SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors

Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to the rhabdoid tumor family and is usually caused by biallelic inactivation of SMARCB1, encoding a key subunit of SWI/SNF chromatin remodeling complexes. Previous studies proposed that SMARCB1 loss drives rhabdoid tumor by promoting cell cycle through activating transcription of cyclin D1 while suppressing p16. However, low cyclin D1 protein expression is observed in most ATRT patient tumors. The underlying mechanism and therapeutic implication of this molecular trait remain unknown. Here, we show that SMARCB1 loss in ATRT leads to the reduction of cyclin D1 expression by upregulating MIR17HG, a microRNA (miRNA) cluster known to generate multiple miRNAs targeting CCND1. Furthermore, we find that this cyclin D1 deficiency in ATRT results in marked in vitro and in vivo sensitivity to the CDK4/6 inhibitor palbociclib as a single agent. Our study identifies a novel genetic interaction between SMARCB1 and MIR17HG in regulating cyclin D1 in ATRT and suggests a rationale to treat ATRT patients with FDA- approved CDK4/6 inhibitors. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156416/2/path5493.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156416/1/path5493_am.pd

Suspected Motor Problems and Low Preference for Active Play in Childhood Are Associated with Physical Inactivity and Low Fitness in Adolescence

Background - This prospective longitudinal study investigates whether suspected motor problems and low preference for active play in childhood are associated with physical inactivity and low cardiorespiratory fitness in adolescence. Methodology/Principal Findings - The study sample consisted of the Northern Finland Birth Cohort 1986 (NFBC 1986) composed of 5,767 children whose parents responded to a postal inquiry concerning their children's motor skills at age 8 years and who themselves reported their physical activity at age 16 years. Cardiorespiratory fitness was measured with a cycle ergometer test at age 16 years. Odds ratios (OR) and their 95% confidence intervals (95% CI) for the level of physical activity and fitness were obtained from multinomial logistic regression and adjusted for socio-economic position and body mass index. Low preference for active play in childhood was associated with physical inactivity (boys: OR 3.31, 95% CI 2.42–4.53; girls: OR 1.79, 95% CI 1.36–2.36) and low cardiorespiratory fitness (boys: OR 1.87, 95% CI 1.27–2.74; girls: OR 1.52, 95% CI 1.09–2.11) in adolescence. Suspected gross (OR 2.16, 95% CI 1.33–3.49) and fine (OR 1.88, 95% CI 1.35–2.60) motor problems were associated with physical inactivity among boys. Children with suspected motor problems and low preference for active play tended to have an even higher risk of physical inactivity in adolescence. Conclusions/Significance - Low preference for active play in childhood was associated with physical inactivity and low cardiorespiratory fitness in adolescence. Furthermore, children with suspected motor problems and low preference for active play tended to have an even higher risk of physical inactivity in adolescence. Identification of children who do not prefer active play and who have motor problems may allow targeted interventions to support their motor learning and participation in active play and thereby promote their physical activity and fitness in later life.peerReviewe

Hospital outpatient perceptions of the physical environment of waiting areas: the role of patient characteristics on atmospherics in one academic medical center

<p>Abstract</p> <p>Background</p> <p>This study examines hospital outpatient perceptions of the physical environment of the outpatient waiting areas in one medical center. The relationship of patient characteristics and their perceptions and needs for the outpatient waiting areas are also examined.</p> <p>Method</p> <p>The examined medical center consists of five main buildings which house seventeen primary waiting areas for the outpatient clinics of nine medical specialties: 1) Internal Medicine; 2) Surgery; 3) Ophthalmology; 4) Obstetrics-Gynecology and Pediatrics; 5) Chinese Medicine; 6) Otolaryngology; 7) Orthopedics; 8) Family Medicine; and 9) Dermatology. A 15-item structured questionnaire was developed to rate patient satisfaction covering the four dimensions of the physical environments of the outpatient waiting areas: 1) visual environment; 2) hearing environment; 3) body contact environment; and 4) cleanliness. The survey was conducted between November 28, 2005 and December 8, 2005. A total of 680 outpatients responded. Descriptive, univariate, and multiple regression analyses were applied in this study.</p> <p>Results</p> <p>All of the 15 items were ranked as relatively high with a range from 3.362 to 4.010, with a neutral score of 3. Using a principal component analysis' summated scores of four constructed dimensions of patient satisfaction with the physical environments (i.e. visual environment, hearing environment, body contact environment, and cleanliness), multiple regression analyses revealed that patient satisfaction with the physical environment of outpatient waiting areas was associated with gender, age, visiting frequency, and visiting time.</p> <p>Conclusion</p> <p>Patients' socio-demographics and context backgrounds demonstrated to have effects on their satisfaction with the physical environment of outpatient waiting areas. In addition to noticing the overall rankings for less satisfactory items, what should receive further attention is the consideration of the patients' personal characteristics when redesigning more comfortable and customized physical environments of waiting areas.</p

Understanding the benefit of metformin use in cancer treatment

Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR) signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed

Cell–cell and cell–matrix dynamics in intraperitoneal cancer metastasis

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis