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Background: Lymphovascular invasion (LVI) is associated with a poor outcome in breast cancer. The purpose of this study was to evaluate the clinical significance of LVI in primary breast cancer and to investigate disease-free survival (DFS) as a prognostic marker according to the breast cancer subtypes. The clinical significance of LVI was analyzed to investigate the biology and prognosis. Patients and Methods: This study examined 4,652 consecutive invasive breast cancer cases excluding the patients with non-invasive cancer, Stage IV and neo-adjuvant therapy from February 2002 to February 2021. Clinicopathological characteristics and prognosis of LVI positive and negative tumors were compared. LVI was evaluated in hematoxylin and eosin staining specimen from surgically resected samples. The ER, PgR, Ki-67, p53, HER2 status were evaluated using immunohistochemistry (IHC). Breast cancer subtypes were categorized based on the IHC data derived from ER/PgR, HER2 and Ki-67 (cutoff point: 20%) in invasive tumors. The median follow-up period was 95 months. Results: The LVI expression rates were 29.2%(low: 19.7% and high: 9.5%)in all primary cases. The LVI positive rate significantly correlated with ER/PgR negative, HER2 positive, p53 overexpression, higher Ki-67 index values, higher nuclear grade, positive nodes, and larger tumor. Moreover, the subtypes significantly correlated with LVI positivity; 20% in Luminal A, 34.6% in Luminal B, 40.9% in Lumina/HER2, 38.1% in HER2 enriched, and 29.8% in Triple Negative (TN). There were significant differences in DFS between LVI status in Luminal A, Luminal B, and TN subtypes, but there were no difference in the Luminal/HER2 and HER2 enriched subtypes. A multivariate analysis revealed that LVI was a significant factor in Luminal B and TN subtypes. Conclusion: LVI significantly correlated with the advanced and aggressive characteristics in breast cancer. Luminal A type had a lower LVI rate and HER2 type had a higher rate. Moreover, LVI was a significant prognostic factor in Luminal B and TN subtypes. These data suggest that the LVI status was useful in predicting the prognosis in HER2 negative breast cancer. Citation Format: Reiki Nishimura, Tomofumi Osako, Yasuhiro Okumura, Masahiro Nakano, Hiroko Otsuka, Mamiko Fujisue, Nobuyuki Arima. An evaluation of lymphovascular invasion in relation to biology and prognosis according to subtypes in invasive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-12.

Background: Triple negative breast cancer (TNBC) is a subtype of breast cancer which lacks hormone receptor (HR) expression and HER2 gene amplification, and is the most aggressive subtype with a heterogeneous genetic profile. Menopausal status is an important factor when considering endocrine therapy for patients with HR-positive tumors. Breast cancer in younger women can be more aggressive than in older women. Moreover, the menopausal status has limited predictive power for distant recurrence and overall survival (OS) in HR-positive cases. The aim of this retrospective study is to evaluate the clinical significance of menopausal status in breast cancer subtypes, especially TNBC. Methods: Primary breast cancer patients who underwent curative surgery from January 2002 to March 2021 were enrolled in this study. A total of 5153 invasive breast cancer cases with Stage I-III were analyzed. The distribution of cases according to the menopausal status was investigated according to each subtype, and the clinicopathological characteristics and prognosis were compared between pre- and postmenopausal TNBC patients. The factors investigated included nodal status, tumor size, nuclear grade, ER/PgR and HER2 status, p53 overexpression, and the Ki-67 index value. Breast cancer subtypes were categorized based on the immunohistochemistry (IHC) data derived from ER/PgR, HER2 and Ki-67 (cutoff: 20%) in invasive tumors. The disease-free survival (DFS) was compared between menopausal status in each subtype using the Kaplan-Meier and the log-rank test. Cox's proportional hazard model was used to perform univariate and multivariate analyses of the factors related to DFS. The median follow-up period was 95 months. Results:. 1. There were significant differences in menopausal status among the subtypes. TNBC was frequently seen in postmenopausal patients, and Luminal B and Luminal/HER2 subtypes were more common in premenopausal patients. 2. There was no difference in DFS in Luminal A/B and HER2 subtypes, but a significant difference was seen in the TNBC patients (premenopausal patients had a poorer DFS than the postmenopausal patients). 3. There was no significant correlation between menopausal status, tumor size and nodal status in TNBC. On the other hand, premenopausal patients significantly correlated with a higher Ki-67 index value, p53 overexpression and a higher nuclear grade. 4. Moreover, premenopausal patients often received (neo)adjuvant chemotherapy, but there was no significant difference in the pCR rate between the pre- and postmenopausal status. 5. A multivariate analysis revealed that menopausal status, nodal status and tumor size were significant factors for DFS in TNBC. Conclusion: Menopausal status significantly correlates with breast cancer subtypes. TNBC was often seen in postmenopausal patients, and these patients tend to have more favorable factors and a better DFS than premenopausal patients. These findings suggest that menopausal status is an important factor for evaluating the biology and prognosis in TNBC cases. Citation Format: Nobuyuki Arima, Reiki Nishimura, Tomofumi Osako, Yasuhiro Okumura, Masahiro Nakano, Mamiko Fujisue, Hiroko Otsuka. Triple negative breast cancer: An analysis of the subtypes and the effects of menopausal status on invasive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-09.

Background We previously reported that, among asymptomatic patients with type 2 diabetes mellitus (T2DM) without a history of cardiovascular disease (CVD), up to 19% of the patients with myocardial ischemia were detected by annual cardiovascular screening tests (ACVSTs). Thus, the present study assessed the long-term clinical outcomes of ACVSTs in those patients. Methods Six hundred and fifty-seven outpatients with T2DM who received ACVSTs at least once or not at all from April 2014 to March 2018 were defined as the S and NS groups, respectively. The data were compared between these two groups. Results This study revealed that, among outpatients with T2DM in our hospital over those four years, with the increasing frequency of receiving ACVSTs, 1) the frequency of the internal use of statins, anti-platelets, and renin-angiotensin system inhibitors, which are well-known as medications for preventing CVD, significantly increased; 2) low-density lipoprotein-cholesterol and triglyceride levels significantly improved; 3) levels of highly sensitive C-protein, a strong predictors of CVD, were significantly suppressed; 4) the progression of renal dysfunction was significantly suppressed; 5) the cumulative of four-point major adverse cardiovascular events and admissions due to heart failure significantly decreased; and 6) the cumulative of all-cause mortality was significantly suppressed. Conclusions Given the above, it may be important to continue ACVSTs in outpatients with T2DM without a history of CVD for several years.

This paper discusses the Japanese semi aspectual forms -teshimau and -teoku function as discourse markers which serve as speaker’s intentions of utterances for rapport management. In general, the semantic function of the morphological semi aspectual forms such as -teshimau and -teoku are explained as expressions of feelings of remorse or regret as well as preparatory actions, respectively. Both of them derived from the explanation of “completion” as a core meaning. The meanings mentioned above are also learned in elementary and pre-intermediate levels of Japanese language learning as a second language. However, the results of this research, which derived from analysis using I-JAS corpus dialogue data, indicate that in interpersonal discourse, these aspectual forms are used to show self-deprecating and modest attitudes, sentimental mood, or inevitable and difficult situations. Additionally, as a discourse marker, they are used to express utterance intentions such as showing speaker’s responsible recognition for the situation occurred, respecting the opinion of the interlocutor, and avoiding current topic to be continued. They also function as act of politeness due to the effects of “down graders” and “upgraders” in Spencer-Oatey's theory of rapport management, while in this research indicates that improperly use of -teoku might sound impolite depending on the utterance situations. Furthermore, it was found that they work as discourse markers for rounding up dialogs or shifting topics, and there are differences between -teshimau and -teoku in whether it is the interlocutor’s topic or the speaker’s topic that was being rounded up. For these reasons, second language acquisition requires learning about indicative meanings of these forms that function in the contexts and utterance situations, and the findings of this research will also contribute to the research of Japanese language teaching materials.

国立国語研究所, はこだて未来大学, National Institute for Japanese Language and Linguistics, FUTURE UNIVERSITY HAKODATE

Background: Triple negative breast cancer (TNBC) is a subtype of breast cancer which lacks hormone receptor (HR) expression and HER2 gene amplification and is the most aggressive subtype, with a heterogeneous genetic profile. The aim of this retrospective study was to evaluate the clinical significance of menopausal status in breast cancer cases with TNBC. Methods: Primary breast cancer patients who underwent curative surgery were enrolled in this retrospective study. A total of 5153 invasive breast cancer cases with Stage I–III were analyzed. The distribution of cases according to the menopausal status and subtypes was investigated and the clinicopathological characteristics and prognosis were compared between pre- and postmenopausal TNBC patients. Results: TNBC was frequently seen in postmenopausal patients and Luminal B and Luminal/HER2 subtypes were more common in premenopausal patients. There was no difference in DFS in the Luminal A/B and HER2 subtypes, but a significant difference was seen in the TNBC patients. Premenopausal patients with TNBC frequently had an overexpression of the p53 protein, a significantly higher Ki-67 index value, and a higher nuclear grade. A multivariate analysis revealed that menopausal status, nodal status, and tumor size were significant factors for DFS in TNBC cases. Conclusion: Menopausal status significantly correlates with breast cancer subtypes. TNBC was often seen in postmenopausal patients and these patients tend to have more favorable factors and a better DFS than premenopausal patients. These findings suggest that menopausal status is an important factor for evaluating biology and prognosis in TNBC cases.

Background The bed nucleus of the stria terminalis (BNST) contains the highest density of corticotropin-releasing factor (CRF)-producing neurons in the brain. CRF-immunoreactive neurons show a female-biased sexual dimorphism in the dorsolateral BNST in the rat. Since CRF neurons cannot be immunostained clearly with available CRF antibodies in the mouse, we used a mouse line, in which modified yellow fluorescent protein (Venus) was inserted to the CRF gene, and the Neo cassette was removed, to examine the morphological characteristics of CRF neurons in the dorsolateral BNST. Developmental changes of CRF neurons were examined from postnatal stages to adulthood. Gonadectomy (GDX) was carried out in adult male and female mice to examine the effects of sex steroids on the number of CRF neurons in the dorsolateral BNST. Methods The number of Venus-expressing neurons, stained by immunofluorescence, was compared between male and female mice over the course of development. GDX was carried out in adult mice. Immunohistochemistry, in combination with Nissl staining, was carried out, and the effects of sex or gonadal steroids were examined by estimating the number of Venus-expressing neurons, as well as the total number of neurons or glial cells, in each BNST subnucleus, using a stereological method. Results Most Venus-expressing neurons co-expressed Crf mRNA in the dorsolateral BNST. They constitute a group of neurons without calbindin immunoreactivity, which makes a contrast to the principal nucleus of the BNST that is characterized by calbindin immunostaining. In the dorsolateral BNST, the number of Venus-expressing neurons increased across developmental stages until adulthood. Sexual difference in the number of Venus-expressing neurons was not evident by postnatal day 5. In adulthood, however, there was a significant female predominance in the number of Venus expressing neurons in two subnuclei of the dorsolateral BNST, i.e., the oval nucleus of the BNST (ovBNST) and the anterolateral BNST (alBNST). The number of Venus-expressing neurons was smaller significantly in ovariectomized females compared with proestrous females in either ovBNST or alBNST, and greater significantly in orchiectomized males compared with gonadally intact males in ovBNST. The total number of neurons was also greater significantly in females than in males in ovBNST and alBNST, but it was not affected by GDX. Conclusion Venus-expressing CRF neurons showed female-biased sexual dimorphism in ovBNST and alBNST of the mouse. Expression of Venus in these subnuclei was controlled by gonadal steroids.

Epstein-Barr virus (EBV) causes malignant carcinomas including B cell lymphomas accompanied by the systemic inflammation. Previously, we observed that phosphatidylserine (PS)-exposing subset of extracellular vesicles (EVs) secreted from an EBV strain Akata-transformed lymphoma (Akata EVs) convert surrounding phagocytes into tumor-associated macrophages (TAMs) via induction of inflammatory response, which is in part mediated by EBV-derived micro RNAs. However, it is still unclear about EV-carried other potential inflammatory factors associated with TAM formation in EBV lymphomas. To this end, we sought to explore proteomic and phospholipidomic profiles of PS-exposing EVs derived from EBV-transformed lymphomas. Mass spectrometric analysis revealed that several immunomodulatory proteins including integrin αLβ2 and fibroblast growth factor 2 (FGF2) were highly expressed in PS-exposing Akata EVs compared with another EBV strain B95-8-transformed lymphoma-derived counterparts which significantly lack TAM-inducing ability. Pharmacological inhibition of either integrin αLβ2 or FGF2 hampered cytokine induction in monocytic cultured cells elicited by PS-exposing Akata EVs, suggesting the involvement of these proteins in EV-mediated TAM induction in EBV lymphomas. In addition, phospholipids containing precursors of immunomodulatory lipid mediators were also enriched in PS-exposing Akata EVs compared with B95-8 counterparts. Phospholipidomic analysis of fractionated Akata EVs by density gradient centrifugation further demonstrated that PS-exposing Akata EVs might be identical to certain Akata EVs in low density fractions containing exosomes. Therefore, we concluded that a variety of immunomodulatory cargo molecules in a certain EV subtype are presumably conducive to the development of EBV lymphomas.

There has been a concern that sodium–glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia.

Background We previously reported that, among the asymptomatic patients with type 2 diabetes mellitus (T2DM) without history of cardiovascular disease (CVD), up to 19% of the patients with myocardial ischemia were detected by cardiovascular screening tests (CVSTs). We concluded that the CVSTs in patients with T2DM may be one of the most effective strategies to find CVD in those patients. Thus, the aim of the study was to assess the long-term clinical outcomes of CVSTs in patients with T2DM without previous histories of CVD. Methods Six hundred fifty-seven out-patients with T2DM who received CVSTs at least more than one time or not at all from April in 2014 to March in 2019 were defined as the S group or NS group, respectively. The data in 2104 and 2018 were collected from the medical records, and compared between the S and NS groups. Results This study revealed that, in the out-patients with T2DM in our hospital over those 5 years; 1) the frequency of receiving CVSTs was significantly increasing, 2) in accordance with that increase, the frequency of the internal use for CVD of statins, anti-platelets, and renin-angiotensin system inhibitors, which are well-known as medications for preventing CVD, was significantly increasing, 3) however, there was only a small increase in the internal use of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptors, which are well-known to suppress cardiovascular events in patients with T2DM, 4) LDL-cholesterol and triglycerides significantly improved more in the S group than the NS group, 5) highly sensitive C-protein, which is one of the strongest predictors of CVD, was significantly suppressed by CVSTs, 6) the progression of renal dysfunction was significantly more suppressed in the S group than the NS group, 7) in an inverse proportion to the CVST increase, the frequency of acute coronary syndrome, cerebral infarctions, 4-point major adverse cardiovascular events, and admissions due to heart failure were significantly decreasing, and 8) finally, the frequency of all-cause mortality was significantly suppressed during those 5 years. Conclusions Thus, it may be important to continue CVSTs in out-patients with T2DM without a previous history of CVD for several years.

In previous researches Japanese voice constructions were examined as devices for managing discourse coherence by indicating a person as the focus of attention or of spearker’s empathy. However, in that discourse function a speaker cannot choose the function because it is automatically determined by grammatical and cognitive ways. Previous studies rarely studied the context constitutive choice made by a speaker in every actual language use. This paper aims to explain the functions of Japanese voice constructions which can potentially be a set of options for a speaker’s choice in a discourse, and then examines the speaker’s motivation for the choice made. Introspective and intuitive research method is used to explain the set of options and motivations of speaker’s choice, and each set is assumed to be formed paradigmatically based on functional linguistic theory. The functions of constructions are explained as indexical functions which is developed in the theory of anthropological linguistics. Indexical functions examined here are conventional grammatical knowledges shared in a particular language community. The data used are personal narrative ones. Therefore, the speaker’s focus of attention or empathy no longer need to be questioned here, because in the personal narratives the speaker itself is cognitively the focus of attention. The analysis shows that the indexical functions of constructions chosen by the speaker is roughly divided into two types of indexicals, the first is referential indexicals which express the locus of speaker, directionality, causality, and affectedness of actions, evaluative attitudes towards events, social statuses and powers, and mental attitudes. The second is nonreferential indexicals that express socio-cultural attitudes.

In intercultural communications, we can anticipate the occurrence of unintended face-threatening acts (FTA) which leads to miscommunication. This study discusses the possible FTA by the speaker who does not intend to threaten the interlocutor’s positive and negative face by using one of the Japanese temporal adverbs, yatto. This adverb expresses the speaker’s evaluative meaning, is achieved through various obstacles and the effect takes a long time to achieve. In addition, the word yatto also implies an achievement that is attained by either barely sufficient abilities or because of an immediate deadline. Therefore, when being used to talk about the interlocutor's or the other person’s action, it can threaten his/her face. It is necessary to clarify the possibility of threatening other people's positive and negative faces even though it is unintentional because Japanese teachers and learners are mostly unaware of it. Many of them associate the word yatto as akhirnya in Bahasa Indonesia or finally in English, which does not contain the speaker’s evaluative meaning. Accordingly, the subject of this study is to clarify the conditions of use when the word yatto becomes an FTA. To clarify the problem, this study uses descriptive and qualitative methods and employs the theory of politeness, especially the theory of face-threatening acts (FTA) by Brown and Levinson (1987). Inspired by Kamio (1990)’s notion of the territory of information, there are three types of the territory of information for the yatto adverb; (a) the information that falls to the territory of the speaker, (b) to both of the speaker’s and the interlocutor’s or the other person’s, and (c) to the interlocutor. As the main finding of the research, the factor causing FTA for positive and negative faces, namely FTA which occurs when the speaker talks about the action, falls to (c) the third territory. In the case of the benefactive -tekureru or -temorau forms used together, the meaning appreciating the actions of the interlocutor or the third person, it works as positive politeness to them as an agent. On the contrary, expressing thanks threaten the speaker's negative face.

Endoscopic submucosal dissection(ESD)for colorectal tumors has been covered by the national health insurance system in Japan since April 2012, and is widely used. We analyzed colorectal ESD cases we performed.We investigated 515 patients with colorectal lesions(580 lesions)for whom ESD was performed between November 2005 and April 2017. Clinicopathological data, technical methods, complications, and outcomes were analyzed.Most tumors were found in the transverse colon(134 lesions). The average diameter was about 26 mm. The largest lesion was 120 mm. The en bloc resection rate was high(96.2%). The average operative time was 51 minutes. Among complications, the number of delayed major bleeding cases was 7(1.2%). Minor perforations occurred in 3 cases(0.5%). The perforation could be closed with endoscopic clips. About 70% of the cases were adenomas, and the remainder were carcinomas. One patient with carcinoma in situ showed a mucosal recurrence 4 months later and received repeat endoscopic treatment. The cure rate was 99.8%. Among 29 deep submucosal invasion cases, additional colectomy was performed in 21; 3 patients had persistent carcinoma in the colonic wall and another patient had lymph node metastasis.Colorectal ESD can be performed for all sites in the large intestine, and en bloc resection was possible for a large lesion. A good outcome was observed for "Loco-Regional Cancer Therapy" in early colorectal carcinoma.

The bed nucleus of the stria terminalis (BNST) contains the highest density of corticotropin-releasing factor (CRF)-producing neurons in the brain. CRF-immunoreactive neurons show a female-biased sexual dimorphism in the dorsolateral BNST in the rat. Since CRF neurons cannot be immunostained clearly with available CRF antibodies in the mouse, we used a mouse line, in which modified yellow fluorescent protein (Venus) was inserted to the CRF gene, and the Neo cassette was removed, to examine the morphological characteristics of CRF neurons in the dorsolateral BNST. Developmental changes of CRF neurons were examined from postnatal stages to adulthood. Gonadectomy (GDX) was carried out in adult male and female mice to examine the effects of sex steroids on the number of CRF neurons in the dorsolateral BNST.The number of Venus-expressing neurons, stained by immunofluorescence, was compared between male and female mice over the course of development. GDX was carried out in adult mice. Immunohistochemistry, in combination with Nissl staining, was carried out, and the effects of sex or gonadal steroids were examined by estimating the number of Venus-expressing neurons, as well as the total number of neurons or glial cells, in each BNST subnucleus, using a stereological method.Most Venus-expressing neurons co-expressed Crf mRNA in the dorsolateral BNST. They constitute a group of neurons without calbindin immunoreactivity, which makes a contrast to the principal nucleus of the BNST that is characterized by calbindin immunostaining. In the dorsolateral BNST, the number of Venus-expressing neurons increased across developmental stages until adulthood. Sexual difference in the number of Venus-expressing neurons was not evident by postnatal day 5. In adulthood, however, there was a significant female predominance in the number of Venus expressing neurons in two subnuclei of the dorsolateral BNST, i.e., the oval nucleus of the BNST (ovBNST) and the anterolateral BNST (alBNST). The number of Venus-expressing neurons was smaller significantly in ovariectomized females compared with proestrous females in either ovBNST or alBNST, and greater significantly in orchiectomized males compared with gonadally intact males in ovBNST. The total number of neurons was also greater significantly in females than in males in ovBNST and alBNST, but it was not affected by GDX.Venus-expressing CRF neurons showed female-biased sexual dimorphism in ovBNST and alBNST of the mouse. Expression of Venus in these subnuclei was controlled by gonadal steroids.

目的：FFS（Family Functioning Scale）日本語版の信頼性と妥当性を検討する．方法：作成したFFS日本語版を用いて予備調査の後，3歳以下の乳幼児を養育中の母親501名を対象にFFS日本語版と属性からなる質問紙調査を行い，信頼性と妥当性を分析した．結果：FFS日本語版はFamily APGAR Scoreとの有意な正の相関（Spearman's ρ=0.63，p

The purpose of this paper is to propose a workshop-based educational program for undergraduates to foster their communication abilities. In the recent trend of citizen involvement, engineers and scientists have been required to acquire the abilities to communicate not only with specialists of other fields but also with lay citizens. More specifically, it is important for them to foster the ability to share and solve the problem through discussion with people who have different backgrounds. To respond to these emerging social demands, we developed the educational program for undergraduates to foster such communication abilities that include the basic communicative skills, the ability to think logically, and the ability of explaining. The program consists of activities such as group discussions, problem-solving in a group, and making a presentation of their ideas in an easily comprehensible manner, in terms of which students trained their communication abilities. The program is designed as versatile so that it can be carried out by any teachers at any universities. We report the cases in which the program was conducted at several universities and show the results of questionnaires on the satisfaction of the program targeting both teachers and students who joined it.

Penelitian ini membahas fungsi dan makna indeksikal konstruksi diatesis bahasa Jepang. Dalam tradisi linguistik Barat, konstruksi diatesis merupakan piranti untuk menyatakan makna proposisional mengenai hubungan di antara partisipan dengan situasi yang digambarkan verba. Dengan menggunakan kerangka indeksikal referensial dan nonreferensial, penelitian ini mencoba menjelaskan fungsi konstruksi diatesis bahasa Jepang bermakna nonproposisional. Fungsi dan makna indeksikal dijelaskan melalui pengontrasan paradigmatis terkait makna konstruksi yang membentuk seperangkat opsi terbatas dalam penentuan pilihan penutur. Penelitian ini menjelaskan bahwa indeksikal referensial berfungsi pula menyatakan makna evaluatif penutur seperti ‘stance’ afektif/emotif terhadap partisipan peristiwa yang selama ini oleh peneliti dianggap dinyatakan melalui indeksikal nonreferensial. Penelitian ini menjelaskan pula bahwa makna indeksikal nonreferensial konstruksi diatesis bahasa Jepang dapat mencakup sikap mental yang meliputi sikap menjaga citra diri, sikap menimbang rasa orang lain dan sebagainya. Hasil penelitian membuktikan bahwa fungsi indeksikal referensial maupun nonreferensial pada konstruksi diatesis bahasa Jepang berhubungan erat dengan kehidupan sosial budaya Jepang.

