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Delay-discounting, wherein the subjective value for delayed gain or loss decreases, has been attracting much attention from the social sciences as well as neuroscience and has been suggested asbeing related to reward processing in the brain. As reported, the feedback-related negativity (FRN), an electrophysiological measure of reward processing, increased by delayed-monetary gain and ΔFRN, which is the difference in FRNs for loss and gain at a certain time point, had no significant correlation with delay-discounting for gain. Thus, although a delay for gain could affect FRN, it is unclear whether FRN capturing such a delay effect has a direct relationship with delay-discounting in both gain and loss domains.In this study, we introduced a delay-specific indicator, ΔFRNdelay, that is, the difference between FRN with and without delays, and investigated its direct relationship during the doors task with the discounting rate measured by the delay-discounting task in both the gain and loss domains.We found that, for loss, the delay enhanced FRN, whereas no such effect was observed for gains, and that this indicator was significantly correlated with delay-discounting in both domains.To our knowledge, this study is the first to suggest that FRN is sensitive to the effects of delay in losses on reward processing and that the new indicator directly corresponds to changes in subjective value as measured by delay-discounting.

The COVID-19 pandemic caused drastic social changes for many people, including separation from friends and coworkers, enforced close contact with family, and reductions in mobility. Here we assess the extent to which people's evolutionarily-relevant basic motivations and goals—fundamental social motives such as Affiliation and Kin Care—might have been affected. To address this question, we gathered data on fundamental social motives in 42 countries (N = 15,915) across two waves, including 19 countries (N = 10,907) for which data were gathered both before and during the pandemic (pre-pandemic wave: 32 countries, N = 8998; 3302 male, 5585 female; Mage = 24.43, SD = 7.91; mid-pandemic wave: 29 countries, N = 6917; 2249 male, 4218 female; Mage = 28.59, SD = 11.31). Samples include data collected online (e.g., Prolific, MTurk), at universities, and via community sampling. We found that Disease Avoidance motivation was substantially higher during the pandemic, and that most of the other fundamental social motives showed small, yet significant, differences across waves. Most sensibly, concern with caring for one's children was higher during the pandemic, and concerns with Mate Seeking and Status were lower. Earlier findings showing the prioritization of family motives over mating motives (and even over Disease Avoidance motives) were replicated during the pandemic. Finally, well-being remained positively associated with family-related motives and negatively associated with mating motives during the pandemic, as in the pre-pandemic samples. Our results provide further evidence for the robust primacy of family-related motivations even during this unique disruption of social life.

Purpose:PIK3CA encodes the catalytic subunit of PI3K, p110α. Mutant PIK3CA stimulates the AKT pathway and promotes cancer cell proliferation. PIK3CA mutations have been associated with poor prognosis in patients with colorectal or lung cancer. In contrast, the relationship between PIK3CA mutations and favorable prognoses has been shown in breast cancer. However, the influence of PIK3CA mutations on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains unclear.Experimental Design: Using a nonbiased database of 219 curatively resected ESCCs and eight esophageal cancer cell lines, we evaluated PIK3CA mutational status by pyrosequencing. The expression of p53 and phosphorylated AKT (i.e., AKT activation) was evaluated by immunohistochemistry.Results:PIK3CA mutations in exon 9 and/or 20 were detected in 46 cases (21%). No ESCC cell line harbored PIK3CA mutations. PIK3CA mutations were significantly associated with phosphorylated AKT expression, but not with p53 expression, sex, age at surgery, tobacco use, alcohol use, or histologic grade. Compared with wild-type PIK3CA cases, patients with PIK3CA mutations in exons 9 and/or 20 experienced significantly better disease-free survival [log-rank P = 0.0089; univariate HR: 0.37, 95% confidence interval (CI): 0.15–0.75, P = 0.0042; multivariate HR: 0.34, 95% CI: 0.10–0.86, P = 0.021] and overall survival (log-rank P = 0.012; univariate HR: 0.38, 95% CI: 0.16–0.78, P = 0.0060; multivariate HR: 0.35, 95% CI: 0.10–0.90, P = 0.028).Conclusion:PIK3CA mutations in ESCC are associated with longer survival, suggesting its role as a prognostic biomarker. Future studies are needed to confirm this association and to elucidate the exact mechanisms by which PIK3CA mutations affect tumor behavior. Clin Cancer Res; 19(9); 2451–9. ©2013 AACR.

