Abstract
Despite development of novel agents targeting oncogenic pathways, matching targeted therapies to the genetic status of individual tumors is proving to be a daunting task for clinicians. To ...improve the clinical efficacy and to reduce the toxic side effects of treatments, a deep characterization of genetic alterations in different tumors is required. The mutational profile often evidences a gain of function or hyperactivity of phosphoinositide 3-kinases (PI3Ks) in tumors. These enzymes are activated downstream tyrosine kinase receptors (RTKs) and/or G proteins coupled receptors (GPCRs) and, via AKT, are able to induce mammalian target of rapamycin (mTOR) stimulation. Here, we elucidate the impact of class I (p110α, β, γ, and δ) catalytic subunit mutations on AKT-mediated cellular processes that control crucial mechanisms in tumor development. Moreover, the interrelation of PI3K signaling with mTOR, ERK, and RAS pathways will be discussed, exploiting the potential benefits of PI3K signaling inhibitors in clinical use.
Class II PI3K Functions in Cell Biology and Disease Gulluni, Federico; De Santis, Maria Chiara; Margaria, Jean Piero ...
Trends in cell biology,
April 2019, 2019-04-00, 20190401, Letnik:
29, Številka:
4
Journal Article
Recenzirano
The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate inositol phospholipids, thereby controlling membrane lipid composition and regulating a wide range of ...intracellular processes, including vesicular trafficking and signal transduction. Despite the vast knowledge on class I PI3Ks, recent studies are only now revealing the importance of class II PI3Ks in cell proliferation, survival, and migration. Increasing evidence suggests that the three class II PI3Ks isoforms (PI3K-C2α, PI3K-C2β, and PI3K-C2γ) have distinct and non-overlapping cellular roles. Here, we focus on the cellular functions of class II PI3Ks in different cell systems and underline the emerging importance of these enzymes in various physiological and pathological contexts.
Class II PI3Ks synthetize two different phosphoinositides, PI(3)P and PI(3,4)P2, in distinct cellular compartments.
PI3K-C2α plays a central role in clathrin-mediated endocytosis, vesicular trafficking, and mitosis.
PI3K-C2β is activated by growth factors and is involved in cell migration and mTOR signaling repression.
PI3K-C2γ localizes on early endosomes and controls Akt2 activation and glycogen storage in the liver.
Abstract
Non-cystic white matter (WM) injury has become prevalent among preterm newborns and is associated with long-term neurodevelopmental impairment. Magnetic resonance is the gold-standard for ...diagnosis; however, cranial ultrasound (CUS) is more easily available but limited by subjective interpretation of images. To overcome this problem, we enrolled in a prospective observational study, patients with gestational age at birth < 32 weeks with normal CUS scans or grade 1 WM injury. Patients underwent CUS examinations at 0–7 days of life (T
0
), 14–35 days of life (T
1
), 37
0/7
–41
6/7
weeks’ postmenstrual age (T
2
), and 42
0/7
–52
0/7
weeks’ postmenstrual age (T
3
). The echogenicity of parieto-occipital periventricular WM relative to that of homolateral choroid plexus (RE
CP
) was calculated on parasagittal scans by means of pixel brightness intensity and its relationship with Bayley-III assessment at 12 months’ corrected age was evaluated. We demonstrated that: (1) Left RE
CP
values at T
1
negatively correlated with cognitive composite scores; (2) Right RE
CP
values at T
2
and T
3
negatively correlated with language composite scores; (3) Left RE
CP
values at T
1
and T
2
negatively correlated with motor composite scores. Thus, this technique may be used as screening method to early identify patients at risk of neurodevelopmental issues and promptly initiate preventive and therapeutic interventions.
Background
Preterm birth and admission to the neonatal intensive care unit (NICU) could induce post-traumatic stress disorder (PTSD). PTSD is an important factor to focus on, as it is associated with ...parental mental health difficulties and with changes in caregiving quality such as increased intrusiveness, reduced sensitivity, and increased attachment insecurity for the child.
Aims
We aimed to study the main risk factors, in the early life of newborns, and preventive measures for PTSD in parents of neonates hospitalized in the NICU.
Methods
We included parents of preterm newborns, consecutively admitted to the NICU of the University La Sapienza of Rome. The presence of PTSD following preterm birth and NICU admission was assessed using the Clinician-administered PTSD scale (CAPS) at enrollment and at 28–30 days following NICU admission or the moment of discharge. We also evaluated the Family Environment Scale which measures the social environment of all types of families; the Parental Stressor Scale which measures parental anxiety and stress; the Spielberger State-Trait Anxiety Inventory consisting of two parts measuring the State (response to present situation) and Trait (pre-disposition to be anxious) anxieties separately, and the Beck Depression Inventory Second Edition assessing depressive symptoms.
Results
We found, in a multivariate analysis, that the gestational age of newborns admitted to NICU significantly (β = 2.678;
p
= 0.040) influences the occurrence of PTSD. We found that the cases showed significantly (β = 2.443;
p
= 0.020) more pathological Parental Stressor Scale sights and sounds scores compared to controls. The early Kangaroo-Care (KC) significantly (β = −2.619;
p
= 0.015) reduces the occurrence of PTSD.
Conclusion
Post-traumatic stress disorder in parents of preterm newborns is a pathological condition that should be properly managed, in the very first days after birth. The NICU environment represents a main risk factor for PTSD, whereas KC has been demonstrated to have a protective role in the occurrence of PTSD.
The phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) are central regulators of glycolysis, cancer metabolism, and cancer cell ...proliferation. At the molecular level, PI3K signaling involves the generation of the second messenger lipids phosphatidylinositol 3,4,5-trisphosphate PI(3,4,5)P3 and phosphatidylinositol 3,4-bisphosphate PI(3,4)P2. There is increasing evidence that PI(3,4)P2 is not only the waste product for the removal of PI(3,4,5)P3 but can also act as a signaling molecule. The selective cellular functions for PI(3,4)P2 independent of PI(3,4,5)P3 have been recently described, including clathrin-mediated endocytosis and mTOR regulation. However, the specific spatiotemporal dynamics and signaling role of PI3K minor lipid messenger PI(3,4)P2 are not well-understood. This review aims at highlighting the biological functions of this lipid downstream of phosphoinositide kinases and phosphatases and its implication in cancer metabolism.
BACKGROUND:Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by ...cardiotoxicity. This study sought to investigate the role of phosphoinositide 3-kinase γ (PI3Kγ) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kγ inhibition.
METHODS:Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ-selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography, and DOX-mediated signaling was assessed in whole hearts or isolated cardiomyocytes. The dual cardioprotective and antitumor action of PI3Kγ inhibition was assessed in mouse mammary tumor models.
RESULTS:PI3Kγ kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kγ inhibition were causally linked to enhanced autophagic disposal of DOX-damaged mitochondria. Consistently, either pharmacological or genetic blockade of autophagy in vivo abrogated the resistance of PI3Kγ kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kγ was triggered in DOX-treated hearts, downstream of Toll-like receptor 9, by the mitochondrial DNA released by injured organelles and contained in autolysosomes. This autolysosomal PI3Kγ/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kγ blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity.
CONCLUSIONS:Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.
The interplay between rewiring tumor metabolism and oncogenic driver mutations is only beginning to be appreciated. Metabolic deregulation has been described for decades as a bystander effect of ...genomic aberrations. However, for the biology of malignant cells, metabolic reprogramming is essential to tackle a harsh environment, including nutrient deprivation, reactive oxygen species production, and oxygen withdrawal. Besides the well-investigated glycolytic metabolism, it is emerging that several other metabolic fluxes are relevant for tumorigenesis in supporting redox balance, most notably pentose phosphate pathway, folate, and mitochondrial metabolism. The relationship between metabolic rewiring and mutant genes is still unclear and, therefore, we will discuss how metabolic needs and oncogene mutations influence each other to satisfy cancer cells' demands. Mutations in oncogenes, i.e., PI3K/AKT/mTOR, RAS pathway, and MYC, and tumor suppressors, i.e., p53 and liver kinase B1, result in metabolic flexibility and may influence response to therapy. Since metabolic rewiring is shaped by oncogenic driver mutations, understanding how specific alterations in signaling pathways affect different metabolic fluxes will be instrumental for the development of novel targeted therapies. In the era of personalized medicine, the combination of driver mutations, metabolite levels, and tissue of origins will pave the way to innovative therapeutic interventions.
Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral ...replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine.
Lung diseases are the most common conditions in newborns, infants, and children and are also the primary cause of death in children younger than 5 years old. Traditionally, the lung was not thought ...to be a target for an ultrasound due to its inability to penetrate the gas-filled anatomical structures. With the deepening of knowledge on ultrasound in recent years, it is now known that the affected lung produces ultrasound artifacts resulting from the abnormal tissue/gas/tissue interface when ultrasound sound waves penetrate lung tissue. Over the years, the application of lung ultrasound (LUS) has changed and its main indications in the pediatric population have expanded. This review analyzed the studies on lung ultrasound in pediatrics, published from 2010 to 2020, with the aim of highlighting the usefulness of LUS in pediatrics. It also described the normal and abnormal appearances of the pediatric lung on ultrasound as well as the benefits, limitations, and possible future challenges of this modality.
Data about classification of hypogonadism and estrogen deficiency in male people living with HIV (PLWH) are scanty.
To investigate the prevalence and characterization of biochemical hypogonadism and ...relative estrogen deficiency in male PLWH aged < 50 comparing liquid chromatography-tandem mass spectrometry (LC-MS/MS) with chemiluminescent immunoassay (CI), and combining gonadotropin, sex hormone-binding globulin (SHBG) and serum estradiol (E2) measurements.
Prospective, cross-sectional, observational study. Serum total testosterone (TT), E2, gonadotropins, SHBG were measured by CI. TT and E2 were also assessed by LC-MS/MS. Free testosterone (cFT) was calculated by Vermeulen equation.
A total of 316 PLWH (45.3 ± 5.3 years) were enrolled. TT and cFT by LC-MS/MS were lower compared to CI (p < 0.0001). The prevalence of biochemical hypogonadism was higher with LC-MS/MS than CI, both for TT (5.1% vs 3.2%, p < 0.0001) or cFT (9.5% vs 7%, p < 0.0001). The prevalence of hypogonadism (overt + compensated) was 17.1% for cFT using LC-MS/MS. Secondary form of hypogonadism was more prevalent than primary. The prevalence of relative estrogen deficiency was of 30.0% among hypogonadal patients and 15.5% among eugonadal.
The prevalence of male hypogonadism results underestimated by CI compared to LC-MS/MS in PLWH, both for TT and cFT. SHBG and gonadotropins are essential for detecting T deficiency.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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