Gastric-Type Adenocarcinoma of the Uterine Cervix Associated with Poor Response to Definitive Radiotherapy.

We aimed to evaluate the response to definitive radiotherapy (RT) for cervical cancer based on histological subtypes and investigate prognostic factors in adenocarcinoma (AC). Of the 396 patients treated with definitive RT between January, 2010 and July, 2020, 327 patients met the inclusion criteria, including 275 with squamous cell carcinoma (SCC) and 52 with AC restaged based on the 2018 International Federation of Gynecology and Obstetrics staging system. Patient characteristics, response to RT, and prognoses of SCC and AC were evaluated. The complete response (CR) rates were 92.4% and 53.8% for SCC and AC, respectively (p < 0.05). Three-year overall survival and progression-free survival (PFS) rates of SCC were significantly higher than those of AC (88.6% vs. 74.1%, p < 0.05 and 76.3% vs. 59.3%, p < 0.05, respectively). Among the AC population, univariate and multivariate analyses were performed to examine prognostic factors associated with non-complete response (CR). In the multivariate analysis, gastric-type adenocarcinoma (GAS) was associated with non-CR in AC (adjusted odds ratio, 12.2; 95% confidence interval 1.0−145.6; p < 0.05). The 3-year PFS rate in patients with GAS was significantly lower than that in patients with other histological types of AC (44.4% vs. 66.7%, p < 0.05). Definitive RT for cervical cancer was significantly less effective for AC than for SCC. GAS was the only independent prognostic factor associated with non-CR in AC.

Sleeping Beauty Transposon Mutagenesis Identifies Genes Driving the Initiation and Metastasis of Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is a malignancy, which arises from the uterine smooth muscle. Because of its rarity, aggressive nature, and extremely poor prognosis, the molecular mechanisms driving ULMS remain elusive. To identify candidate cancer genes (CCG) driving ULMS, we conducted an in vivo Sleeping Beauty (SB) transposon mutagenesis screen in uterine myometrium-specific, PTEN knockout, KRAS mutant (PTEN KO/KRAS) mice. ULMS quickly developed in SB PTEN KO/KRAS mice, but not in PTEN KO/KRAS mice, demonstrating the critical importance of SB mutagenesis for driving ULMS in this model. Subsequent sequencing of SB insertion sites in these tumors identified 19 ULMS CCGs that were significantly enriched in known cancer genes. Among them, Zfp217 and Sfmbt2 functioned at early stages of tumor initiation and appeared to be oncogenes. Expression of ZNF217, the human homolog of ZFP217, was shown to be elevated in human ULMS compared with paired normal uterine smooth muscle, where it negatively correlated with patient prognosis. Inhibition of ZNF217 suppressed, whereas overexpression induced, proliferation, survival, migration, and stemness of human ULMS. In a second ex vivo ULMS SB metastasis screen, three CCGs were identified that may drive ULMS metastasis to the lung. One of these CCGs, Nrd1 (NRDC in humans), showed stronger expression in human metastatic tumors compared with primary ULMS and negatively associated with patient survival. NRDC knockdown impaired migration and adhesion without affecting cell proliferation, whereas overexpression had the opposite effect. Together, these results reveal novel mechanism driving ULMS tumorigenesis and metastasis and identify ZNF217 and NRDC as potential targets for ULMS therapy. SIGNIFICANCE: An in vivo Sleeping Beauty transposon mutagenesis screen identifies candidate cancer genes that drive initiation and progression of uterine leiomyosarcoma and may serve as therapeutic targets.

Magnetic resonance imaging evaluation of pelvic floor structure during pregnancy.

OBJECTIVE: Among the various risk factors of pelvic floor disorders, pregnancy has been reported to affect the pelvic floor structure; however, not all these effects have been understood yet. The aim of this study is to elucidate how pregnancy affects pelvic floor structure via magnetic resonance imaging (MRI). STUDY DESIGN: We conducted a retrospective study between January 2010 and December 2019 to extract clinical records of pregnant and non-pregnant women, who underwent MRI for obstetrical diseases and ovarian benign tumors, respectively. The data on age, body mass index (BMI), complications, gravida, parity, gestational age, and obstetrical history were collected, and pubo-coccygeal line (PCL), pubo-rectal line (PRL), and M line (ML) on their MR images were measured. Statistical analyses were performed with Wilcoxon test, chi-square test, and Kruskal-Wallis test with Steel-Dwass post hoc test as appropriate. Statistical significance was set at P < 0.05. RESULTS: We analyzed the reports of 56 (pregnancy group) and 106 women (non-pregnancy group). There was no significant difference in age or BMI, while the obstetric history was significantly different between these groups. Median PCL, PRL, and ML in the pregnancy group were significantly longer than those in the non-pregnancy group (114.1 mm vs. 110.0 mm, P = 0.018; 48.6 mm vs. 41.6 mm, P < 0.0001 and 21.7 mm vs. 10.0 mm, p < 0.0001. respectively). The subgroup analysis of the effect of pregnancy and vaginal delivery (VD) history on changes in these lines revealed that pregnancy-induced PRL increase tended to recover to the reference level of "non-pregnant without VD," but ML increase did not fully recover. CONCLUSION: MRI revealed a strong effect of pregnancy on pelvic floor structure.

