The Placental Transcriptome in Late Gestational Hypoxia Resulting in Murine Intrauterine Growth Restriction Parallels Increased Risk of Adult Cardiometabolic Disease.

Intrauterine growth restriction (IUGR) enhances risk for adult onset cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though inadequate blood flow and oxygen/nutrient provision are considered common endpoints. Based on evidence in humans linking IUGR to adult CVD, we hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) placental transcriptome changes linked to risk for later CVD, and 2) adult phenotypes of CVD in the IUGR offspring. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we undertook RNA sequencing from GD19 placentas. Functional analysis suggested multiple changes in structural and functional genes important for placental health and function, with maximal dysregulation involving vascular and nutrient transport pathways. Concordantly, a ~10% decrease in birthweights and ~30% decrease in litter size was observed, supportive of placental insufficiency. We also found that the LG-H IUGR offspring exhibit increased risk for CVD at 4 months of age, manifesting as hypertension, increased abdominal fat, elevated leptin and total cholesterol concentrations. In summary, this animal model of IUGR links the placental transcriptional response to the stressor of gestational hypoxia to increased risk of developing cardiometabolic disease

The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the “Seed” and the “Soil”?

Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic microenvironments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic microenvironments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation

Natural background levels of primary biogenic amines in water samples from lakes and rivers around Stoke-on-Trent

Searching for victims of crime who have been buried in hidden (clandestine) graves or dumped into water courses currently utilises a number of techniques such as victim recovery dogs or ground penetrating radar. The development of chemical techniques would offer further assistance in body location and previous research has shown that primary biogenic amines are potential chemical markers of decomposition. There is a paucity of information about the natural abundance of the primary biogenic amines cadaverine, methylamine and putrescine in different water courses and an understanding of this natural abundance would allow for more accurate detection. This work aimed to chemically detect the natural background levels of primary biogenic amines (cadaverine, methylamine, and putrescine) in water samples taken from canals, lakes and rivers around Stoke-on-Trent (UK), These amines were quantified using gas chromatography-mass spectrometry (GC-MS). Water samples from the Hanley Park in Stoke-on-Trent were examined. In Hanley Park, there is a lake fed by a canal. It was determined that 0.002 mM putrescine was present in the analysed water samples from the park; cadaverine could not be detected. For comparison, in previously analysed leachate samples of buried porcine material with a post-burial interval of 350 days, putrescine had a concentration of 0.374 mM and cadaverine had a concentration of 0.323 mM. These data suggest that background levels of key bioamines are much lower than those found from buried material and it expected that this will be the scenario for bodies found in water

The prevalence of constant supportive observations in a high, medium and low secure service

Aims and Method We explored the prevalence and use of constant supportive observations (CSO) in high, medium and low secure in-patient services in a single NHS mental health trust. From clinical records, we extracted data on the length of time on CSO, the reason for the initiation of CSO and associated adverse incidents for all individuals who were placed on CSO between July 2013 and June 2014. Results A small number of individuals accounted for a disproportionately large amount of CSO hours in each setting. Adverse incident rates were higher on CSO than when not on CSO. There was considerable variation between different settings in terms of CSO use and the reasons for commencing CSO. Clinical Implications The study describes the prevalence and nature of CSO in secure forensic mental health services and the associated organisational costs. The marked variation in CSO use between settings suggests that mental health services continue to face challenges in balancing risk management with minimising restrictive interventions

How Children Move: Activity Pattern Characteristics in Lean and Obese Chinese Children

Physical activity and sedentary behavior are central components of lifetime weight control; however, our understanding of dimensions of these behaviors in childhood is limited. This study investigated free-living activity pattern characteristics and the individual variability of these characteristics in 84 lean and obese Chinese children (7–9 y) during the school day and over the weekend. Activity pattern characteristics were established from triaxial accelerometry (StayHealthy RT3). Results indicated that children's free-living activity is characterized by many short-duration, low-intensity bouts of movement. Obese children take longer rest intervals between bouts and engage in fewer activity bouts both at school and at home. Intraindividual variability in activity patterns was low during school days but high for the rest intervals between bouts and number of activity bouts per day at the weekend. Finding ways to reduce the rest time between bouts of movement and increase the number of movement bouts a child experiences each day is an important next step

