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c BHLHE40 and BHLHE41 (BHLHE40/41) are basic helix-loop-helix type transcription factors that play key roles in multiple cell behaviors. BHLHE40/41 were recently shown to be involved in an epithelial-to-mesenchymal transition (EMT). However, the precise mechanism of EMT control by BHLHE40/41 remains unclear. In the present study, we demonstrated that BHLHE40/41 expression was controlled in a pathological stage-dependent manner in human endometrial cancer (HEC). Our in vitro assays showed that BHLHE40/41 suppressed tumor cell invasion. BHLHE40/41 also suppressed the transcription of the EMT effectors SNAI1, SNAI2, and TWIST1. We identified the critical promoter regions of TWIST1 for its basal transcriptional activity. We elucidated that the transcription factor SP1 was involved in the basal transcriptional activity of TWIST1 and that BHLHE40/41 competed with SP1 for DNA binding to regulate gene transcription. This study is the first to report the detailed functions of BHLHE40 and BHLHE41 in the suppression of EMT effectors in vitro. Our results suggest that BHLHE40/41 suppress tumor cell invasion by inhibiting EMT in tumor cells. We propose that BHLHE40/41 are promising markers to predict the aggressiveness of each HEC case and that molecular targeting strategies involving BHLHE40/41 and SP1 may effectively regulate HEC progression. Basic helix-loop-helix (bHLH) type transcription factors play key roles in cell differentiation, proliferation, apoptosis, and metabolism. BHLHE40 (basic helix-loop-helix family member e40 gene) and BHLHE41 are members of the Hairy/E(spl)/HES family. BHLHE40 and BHLHE41 (BHLHE40/41) exhibit more than 90% similarity in the bHLH region and approximately 50% in total. BHLHE40/41 have been shown to function as transcriptional repressors by binding to the class B E-box. BHLHE40/41 interact with TF2B, TBP, or TF2D or recruit a histone deacetylase at the E-box site (1-5). On the other hand, BHLHE40/41 were previously reported to modulate the expression of some genes in an E-box-independent manner. BHLHE40 has been shown to associate with SP1 binding sites in the BIRC5 promoter to activate its transcription (6) and with STAT3 to regulate the transcription of STAT3-dependent target genes (7). BHLHE41 suppressed VEGF transcription by interacting with HIF1A (8). BHLHE40 and BHLHE41 were reported to associate with retinoid X receptor (RXR), MYOD1, or CEBP in order to regulate the transcription of their target genes (9-12).In diverse types of cancer species, such as colon, oral, and liver cancer or brain tumors, BHLHE40 expression levels were found to be higher in tumors than in adjacent normal tissues (13-15). On the other hand, in human endometrial cancer (HEC) and nonsmall-cell lung cancer, no changes in BHLHE40 expression were reported between cancer and normal tissues (16,17). Regarding expression profiles with the development of cancer, studies on oral, lung, liver, and esophageal cancer showed that BHLHE40 expression inversely correlated with the tumor stage or differentiation grade (18-21)...

Aim We examined whether a newly developed computer‐aided neuropsychiatric series of test, CogEvo, is necessary and sufficient for the evaluation of cognitive function in older people. Methods A total of 272 participants in worthwhile life activity for the prevention of decline in mobility and cognitive function were administered tests every week at 33 locations in Fukaura‐machi, Japan. Basic profile information, a Mini‐Mental State Examination (MMSE), a CogEvo and a clock drawing test were used in the present study. Results Our results are summarized as: (i) the total score of the CogEvo and MMSE tests decreased significantly according to age and in age group analysis; (ii) scores from the CogEvo and MMSE tests showed a significant correlation; (iii) MMSE scores showed marked ceiling effects; (iv) analysis of cognitive domains, such as orientation, attention, memory and executive function, and spatial cognition using CogEvo showed significant age‐dependent impairment; (v) CogEvo discriminated three score groups of MMSE results with sensitivity and specificity of 70% and 60% in the <23 score group, 78% and 54% in the 24–26 score group, and 85% and 70% in the >27 score group, respectively; (vi) CogEvo memory tests reflected more detailed recall function than registration function; and (vii) CogEvo spatial cognition test results were correlated with test items of the MMSE and clock drawing tests. Conclusions CogEvo is an easy and potentially useful computer‐aided test battery that can be used to evaluate age‐related or pathological decline in cognitive function from middle age and in preclinical stages of dementia. Geriatr Gerontol Int 2019; ••: ••–••.

The administration of aprepitant did not have a prophylactic effect on the HSR but was effective in reducing nausea and vomiting in gynecologic cancer patients receiving TC combination chemotherapy.

p21WAF(1)/CIP(1) is a well-known cell cycle regulatory protein which is overexpressed in several cancer cell lines, and known to determine cell fate. We generated three recombinant adenovirus vectors that expressed either the full-length p21 (Ad-p21F), a p21 mutant with a deletion of the C-terminal proliferative cell nuclear antigen (PCNA) binding domain (Ad-p21N), or a p21 mutant with a deletion of the N-terminal cyclindependent kinase binding domain (Ad-p21C). We transfected these vectors into five cancer cell lines. Premature senescence was induced in all of the lines only following transfection with Ad-p21N and Ad-p21F. In addition, apoptosis was also induced in LoVo and HCT116 cells that harbored wild-type p53 and the reactive oxygen species (ROS) level was higher than in senescent cells. Finally, the induction of apoptosis was inhibited by using siRNA to downregulate p53. This observation implies that there is a feedback signaling loop involving p21/ROS/p53 in apoptotic responses. It appears to be, at least in part, driven by high levels of p21 protein. Next, we investigated the cell death effect of endogenous p21 protein on cell fate using sodium butyrate (NaB). Treatment with 1 mM NaB or 2 to 5 mM NaB induced senescence or apoptosis, respectively. The level of intracellular ROS in 5 mM NaB treated cells was 2-fold higher, compared with that in 1 mM NaB treated cells. We also demonstrated that DNA damage response signals including ataxia telangiectasia mutated, gH2AX, and p38 MAPK were involved in NaB-induced cell death. The magnitude of intracellular ROS levels in response to p21 elicited either senescence or apoptosis in the cancer cell lines. (Cancer Sci 2009; 100: 1275-1283)