Purpose: Global DNA hypomethylation plays a crucial role in genomic instability and carcinogenesis. DNA methylation of the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level, and is attracting interest as a useful marker for predicting cancer prognosis. Our previous study using more than 200 esophageal squamous cell carcinoma (ESCC) specimens demonstrated the significant relationship between LINE-1 hypomethylation and poor prognosis. However, the mechanism by which LINE-1 hypomethylation affects aggressive tumor behavior has yet to be revealed.Experimental Design: To examine the relationship between LINE-1 hypomethylation and DNA copy number variations, we investigated LINE-1–hypomethylated and LINE-1–hypermethylated ESCC tumors by comparative genomic hybridization array.Results: LINE-1–hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6. LINE-1 methylation levels were significantly associated with CDK6 mRNA and CDK6 protein expression levels in ESCC specimens. In our cohort of 129 patients with ESCC, cases with CDK6-positive expression experienced worse clinical outcome compared with those with CDK6-negative expression, supporting the oncogenic role of CDK6 in ESCC. In addition, we found that the prognostic impact of LINE-1 hypomethylation might be attenuated by CDK6 expression.Conclusion: LINE-1 hypomethylation (i.e., global DNA hypomethylation) in ESCC might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as CDK6. Clin Cancer Res; 20(5); 1114–24. ©2014 AACR.

PDF File - 95K, K-M curves according to mutation sites.

PDF File - 28K, Number at risk in survival analyses.

PDF file - 55K, Signal counts of CDK6 and chromosome 7centromere in TE11 cells.

PDF file - 56K, LINE-1 methylation level in 129 esophageal cancers, and the association with the clinical and tumor features.

PDF file - 40K, Clinical and pathological characteristics of 6 cases selected for CGH array.

PDF File - 44K, PIK3CA mutations in ESCC.

PDF File - 358K, Immunohistochemistry for p-AKT and p53.

PDF file - 195K, The result of CGH arrays in 6 cases.

PDF File - 127K, K-M curves in cases without preoperative treatment (left panel) and in cases with preoperative treatment (right panel).

PDF file - 188K, Cyclin D1 expression, LINE-1 methylation level, and patient prognosis in esophageal cancer.

What motives do people prioritize in their social lives? Historically, social psychologists, especially those adopting an evolutionary perspective, have devoted a great deal of research attention to sexual attraction and romantic-partner choice (mate seeking). Research on long-term familial bonds (mate retention and kin care) has been less thoroughly connected to relevant comparative and evolutionary work on other species, and in the case of kin care, these bonds have been less well researched. Examining varied sources of data from 27 societies around the world, we found that people generally view familial motives as primary in importance and mate-seeking motives as relatively low in importance. Compared with other groups, college students, single people, and men place relatively higher emphasis on mate seeking, but even those samples rated kin-care motives as more important. Furthermore, motives linked to long-term familial bonds are positively associated with psychological well-being, but mate-seeking motives are associated with anxiety and depression. We address theoretical and empirical reasons why there has been extensive research on mate seeking and why people prioritize goals related to long-term familial bonds over mating goals. Reallocating relatively greater research effort toward long-term familial relationships would likely yield many interesting new findings relevant to everyday people’s highest social priorities.

To evaluate the clinicopathological features of and prognosis associated with sporadic colorectal cancer (CRC) in Japanese patients younger than 40 years old. The subjects of this study were patients with sporadic stage 0–III CRC, who underwent curative resection between 2004 and 2012 at the Cancer Institute Hospital. Clinicopathological characteristics and survival were compared between the young (

// Asuka Murata 1, * , Yoshifumi Baba 1, * , Takatsugu Ishimoto 1 , Keisuke Miyake 1 , Keisuke Kosumi 1 , Kazuto Harada 1 , Junji Kurashige 1 , Shiro Iwagami 1 , Yasuo Sakamoto 1 , Yuji Miyamoto 1 , Naoya Yoshida 1 , Manabu Yamamoto 2 , Shinya Oda 3 , Masayuki Watanabe 4 , Mitsuyoshi Nakao 5 , Hideo Baba 1 1 Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan 2 Department of Surgery, National Hospital Organization Kyushu Cancer Center, Japan 3 Department of Cancer Biology, National Kyushu Cancer Center Clinical Research Institute, Japan 4 Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Japan 5 Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Japan * These authors have contributed equally to this work Correspondence to: Yoshifumi Baba, e-mail: y-baba@kumamoto-u.ac.jp Keywords: epigenetics, markers, demethylation, TET Received: April 17, 2015 Accepted: May 26, 2015 Published: June 08, 2015 ABSTRACT Mammalian DNA is epigenetically marked by 5′-cytosine methylation (5-methylcytosine [5-mC]). The Ten-eleven translocation (TET) enzymes (TET1, TET2, and TET3) are implicated in DNA demethylation, through dioxygenase activity that converts 5-mC to 5-hydroxymethylcytosine (5-hmC). Although decreased TET is reportedly associated with decreased 5-hmC levels in various cancers, functions of 5-hmC and TET expression in esophageal squamous cell carcinoma (ESCC) are unclear. We used ELISA and immunohistochemistry tests to analyze 5-hmC status in ESCC tissues, RT-qPCR to analyze TET family mRNA expression in normal and tumor tissues, and pyrosequencing to quantify LINE-1 (i.e., global DNA methylation) levels. ELISA and immunohistochemical testing showed 5-hmC levels were significantly lower in ESCC than in paired normal tissues ( P < 0.0001). TET2 expression was significantly lower in ESCCs than paired normal tissues ( P < 0.0001), and significantly associated with 5-hmC levels in ESCCs ( P = 0.003, r = 0.33). 5-hmC levels were also significantly associated with LINE-1 methylation level ( P = 0.0002, r = 0.39). Patients with low 5-hmC levels had shorter overall survival than those with higher levels, although not significantly so ( P = 0.084). In conclusion, 5-hmC expression was decreased in ESCC tissues, and was associated with TET2 expression level. TET2 reduction and subsequent 5-hmC loss might affect ESCC development.