Soluble bone-derived osteopontin promotes migration and stem-like behavior of breast cancer cells

Breast cancer is a leading cause of cancer death in women, with the majority of these deaths caused by metastasis to distant organs. The most common site of breast cancer metastasis is the bone, which has been shown to provide a rich microenvironment that supports the migration and growth of breast cancer cells. Additionally, growing evidence suggests that breast cancer cells that do successfully metastasize have a stem-like phenotype including high activity of aldehyde dehydrogenase (ALDH) and/or a CD44(+)CD24(-)phenotype. In the current study, we tested the hypothesis that these ALDH (hi) CD44 (+) CD24(-)breast cancer cells interact with factors in the bone secondary organ microenvironment to facilitate metastasis. Specifically, we focused on bone-derived osteopontin and its ability to promote the migration and stem-like phenotype of breast cancer cells. Our results indicate that bone-derived osteopontin promotes the migration, tumorsphere-forming ability and colony-forming ability of whole population and ALDH hi CD44(+)CD24-breast cancer cells in bone marrow-conditioned media (an ex vivo representation of the bone microenvironment) (p \u3c= 0.05). We also demonstrate that CD44 and RGD-dependent cell surface integrins facilitate this functional response to bone-derived osteopontin (p \u3c= 0.05), potentially through activation of WNK-1 and PRAS40-related pathways. Our findings suggest that soluble bone-derived osteopontin enhances the ability of breast cancer cells to migrate to the bone and maintain a stem-like phenotype within the bone microenvironment, and this may contribute to the establishment and growth of bone metastases

Generation of Organ-conditioned Media and Applications for Studying Organ-specific Influences on Breast Cancer Metastatic Behavior

Breast cancer preferentially metastasizes to the lymph node, bone, lung, brain and liver in breast cancer patients. Previous research efforts have focused on identifying factors inherent to breast cancer cells that are responsible for this observed metastatic pattern (termed organ tropism), however much less is known about factors present within specific organs that contribute to this process. This is in part because of a lack of in vitro model systems that accurately recapitulate the organ microenvironment. To address this, an ex vivo model system has been established that allows for the study of soluble factors present within different organ microenvironments. This model consists of generating conditioned media from organs (lymph node, bone, lung, and brain) isolated from normal athymic nude mice. The model system has been validated by demonstrating that different breast cancer cell lines display cell-line specific and organ-specific malignant behavior in response to organ-conditioned media that corresponds to their in vivo metastatic potential. This model system can be used to identify and evaluate specific organ-derived soluble factors that may play a role in the metastatic behavior of breast and other types of cancer cells, including influences on growth, migration, stem-like behavior, and gene expression, as well as the identification of potential new therapeutic targets for cancer. This is the first ex vivo model system that can be used to study organ-specific metastatic behavior in detail and evaluate the role of specific organ-derived soluble factors in driving the process of cancer metastasis

