The Role of Nuclear Phosphoinositides in the p53-MDM2 Nexus.

Recent insights into the p53-MDM2 nexus have advanced deeper understanding of their regulation and potent impact on cancer heterogeneity. The roles of nuclear phosphoinositide (PIPs) in modulating this pathway are emerging as a key mechanism. Here, we dissect the molecular mechanisms by which nuclear PIPs stabilize p53 through the recruitment of small heat shock proteins (sHSPs), activate the nuclear phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascade, and modulate MDM2 function to regulate the p53-MDM2 interaction.

Predicting ovarian function loss after chemotherapy and anti-HER2 therapy in young breast cancer patients.

Background: The ability to predict ovarian function loss after anticancer treatment is important for appropriate oncofertility counselling and to aid in therapy decision-making for young women with early breast cancer (eBC).

Methods: This biomarker analysis of the BETH (NCT00625898) and KAITLIN (NCT01966471) randomized trials investigated anti-Müllerian hormone (AMH) use, alone and combined with follicle stimulating hormone (FSH) and estradiol (E2), for predicting ovarian function loss following currently adopted chemotherapy and anti-HER2 therapy in premenopausal women with HER2-positive eBC.Serum samples were centrally tested measuring AMH, FSH and E2 using Roche Elecsys assays.

Regulation of the MDM2-p53 nexus by a nuclear phosphoinositide and small heat shock protein complex.

The tumor suppressor p53 maintains genome stability in the setting of cellular stress and is frequently mutated in cancer. The stability of p53 is regulated by its interaction with the oncoprotein MDM2, a ubiquitin E3 ligase. Recently, nuclear phosphoinositides were reported to bind and stabilize p53.

Agonist- and stress-driven compartmentalized phosphoinositide signaling in cells.

Phosphoinositides (PIPs) are essential lipid messengers that regulate cellular responses to external stimuli and stress through spatially organized signaling pathways. In recent years, compartment-specific mechanisms by which PIP signaling integrates diverse cellular processes have been extensively expanded. This review discusses the distinct roles of PIP signaling across cellular compartments, including the plasma membrane, endosomes, lysosomes, protein scaffolds, and the nucleus.

The poly(A) polymerase Star-PAP is regulated by stably associated phosphoinositide messengers.

Star-PAP is a noncanonical poly(A) polymerase that controls gene expression. Star-PAP was previously reported to bind PIPKI⍺ and its product PI(4,5)P, which regulate Star-PAP activity and expression of specific genes. Recent studies have revealed a nuclear p53-phosphoinositide signaling pathway in which the phosphatidylinositol transfer proteins (PITPs) and phosphoinositide kinases/phosphatases bind p53 to sequentially modify p53-linked phosphoinositides and regulate p53 function.

Regulation of NRF2 by stably associated phosphoinositides and small heat shock proteins in response to stress.

Reactive oxygen species are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1).

Regulation of the MDM2-p53 Nexus by a Nuclear Phosphoinositide and Small Heat Shock Protein Complex.

The tumor suppressor p53 maintains genome stability in the setting of cellular stress and is frequently mutated in cancer. The stability of p53 is regulated by its interaction with the oncoprotein MDM2, a ubiquitin E3 ligase. Recently, nuclear phosphoinositides were reported to bind and stabilize p53.

The nuclear phosphoinositide-p53 signalosome in the regulation of cell motility.

Dysregulation of p53 and phosphoinositide (PIPn) signaling are both key drivers of oncogenesis and metastasis. Our recent findings reveal a previously unrecognized interaction between these pathways, converging in the nucleus to form a PIPn-p53 signalosome that modulates nuclear AKT activation and downstream signaling, thereby influencing cancer cell survival and motility. This review examines recent insights into nuclear PIPn signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIPns interact with p53 to form signalosomes that affect cell motility.

Modeling the extension of ovarian function after therapeutic targeting of the primordial follicle reserve.

Background: Women are increasingly choosing to delay childbirth, and those with low ovarian reserves indicative of primary ovarian insufficiency are at risk for sub- and infertility and also the early onset of menopause. Experimental strategies that promise to extend the duration of ovarian function in women are currently being developed. One strategy is to slow the rate of loss of existing primordial follicles (PFs), and a second is to increase, or 'boost', the number of autologous PFs in the human ovary.