Previous work shows that as compared to European Americans, Asians are more holistic (or less focused) in perceptual processing. Drawing on this evidence, we expected that extra attention control would be recruited to perform focused processing for Asians and holistic processing for European Americans. Eight Asian American and 13 European American young adults judged whether a given framed-line was the same in length as the framed-line shown on the previous trial on the basis of either an absolute or relative criterion. Their brain activities were monitored with functional near infrared spectroscopy. As predicted, Asian Americans showed an increased activation in the parietal regions during the absolute (vs. relative) task, whereas European Americans showed an increased activation in the same regions during the relative (vs. absolute) task. No comparable pattern was observed for performance. The current work provides further evidence for compensatory attention that is engaged during culturally non-preferred tasks.

Previous work shows that European Americans are more likely than Asians to focus their attention on a central object. The authors investigated the time course of this cultural difference by examining event-related potentials (ERPs) as participants tried to detect a low-frequency target (an image of a coffee mug) embedded in a series of standard stimuli (animal images). The authors identified a reliable cultural difference as early as 200 ms posttarget, with a significantly larger negativity at the frontal region of the brain (called N2; indicative of early orienting) for European Americans than for Asian Americans. Furthermore, a slow wave component starting around 700 ms posttarget (indicative of elaborative processing) was also larger for European Americans than for Asian Americans. Together, the current evidence suggests that as compared to Asians, European Americans allocate more attention to a goal-relevant object from the very beginning of stimulus processing. Implications for social vision are disc...

Background: LINE-1 methylation level is a surrogate marker of global DNA methylation. LINE-1 methylation in primary colorectal cancers (CRCs) is highly variable and strongly associated with a poor prognosis. However, no study has examined LINE-1 methylation levels of metastatic CRCs in relation to prognosis or assessed the heterogeneity of LINE-1 methylation level within the primary CRCs. Methods: Pyrosequencing was used to quantify LINE-1 methylation level in 42 liver metastases, 26 matched primary tumours, and 6 matched lymph node (LN) metastases. KRAS, BRAF, and PIK3CA mutation status and microsatellite instability (MSI) status were also examined. Results: The distribution of LINE-1 methylation level in liver metastases was as follows: mean, 67.3; range, 37.1–90.1. Primary tumours showed LINE-1 methylation levels similar to those of matched liver and LN metastases. The difference in LINE-1 methylation level between superficial areas and invasive front areas was within 7.0 in all six cases evaluated. Prognostic impact of LINE-1 hypomethylation in liver metastases on overall survival was not observed. The concordance rate was 94% for KRAS, 100% for BRAF, 88% for PIK3CA, and 97% for MSI. Conclusion: Alteration of LINE-1 methylation level may occur in early CRC tumorigenesis, and the LINE-1 methylation level is relatively stable during CRC progression.

Although different types of granulocyte-colony-stimulating factor (G-CSF)-producing carcinomas have been reported, G-CSF-producing esophageal squamous cell carcinoma (SCC) is extremely rare. The prognosis of G-CSF-producing esophageal cancer has generally been reported to be very poor. Here, we report three cases of G-CSF-producing SCC who were successfully treated by use of multimodal therapy.

Background Epidermal growth factor receptor (EGFR) signaling is one of the most promising targets for molecular-targeted therapies in esophageal squamous cell carcinoma (ESCC). Thus, the molecular diagnosis of KRAS and BRAF mutations is clinically important in therapeutic decision making. However, the frequency of KRAS and BRAF mutations in ESCCs remains inconclusive because of the limited sample sizes of previous studies (all N ≤ 80). Pyrosequencing is a nonelectrophoretic nucleotide extension sequencing technology that can be used for mutation testing. Methods The frequency of KRAS and BRAF mutations was examined using a nonbiased database of 203 resected ESCCs and a high-throughput pyrosequencing assay. Results The validity of the KRAS pyrosequencing method was initially demonstrated by detection of all 4 types of KRAS mutations [c.35G>T (codon 12 GGT>GTT), c.35G>A (codon 12 GGT>GAT), c.34G>T (codon 12 GGT>TGT), c.38G>A mutation (codon 13 GGC>GAC)], which had been previously diagnosed using Scorpion-ARMS technology, in 9 colon cancer tissues (9 of 9; 100 %). Similar results were demonstrated for BRAF mutational status in 3 colon cancer cell lines (HCT116, Colo201, and HT29), which were validated by Sanger dideoxy sequencing. Subsequently, the KRAS mutation was found to be extremely rare (1 of 203; 0.5 %), and the BRAF mutation was absent (0 of 203; 0 %), in the dataset of 203 ESCCs. Conclusions These results suggest that KRAS and BRAF mutations play a limited role in the development of ESCC and that mutation analysis is not useful as a screening test for sensitivity to anti-EGFR therapy in ESCC.

