The microtubule inhibitor eribulin demonstrates efficacy in platinum-resistant and refractory high-grade serous ovarian cancer patient-derived xenograft models.

Background: Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have platinum-refractory disease.

Objectives: To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC.

Design And Methods: Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either or (, four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic.

A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review.

Background: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a gene fusion in approximately 90% of cases, or a gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia.

Targeting homologous recombination deficiency in uterine leiomyosarcoma.

Background: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting.

Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin.

Unlabelled: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal.

Exploring the Relationship Between Maternal Circulating Hormones and Gestational Weight Gain in Women Without Obesity: A Cross-Sectional Study.

Background: Central homeostatic regulation of fat stores is attenuated during pregnancy, to allow for adequate fat deposition to support fetal development and lactation. What factors particular to pregnancy facilitate fat accumulation, and why gestational weight gain (GWG) is so variable, are not clear. The aim of this cross-sectional study was to examine the associations between GWG and circulating hormones with known effects on appetite and growth.

Inhibition of GPR91 Reduces Inflammatory Mediators Involved in Active Labor in Myometrium.

Results: GPR91 mRNA expression was significantly higher in myometrium from women during term spontaneous labor compared to no labor. Likewise, in mice, GPR91 mRNA expression was significantly upregulated in myometrium during inflammation-induced preterm labor compared to preterm no labor. In myometrial cells, IL1B and TNF significantly increased GPR91 mRNA expression.

In vitro selenium supplementation suppresses key mediators involved in myometrial activation and rupture of fetal membranes.

Spontaneous preterm birth, which can affect up to 20% of all pregnancies, is the greatest contributor to perinatal morbidity and mortality. Infection is the leading pathological cause of spontaneous preterm birth. Infection activates the maternal immune system, resulting in the upregulation of pro-inflammatory and pro-labor mediators that activate myometrial contractions and rupture of fetal membranes.

The short-chain fatty acids butyrate and propionate protect against inflammation-induced activation of mediators involved in active labor: implications for preterm birth.

Spontaneous preterm birth is a global health issue affecting up to 20% of pregnancies and leaves a legacy of neurodevelopmental complications. Inflammation has been implicated in a significant proportion of preterm births, where pro-inflammatory insults trigger production of additional pro-inflammatory and pro-labor mediators. Thus, novel therapeutics that can target inflammation may be a novel avenue for preventing preterm birth and improving adverse fetal outcomes.

Role of IRG1 in Regulating Pro-inflammatory and Pro-labor Mediators in Human Myometrium.

Preterm birth is a major contributor to neonatal deaths and associated long-term morbidities for the survivors, yet therapies remain elusive, given our incomplete understanding of the mechanisms driving human labor and delivery. Human labor is an inflammatory process, and we investigated whether IRG1 (immunoresponsive gene-1) plays a role in these processes. We demonstrate that IRG1 mRNA and protein expression is significantly increased in myometrium with human term labor, compared to no labor samples, and with preterm (LPS) labor in a mouse model.

Targeting bromodomain-containing proteins to prevent spontaneous preterm birth.

Preterm birth is a global healthcare challenge. Spontaneous preterm birth (sPTB) is commonly caused by inflammation, yet there are currently no effective therapies available. The Bromodomain and Extra-Terminal motif (BET) proteins, Bromodomain-containing protein (Brd) 2 (Brd2), Brd3 and Brd4 regulate inflammation in non-gestational tissues.

Obesity in older adults: Effect of degree of weight loss on cardiovascular markers and medications.

Obesity worsens the age-related tendency towards cardiovascular disease and diabetes. Older adults are vulnerable to medication adverse effects. Intentional weight loss in older adults with obesity has been shown to improve cardiovascular and glycaemic markers.

Novel anti-inflammatory actions of TIPE2 in human primary amnion and myometrial cells.

Inflammation plays a pivotal role in the terminal process of human labor and delivery, including myometrial contractions and membrane rupture. TNF-alpha-induced protein 8-like-2 (TIPE2) is a novel inflammation regulator; however, there are no studies on the role of TIPE2 in human labor. We report that in myometrium, there is decreased TIPE2 mRNA expression during late gestation which was further decreased in labor.

GIT2 deficiency attenuates inflammation-induced expression of pro-labor mediators in human amnion and myometrial cells†.

Untimely activation of the inflammatory response by sterile or infective insults in uterine tissues can result in preterm birth. Pro-inflammatory cytokines and pathogenic activation of toll-like receptors (TLRs) initiate a biochemical cascade of events leading to myometrial activation and contractility, cervical dilatation, and rupture of the chorioamniotic membranes. GIT2 is a signaling protein known to play a role in innate and adaptive immunity; however, its role in the inflammatory pathways of human labor is not known.