Oocyte development: it's all about quality.

Mammalian fertility depends on the production of an oocyte capable of fertilization and supporting early embryo development. This requires both cytoplasmic and nuclear, i.e.

A core outcome set for future male infertility research: development of an international consensus.

Objective: To develop a core outcome set for male infertility trials.

Design: A two-round Delphi survey and consensus development workshop were undertaken with healthcare professionals, researchers and clinicians globally.

Subjects: 334 participants from 39 countries participated in the Delphi Survey, while 44 participants from 21 countries participated in the consensus development workshop.

A core outcome set for future male infertility research: development of an international consensus.

Study Question: Can a core outcome set be developed through a global consensus to standardize outcome selection, collection, comparison, and reporting in future male infertility trials?

Summary Answer: A minimum dataset, known as a 'core outcome set', has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential interventions for male infertility.

What Is Known Already: Numerous factors, including a failure to consider the perspectives of men with lived experiences of infertility or their partners when developing and conducting RCTs can limit their clinical utility. Selection of outcomes, variations in outcome definitions, and the selective reporting of outcomes based on statistical analysis make the results of infertility research challenging to interpret, compare, and implement.

Phosphoinositide signaling at the cytoskeleton in the regulation of cell dynamics.

The cytoskeleton, composed of microfilaments, intermediate filaments, and microtubules, provides the structural basis for cellular functions such as motility and adhesion. Equally crucial, phosphoinositide (PIP) signaling is a critical regulator of these processes and other biological activities, though its precise impact on cytoskeletal dynamics has yet to be systematically investigated. This review explores the complex interplay between PIP signaling and the cytoskeleton, detailing how PIP modulates the dynamics of actin, intermediate filaments, and microtubules to shape cellular behavior.

Phosphoinositide signalling in cell motility and adhesion.

Cell motility and adhesion are fundamental components for diverse physiological functions, including embryonic development, immune responses and tissue repair. Dysregulation of these processes can lead to a range of diseases, including cancer. Cell motility and adhesion are complex and often require regulation by an intricate network of signalling pathways, with phosphatidylinositol phosphates (PIPs) having a central role.

Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.

The distinctive colour of brown adipose tissue (BAT) is attributed to its high content of haem-rich mitochondria. However, the mechanisms by which BAT regulates intracellular haem levels remain largely unexplored. Here we demonstrate that haem biosynthesis is the primary source of haem in brown adipocytes.

NK3 receptor antagonist alters the centrally controlled perception of menopausal flushing - a pilot study.

Objective: Kisspeptin/neurokinin/dynorphin (KNDy) signaling links reproductive and thermoregulatory systems, and improvements in menopausal flushing are reported with neurokinin 3 receptor (NK3R) antagonists. A rise in brainstem activity preceding a flush has been proposed as its functional origin, with subsequent activity in the insula and prefrontal cortices reflecting individual perception. Using functional magnetic resonance imaging (fMRI), this study investigated the central effect of the NK3R antagonist MLE4901 during a flush, particularly functional connectivity changes in the salience network.

Comparison of large single and small multiple doses of cyclophosphamide exposure in mice during early prepubertal age on fertility outcome.

Cyclophosphamide (CY) exposure is known to affect the ovary and impair fertility. Clinically, treatment is generally given over multiple doses, but research models have generally used single doses. The relative effects of administering multiple small doses of CY in the prepubertal period are not elucidated.

Evidence-based guideline: premature ovarian insufficiency.

Study Question: How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature?

Summary Answer: The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI.

What Is Known Already: Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health.

Evidence-based guideline: Premature Ovarian Insufficiency.

Study Question: How should premature/primary ovarian insufficiency (POI) be diagnosed and managed, based on the best available evidence from published literature?

Summary Answer: The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae and treatment of POI.

What Is Known Already: Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular and cognitive health.

Evidence-based guideline: premature ovarian insufficiency.

Study Question: How should premature/primary ovarian insufficiency (POI) be diagnosed and managed, based on the best available evidence from published literature?

Summary Answer: The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae and treatment of POI.

What Is Known Already: POI presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life, on fertility and on bone, cardiovascular and cognitive health.