Background Genome-wide DNA hypomethylation plays an important role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level. In some types of human neoplasms, LINE-1 methylation level is attracting interest as a predictive marker for patient prognosis. However, the prognostic significance of LINE-1 hypomethylation in gastric cancer remains unclear. Methods Using 203 resected gastric cancer specimens, we quantified LINE-1 methylation using bisulfite-pyrosequencing technology. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for the clinical and pathological variables. Results Gastric cancers showed significantly lower LINE-1 methylation levels compared to matched normal gastric mucosa (p 0.25). Conclusions LINE-1 hypomethylation in gastric cancer is associated with shorter survival, suggesting that it has potential for use as a prognostic biomarker.

Previous work has shown that emotional control is highly valued in Asian culture. However, little is known about how this cultural value might influence emotional processing. Here, we hypothesized that Asians are 'culturally trained' to down-regulate emotional processing when required to suppress emotional expressions. Such down-regulation, however, is unlikely for European Americans because their culture values emotional expression (vs control) more. To test these predictions, we adopted the parietal late positive potential (LPP) of the event-related potential as an objective indicator of emotional processing. Both Asian and European Americans were exposed to either unpleasant or neutral pictures while instructed to either attend or suppress expression of emotions. Both groups showed an equally pronounced parietal positivity ∼600 ms post-stimulus. As predicted, however, Asians subsequently showed a significant decrease of the parietal LPP in the suppression (vs attend) condition. The initial positivity completely disappeared 2000 ms post-stimulus. In contrast, for European Americans the parietal LPP suppression effect was completely absent although there was an early occurring, sustained increase in frontal positivity in the suppression (vs attend) condition. Implications for culture and emotion research are discussed.

A 49-year-old woman was admitted to our hospital under suspicion of an enlarging hepatic tumor, which had been previously diagnosed to be a cavernous hemangioma. Computed tomography revealed three enhanced tumors, one measuring 15 cm in diameter within the right lobe of the liver and two intrahepatic metastases in Couinaud's hepatic segments 3 and 5. We diagnosed the patient to have primary liver cancer, and suspected a combined liver tumor preoperatively. We performed a right trisectionectomy with radiofrequency ablation of the intrahepatic metastasis in S3. According to the immunohistochemical findings of the resected specimen and the findings of postoperative imaging studies, the tumor was diagnosed to be a primary neuroendocrine tumor in the liver. The patient is presently alive without recurrence at 33 months after the operation.

The DNA methylation alterations occurring in human cancers have two types: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Recently, to assess global DNA methylation, long interspersed nucleotide element 1 (LINE-1) retrotransposons, constituting a substantial portion of the human genome, attracts much attention. The aim of the current study was to clarify the significance of LINE-1 methylation level for epigenetic field defects and the relationships among LINE-1 methylation level in gastric mucosae, clinical and pathological features, including infection by Helicobacter pylori (H. pylori), a bacterium implicated in gastric cancer. By bisulfite-PCR pyrosequencing, we quantified the LINE-1 methylation levels in noncancerous gastric mucosae and cancer tissues from 87 gastric cancer patients, in gastric mucosae from 17 autopsied individuals without gastric cancers and in 20 gastric fresh frozen samples from non-gastric cancer patients. LINE-1 methylation in the noncancerous gastric mucosae of gastric cancer patients was significantly higher than in cancer tissues (P = 0.0006), but significantly lower than in the gastric mucosae of the autopsied individuals (P = 0.026), suggesting the formation of epigenetic field defect in noncancerous gastric mucosae. Moreover, LINE-1 hypomethylation of noncancerous gastric mucosae in gastric cancer patients significantly correlated with H. pylori infection (P = 0.037). We prospectively confirmed the similar result in 20 non-gastric cancer patients (P = 0.010). LINE-1 hypomethylation of gastric mucosae significantly correlated with H. pylori infection, supporting the potential of LINE-1 methylation level as a surrogate marker of epigenetic field defects for gastric cancer cancerization, particularly induced by H. pylori.

Error-related negativity is an event-related potential component that is observed when participants make errors and reflects action monitoring that involves error detection. In this study, an over-response error (responding with both hands when participants were asked to respond with only one hand) and an under-response error (responding with one hand when asked to respond with both hands) were assessed by the characteristics of the error-related negativity during a modified Eriksen flankers task. The results indicated that a bimanual response error also elicited the error-related negativity, and that the onset latency of the error-related negativity was shorter for an over-response error than for an under-response error. Thus, these results suggest that the error-detection process is more sensitive to an unnecessary response than to an insufficient response.

Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare carcinoma with distinct characteristics, and was recently recognized as a variant of squamous cell carcinoma (SCC). We previously revealed genetic and epigenetic alterations associated with esophageal SCCs in relation to clinical outcome, including mutations in KRAS, BRAF, and PIK3CA, p53 expression, and long interspersed nucleotide element-1 (LINE-1) methylation, a surrogate marker for global DNA methylation level. In this study, we explored these features in BSCC. A database of 502 esophageal cancers was used to evaluate the clinical and molecular characteristics of BSCC. KRAS, BRAF, and PIK3CA mutations and LINE-1 methylation were analyzed by pyrosequencing. Of 502 tumors, 22 (4.4 %) were pathologically diagnosed as BSCC, and 440 (87 %) as SCC. No prognostic differences between BSCC and SCC cases were identified (p = 0.41). KRAS or BRAF mutations were not observed in BSCCs. While 23 % of SCC tumors harbored a PIK3CA mutation, all BSCC cases were wild-type for PIK3CA (p = 0.002), and there were no differences in p53 expression between BSCCs and SCCs (p = 0.57), as assessed by immunohistochemistry. Furthermore, BSCC tissues exhibited significantly lower levels of LINE-1 methylation than SCC tissues (p

The luc gene, from firefly, was ligated into the multiple cloning site of the pBI121 plasmid and was then incorporated into Agrobacterium tumefaciens strain LBA4404. This vector containing a CaMV 35S promoter, a NOS terminator, a NPTII gene and a NOS promoter was used to transform ‘Hibush’ eggplant (Solanum melongena). Genomic DNA from the transformants was analyzed by assay of both PCR and southern blotting, which confirmed the presence of an expected luc fragment. Four transformants were chosen for an extended LUC assay. During the course of one year, LUC activity fluctuated, but was maintained at the initial activity even after 50 weeks. Expression of the luc gene in transgenic calli revealed that fluctuation of the LUC activity was due to changes in the environmental temperature. Luminescence from transgenic eggplant was detected using image analysis and light emission was found to be intense throughout the whole plant.

Insulin like growth factor 2 gene (IGF2) is normally imprinted. Loss of imprinting (LOI) of IGF2 in humans is associated with an increased risk of cancer and is controlled by CpG-rich regions known as differentially methylated regions (DMRs). Specifically, the methylation level at IGF2 DMR0 is correlated with IGF2 LOI and is a suggested surrogate marker for IGF2 LOI. A relationship between IGF2 DMR0 hypomethylation and poor prognosis has been shown in colorectal cancer. However, to our knowledge, no study has examined the relationships among the IGF2 DMR0 methylation level, LOI, and clinical outcome in esophageal squamous cell carcinoma (ESCC). The IGF2 imprinting status was screened using ApaI polymorphism, and IGF2 protein expression was evaluated by immunohistochemistry with 30 ESCC tissue specimens. For survival analysis, IGF2 DMR0 methylation was measured using a bisulfite pyrosequencing assay with 216 ESCC tissue specimens. Twelve (40 %) of 30 cases were informative (i.e., heterozygous for ApaI), and 5 (42 %) of 12 informative cases displayed IGF2 LOI. IGF2 LOI cases exhibited lower DMR0 methylation levels (mean 23 %) than IGF2 non-LOI cases (37 %). The IGF2 DMR0 methylation level was significantly associated with IGF2 protein expression. Among 202 patients eligible for survival analysis, IGF2 DMR0 hypomethylation was significantly associated with higher cancer-specific mortality. The IGF2 DMR0 methylation level in ESCC was associated with IGF2 LOI and IGF2 protein expression. In addition, IGF2 DMR0 hypomethylation was associated with a shorter survival time, suggesting its potential role as a prognostic biomarker.

Purpose: PIK3CA encodes the catalytic subunit of PI3K, p110α. Mutant PIK3CA stimulates the AKT pathway and promotes cancer cell proliferation. PIK3CA mutations have been associated with poor prognosis in patients with colorectal or lung cancer. In contrast, the relationship between PIK3CA mutations and favorable prognoses has been shown in breast cancer. However, the influence of PIK3CA mutations on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains unclear. Experimental Design: Using a nonbiased database of 219 curatively resected ESCCs and eight esophageal cancer cell lines, we evaluated PIK3CA mutational status by pyrosequencing. The expression of p53 and phosphorylated AKT (i.e., AKT activation) was evaluated by immunohistochemistry. Results: PIK3CA mutations in exon 9 and/or 20 were detected in 46 cases (21%). No ESCC cell line harbored PIK3CA mutations. PIK3CA mutations were significantly associated with phosphorylated AKT expression, but not with p53 expression, sex, age at surgery, tobacco use, alcohol use, or histologic grade. Compared with wild-type PIK3CA cases, patients with PIK3CA mutations in exons 9 and/or 20 experienced significantly better disease-free survival [log-rank P = 0.0089; univariate HR: 0.37, 95% confidence interval (CI): 0.15–0.75, P = 0.0042; multivariate HR: 0.34, 95% CI: 0.10–0.86, P = 0.021] and overall survival (log-rank P = 0.012; univariate HR: 0.38, 95% CI: 0.16–0.78, P = 0.0060; multivariate HR: 0.35, 95% CI: 0.10–0.90, P = 0.028). Conclusion: PIK3CA mutations in ESCC are associated with longer survival, suggesting its role as a prognostic biomarker. Future studies are needed to confirm this association and to elucidate the exact mechanisms by which PIK3CA mutations affect tumor behavior. Clin Cancer Res; 19(9); 2451–9. ©2013 AACR.