We report a 17-year-old woman with refractory high-grade breast cancer who died early after surgery, with reference to the histogenesis of the cancer. Macroscopically, the tumor was cystic, composed of a mixture of solid and myxomatous areas. Histologically, the tumor exhibited ductal structures and areas with squamoid features. Cancer cells were markedly atypical and polymorphic, and included a mixture of bizarre and eosinophilic cells with rhabdoid feature-like free cells. Immunohistochemically, cytokeratin (CK) 8, CK 18, 34 beta E12, CD10, involucrin, CK14, and vimentin were partially positive, whereas estrogen and progesterone receptors and HER-2 were negative. These findings suggest an undifferentiated cancer whose cells have multilineage potential to differentiate into mesenchymal, basal, and squamoid cells, and it was diagnosed as pleomorphic carcinoma, which is a histological type hitherto unreported in young girls. The cancer was refractory to treatment, and the patient died 1 year and 5 months after surgery despite chemotherapy and radiotherapy.

A rare case of neuroendocrine small cell carcinoma (SmCC) of the breast is reported. A 51-year-old postmenopausal woman noticed a nodule approximately 3 cm in diameter in her right upper breast. Histologically, the tumor consisted of small ovoid to pleomorphic cells with hyperchromatic nuclei, and a large central area was occupied by acellular amorphous tissue. Extensive lymphatic permeation was seen around the tumor. Invasive and in situ ductal carcinoma foci were not observed in and surrounding the tumor. Immunohistochemically, estrogen and progesterone receptors and HER2/neu were all negative in the tumor cells. Synaptophysin and chromogranin A were diffusely positive in the tumor cells. Cytokeratin 8 was only positive in a few tumor cells. The labeling indices of Ki-67 and p53 were high in the tumor. Postoperatively, systemic studies including positron emission tomography were performed but failed to reveal any other possible primary sites, including lung. Based on these findings, the tumor was diagnosed as neuroendocrine primary SmCC of the breast. Postoperatively, the patient received a course of weekly paclitaxel. However, pelvic bone metastasis was identified on a bone scintigram 1 year after surgery. Mammary SmCC showing high Ki-67 and p53 index should be treated carefully because of their aggressive clinical behavior.

In this study we investigated the nature of disagreement, which is a necessary component of a good discussion. We obtained 27 group discussion scenes by Japanese undergraduates that were evaluated by two ways: impression rating and ranking. As a result of factor analysis for the impression rating data, five factors were extracted: activeness, multidirection and unificationof discussion, relationships of participants, development and sophistication of discussion, and sincerity of the participants, and each factor scores of each scene was simultaneously calculated. Each scene’s rank score was also calculated by relative comparisons. A significant positive correlation was found between the mean factor and the rank scores except for Factor 3 (relationships of participants). To consider the reason for the difference relating to Factor 3’s score, we scrutinized the discussion process of four scenes of the different patterns of the factor and rank scores. From the analysis of conversations, we suggested that this difference reflected ways of disagreement. By introducing a probative discourse tags for discussion (pDTD), we reasoned that the frequency of disagreement made Factor 3’s score negative and the absence of the second part of adjacency pairs made the rank score worse. The explicit speech and actions of blame such as emotional and aggressive expression, and neglect of treatment for the minor opinion made also the discussion unfair, but we think that these behaviors might erupt from the ground made by the accumulated implicit behaviors such as the absence of the second part. We finally concluded that the criticism type of disagreement increased the rank scores, and its censure type produced lower results, and the proper ways of disagreement in group discussions were discussed.

The purposes of this study are (a) to establish a measurement for evaluating conversational impressions of group discussions, and (b) to make an exploratory investigation on their interactional processes which may affect to form those impressions. The impression rating and factor analysis undertaken first give us four factors concerning conversational impressions of “focus group interviews (FGIs)”: conversational activeness, conversational sequencing, the attitudes of participants and the relationships of participants. In relation to the factors of conversational activeness and conversational sequencing in particular, the microanalysis of four selected topical scenes from our database further shows that the behavior of the moderator and the interviewees is organized not independently but with reference to each other. The study thus emphasizes the importance of the integration of quantitative and qualitative approaches towards human interactions.

While cancer immunity is involved in tumour progression from the very early stage, no detailed study has been reported on the relationship between 'early-stage' breast cancer and tumour-infiltrating lymphocytes (TILs). We focused on microinvasive carcinoma to investigate the relationship between histological tumour factors and immunity in 'early' breast cancer.Of 2593 resected breast carcinomas, 46 microinvasive carcinomas (1.8%) were included. The relationships between tumour characteristics (invasive form, grade, comedo, subtype) and immunological characteristics (TIL, healing) were examined. The invasive form was divided into 'cluster-like' (ie, invasive foci consisted of a small number of cancer cells) and 'non-cluster-like' (ie, nested and classifiable into particular histological type).Among all cases, 34.8% were grade 1. ER+HER2-, ER+HER2+, ER-HER2+ and ER-HER2- accounted for 58.7%, 8.7%, 28.3% and 4.3%, respectively. Compared with ER+HER2-, ER-HER2+ cases had a significantly stronger association with grade 3 (92.3% vs 0%), comedo (100% vs 55.6%), high TIL (100% vs 29.3%), high CD8+ TIL (92.3% vs 33.3%) and healing (76.9% vs 14.8%) (p0.001). Compared with 'non-cluster-like', 'cluster-like' carcinoma showed significantly higher rates of HER2 positivity (69.2% vs 24.2%), high TIL (92.3% vs 42.4%) and high CD8+ TIL (76.9% vs 39.4%) (p0.01).Our study revealed that microinvasive carcinoma has two progressive pathways; 'low-grade luminal pathway' and 'high-grade HER2 pathway'. HER2-positive cases showed the following unique characteristics: 'high-grade; comedo, high TIL and CD8+ TIL; healing; cluster-like invasion'. These results suggest that the cluster-like invasion might occur because of tumour immunity that leads to disruption of the duct and formation of microinvasive carcinoma in HER2-positive cases.

This study aimed to identify self-care strategies and assess physical and psychosocial factors associated with premenstrual distress among high school students. A cross-sectional survey of 217 adolescent girls aged 15 to 18 years was conducted in October 2009. Most (84.3 percent) had at least one or more symptoms of premenstrual distress. Premenstrual distress interfered with normal school activity in 51.2 percent. Most participants (57.1 percent) did not perform any self-care strategies for premenstrual distress. A hierarchical multiple linear regression analysis was conducted. Comprehension of one's own physical and mental states during premenstrual phases mediated the relationship between neuroticism and premenstrual distress. Activity restrictions due to menstrual distress mediated the relationship between the family's understanding of one's behavior during premenstrual phases and premenstrual distress. Findings suggest that, even if girls have neuroticism, it will be important to teach them to address the comprehension of one's own physical and mental states so that perceptions of both premenstruation and menstruation become more positive. Findings also suggest that the family's understanding was associated with alleviation of premenstrual distress. This study suggests the need for education to help adolescent girls and their families manage premenstrual distress and increase awareness of the benefit of managing its associated symptoms.

Background/Aims: Histamine H2 receptor antagonists are considered to exert their effects on gastric acid secretion more rapidly than proton pump antagonists. However, there are no reports concerning the direct interaction of a histamine H2 receptor antagonist with the human H2 receptor in terms of onset of action. This study aims to characterize how rapidly famotidine and ranitidine, the most widely used histamine H2 receptor antagonists, interact with the human histamine H2 receptor. Methods: HEK293 cell lines, stably expressing human histamine H2 receptors, were obtained. The dose- and time-dependent effects of famotidine and ranitidine on [3H]-tiotidine binding and histamine-stimulated cAMP production were analyzed. Results: Ranitidine inhibited both [3H]-tiotidine binding and histamine-stimulated cAMP production more promptly than did famotidine. Inhibition of histamine-stimulated cAMP production by Cmax doses of famotidine (20 mg p.o.) and ranitidine (150 mg p.o.) peaked by 15 and 2 min, respectively. [3H]-Tiotidine binding was not saturated by 60 min at the famotidine Cmax, while the ranitidine Cmax had produced saturation by 15 min. Conclusion: Ranitidine inhibits the human histamine H2 receptor very rapidly.

Phytoestrogens are assumed to affect the endocrine system of animal species similarly to other man-made endocrine disrupters and to exert their effects through estrogen receptors, specifically ER(alpha) and ERbeta. However, these molecular mechanisms are not fully understood. In this study, 19 phytochemicals were surveyed for agonist and antagonist activities of ER(alpha) and ERbeta using an ERE-luciferase reporter assay. The results showed that ferutinine is an agonist for ER(alpha) and an agonist/antagonist for ERbeta, tschimgine is an agonist for both ER(alpha) and ERbeta, and tschimganidine is an agonist for only ER(alpha). Ferutinine and tschimganidine are sesquiterpenoids, and tschimgine is a monoterpenoid derived from the Umbelliferae family. A competitive binding assay showed that ferutinine has higher binding affinities than tamoxifen for both ERs. Co-transfections of coactivators such as SRC-1, TIF2, AIB1, and TRAP220 in 293T cells and use of the luciferase assay revealed that TRAP220 failed to enhance the transcription mediated by ERbeta in the presence of ferutinine. Moreover, a GST pull-down assay showed that TRAP220 marginally bound to ERbeta ligand binding domain in the presence of ferutinine. These results suggest that the conformation of ferutinine-liganded ERbeta is difficult for TRAP220 to recognize. Taken together, this suggests that some terpenoids can modulate estrogen signaling as ER subtype-selective phytoestrogens similar to SERMs (selective estrogen receptor modulators).

Aralin from Aralia elata is a newly identified type II ribosome- inactivating protein, which preferentially induces apoptosis in cancer cells. In this study, we identified that the aralin receptor is a 110-kDa high-density lipoprotein-binding protein (HDLBP), which functions as a HDL receptor. The sensitivities of tumor cell lines to aralin were dependent on the expression levels of the 110-kDa HDLBP and its forced expression in aralin-resistant Huh7 cells conferred aralin sensitivity. HDLBP-knockdown HeLa cells showed a significant aralin resistance in vitro and in vivo. Conversely, ectopic expression of the 150-kDa HDLBP resulted in increased aralin sensitivity in vivo, accompanying enhanced expression of the 110-kDa HDLBP. Thus, these results showed that the 110-kDa HDLBP in lipid rafts acted as an aralin receptor and that its expression levels determined aralin sensitivity, suggesting that aralin could be a promising anticancer drug for HDLBP-overexpressing tumors.

We present a rather new task of detecting and collecting tweets that contain heartwarming stories from a huge amount of tweets on Twitter in this paper. We also present a method for identifying heartwarming tweets. Our prediction method is based on a supervised learning algorithm in SVM along with features from the tweets. We found by comparing the feature sets that adding sentiment features mostly improves the performance. However, simply adding the features for detecting a story in a tweet (past tense and tweet length) cannot contribute to improving the performance, while adding all the features to the baseline feature set mostly yields the best performance from among the feature sets.

