Population-based cohort study assessing the efficacy of cervical cytology (Pap smear) and human papillomavirus (HPV) testing as modalities for cervical cancer screening.

In cervical cancer screening, several trials have shown that human papillomavirus (HPV) testing or combined HPV testing and cytology leads to earlier detection of cervical intraepithelial neoplasia Grade 3 or worse (CIN3+) compared with cytology alone. However, the availability of similar evidence in our country remains limited. In 2013, 34 local governments were selected to administer a cervical cancer screening program utilizing either cytology alone or in combination with HPV testing. We planned a cohort study to assess the effectiveness of HPV testing as a modality for cervical cancer screening. The primary outcome of this study was the incidence of CIN3+ in each group, as well as to assess the risks and benefits of receiving screening for women in both groups. These results will contribute to elucidating the details of the positive and negative impacts of introducing HPV testing into a population-based cervical cancer screening program in Japan.

Inhibition of RHO-ROCK signaling enhances ICM and suppresses TE characteristics through activation of Hippo signaling in the mouse blastocyst.

Specification of the trophectoderm (TE) and inner cell mass (ICM) lineages in the mouse blastocyst correlates with cell position, as TE derives from outer cells whereas ICM from inner cells. Differences in position are reflected by cell polarization and Hippo signaling. Only in outer cells, the apical-basal cell polarity is established, and Hippo signaling is inhibited in such a manner that LATS1 and 2 (LATS1/2) kinases are prevented from phosphorylating YAP, a key transcriptional co-activator of the TE-specifying gene Cdx2. However, the molecular mechanisms that regulate these events are not fully understood. Here, we showed that inhibition of RHO-ROCK signaling enhances ICM and suppresses TE characteristics through activation of Hippo signaling and disruption of apical-basal polarity. Embryos treated with ROCK inhibitor Y-27632 exhibited elevated expression of ICM marker NANOG and reduced expression of CDX2 at the blastocyst stage. Y-27632-treated embryos failed to accumulate YAP in the nucleus, although it was rescued by concomitant inhibition of LATS1/2. Segregation between apical and basal polarity regulators, namely PARD6B, PRKCZ, SCRIB, and LLGL1, was dampened by Y-27632 treatment, whereas some of the polarization events at the late 8-cell stage such as compaction and apical localization of p-ERM and tyrosinated tubulin occurred normally. Similar abnormalities of Hippo signaling and apical-basal polarization were also observed in embryos that were treated with RHO GTPases inhibitor. These results suggest that RHO-ROCK signaling plays an essential role in regulating Hippo signaling and cell polarization to enable proper specification of the ICM and TE lineages.

4-Hydroxynonenal induces persistent insolubilization of TDP-43 and alters its intracellular localization.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of motor neurons. TDP-43 has been found to be a major component of ubiquitin-positive inclusions in ALS. Aberrant TDP-43, which is found in inclusions, is phosphorylated and is re-distributed from the nucleus to the cytoplasm. Alterations of TDP-43 protein, particularly insolubilization/aggregation and cytosolic distribution are thought to be involved in the pathogenesis of ALS. Levels of 4-hydroxynonenal (HNE), a marker of oxidative stress, have been reported to be elevated in sporadic ALS patients. However, the effects of HNE on TDP-43 are unclear. In this study, we found that HNE treatment of cells causes insolubilization, phosphorylation, and partial cytosolic localization of TDP-43. HNE-induced cytosolic TDP-43 was diffusely localized and only a small proportion of TDP-43 localized to stress granules, which are transient structures. HNE-induced TDP-43 insolubilization and phosphorylation were even observed 24 h after washout of HNE. We also showed that the cysteine residues of TDP-43 are responsible for HNE-induced insolubilization of TDP-43. Our results indicate that HNE can cause biochemical changes of TDP-43, which resemble the aberrant alterations of this protein in ALS, and suggest that upregulation of HNE could be a risk factor for ALS.

Sex Differences in Intestinal Microbiota and Their Association with Some Diseases in a Japanese Population Observed by Analysis Using a Large Dataset.

In recent years, many studies have focused on the relationship between intestinal microbiota and human health, but the impact of sex has not yet been sufficiently investigated. In this study, sex differences in the intestinal microbiota of a Japanese population were investigated by age group, using a large dataset constructed for a cross-sectional study. α-diversity analysis indicated that the impact of sex differences varied among the 20s-50s age groups but tended to be smaller among the 60s-70s age groups. Fusobacterium, Megamonas, Megasphaera, Prevotella, and Sutterella were more common among males, whereas Alistipes, Bacteroides, Bifidobacterium, Odoribacter, and Ruthenibacterium were common among females. Next, intestinal bacteria potentially associated with 12 diseases were investigated for each sex. The results indicate that many of these differ between males and females, and among age groups. Thus, sex and age should be considered for studies on intestinal microbiota and disease association, prevention, and treatment approaches that target them.