We evaluated the need for primary tumor resection in patients with colorectal cancer (CRC) and synchronous unresectable metastases who underwent chemotherapy, and identified the associations between the primary tumor characteristics and risk of intestinal obstruction or perforation.We retrospectively analyzed the survival and complication rates of patients with synchronous metastatic CRC treated between April 2005 and December 2011.Of 131 patients, 68 underwent primary tumor resection before chemotherapy, and 63 were treated without resection before chemotherapy. The overall survival (OS) did not significantly differ between the two groups (log-rank P = 0.53). In the resection group, 12 patients (17.6%) developed postoperative complications. In the non-resection group, 16 patients (25.4%) required surgical intervention owing to obstruction or perforation during their treatment. Surgical intervention did not affect the OS. A circumferential tumor was a risk factor for obstruction or perforation of the colorectum in non-resected patients (odds ratio = 11.163; P = 0.006).Resection of primary tumors before chemotherapy is unnecessary in selected patients with synchronous metastatic colorectal cancer. A circumferential tumor is a risk factor for obstruction or perforation during chemotherapy in cases without primary tumor resection.

An emerging literature indicates that dispositional bias in causal attribution of social behavior is weaker for people with working-class (vs. middle-class) backgrounds. However, it is unknown whether this difference is also present in spontaneous forms of trait inference. In the current work, American undergraduates were asked to merely memorize many pairings of a target face and a trait-implying behavior. In a subsequent lexical judgment task, after each face was presented as a fixation, either an implied trait or its antonym was given as a target. As expected, participants with college-educated parents (middle class) showed a strong N400 event-related potential component to the antonym (vs. the implied trait), suggesting spontaneous trait inference during the memorization phase. In contrast, those with high-school-educated parents (working class) showed no such effect. It is important to note that the N400 spontaneous trait inference effect was associated with perceived significance of dispositions in accounting for social behaviors.

Objectives:Cancer cells exhibit 2 types of deoxyribonucleic acid (DNA) methylation alterations: genome-wide DNA hypomethylation and site-specific CpG island promoter hypermethylation. Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. As long interspersed nucleotide element-1 (LINE-1) retrotransposon constitutes a substantial portion (approximately 17%) of the humangenome, the level of LINE-1 methylation is regarded to be a surrogate marker of genome-wide DNA methylation. Importantly, LINE-1 hypomethylation is associated with poor prognosis in several type of cancers, suggesting the potencial role of the LINE-1 methylation level as a useful marker for predicting cancer prognosis. However, clinical, pathological and prognostic significance of LINE-1 hypomethylaiton in hepatocellular carcinoma (HCC) remains unclear. Methods: Using 160 HCC resected specimens, we quantified the LINE-1 methylation by utilizing the bisulfite pyrosequencing technology. This assay amplifies a region of LINE-1 element (position 305-331 in accession no. X58075), which includes 4 CpG cites. The average of the relative amounts of C in the 4 CpG sites was used as the overall LINE-1 methylation level.Results: We first examined the LINE-1 methylation level in 85 HCC tissues and matched normal hepatic parenchyma samples. The cancer tissues exhibited significantly lower levels of LINE-1 methylation (median, 64.5 ; range, 99.1-21.5) than the matched normal hepatic parenchyma (median, 81.0 ; range, 97.2-35.8) (P < 0.0001 by the paired t test). The LINE-1 methylation level of HCC was not associated with any of theclinical, epidemiological, or pathological characteristics, including sex, age, AFP, PIVKA-II, infection of hepatitis B virus and hepatitis C virus, ICG-R15, stage of fibrosis, differentiation, tumor size, tumor type, vascular invasion and stage (all P > 0.09). In the Kaplan-Meier analysis, LINE-1 hypomethylators (methylation level < 74.4) experienced significantly shorter disease-free survival than those with hypermethylators (log-rank P=0.029). Over-all survival is not associated with LINE-1 methylation ( log-rank P=0.16). Conclusions: Genome-wide DNA hypomethylation, as measured in LINE-1, is associated with disease-free survival among patients with HCC, suggesting that LINE-1 hypomethylation may be a biomarker that can be used to identify patients who will experience an inferior outcome. Citation Format: kazuto harada, Yoshirumi Baba, Akira Chikamoto, Takatsugu Ishimoto, Keisuke Kosumi, Asuka Murata, Naoya Yoshida, Toru Beppu, Hideo Baba. Clinical, pathological and prognostic value of LINE-1 methylation in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1357. doi:10.1158/1538-7445.AM2014-1357

