PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma

High-grade serous ovarian carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages derived from peritoneal fluid macrophages and had a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. Furthermore, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in HGSC patients. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC

A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19). METHODS: ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case-control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test. RESULTS: Cochran-Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10(-4) (rs3815676) and for ABCB4 it was 4.6×10(-7)(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings. CONCLUSIONS: Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility

Liver X receptors and male (In)fertility

Liver X receptors (LXRs) are ligand-dependent transcription factors acting as ‘cholesterol sensors’ to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. Both are activated by oxidised cholesterol metabolites, endogenously produced oxysterols. LXRs have important roles in lipid metabolism and inflammation, plus a number of newly emerging roles. They are implicated in regulating lipid balance in normal male reproductive function and may provide a link between male infertility and lipid disorders and/or obesity. Studies from Lxr knockout mouse models provide compelling evidence to support this. More recently published data suggest distinct and overlapping roles of the LXR isoforms in the testis and recent evidence of a role for LXRs in human male fertility. This review summarises the current literature and explores the likely link between LXR, lipid metabolism and male fertility as part of a special issue on Liver X receptors in International Journal of Molecular Sciences

Pilot study: performance and acceptability of a portable ECG monitor in pregnant women with palpitations

Palpitations in pregnancy are common. The majority of palpitations are caused by ectopic beats or an inappropriate sinus tachycardia, but a minority are caused by arrhythmias, the commonest of which is supraventricular tachycardia. The diagnosis relies on accurate detection of events by electrocardiography (ECG). It is critical to make an accurate and timely diagnosis as prompt intervention, or more commonly reassurance, can significantly impact the wellbeing of both mother and baby. The current standard of care is suboptimal for the identification of arrhythmias in pregnancy. Continuous ambulatory ECG recording can be performed for 1 to 7 days, but efficacy relies on episodes occurring during the monitoring period. The unpredictable nature of palpitations leads to a relative low diagnostic yield from intermittent monitoring. The longer the recording period, the longer a woman has to wait to have the monitor attached, due to limited availability of monitoring devices. The performance of this test, as well as the time required for analysis of the results, therefore may take several weeks. This is very significant given the limited duration of pregnancy and the importance of starting treatment in a timely fashion if an abnormality is present. There is therefore a role for a simple and reliable method for anytime ECG recording. The Kardia 6L is a simple method to obtain a six-lead electrocardiogram (ECG), using a small handheld device which communicates with the associated App on a compatible smartphone via Bluetooth, producing a real-time ECG recording. We hypothesize that Kardia 6L will expedite rhythm identification whilst being user-friendly and well-received by pregnant women reporting palpitations

Pregnancy outcomes in women with primary biliary cholangitis and primary sclerosing cholangitis: a retrospective cohort study

Objective To determine maternal, obstetric and neonatal outcomes in a cohort of women with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) Design Retrospective cohort study. Setting 10 specialist centres managing pregnant women with liver disease Population Women with a diagnosis of PBC and PSC and a pregnancy of ≥20 completed weeks’ gestation. Methods Retrospective case notes review Main outcome measures Adverse outcomes were defined as maternal: development of ascites, variceal bleeding, encephalopathy and jaundice; obstetric events: gestational hypertension, pre-eclampsia and postpartum haemorrhage; and neonatal: stillbirth, preterm delivery, and admission to neonatal unit. The relationship of alanine transferase (ALT) and bile acid levels with gestation at delivery was studied. Results The first recorded pregnancies of 34 women with PSC and 27 with PBC were analysed. There were 60 livebirths and one intrapartum stillbirth that did not occur in the context of maternal cholestasis. Overall median gestation of delivery was 38 weeks, but the rate of preterm birth was 28% (17/61 deliveries) of which 76% (13/17) were spontaneous. Gestation at birth negatively correlated with maternal serum ALT concentration at booking (p=0.017) and serum bile acid concentration during pregnancy (p=0.016). There were no other significant correlations and maternal and neonatal outcomes were good. Conclusion Pregnancy in PBC and PSC is well tolerated, but women should be counselled regarding the increased risk of preterm birth. Measurement of maternal ALT and bile acids may help identify women at risk of preterm delivery