Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis.

Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD.

IFPA meeting 2016 workshop report III: Decidua-trophoblast interactions; trophoblast implantation and invasion; immunology at the maternal-fetal interface; placental inflammation.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At IFPA meeting 2016 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of decidual-trophoblast interaction, regulation of trophoblast invasion, immune cells at the maternal-fetal interface, and placental inflammation.

Clinical practice guideline: management of acute pancreatitis.

There has been an increase in the incidence of acute pancreatitis reported worldwide. Despite improvements in access to care, imaging and interventional techniques, acute pancreatitis continues to be associated with significant morbidity and mortality. Despite the availability of clinical practice guidelines for the management of acute pancreatitis, recent studies auditing the clinical management of the condition have shown important areas of noncompliance with evidence-based recommendations.

RNA Interference Screen to Identify Kinases That Suppress Rescue of ΔF508-CFTR.

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the Cystic fibrosis transmembrane conductance regulator (CFTR). ΔF508-CFTR, the most common disease-causing CF mutant, exhibits folding and trafficking defects and is retained in the endoplasmic reticulum, where it is targeted for proteasomal degradation. To identify signaling pathways involved in ΔF508-CFTR rescue, we screened a library of endoribonuclease-prepared short interfering RNAs (esiRNAs) that target ∼750 different kinases and associated signaling proteins.

Regulation of neuronal migration by Dchs1-Fat4 planar cell polarity.

Planar cell polarity (PCP) describes the polarization of cell structures and behaviors within the plane of a tissue. PCP is essential for the generation of tissue architecture during embryogenesis and for postnatal growth and tissue repair, yet how it is oriented to coordinate cell polarity remains poorly understood [1]. In Drosophila, PCP is mediated via the Frizzled-Flamingo (Fz-PCP) and Dachsous-Fat (Fat-PCP) pathways [1-3].

A genome-wide association meta-analysis of preschool internalizing problems.

Objective: Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL).

DREAM mediated regulation of GCM1 in the human placental trophoblast.

The trophoblast transcription factor glial cell missing-1 (GCM1) regulates differentiation of placental cytotrophoblasts into the syncytiotrophoblast layer in contact with maternal blood. Reduced placental expression of GCM1 and abnormal syncytiotrophoblast structure are features of hypertensive disorder of pregnancy--preeclampsia. In-silico techniques identified the calcium-regulated transcriptional repressor--DREAM (Downstream Regulatory Element Antagonist Modulator)--as a candidate for GCM1 gene expression.

Turning a blind eye to anti-VEGF toxicities.

Excessive blood vessel growth is a key feature of many retinal diseases, and recently, anti-VEGF therapy has been successfully applied to treat neovascular age-related macular degeneration (AMD), diabetic macular edema, and retinal vein occlusion. In this issue of the JCI, Kurihara et al. reveal an essential role of Vegfa in maintaining choroid vasculature and cone photoreceptors, critical for central and color vision.

Effect of long-term combined oral contraceptive pill use on endometrial thickness.

Objective: To estimate whether there is any association of long-term use of combined oral contraceptive pills (OCP) with adverse endometrial growth.

Methods: We reviewed the charts of 137 patients with history of OCP use undergoing endometrial preparation with estrogen for frozen embryo transfer. Endometrial thickness was measured by transvaginal ultrasonography on day 10 after menses and patients were divided into two groups (less than 7 mm and 7 mm or more).

A new Cre driver mouse line, Tcf21/Pod1-Cre, targets metanephric mesenchyme.

Conditional gene targeting in mice has provided great insight into the role of gene function in kidney development and disease. Although a number of Cre-driver mouse strains already exist for the kidney, development of additional strains with unique expression patterns is needed. Here we report the generation and validation of a Tcf21/Pod1-Cre driver strain that expresses Cre recombinase throughout the condensing and stromal mesenchyme of developing kidneys and in their derivatives including epithelial components of the nephron and interstitial cells.

Prolonged postovulatory proinflammatory signaling in the fallopian tube epithelium may be mediated through a BRCA1/DAB2 axis.

Purpose: To assess inflammation-related gene expression in nonmalignant fallopian tube epithelium (FTE) from BRCA1/2 mutation carriers and control patients obtained during the luteal and follicular phase, and to determine the impact of BRCA1 and disabled homolog 2 (DAB2) on NF-κB-mediated proinflammatory signaling.

Experimental Design: A list of inflammation-related and NF-κB-responsive genes was compiled through gene set enrichment and PubMed database search, corresponding probes identified, and unpaired t tests conducted to identify differentially expressed genes in previously profiled FTE samples. ES2 and A549 cells were cotransfected with DAB2- or BRCA1-targeting siRNA and an NF-κB-responsive luciferase reporter, treated with TNF-α and luciferase activity determined.

Obesity and insulin resistance in breast cancer--chemoprevention strategies with a focus on metformin.

Obesity and insulin resistance have been associated with breast cancer risk, and breast cancer outcomes. Recent research has focused on insulin as a potential biologic mediator of these effects given frequent expression of insulin/IGF-1 receptors on breast cancer cells which, when activated, can stimulate signaling through PI3K and Ras-Raf signaling pathways to enhance proliferation. Metformin, a commonly used diabetes drug, lowers insulin in non-breast diabetic cancer patients, likely by reducing hepatic gluconeogenesis; it also appears to have potential insulin independent direct effects on tumor cells which are mediated by activation of AMPK with downstream inhibition of mTOR.