High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability

Cancer stem cells (CSCs) have recently been identified in leukaemia and solid tumours; however, the role of CSCs in metastasis remains poorly understood. This dearth of knowledge about CSCs and metastasis is due largely to technical challenges associated with the use of primary human cancer cells in pre-clinical models of metastasis. Therefore, the objective of this study was to develop suitable pre-clinical model systems for studying stem-like cells in breast cancer metastasis, and to test the hypothesis that stem-like cells play a key role in metastatic behaviour. We assessed four different human breast cancer cell lines (MDA-MB-435, MDA-MB-231, MDA-MB-468, MCF-7) for expression of prospective CSC markers CD44/CD24 and CD133, and for functional activity of aldehyde dehydrogenase (ALDH), an enzyme involved in stem cell self-protection. We then used fluorescence-activated cell sorting and functional assays to characterize differences in malignant/metastatic behaviour in vitro (proliferation, colony-forming ability, adhesion, migration, invasion) and in vivo (tumorigenicity and metastasis). Sub-populations of cells demonstrating stem-cell-like characteristics (high expression of CSC markers and/or high ALDH) were identified in all cell lines except MCF-7. When isolated and compared to ALDHlowCD44low/- cells, ALDHhiCD44+CD24- (MDA-MB-231) and ALDHhiCD44+CD133+ (MDA-MB-468) cells demonstrated increased growth (P \u3c 0.05), colony formation (P \u3c 0.05), adhesion (P \u3c 0.001), migration (P \u3c 0.001) and invasion (P \u3c 0.001). Furthermore, following tail vein or mammary fat pad injection of NOD/SCID/IL2 gamma receptor null mice, ALDHhiCD44+CD24- and ALDHhiCD44+CD133+ cells showed enhanced tumorigenicity and metastasis relative to ALDHlowCD44low/- cells (P \u3c 0.05). These novel results suggest that stem-like ALDHhiCD44+CD24- and ALDHhiCD44+CD133+ cells may be important mediators of breast cancer metastasis

Genes invoked in the ovarian transition to menopause

Menopause and the associated declines in ovarian function are major health issues for women. Despite the widespread health impact of this process, the molecular mechanisms underlying the aging-specific decline in ovarian function are almost completely unknown. To provide the first gene–protein analysis of the ovarian transition to menopause, we have established and contrasted RNA gene expression profiles and protein localization and content patterns in healthy young and perimenopausal mouse ovaries. We report a clear distinction in specific mRNA and protein levels that are noted prior to molecular evidence of steroidogenic failure. In this model, ovarian reproductive aging displays similarities with chronic inflammation and increased sensitivity to environmental cues. Overall, our results indicate the presence of mouse climacteric genes that are likely to be major players in aging-dependent changes in ovarian function

Severe Retinopathy of Prematurity Is Not Independently Associated With Worse Neurodevelopmental Outcomes in Preterm Neonates

Purpose: To evaluate the relationship between retinopathy of prematurity (ROP) severity and neurodevelopmental outcomes in premature neonates at 0–36 months corrected age.Methods: A retrospective chart review was performed on 228 neonates screened for ROP at the UCLA Mattel Children's Hospital between 2011 and 2018. Demographic information, clinical outcomes, ROP severity (no ROP, type 1 ROP, type 2 ROP), and Bayley-III neurodevelopmental scores were collected. Infants were grouped into corrected age cohorts (0–12, 12–24, and 24–36 months) to assess neurodevelopmental outcomes with increasing age. Within each age cohort, ANOVA and Chi-Square testing were used to detect differences in birth characteristics and neurodevelopmental scores between infants with type 1 ROP, type 2 ROP, or no ROP. Univariable analyses assessed the relationship between ROP severity and neurodevelopmental outcomes within each age cohort. A multivariable analysis was then performed to determine if ROP severity remained significantly associated with worse neurodevelopmental scores after controlling for birth weight (BW), intraventricular hemorrhage grade (IVH), health insurance type, male sex, and age at Bayley testing.Results: Without controlling for factors associated with prematurity, neonates with type 1 ROP had poorer cognition (p = 0.001) and motor (p = 0.006) scores at ages 0–12 months and poorer cognition (p = 0.01), language (p = 0.04) and motor (p = 0.04) scores at ages 12–24 months than infants without ROP, but no significant differences were detected at ages 24–36 months. After adjusting for BW, IVH, insurance type, male sex, and age at Bayley testing, ROP severity was no longer associated with worse neurodevelopmental scores in any domain.Conclusion: This study emphasizes that poorer neurodevelopmental outcomes in preterm neonates are most likely related to lower birthweight, associated co-morbidities of prematurity, and socioeconomic factors such as health insurance, not severity of ROP itself