Objective: DNA methylation is a fundamental epigenetic process that modulates gene expression. Cancer cells exhibit two types of DNA methylation alterations: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Although the base 5-methylcytosine (5mc) and the DNA methyltransferase (DNMT) family of enzymes that catalyze DNA methylation are well-studied, the mechanisms of DNA demethylation are poorly understood. The Ten-eleven translocation (Tet) family of enzymes (Tet1, Tet2, and Tet3) has been implicated in DNA demethylation. These enzymes possess the dioxygenase activity and convert 5-mC to 5-hydroxymethylcytosine (5-hmC). Frequent Tet mutational inactivation or reduction has been reported to associate with decreased 5-hmC levels in various types of myeloid leukemia and melanoma. However, the status of 5hmC and Tet expression in esophageal squamous cell carcinoma (ESCC) remains still unknown. Method: We analyzed the 5-hmC status in DNA from ESCC frozen tissues utilizing the ELISA test, and 5-hmC expression was evaluated by immunohistochemistry. We next examined the expression levels of Tet family mRNA in both normal and tumor tissues by RT-qPCR. Results: 5-hmC level was significantly lower in ESCC than in paired normal tissue in ELISA test (n=33, P Conclusion: The 5hmC expression was decreased in ESCC tissues, and was associated with Tet2 expression level, suggesting that 5hmC and Tet2 might play a crucial role in the development of ESCCs. Citation Format: Asuka Murata, Yoshifumi Baba, Ryuichi Karashima, Satoshi Ida, Yu Imamura, Takatsugu Ishimoto, Shiro Iwagami, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Tet family proteins and 5-hydroxymethylcytosine in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 420. doi:10.1158/1538-7445.AM2014-420

11065 Background: The insulin-like growth factor 2 gene (IGF2) is normally imprinted. Loss of imprinting (LOI) of IGF2 in humans is associated with an increased risk of cancer and is controlled by CpG-rich regions known as differentially methylated regions (DMRs). Specifically, the methylation level at IGF2 DMR0 is correlated with IGF2 LOI and is a suggested surrogate marker for IGF2 LOI. A relationship between IGF2 DMR0 hypomethylation and poor prognosis has been shown in colorectal cancer. However, no study has examined the relationships among the IGF2 DMR0 methylation level, LOI, and clinical outcome in esophageal squamous cell carcinoma (ESCC). Methods: The IGF2 imprinting status was screened using ApaI polymorphism, and IGF2 protein expression was evaluated by immunohistochemistry with 30 ESCC tissue specimens. For survival analysis, IGF2 DMR0 methylation was measured using a bisulfite-pyrosequencing assay with 216 ESCC tissue specimens. The Cox proportional hazards model was used to calculate mortality hazard ratios (HR) adjusted for clinical, epidemiologic, and pathological variables.The term “prognostic marker” is used throughout this article according to the REMARK Guidelines. Results: Twelve (40%) of 30 cases were informative (i.e., heterozygous for ApaI), and 5 (42%) of 12 informative cases displayed IGF2 LOI. IGF2 LOI cases exhibited lower DMR0 methylation levels (mean, 23%) than IGF2 non-LOI cases (37%). The IGF2 DMR0 methylation level was significantly associated with IGF2 protein expression. Among 202 patients eligible for survival analysis, IGF2 DMR0 hypomethylation was significantly associated with higher cancer-specific mortality (log-rank P=0.013; univariate HR=2.03, 95% confidence interval: 1.14–3.58, P=0.017; multivariate HR=2.34, 95% CI: 1.29-4.22, P=0.0054). Conclusions: The IGF2 DMR0 methylation level in ESCC was associated with IGF2 LOI and IGF2 protein expression. In addition, IGF2 DMR0 hypomethylation was associated with a shorter survival time, suggesting its potential role as a prognostic biomarker.