Background/Aim: Based on animal models, lafutidine, a novel histamine H2 receptor (H2R) antagonist, is reported to show potent and long-lasting antagonisms of histamine H2R-mediated effects. However, no reports have been published concerning its direct interaction with the human H2R. This study aims at characterizing its interaction with human H2R. Methods: Chinese hamster ovary cell lines stably expressing human H2Rs were obtained. The dose-dependent effects of lafutidine and famotidine on [3H]tiotidine binding and histamine-stimulated cAMP production were analyzed. The effects of preincubation with 2.78 × 10–7M of lafutidine or famotidine for 30 min on histamine-dependent cAMP production and [3H]tiotidine binding were also examined after 0, 1, 2, 4, and 12 h. This concentration is below the Cmax of lafutidine (10 mg p.o.) and above the Cmax of famotidine (20 mg p.o.). Results: Lafutidine inhibited [3H]tiotidine binding and histamine-stimulated cAMP production as or more potently than famotidine. At higher concentrations lafutidine was more potent than famotidine. In addition, preincubation with 2.78 × 10–7M lafutidine, but not with 10–5M famotidine, had marked inhibitory effects which persisted as long as after extensive washing. Conclusion: Lafutidine shows a potent and long-lasting antagonism on the human H2R.

Based on animal models, IT-066, a histamine H2-receptor antagonist, is reported to possess potent and long-lasting antagonisms on histamine H2 receptor (H2R) -mediated effects. However, no reports have been published concerning its interaction with the human H2R. The aim of this study is to characterize its interaction with human H2R. Chinese hamster ovary cell lines stably expressing human H2Rs were obtained. The effects of IT-066, famotidine, and ranitidine on tiotidine binding and histamine-stimulated cAMP production were analyzed. IT-066 inhibited [3H]tiotidine binding and histamine-stimulated cAMP production more potently than famotidine or ranitidine. In addition, preincubation with 10(-5) M IT-066, but not with 10(-5) M famotidine or 10(-4) M ranitidine, had marked inhibitory effects long after extensive washing. Paraformaldehyde fixation of the cells blunted inhibition of [3H]tiotidine binding induced by preincubation with IT-066, but not that by preincubation with famotidine or ranitidine. IT-066 has potent and long-lasting antagonisms on human H2R. At least one of the IT-066 binding sites is not shared by famotidine, ranitidine, or tiotidine and is affected by paraformaldehyde fixation.

Introduction Since treatment modalities for metastatic recurrent triple-negative breast cancer (mrTNBC) are limited, a novel treatment approach including immunotherapy is required. We have developed a novel regimen of personalized peptide vaccination (PPV), in which vaccine antigens are individually selected from a pool of different peptide candidates based on the pre-existing host immunity. Herein we conducted a phase II study of PPV for metastatic recurrent breast cancer patients to investigate the feasibility of PPV for mrTNBC. Methods Seventy-nine patients with metastatic recurrent breast cancer who had metastases and had failed standard chemotherapy and/or hormonal therapy were enrolled. They were subgrouped as the mrTNBC group (n = 18), the luminal/human epidermal growth factor receptor 2 (HER2)-negative group (n = 41) and the HER2-positive group (n = 18), while the remaining two patients had not been investigated. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher peptide-specific immunoglobulin G (IgG) responses in pre-vaccination plasma were selected from 31 pooled peptide candidates applicable for the four HLA-IA phenotypes (HLA-A2, -A24, or -A26 types, or HLA-A3 supertypes), and were subcutaneously administered weekly for 6 weeks and bi-weekly thereafter. Measurement of peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses along with other laboratory analyses were conducted before and after vaccination. Results No severe adverse events associated with PPV were observed in any of the enrolled patients. Boosting of CTL and/or IgG responses was observed in most of the patients after vaccination, irrespective of the breast cancer subtypes. There were three complete response cases (1 mrTNBC and 2 luminal/HER2-negative types) and six partial response cases (1 mrTNBC and 5 luminal/HER2-negative types). The median progression-free survival time and median overall survival time of mrTNBC patients were 7.5 and 11.1 months, while those of luminal/HER2-negative patients were 12.2 and 26.5 months, and those of HER2-positive patients were 4.5 and 14.9 months, respectively. Conclusions PPV could be feasible for mrTNBC patients because of the safety, immune responses, and possible clinical benefits. Clinical Trial Registration Number UMIN000001844 (Registration Date: April 5, 2009)

We investigated the efficacy and safety of metronomic chemotherapy with combined irinotecan and tegafur-gimeracil-oteracil potassium (TS-1) in patients with metastatic and recurrent breast cancer (MRBC), and the association between irinotecan metabolizing enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms and adverse events.The study group comprised 40 patients aged 35-79 years. Irinotecan (60 mg/m(2) in 5 % dextrose) was administered by 120-min infusion on days 1, 8, and 15 every 4 weeks. TS-1 (prescribed in a standard quantity) was administered at 80 mg/m(2)/day orally on days 3-7, 10-14, and 17-21 every 4 weeks.Tumor response data were available for 34 patients. Median follow-up was 12 months (range 1-45 months). Response rate was 47 % (one complete and 15 partial responses). Stable disease was observed in 17 patients (50 %). One patient had disease progression (3 %). Median progression-free survival was 14 months [95 % confidence interval (CI), 10-26]. Median overall survival was 26 months (95 % CI not calculable owing to sample size), and 79.3 % of patients survived for 1 year. The most common grade 3 or 4 adverse events were neutropenia (15 %), leukopenia (12.5 %), diarrhea (7.5 %), and anemia (2.5 %). All other adverse events were grade 1 or 2. Treatment-related toxicity was generally modest and manageable. No significant correlation was observed between UGT1A1 polymorphisms and hematological or non-hematological toxicities.Metronomic chemotherapy with combined irinotecan and TS-1 was effective in MRBC patients. Adverse effects were mild and the regimen was safely administered without identifying UGT1A1 polymorphisms.

Effect of various ligands which include imidacloprid related compounds, on the binding of [ 3 Hjphencyclidine (PCP) known as a probe for the allosteric site located in the receptor's ion channel and [ 3 H]α-bungarotoxin (α-BGT) known as a probe for the acetylcholine (ACh) recognition site of the nicotinic acetylcholine receptor with its ion channel from the Torpedo electric organ, was examined. Nicotine and anabasine showed a strong agonistic action like carbachol and cytisine, whereas imidacloprid, 6-Cl-PMN1, acetamiprid, NMTHT, nitenpyram and MTENI were weakly agonistic. NMTHT, nitenpyram and MTENI were also noncompetitive blockers like coniine, DMPP, nereistoxin and d-tubocurarine which interacted with both the ACh recognition site and the allosteric site. PCP, TCP, ketamine, chlorpromazine and mecamylamine were noncompetitive blockers ; also lobeline and trimethaphan were found to be noncompetitive blockers as against text books.

