistant to cytotoxic drug, and produce differentiated daughter cells. In clinical samples, these CXCR4-positive cells were found from not only late metastasis stage (accumulated ascites) but also earlier stage (peritoneal washings). Moreover, treatment with transforming growth factor-β enhanced the anti-cancer effect of docetaxel via induction of cell differentiation/asymmetric cell division of the CXCR4-positive gastric CSCs even in a dormant state. Therefore, differentiation inducers hold promise for obtaining the maximum therapeutic outcome from currently available anti-cancer drugs through re-cycling of CSCs.</p></div

Relationship between tumor phenotypes and <i>CXCR4</i> or <i>CXCR7</i> expression in GC cell lines.

<p>(A) RT-PCR of <i>CXCR4</i> and <i>CXCR7</i> in 6 diffuse-type GC derived cell lines. (B) Macroscopic findings of bloody ascites and multiple tumor nodules (arrowhead or dotted circle) in SCID/SCID mice formed within 3 weeks after inoculation of each cell line.</p