FBXO32-mediated degradation of PTEN promotes lung adenocarcinoma progression.

FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.

Caspase-8 and Tyrosine Kinases: A Dangerous Liaison in Cancer.

Caspase-8 is a cysteine-aspartic acid protease that has been identified as an initiator caspase that plays an essential role in the extrinsic apoptotic pathway. Evasion of apoptosis is a hallmark of cancer and Caspase-8 expression is silenced in some tumors, consistent with its central role in apoptosis. However, in the past years, several studies reported an increased expression of Caspase-8 levels in many tumors and consistently identified novel "non-canonical" non-apoptotic functions of Caspase-8 that overall promote cancer progression and sustain therapy resistance. These reports point to the ability of cancer cells to rewire Caspase-8 function in cancer and raise the question of which are the signaling pathways aberrantly activated in cancer that may contribute to the hijack of Caspase-8 activity. In this regard, tyrosine kinases are among the first oncogenes ever identified and genomic, transcriptomic and proteomic studies indeed show that they represent a class of signaling molecules constitutively activated in most of the tumors. Here, we aim to review and discuss the role of Caspase-8 in cancer and its interplay with Src and other tyrosine kinases.

Caspase-8 as a novel mediator linking Src kinase signaling to enhanced glioblastoma malignancy.

Caspase-8 is a cysteine protease that plays an essential role in apoptosis. Consistently with its canonical proapoptotic function, cancer cells may genetically or epigenetically downregulate its expression. Unexpectedly, Caspase-8 is often retained in cancer, suggesting the presence of alternative mechanisms that may be exploited by cancer cells to their own benefit. In this regard, we reported that Src tyrosine kinase, which is aberrantly activated in many tumors, promotes Caspase-8 phosphorylation on Tyrosine 380 (Y380) preventing its full activation. Here, we investigated the significance of Caspase-8 expression and of its phosphorylation on Y380 in glioblastoma, a brain tumor where both Caspase-8 expression and Src activity are often aberrantly upregulated. Transcriptomic analyses identified inflammatory response as a major target of Caspase-8, and in particular, NFκB signaling as one of the most affected pathways. More importantly, we could show that Src-dependent phosphorylation of Caspase-8 on Y380 drives the assembly of a multiprotein complex that triggers NFκB activation, thereby inducing the expression of inflammatory and pro-angiogenic factors. Remarkably, phosphorylation on Y380 sustains neoangiogenesis and resistance to radiotherapy. In summary, our work identifies a novel interplay between Src kinase and Caspase-8 that allows cancer cells to hijack Caspase-8 to sustain tumor growth.

The Impact of a Precision-Based Exercise Intervention in Childhood Hematological Malignancies Evaluated by an Adapted Yo-Yo Intermittent Recovery Test.

During cancer treatments in childhood hematological malignancies, reduced exercise tolerance is one of the main hardships. Precision-based training programs help children, adolescents, and young adults and their families to resume regular physical activity, exercise, and sports once they return to their communities after the intensive phases spent in hospital. This study was aimed at verifying whether an intermittent recovery test, the Yo-Yo AD, could provide a simple and valid way to evaluate an individual's capacity to perform repeated intense exercise and to follow up on the impact of tailored exercise in children, adolescents, and young adults with hematological malignancies. The Yo-Yo AD involved the repetition of several shuttles to muscle exhaustion, at pre-established speeds (walking and slow running). The heart rate (HR) and oxygen saturation (SaO2) were monitored during the test. The total distance and the walking/running ability, measured as the slope of the HR vs. distance correlation, were investigated before (T0) and after 11 weeks (T1) of precision exercise intervention. The Yo-Yo AD was also performed by healthy children (CTRL). Ninety-seven patients (10.58 ± 4.5 years, 46% female) were enrolled. The Yo-Yo AD showed the positive impact of the exercise intervention by increasing the distance covered by the individuals (T0 = 946.6 ± 438.2 vs. T1 = 1352.3 ± 600.6 m, p < 0.001) with a more efficient walking/running ability (T0 = 2.17 ± 0.84 vs. T1 = 1.73 ± 0.89 slope, p < 0.0164). CTRLs performed better (1754.0 ± 444.0 m, p = 0.010). They were equally skillful (1.71 ± 0.27 slope) when compared to the patients after they received the precision-based intervention. No adverse events occurred during the Yo-Yo AD and it proved to be an accurate way of correctly depicting the changes in performance in childhood hematological malignancies.

Fifteen days of moderate normobaric hypoxia does not affect mitochondrial function, and related genes and proteins, in healthy men.

PURPOSE: To investigate within the one study potential molecular and cellular changes associated with mitochondrial biogenesis following 15 days of exposure to moderate hypoxia. METHODS: Eight males underwent a muscle biopsy before and after 15 days of hypoxia exposure (FiO2 = 0.140-0.154; ~ 2500-3200 m) in a hypoxic hotel. Mitochondrial respiration, citrate synthase (CS) activity, and the content of genes and proteins associated with mitochondrial biogenesis were investigated. RESULTS: Our main findings were the absence of significant changes in the mean values of CS activity, mitochondrial respiration in permeabilised fibers, or the content of genes and proteins associated with mitochondrial biogenesis, after 15 days of moderate normobaric hypoxia. CONCLUSION: Our data provide evidence that 15 days of moderate normobaric hypoxia have negligible influence on skeletal muscle mitochondrial content and function, or genes and proteins content associated with mitochondrial biogenesis, in young recreationally active males. However, the increase in mitochondrial protease LON content after hypoxia exposure suggests the possibility of adaptations to optimise respiratory chain function under conditions of reduced O2 availability.

Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma.

Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials.

ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?

Increasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis: activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed.

Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma.

Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality.

Implantable cardioverter defibrillator management: an update.

Implantable cardioverter defibrillator (ICD) is the cornerstone of primary and secondary prevention of sudden cardiac death. In 35 years of technologic improvement and clinical trials, there has been a continuous increase in implantation rate. Purpose of this review is to point out and discuss every aspect related to actual ICD management, investigating implantation procedure and predischarge care, office and remote monitoring follow-up, diagnostic evaluations, management of patients with suspected therapies or malfunctions, heart failure, surgery, radiotherapy and endoscopic procedures. Also, ICD backface such as infections and other complications will be discussed. Finally, we will focus on interesting future perspectives for this setting of patients.

Platelet aggregation values in patients with cardiovascular risk factors are reduced by verbascoside treatment. A randomized study.

Verbascoside, a phenolic compound, showed several favorable biological activities, including an antiplatelet activity. No in vivo studies tested its efficacy and safety in subjects with cardiovascular (CV) factors. The aim of this randomized, single-center, double-blind, phase II study was to assess the efficacy and tolerability of verbascoside intake for the modulation of platelet aggregation (PA) values in subjects with cardiovascular (CV) risk factors. One-hundred subjects with at least one CV risk factor (age >65 years, diabetes mellitus, hypertension, current cigarettes use, hyperlidemia, waist circumference >102 cm in male or >88 cm in female) were enrolled and randomly assigned to receive placebo or verbascoside 50mg or verbascoside 100mg. PA was measured at baseline and after 2 weeks of study drug assumption, with light transmittance aggregometry (arachidonic acid, AA, 1 µM and adenosine diphosphate, ADP, 5 µM). Two weeks of treatment with placebo or verbascoside 50mg did not modify PA values (both after AA and ADP stimuli). On the contrary, after 2 weeks of verbascoside 100mg, PA values decreased significantly (from 51 ± 13% to 39 ± 15%, p<0.01 after AA; from 60 ± 12% to 49 ± 15%, p = 0.01 after ADP). No serious adverse events were reported during the study, and no subjects discontinued the study because of adverse events. We conclude that long-term intake of verbascoside 100mg significantly reduces PA values in subjects with CV risk factors.

Near infrared spectroscopy (NIRS) as a new non-invasive tool to detect oxidative skeletal muscle impairment in children survived to acute lymphoblastic leukaemia.

BACKGROUND: Separating out the effects of cancer and treatment between central and peripheral components of the O2 delivery chain should be of interest to clinicians for longitudinal evaluation of potential functional impairment in order to set appropriate individually tailored training/rehabilitation programmes. We propose a non-invasive method (NIRS, near infrared spectroscopy) to be used in routine clinical practice to evaluate a potential impairment of skeletal muscle oxidative capacity during exercise in children previously diagnosed with acute lymphoblastic leukaemia (ALL). The purpose of this study was to evaluate the capacity of skeletal muscle to extract O2 in 10 children diagnosed with ALL, 1 year after the end of malignancy treatment, compared to a control group matched for gender and age (mean±SD = 7.8±1.5 and 7.3±1.4 years, respectively). METHODS AND FINDINGS: Participants underwent an incremental exercise test on a treadmill until exhaustion. Oxygen uptake ([Formula: see text]), heart rate (HR), and tissue oxygenation status (Δ[HHb]) of the vastus lateralis muscle evaluated by NIRS, were measured. The results showed that, in children with ALL, a significant linear regression was found by plotting [Formula: see text] vs Δ[HHb] both measured at peak of exercise. In children with ALL, the slope of the HR vs [Formula: see text] linear response (during sub-maximal and peak work rates) was negatively correlated with the peak value of Δ[HHb]. CONCLUSIONS: The present study proves that the NIRS technique allows us to identify large inter-individual differences in levels of impairment in muscle O2 extraction in children with ALL. The outcome of these findings is variable and may reflect either muscle atrophy due to lack of use or, in the most severe cases, an undiagnosed myopathy.

Impaired oxygen extraction in metabolic myopathies: detection and quantification by near-infrared spectroscopy.

Patients with mitochondrial myopathies (MM) or myophosphorylase deficiency (McArdle's disease, McA) show impaired capacity for O(2) extraction, low maximal aerobic power, and reduced exercise tolerance. Non-invasive tools are needed to quantify the metabolic impairment. Six patients with MM, 6 with McA, 25 with symptoms of metabolic myopathy but negative biopsy (patient-controls, P-CTRL) and 20 controls (CTRL) underwent an incremental cycloergometric test. Pulmonary O(2) uptake (VO(2)) and vastus lateralis oxygenation indices (by near-infrared spectroscopy, NIRS) were determined. Concentration changes of deoxygenated hemoglobin and myoglobin (Delta[deoxy(Hb + Mb)]) were considered an index of O(2) extraction. Delta[deoxy(Hb + Mb)] peak (percent limb ischemia) was lower in MM (25.3 +/- 12.0%) and McA (18.7 +/- 7.3) than in P-CTRL (62.4 +/- 3.9) and CTRL (71.3 +/- 3.9) subjects. VO(2) peak and Delta[deoxy(Hb + Mb)] peak were linearly related (r(2) = 0.83). In these patients, NIRS is a tool to detect and quantify non-invasively the metabolic impairment, which may be useful in the follow-up of patients and in the assessment of therapies and interventions.