Estrogen receptor ß regulates AKT activity through up-regulation of INPP4B and inhibits migration of prostate cancer cell line PC-3.

Loss of the tumor suppressor, PTEN, is one of the most common findings in prostate cancer (PCa). This loss leads to overactive Akt signaling, which is correlated with increased metastasis and androgen independence. However, another tumor suppressor, inositol-polyphosphate 4-phosphatase type II (INPP4B), can partially compensate for the loss of PTEN. INPP4B is up-regulated by androgens, and this suggests that androgen-deprivation therapy (ADT) would lead to hyperactivity of AKT. However, in the present study, we found that in PCa, samples from men treated with ADT, ERß, and INPP4B expression were maintained in some samples. To investigate the role of ERß1 in regulation of INPPB, we engineered the highly metastatic PCa cell line, PC3, to express ERß1. In these cells, INPP4B was induced by ERß ligands, and this induction was accompanied by inhibition of Akt activity and reduction in cell migration. These findings reveal that, in the absence of androgens, ERß1 induces INPP4B to dampen AKT signaling. Since the endogenous ERß ligand, 3ß-Adiol, is lost upon long-term ADT, to obtain the beneficial effects of ERß1 on AKT signaling, an ERß agonist should be added along with ADT.

Retinal and optic nerve degeneration in liver X receptor ß knockout mice.

The retina is an extension of the brain. Like the brain, neurodegeneration of the retina occurs with age and is the cause of several retinal diseases including optic neuritis, macular degeneration, and glaucoma. Liver X receptors (LXRs) are expressed in the brain where they play a key role in maintenance of cerebrospinal fluid and the health of dopaminergic neurons. Herein, we report that LXRs are expressed in the retina and optic nerve and that loss of LXRß, but not LXRα, leads to loss of ganglion cells in the retina. In the retina of LXRß-/- mice, there is an increase in amyloid A4 and deposition of beta-amyloid (Aß) aggregates but no change in the level of apoptosis or autophagy in the ganglion cells and no activation of microglia or astrocytes. However, in the optic nerve there is a loss of aquaporin 4 (AQP4) in astrocytes and an increase in activation of microglia. Since loss of AQP4 and microglial activation in the optic nerve precedes the loss of ganglion cells, and accumulation of Aß in the retina, the cause of the neuronal loss appears to be optic nerve degeneration. In patients with optic neuritis there are frequently AQP4 autoantibodies which block the function of AQP4. LXRß-/- mouse is another model of optic neuritis in which AQP4 antibodies are not detectable, but AQP4 function is lost because of reduction in its expression.

Estrogen receptor ß exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity.

Estrogen receptor ß (ERß) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ERß, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ERß is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ERß and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ERß. Transcriptomic analysis indicated relatively few changes in gene expression with ERß overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, estradiol and LY3201 as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ERß activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ERß. These findings suggest that ERß-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ERß in PCa.

Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment.

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ-IL4rα and IL2rγ-IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ-IL4rα and IL2rγ-IL13rα1 receptors signal primarily via JAK1-STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC. SIGNIFICANCE: Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell-intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.

Two thirds of the most disadvantaged Dalit population of Nepal still do not deliver in health facilities despite impressive success in maternal health.

INTRODUCTION: The gains in maternal and child health in Nepal was impressive in the last two decade but success was unevenly distributed. The Dalits of Nepal are the most disadvantaged caste group and have benefitted least from the advances in maternal health service. This study investigated the rate of and factors associated with the institutional delivery among the Dalit women of the Mahottari, Nepal. MATERIALS AND METHODS: A cross-sectional study was conducted during July-December 2014 using a structured questionnaire. A total of 328 mothers who had their childbirth within one year were interviewed. Descriptive statistics followed by binary and multivariable logistic regression analyses were computed to find the association of key variables with institutional delivery. RESULTS: In this study, only 30% of the mother had institutional delivery. Fifty eight percent mothers had no any birth preparedness and complication readiness. Four or more antenatal visits (Adjusted Odds Ratio (AOR): 3.54, CI: 1.82-6.90), birth preparedness (AOR: 3.15, CI: 1.61-6.18), planned pregnancy (AOR: 2.63, CI: 1.37-5.06) and receiving advice from health staffs (AOR: 3.96, CI: 2.00-7.86) and mother's autonomy (AOR: 2.25, CI: 1.03-4.49) were associated with child birth at the health facility. CONCLUSION: This study indicated that birth preparedness, ANC visit frequency, planning of pregnancy, advice for institutional delivery and mother's autonomy were significantly associated with health facility delivery. Less than one-third mothers had institutional delivery and reasons were feeling of un-necessary, far distance, lack of transportation and associated cost; and birth preparedness is also low. Hence, promotion of birth preparedness, uptake of ANC service, proper counselling for institutional delivery, promoting women autonomy and strengthening women to have planned pregnancy were some recommendation to promote institutional delivery for such disadvantage community.

Determinants of severe acute malnutrition among children under 5 years of age in Nepal: a community-based case-control study.

BACKGROUND: Malnutrition is one of the leading causes of morbidity and mortality among children under the age of 5 years in low and middle income countries like Nepal. Children with severe acute malnutrition (SAM) are nine times more likely to die than children without malnutrition. The prevalence of SAM has increased in Nepal over the past 15 years; however, the determinants of SAM have not been clearly assessed in the country. OBJECTIVE: To assess the determinants of SAM among children aged 6-59 months in the Bara district of Nepal. SETTING: A community-based case-control study was conducted in 12 randomly selected Village Development Committees (VDCs) of the Bara district of Nepal. PARTICIPANTS: A random sample of 292 children aged 6-59 months (146 as cases and 146 as controls) from 12 VDCs were included in this study. RESULTS: The prevalence of SAM among children under the age of 5 years was 4.14%. The following factors were significantly associated with SAM: low socioeconomic status (adjusted odds ratio (AOR) 17.13, 95% CI 5.85 to 50.13); mother's age at birth <20 or >35 years (AOR 3.21, 95% CI 1.30 to 7.94); birth interval <24 months (AOR 4.09, 95% CI 1.87 to 8.97); illiterate father (AOR 3.65, 95% CI 1.62 to 8.20); bottle feeding (AOR 2.19, 95% CI 1.73 to 12.03); and not initiating complementary feeding at the age of 6 months (AOR 2.91, 95% CI 1.73 to 12.03). Mother's educational level, initiation of breastfeeding, colostrum feeding, and exclusive breastfeeding were not significantly associated with SAM. CONCLUSION: The mother's age at birth, birth interval, socioeconomic status, father's educational level and initiation of complementary feeding at the age of 6 months were important determinants of SAM among children. A multi-sector approach is essential to address SAM. There is a need for further studies not only focusing on SAM but also moderate acute malnutrition.