Mouse models to study kidney development, function and disease.

Purpose Of Review: The mouse is the most widely used model organism to study gene function in the kidney in vivo. Here we review recent advances in technologies to manipulate the mouse genome and gene function to study renal biology. We discuss strengths and weaknesses of the approaches and provide examples in which they have been used to address renal questions.

Angiogenic response of placental villi to heparin.

Objective: To estimate the angiogenic effect of heparin on human umbilical vein endothelial cells cultured in conditioned media from normal and severely pre-eclamptic human placental villi.

Methods: Normal first- and second-trimester floating placental villi were explanted in control conditions and increasing concentrations of heparin (unfractionated and low molecular weight heparin) across the clinical prophylactic and therapeutic range (0.025-25 units/mL).

Body mass index in early adulthood and endometrial cancer risk for mismatch repair gene mutation carriers.

Objective: To investigate the association of body mass index (BMI) in early adulthood and endometrial cancer risk for carriers of a germline mutation in a DNA mismatch repair gene.

Methods: We estimated the association between BMI at age 18-20 years and endometrial cancer risk for mismatch repair gene mutation carriers and, as a comparison group, noncarriers using 601 female carriers of a germline mutation in a mismatch repair gene (245 MLH1, 299 MSH2, 38 MSH6, and 19 PMS2) and 533 female noncarriers from the Colon Cancer Family Registry using a weighted Cox proportional hazards regression.

Results: During 51,693 person-years of observation, we observed diagnoses of endometrial cancer for 126 carriers and eight noncarriers.

Decreased progesterone receptor isoform expression in luteal phase fallopian tube epithelium and high-grade serous carcinoma.

We previously reported that BRCA1/2-mutated fallopian tube epithelium (FTE) collected during the luteal phase exhibits gene expression profiles more closely resembling that of high-grade serous carcinoma (HGSC) specimens than FTE collected during the follicular phase or from control patients. Since the luteal phase is characterised by high levels of progesterone, we determined whether the expression of progesterone receptor (PR) and PR-responsive genes was altered in FTE obtained from BRCA mutation carriers during the luteal phase of the menstrual cycle. RT-qPCR confirmed a decreased expression of PR mRNA in FTE during the luteal phase relative to follicular phase, in both BRCA1/2 mutation carriers and control patients.

Calcium signaling in placenta.

The placenta sustains the developing fetus throughout gestation and its major functions include nutrition, gas and waste exchange via a variety of passive or active mechanisms. Up to 30 g of calcium (Ca(2+)) actively crosses the trophoblast layer during human pregnancy. The Ca(2+) ion not only plays an important role for skeletal development but is also an essential second messenger.

The Sweet Pee model for Sglt2 mutation.

Inhibiting renal glucose transport is a potential pharmacologic approach to treat diabetes. The renal tubular sodium-glucose transporter 2 (SGLT2) reabsorbs approximately 90% of the filtered glucose load. An animal model with sglt2 dysfunction could provide information regarding the potential long-term safety and efficacy of SGLT2 inhibitors, which are currently under clinical investigation.

Biology of anti-angiogenic therapy-induced thrombotic microangiopathy.

Anti-vascular endothelial growth factor (VEGF) agents are an important component in the treatment of many solid tumors. As the indications for these targeted therapies grow, the expected number of patients to receive these drugs will increase exponentially. Despite the great promise, serious toxicities may arise.

Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents.

Metformin, an inexpensive oral agent commonly used to treat type 2 diabetes, has been garnering increasing attention as a potential anti-cancer agent. Preclinical, epidemiologic, and clinical evidences suggest that metformin may reduce overall cancer risk and mortality, with specific effects in breast cancer. The extensive clinical experience with metformin, coupled with its known (and modest) toxicity, has allowed the traditional process of drug evaluation to be shortened.

Glomerular structure and function require paracrine, not autocrine, VEGF-VEGFR-2 signaling.

VEGF is a potent vascular growth factor produced by podocytes in the developing and mature glomerulus. Specific deletion of VEGF from podocytes causes glomerular abnormalities including profound endothelial cell injury, suggesting that paracrine signaling is critical for maintaining the glomerular filtration barrier (GFB). However, it is not clear whether normal GFB function also requires autocrine VEGF signaling in podocytes.

Overview of colorectal cancer genetics.

Cancer is a genetic disease in which the clonal accumulation of genetic alterations confers a cell with the malignant characteristics of uncontrolled growth, local invasiveness, and metastastic potential. Studies of colorectal cancer and its precursor lesion, the adenomatous polyp, have served as the cornerstone in advancing knowledge of cancer molecular genetics. The past 30 years have ushered in an era of revolutionary increases in understanding colorectal cancer genetics.

Radiation effects and radioprotection in MC3T3-E1 mouse calvarial osteoblastic cells.

Background: Little is known about the mechanisms and treatment of radiation-induced inhibition of craniofacial bone growth. In an earlier study, the radioprotector amifostine (WR-2721) administered to rabbits before irradiation radioprotected cultured orbitozygomatic complex periosteal osteoblast-like cells. This study assessed the effects of amifostine and its active metabolite on the radiation survival, function, and phenotype of mouse calvarial osteoblast-like cells in a cell culture model.