Characteristics of the Gut Microbiota in Japanese Patients with Premenstrual Syndrome.

Purpose: The present study aimed to characterize the gut microbiota of individuals with premenstrual syndrome. Patients and Methods: The gut microbiota of 24 Japanese women with PMS (PMS group) and 144 healthy Japanese women (control group) were compared. Analysis of the α- and ß-diversities and the gut microbial composition at the genus level were performed using 16S rRNA gene sequence data obtained from stool samples. Results: A significant difference in age was observed between the PMS and control groups; however, no significant difference was observed in BMI. The α-diversity measured using the Simpson index was significantly higher in the PMS group than the control group. Visualization of the ß-diversity using non-metric multidimensional scaling and permutational multivariate analysis of variance (PERMANOVA) showed that the distance of the gut microbiota between the PMS and control groups is significantly different. Furthermore, a significant difference in the composition of the gut microbiota was observed between the PMS and control groups. At the genus level, the abundances of Collinsella, Bifidobacterium, and Blautia were significantly higher in the PMS group than in the control group. In particular, the abundance of Collinsella in the PMS group was approximately 4.5 times higher than that in the control group. To rule out the confounding effect of age in the abundances of Bifidobacterium, Blautia, and Collinsella, the gut microbiota of the PMS and control groups were compared by age group. Results showed that Collinsella had the highest effect size in participants of 30-40 years of age (mean age: 36.39 ± 4.68 years). Conclusion: These results suggest that the PMS group possesses a characteristic gut microbiota. In particular, Collinsella was strongly associated with PMS. Since Collinsella has been reported to be associated with diet, dietary interventions such as prebiotics targeting Collinsella may be effective in preventing, improving, and alleviating PMS.

Fluctuations in Intestinal Microbiota Following Ingestion of Natto Powder Containing Bacillus subtilis var. natto SONOMONO Spores: Considerations Using a Large-Scale Intestinal Microflora Database.

Improving the intestinal microbiota using probiotics, prebiotics, and synbiotics has attracted attention as a method of disease prevention and treatment. This is the first study to discuss the effects of food intake on the intestinal microbiota using a large Japanese intestinal microbiota database. Here, as a case study, we determined changes in the intestinal microbiota caused by ingestion of a processed natto food containing B. subtilisvar. natto SONOMONO spores, SONOMONO NATTO POWDER CAPSULESTM, by analyzing 16S rRNA sequence data generated using next-generation sequencing techniques. The results showed that the relative abundance of Bifidobacterium and Blautia as well as the relative abundance of Bifidobacterium were increased in males and females in the ingesting group, respectively. Additionally, the effects of SONOMONO NATTO POWDER CAPSULESTM intake on Bifidobacterium and Blautia abundance depended on the relative abundance of Bifidobacterium at baseline. Finally, analysis of a large Japanese intestinal microbiota database suggested that the bacterial genera that fluctuated with the ingestion of SONOMONO NATTO POWDER CAPSULESTM may be associated with lifestyle-related diseases such as diabetes.

The first-round results of a population-based cohort study of HPV testing in Japanese cervical cancer screening: baseline characteristics, screening results, and referral rate.

OBJECTIVE: In 2013, a cohort study aimed to clarify the positive and negative effects of introducing the human papillomavirus (HPV) testing for population-based cervical cancer screening has been launched in Japan. This study included four screenings during the subsequent 7-year follow-up period. We aim to describe the results of the first round of this study on cervical cancer screening here. METHODS: This study began in September 2013 with recruitment completed in March 2016. Women aged 30-49 years were divided into 2 groups: those who received uterine cervical cytology alone in the first year (control group), or those who received a combination of cytology and HPV testing (intervention group), based on their age. After first screening, women with positive result of cytology or positive HPV test required referral. We summarized the results of the first round of cervical cancer screening. RESULTS: Of the 25,074 women who were eligible for the study, 13,845 women (55.2%) were screened with cytology alone; 11,229 women (44.8%) received a combination of cytology and HPV testing. After screening, 407 women (2.9%) in the control group and 1,003 women (8.9%) in the intervention group required referral, respectively. Adding HPV testing increased referral rate significantly (p<0.001). CONCLUSION: After first screening, introduction of HPV testing appears to contribute to significantly higher referral rates, suggesting that the number of colposcopies as a detailed examination may increase. These preliminary findings suggest that if HPV testing is introduced into screening, medical institutions need to be prepared for an increasing number of follow-up examinations.