Maml1 acts cooperatively with Gli proteins to regulate Sonic hedgheog signaling pathway

Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule cell progenitors (GCPs) and its misregulation is linked to various disorders, including cerebellar cancer medulloblastoma. The effects of Shh pathway are mediated by the Gli family of transcription factors, which controls the expression of a number of target genes, including Gli1. Here, we identify Mastermind-like 1 (Maml1) as a novel regulator of the Shh signaling since it interacts with Gli proteins, working as a potent transcriptional coactivator. Notably, Maml1 silencing results in a significant reduction of Gli target genes expression, with a negative impact on cell growth of NIH3T3 and Patched1−/− mouse embryonic fibroblasts (MEFs), bearing a constitutively active Shh signaling. Remarkably, Shh pathway activity results severely compromised both in MEFs and GCPs deriving from Maml1−/− mice with an impairment of GCPs proliferation and cerebellum development. Therefore Maml1−/− phenotype mimics aspects of Shh pathway deficiency, suggesting an intrinsic requirement for Maml1 in cerebellum development. The present study shows a new role for Maml1 as a component of Shh signaling, which plays a crucial role in both development and tumorigenesis

VirusMINT: a viral protein interaction database

Understanding the consequences on host physiology induced by viral infection requires complete understanding of the perturbations caused by virus proteins on the cellular protein interaction network. The VirusMINT database (http://mint.bio.uniroma2.it/virusmint/) aims at collecting all protein interactions between viral and human proteins reported in the literature. VirusMINT currently stores over 5000 interactions involving more than 490 unique viral proteins from more than 110 different viral strains. The whole data set can be easily queried through the search pages and the results can be displayed with a graphical viewer. The curation effort has focused on manuscripts reporting interactions between human proteins and proteins encoded by some of the most medically relevant viruses: papilloma viruses, human immunodeficiency virus 1, Epstein–Barr virus, hepatitis B virus, hepatitis C virus, herpes viruses and Simian virus 40

Quality of life and emotional distress in sarcoma patients diagnosed during COVID-19 pandemic: a supplementary analysis from the SarCorD study

BackgroundThe COVID-19 outbreak had a negative psychological impact on cancer patients. In this study, we analyzed emotional distress and quality of life in patients diagnosed with sarcoma during the first year of the pandemic compared to the previous year.MethodsWe retrospectively enrolled patients with soft tissue, bone sarcoma, and aggressive benign musculoskeletal diseases diagnosed during the pandemic (COVID group) or the year before (control group) at the IRCCS Regina Elena National Cancer Institute in Rome. Patients who had undergone a psychological assessment with the EORTC QLQ-C30 and the Distress Thermometer at diagnosis were included in the final analysis. We analyzed whether there is a difference in the various domains of quality of life between the two groups and whether there are changes over time in each group.ResultsWe enrolled 114 patients (72 control group; 42 COVID group), affected by soft tissue (64%), bone sarcoma (29%), and aggressive benign musculoskeletal diseases (7%). We did not observe significant differences in the health-related quality of life domains in the control and COVID groups, except for the financial domain (p = 0.039), with 9.7% vs. 23.8% of patients with a score > 0 in the control and COVID groups, respectively. We observed emotional distress at diagnosis in 48.6% of patients in the control group vs. 69.0% in the COVID group (p = 0.034). In the control group, we observed an improvement in physical function (p = 0.043) and in QoL (p = 0.022), while in the COVID group, we observed a deterioration in role function (p = 0.044) during follow-up. In the COVID group, 22.2% of patients were concerned about COVID-19, 61.1% by tumor, 91.1% stated that the pandemic worsened their subjective perception of cancer, and 19.4% perceived that their quality of care had worsened.ConclusionWe observed a higher level of distress among patients diagnosed during the pandemic compared to the year before, probably due to the increased concern for both infection and cancer, the worsened perception of health status, and the perception of a poorer quality of health care

Vitamin C Deficiency in Patients With Acute Myeloid Leukemia

Vitamin C has been shown to play a significant role in suppressing progression of leukemia through epigenetic mechanisms. We aimed to study the role of vitamin C in acute myeloid leukemia (AML) biology and clinical course. To this purpose, the plasma levels of vitamin C at diagnosis in 62 patients with AML (including 5 cases with acute promyelocytic leukemia, APL),7 with myelodysplastic syndrome (MDS), and in 15 healthy donors (HDs) were studied. As controls, vitamins A and E levels were analysed. Expression of the main vitamin C transporters and of the TET2 enzyme were investigated by a specific RQ-PCR while cytoplasmic vitamin C concentration and its uptake were studied in mononuclear cells (MNCs), lymphocytes and blast cells purified from AML samples, and MNCs isolated from HDs. There were no significant differences in vitamin A and E serum levels between patients and HDs. Conversely, vitamin C concentration was significantly lower in AML as compared to HDs (p<0.0001), inversely correlated with peripheral blast-counts (p=0.029), significantly increased at the time of complete remission (CR) (p=0.04) and further decreased in resistant disease (p=0.002). Expression of the main vitamin C transporters SLC23A2, SLC2A1 and SLC2A3 was also significantly reduced in AML compared to HDs. In this line, cytoplasmic vitamin C levels were also significantly lower in AML-MNCs versus HDs, and in sorted blasts compared to normal lymphocytes in individual patients. No association was found between vitamin C plasma levels and the mutation profile of AML patients, as well as when considering cytogenetics or 2017 ELN risk stratification groups. Finally, vitamin C levels did not play a predictive role for overall or relapse-free survival. In conclusion, our study shows that vitamin C levels are significantly decreased in patients with AML at the time of initial diagnosis, further decrease during disease progression and return to normal upon achievement of CR. Correspondingly, low intracellular levels may mirror increased vitamin C metabolic consumption in proliferating AML cells