Background: Epigenetic changes such as DNA methylation, histone modification, and loss of genome imprinting play a crucial role in esophageal squamous cell carcinogenesis, along with genomic and genetic alterations. DNA methylation is a fundamental epigenetic process that modulates gene expression. Cancer cells exhibit two types of DNA methylation alterations: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Genome-wide DNA hypomethylation plays a crucial role in genomic instability and carcinogenesis. Since LINE-1 or the L1 retrotransposon constitutes a substantial portion (17%) of the human genome, the level of LINE-1 methylation is regarded to be a surrogate marker of global DNA methylation. Our group has reported that esophageal squamous cell carcinomas (ESCCs) patients with LINE-1 hypomethylated tumor experience poorer prognosis compared with those with LINE-1 hypermethylated tumors (Ann Surg, 2012). Method: To examine the potential mechanism by which LINE-1 hypomethylation affects tumor aggressive behavior, we performed an array-based comparative genomic hybridization (array-CGH; Agilent 400K) analysis utilizing LINE-1 hypomethylated ESCC tissues (n=3) and LINE-1 hypermethylated ESCC tissues (n=3). In addition, we assessed the relationship between LINE-1 methylation level and mutations of KRAS, BRAF, and PIK3CA using a non-biased cohort of 202 ESCCs and Pyrosequencing technology. Results: Array-CGH analysis revealed that genomic gains and losses frequently occurred only in LINE-1 hypomethylated ESCCs; genomic gains were found at 1q42, 1q44, 2p16, 3q13, 3q29, 6q22, 7p21-22, 7q11, 7q31, 8q11, 8q21, 9q21-22, 10q11, 10q26, 11p11, 11q22, 17q11-12, 17q21, and 20p12, while losses were found at 2q35, 3p21, 3p14, 4q25, 4q28, 5p31 and 6p21. On the other hand, LINE-1 hypermethylated tumors showed no significant genomic gain and bare genomic loss (10q11). KRAS mutation was extremely rare (1/202; 0.5%), and BRAF mutation was absent (0/202; 0%). PIK3CA in exon 9 and/or 20 mutation was detected in 45 of 202 cases (22%). Interestingly, PIK3CA wild-type tumors showed significantly lower LINE-1 methylation level compared with PIK3CA mutated tumors (p=0.027). Conclusion: Our data suggest a relationship between LINE-1 methylation level (global DNA methylation level), allelic imbalances (copy number alterations) and oncogene mutation (PIK3CA). This relationship may confer a poor prognosis in ESCCs. Further studies are necessary to elucidate mechanism(s) by which LINE-1 hypomethylation affects tumor behavior. Citation Format: Yoshifumi Baba, Masayuki Watanabe, Asuka Murata, Hironobu Shigaki, Shiro Iwagami, Masaaki Iwatsuki, Takatsugu Ishimoto, Hideo Baba. Relationship between LINE-1 methylation level, allelic imbalance and PIK3CA mutation in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2965. doi:10.1158/1538-7445.AM2013-2965

Background: Cancer cells exhibit two types of DNA methylation changes: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Genome-wide DNA hypomethylation plays an important role in genomic instability and carcinogenesis. As LINE-1 or L1 retrotransposon constitutes a substantial portion of the human genome, the level of L1 methylation is regarded to be a surrogate marker of global DNA methylation. In Colorectal cancer (CRC), L1 methylation in primary tumor has been shown to be highly variable, and L1 hypomethylation is strongly associated with poor prognosis. Nonetheless, no study has examined L1 methylation level in metastatic lesions [liver, lung, and lymph node (LN)] from CRCs, and assessed the heterogeneity of L1 methylation level within CRC tumor. Methods: A total of 65 patients with liver and/or lung metastases from CRC who were undergoing hepatic and/or lung resection at Kumamoto University Hospital were enrolled in this study. The bisulfite-pyrosequencing technology was utilized to quantify the L1 methylation level in 60 liver metastases, matched 26 primary tumors and matched 6 LN metastases, and 6 paired lung metastatic and primary tumors. The heterogeneity within primary tumor (superficial area vs. invasive area) was also evaluated (n=6). Results: The distribution of the L1 methylation level in liver metastases (n=60) was as follows: mean, 68.9; median, 71.0; SD, 10.8; range, 37.1-90.1 (all in 0-100 scale). L1 methylation level of liver metastases was not associated with sex, age at hepatic resection, tumor stage of primary lesion, or tumor size. L1 methylation level of liver metastases was significantly related with that of matched primary tumors (n=26; Pearson correlation coefficient r=0.71, p=0.0001). LN metastases showed similar L1 methylation level of matched primary tumors and liver metastases (n=6); the distribution of the L1 methylation level in matched 6 LN metastases was as follows: mean, 71.0; SD, 9.37; range, 59.3-81.9. In addition, lung metastases and matched primary tumors exhibited similar L1 methylation level; the distributions of the L1 methylation level in lung metastases and matched primary tumors (n=6) were as follows: mean, 65.6 and 71.3; range, 55.7-82.2 and 66.1-79.6, respectively. Interestingly, the heterogeneity of L1 methylation level was not observed; the difference between superficial area and invasive area was within 7 in all 6 cases. Conclusions: Liver, lung and LN metastases showed similar L1 methylation level with primary tumors. In addition, L1 methylation level of superficial area was roughly in accordance with that of invasive area; thus supporting the absence of heterogeneity of L1 methylation level within one tumor. These results may suggest that cancer cells acquire “global DNA hypomethylation” at the early stage of tumor development, and it is preserved through the process of cancer invasion and metastasis. Citation Format: Asuka Murata, Yoshifumi Baba, Masayuki Watanabe, Hironobu Shigaki, Shiro Iwagami, Yasuo Sakamoto, Yuji Miyamoto, Hideo Baba. Methylation levels of LINE-1 in primary lesion and matched metastatic lesions of colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 648. doi:10.1158/1538-7445.AM2013-648