Adipose Tissue Exosomal Proteomic Profile Reveals a Role on Placenta Glucose Metabolism in Gestational Diabetes Mellitus.

Context: Molecules produced by adipose tissue (AT) function as an endocrine link between maternal AT and fetal growth by regulating placental function in normal women and women with gestational diabetes mellitus (GDM).

Objective: We hypothesized that AT-derived exosomes (exo-AT) from women with GDM would carry a specific set of proteins that influences glucose metabolism in the placenta.

Design: Exosomes were isolated from omental AT-conditioned media from normal glucose tolerant (NGT) pregnant women (n = 65) and pregnant women with GDM (n = 82).

IRF5 is increased in labouring myometrium and regulates pro-labour mediators.

Preterm birth continues to be the leading cause of neonatal mortality and morbidities that can extend into adult life. Few treatment options stem from our incomplete understanding of the mechanisms of human labour and delivery. Activation of the inflammatory response in gestational tissues by inflammation and/or infection leads to the production of pro-inflammatory and pro-labour mediators, thus preterm birth.

The immunoproteasome inhibitor ONX-0914 regulates inflammation and expression of contraction associated proteins in myometrium.

There are currently no effective treatments to prevent spontaneous preterm labor. The precise upstream biochemical pathways that regulate the transition between uterine quiescence during pregnancy and contractility during labor remain unclear. It is well known however that intrauterine inflammation, including infection, is commonly associated with preterm labor.

Pellino 1 is a novel regulator of TNF and TLR signalling in human myometrial and amnion cells.

Preterm birth is the primary cause of neonatal deaths and morbidities. Pathological processes causally linked to preterm birth are inflammation and infection. Pellino-1 (Peli1) has previously been found to regulate the inflammatory response in non-gestational tissues in response to toll-like receptor (TLR) ligands and pro-inflammatory cytokines.

DREAM Is Involved in the Genesis of Inflammation-Induced Prolabour Mediators in Human Myometrial and Amnion Cells.

Preterm birth is the primary cause of perinatal morbidity and mortality worldwide. Inflammation induces a cascade of events leading to preterm birth by activating nuclear factor-B (NF-B). In nongestational tissues, downstream regulatory element antagonist modulator (DREAM) regulates NF-B activity.

NOD-like receptor pyrin domain-containing-3 (NLRP3) regulates inflammation-induced pro-labor mediators in human myometrial cells.

Problem: Inflammation plays a major role in preterm birth. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) plays a role in inflammatory diseases. The aims of this study were to determine the effect of term labor on the expression of NLRP3 in human myometrium and the effect of NLRP3 silencing on pro-labor mediators in myometrial cells.

PARK7 regulates inflammation-induced pro-labour mediators in myometrial and amnion cells.

Preterm birth is a prevalent cause of neonatal deaths worldwide. Inflammation has been implicated in spontaneous preterm birth involved in the processes of uterine contractility and membrane rupture. Parkinson protein 7 (PARK7) has been found to play an inflammatory role in non-gestational tissues.

Formyl peptide receptor-2 is decreased in foetal growth restriction and contributes to placental dysfunction.

Study Question: What is the association between placental formyl peptide receptor 2 (FPR2) and trophoblast and endothelial functions in pregnancies affected by foetal growth restriction (FGR)?

Summary Answer: Reduced FPR2 placental expression in idiopathic FGR results in significantly altered trophoblast differentiation and endothelial function in vitro.

What Is Known Already: FGR is associated with placental insufficiency, where defective trophoblast and endothelial functions contribute to reduced feto-placental growth.

Study Design, Size, Duration: The expression of FPR2 in placental tissues from human pregnancies complicated with FGR was compared to that in gestation-matched uncomplicated control pregnancies (n = 25 from each group).

SMAD7 regulates proinflammatory and prolabor mediators in amnion and myometrium.

Preterm birth continues to be a significant public health problem. Infection (bacterial and or viral) and inflammation, by stimulating proinflammatory cytokines, adhesion molecules, and matrix metalloproteinase 9 (MMP9), play a central role in the rupture of membranes and myometrial contractions. SMAD7 has been implicated in regulating the inflammatory response; however, no studies have been performed with regard to human labor.

TLR2, TLR3 and TLR5 regulation of pro-inflammatory and pro-labour mediators in human primary myometrial cells.

Preterm birth continues to be a significant global health care issue, due to our lack of understanding of the mechanisms that drive human labour and delivery. Toll-like receptors (TLRs) are essential in triggering an inflammatory response in human gestational tissues, leading to the production of pro-inflammatory and pro-labour mediators, and thus preterm birth. The aims of this study were to determine whether the adaptor molecules associated with TLR2, TLR3 and TLR5 signalling are involved in human myometrium.