Ubiquitin specific peptidase 32 acts as an oncogene in epithelial ovarian cancer by deubiquitylating farnesyl-diphosphate farnesyltransferase 1.

Epithelial ovarian cancer (EOC) is the seventh most common cancer worldwide and the deadliest gynecological malignancy because of its aggressiveness and high recurrence rate. To discover new therapeutic targets for EOC, we combined public EOC microarray datasets with our previous in vivo shRNA screening dataset. The top-ranked gene ubiquitin specific peptidase 32 (USP32), coding a deubiquitinating enzyme, is a component of the ubiquitin proteasome system. Clinically, USP32 is expressed in primary ovarian cancer, especially in metastatic peritoneal tumors, and negatively impacts the survival outcome. USP32 regulates proliferative and epithelial mesenchymal transition capacities that are associated with EOC progression. Proteomic analysis identified farnesyl-diphosphate farnesyltransferase 1 (FDFT1) as a novel substrate of USP32 that is an enzyme in the mevalonate pathway, essentially associated with cell proliferation and stemness. USP32 and FDFT1 expression was higher in tumor spheres than in adherent cells. Inhibition of USP32, FDFT1, or mevalonate pathway considerably suppressed tumor sphere formation, which was restored by adding squalene, a downstream product of FDFT1. These findings suggested that USP32-FDFT1 axis contributes to EOC progression, and could be novel therapeutic targets for EOC treatment.

Individual, Psychosocial, and environmental correlates of 4-year declines in walking among middle-to-older aged adults.

BACKGROUND: We examined associations of individual, psychosocial and environmental characteristics with 4-year changes in walking among middle-to-older aged adults; few such studies have employed prospective designs. METHODS: Walking for transport and walking for recreation were assessed during 2003-2004 (baseline) and 2007-2008 (follow-up) among 445 adults aged 50-65 years residing in Adelaide, Australia. Logistic regression analyses examined predictors of being in the highest quintile of decline in walking (21.4 minutes/day or more reduction in walking for transport; 18.6 minutes/day or more reduction in walking for recreation). RESULTS: Declines in walking for transport were related to higher level of walking at baseline, low perceived benefits of activity, low family social support, a medium level of social interaction, low sense of community, and higher neighborhood walkability. Declines in walking for recreation were related to higher level of walking at baseline, low self-efficacy for activity, low family social support, and a medium level of available walking facilities. CONCLUSIONS: Declines in middle-to-older aged adults' walking for transport and walking for recreation have differing personal, psychosocial and built-environment correlates, for which particular preventive strategies may be developed. Targeted campaigns, community-based programs, and environmental and policy initiatives can be informed by these findings.

[Fall risk and fracture. Exercise for fall prevention in the elderly].

On the basis of evidence obtained in previous studies, this paper outlines effective music therapy programs for group instructions and the basic contents of exercise and training that the elderly are able to do at home by themselves in their daily lives to reduce the risk of falls. The contents of effective exercise and training are to take a series of steps as quickly as possible, back and forth and to the right and left, in a standing position in combination with vertical movement in large amplitude for center of gravity. Furthermore, simple movements such as obeying an order of "right face", as well as dynamic movements that mostly involve higher brain functions such as instant thinking and judgment, are more effective. It should be noted that it is not sufficient for instructors to merely demand that the elderly do effective exercise. To prevent falls by the participants and to also obtain comprehensive effects such as satisfaction, amusement, and quality of life (QOL) , it is important to pay appropriate attention to parts other than the narrowly-defined evidence elements, such as modifications to maintain compliance and consideration of people with locomotive syndrome.

High neighborhood walkability mitigates declines in middle-to-older aged adults' walking for transport.

BACKGROUND: Neighborhood walkability shows significant positive relationship with residents' walking for transport in cross-sectional studies. We examined prospective relationships of neighborhood walkability with the change in walking behaviors over 4 years among middle-to-older aged adults (50-65 years) residing in Adelaide, Australia. METHODS: A baseline survey was conducted during 2003-2004, and a follow-up survey during 2007-2008. Walking for transport and walking for recreation were assessed at both times among 504 adults aged 50-65 years living in objectively determined high- and low-walkable neighborhoods. Multilevel linear regression analyses examined the associations of neighborhood walkability with changes over 4 years in walking for transport and walking for recreation. RESULTS: On average, participants decreased their time spent in walking for transport (-4.1 min/day) and for recreation (-3.7 min/day) between the baseline and 4-year follow-up. However, those living in high-walkable neighborhoods showed significantly smaller reduction (adjusted mean change: -1.1 min/day) in their time spent in walking for transport than did those living in low-walkable neighborhoods (-6.7 min/day). No such statistically-significant differences were found with the changes in walking for recreation. CONCLUSIONS: High-walkable neighborhoods may help middle-to-older aged adults to maintain their walking for transport.