Using radioreceptor assay with [ 3 H]α-bungarotoxin (α-BGT) and [ 3 H]phencyclidine (PCP) as probes for the nicotinic acetylcholine receptor (nAChR) in membranes obtained from honeybee heads, the effects of various nAChR ligands, nicotinoids and neonicotinoids were studied. The data indicated differences in pharmacological characteristics between Torpedo electric organ and honeybee brain nAChRs. [ 3 H]α-BGT binds to the acetylcholine (ACh) recognition site of the nAChRs of vertebrate skeletal muscle, Torpedo electric organ and honeybee brain. In vertebrates, [ 3 H]PCP binds to an allosteric site on the receptor's ion channel and its binding is stimulated by receptor activation with agonists. However, the tested vertebrate cholinergic agonists inhibited [ 3 H]α-BGT binding, but did not activate [ 3 H]PCP binding to the honeybee nAChR. Saturation isotherms of the binding of [ 3 H]α-BGT with or without PCP indicated that PCP interacted with the ACh recognition site on the nAChR. Furthermore, nicotine inhibited not only [ 3 H]α-BGT binding but also [ 3 H]PCP binding. Detailed study of [ 3 HjPCP binding indicated that [ 3 H]PCP bound to the honeybee brain membranes both at high and low affinity sites. The former corresponded to the vertebrate allosteric site on the nAChR and the latter to the ACh recognition site. Nicotine, anabasine and nitenpyram bound to both sites, while imidacloprid, 6-Cl-PMN1 and acetamiprid bound selectively to the ACh recognition site. In houseflies, nicotine and imidacloprid produced excitation followed by paralysis, while PCP was anesthetic, even though PCP was as insecticidal as nicotine.

The forkhead box protein 3 (FOXP3) transcription factor is highly expressed in tumor cells as well as in regulatory T cells (Tregs). It plays a tumor-enhancing role in Tregs and suppresses carcinogenesis as a potent repressor of several oncogenes. The clinical prognostic value of FOXP3 expression has not yet been elucidated. In this study, immunohistochemistry was used to investigate the prognostic significance of FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in breast cancer patients. Of the 100 tumor specimens obtained from primary invasive breast carcinoma, 63 and 57% were evaluated as FOXP3+ tumor cells and as being highly infiltrated by FOXP3+ lymphocytes, respectively. Although FOXP3 expression in tumor cells was of no prognostic significance, FOXP3+ lymphocytes were significantly associated with poor overall survival (OS) (n=98, log-rank test P=0.008). FOXP3 exhibited a heterogeneous subcellular localization in tumor cells (cytoplasm, 31%; nucleus, 26%; both, 6%) and, although cytoplasmic FOXP3 was associated with poor OS (P= 0.058), nuclear FOXP3 demonstrated a significant association with improved OS (P=0.016). Furthermore, when patients were grouped according to their expression of tumor cytoplasmic FOXP3 and lymphocyte FOXP3, there were notable differences in the Kaplan-Meier curves for OS (P

Colonoscopy plays an important role in the medical care of patients with colorectal cancer. It is generally used for both the diagnosis of different stages of colorectal cancer and the treatment of early colorectal cancer and its precursors. The recent progress in colonoscopy has been remarkable. Endoscopes with variable rigidity and small diameters provide efficient insertion to the cecum and result in lower distress for patients. Trained colonoscopists can insert endoscopes into the cecum within a few minutes, and it is not necessary to anesthetize patients without severe peritoneal adhesion. We can obtain good-quality pictures and special images to assist in diagnosis by using highvision endoscopes, magnifying endoscopes, dye spray, and narrow-band imaging (NBI). Determining whether a colorectal carcinoma can be curatively resected by endoscopic treatment or whether the carcinoma has a risk of lymph node metastasis is a very delicate and important task. In particular, the depth of cancer invasion is related to lymph node metastasis; therefore, endoscopic ultrasonography and the classification of pit patterns, capillary patterns via NBI, and the lesion-lifted condition are used to diagnose the depth of cancer invasion (Kato, 2001, Sano, 2008). Treatment for colorectal neoplastic lesions begins with hot biopsy and snare polypectomy, and recently, endoscopic submucosal resection (EMR), piecemeal EMR (EPMR), and endoscopic submucosal dissection (ESD) have become available for large and flat lesions of the colon and rectum. Early colorectal carcinoma is defined as a carcinoma within the submucosal layer that is not invading the muscularis propria. Carcinoma in situ (mucosal carcinoma) and carcinoma that slightly invades the submucosa and without risk factors for metastasis do not metastasize into lymph nodes or distant organs. Nonmetastatic carcinoma is cured by local resection with colonoscope. It is important to make an accurate diagnosis by endoscopy and to perform confident resection for pathological evaluation. In this chapter, we describe endoscopic diagnosis for colorectal carcinoma and differential diagnosis, and treatment options for early colorectal cancer without metastasis and for adenoma which is regarded as a precancerous condition. In addition, we briefly discuss risk factors for lymph node metastasis in early colorectal carcinoma.

We present a case of a 57-year-old woman with a giant malignant phyllodes tumor (PT) in her right breast, with maximum diameter of 20 cm. The core-needle and excisional biopsy specimens were diagnosed as suspicious for low-grade myofibroblastic sarcoma (LGMS). The subsequent total mastectomy with partial resection of the pectoral muscles showed predominance of stromal hypercellularity without an epithelial component. However, we diagnosed this as a malignant PT because focal areas showed a leaf-like pattern. In the case of large malignant PTs that exhibit stromal predominance, it can be difficult to distinguish between a pure sarcoma and malignant PT. It is important to thoroughly examine multiple sections from the view point of residual epithelial structure in morphological diagnosis.