A Dynamic Role of Mastermind-Like 1: A Journey Through the Main (Path)ways Between Development and Cancer

Major signaling pathways, such as Notch, Hedgehog (Hh), Wnt/β-catenin and Hippo, are targeted by a plethora of physiological and pathological stimuli, ultimately resulting in the modulation of genes that act coordinately to establish specific biological processes. Many biological programs are strictly controlled by the assembly of multiprotein complexes into the nucleus, where a regulated recruitment of specific transcription factors and coactivators on gene promoter region leads to different transcriptional outcomes. MAML1 results to be a versatile coactivator, able to set up synergistic interlinking with pivotal signaling cascades and able to coordinate the network of cross-talking pathways. Accordingly, despite its original identification as a component of the Notch signaling pathway, several recent reports suggest a more articulated role for MAML1 protein, showing that it is able to sustain/empower Wnt/β-catenin, Hh and Hippo pathways, in a Notch-independent manner. For this reason, MAML1 may be associated to a molecular “switch”, with the function to control the activation of major signaling pathways, triggering in this way critical biological processes during embryonic and post-natal life. In this review, we summarize the current knowledge about the pleiotropic role played by MAML proteins, in particular MAML1, and we recapitulate how it takes part actively in physiological and pathological signaling networks. On this point, we also discuss the contribution of MAML proteins to malignant transformation. Accordingly, genetic alterations or impaired expression of MAML proteins may lead to a deregulated crosstalk among the pathways, culminating in a series of pathological disorders, including cancer development. Given their central role, a better knowledge of the molecular mechanisms that regulate the interplay of MAML proteins with several signaling pathways involved in tumorigenesis may open up novel opportunities for an attractive molecular targeted anticancer therapy.</jats:p

Families Facing Pandemic Modifications of Everyday Life: A Mixed Study on Mothers&rsquo; and Children&rsquo;s Emotional Reactions and Regulation Strategies

The COVID-19 pandemic caused many enduring changes in the everyday life of families, with negative effects on parents&rsquo; and children&rsquo;s wellbeing. However, there is a lack of studies in the literature exploring the emotional reactions and coping strategies of both mothers and children of different ages. Furthermore, most studies used only self-reports. This study aimed to identify the emotions and coping strategies of children, adolescents and their mothers and to verify the association between maternal and child wellbeing. A mixed-method design using interviews and questionnaires was applied to collect information on wellbeing (emotional reactions, behavioral/emotional problems) and coping strategies of both mothers (n = 65; M age = 42.17; SD = 4.40; M age = 41.63; SD = 4.48), and their children (n = 35, 8&ndash;10 year; n = 30, 11&ndash;13 year) during the second wave of the pandemic (December 2020). No differences between the groups emerged concerning the emotional reactions reported. In contrast, mothers and children of different ages reported different self-regulation and other-regulation strategies. Moreover, maternal strategies had different effects on children&rsquo;s wellbeing. The integration of qualitative and quantitative results was informative to understand how families adapted to the radical changes of everyday life related to the pandemic. The implications for developing interventions in such similar stressful situations to promote family wellbeing are discussed

The Economic Burden of Chronic Myeloid Leukemia in Patients with Later Lines: Findings from a Real-World Analysis in Italy

Introduction: Chronic myeloid leukemia (CML) is a hematopoietic myeloproliferative disorder that accounts for 20\% of all leukemias of adults. The introduction of tyrosine kinase inhibitors (TKIs) (imatinib, bosutinib, dasatinib, nilotinib, ponatinib) has yielded significant benefits for patients with CML in terms of sur-vival and quality of life. This real-world analysis evaluated the economic burden for managing patients with CML in 2nd or &gt; 3rd TKI lines in Italian settings of clinical practice.Methods: A retrospective observational analysis was performed exploiting the administrative databases of a sample of entities covering around 15 million inhabitants. From 2015 to 2018, the study included adult patients with at least one prescription for TKIs, (and for some TKI with at least one hospitalization discharge diagnosis for CML, or at least one prescription for BCR-ABL examination). The index date was the first TKI prescription. Healthcare resource consumption and costs for patients with CML in 2nd and &gt; 3rd line treatment with TKIs were analyzed for drug prescriptions, hospitalizations, specialist visits, and diagnostic services.Results: In total 635 patients were included, 491 in 2nd line and 144 in 3rd line with TKIs. Dasatinib was the most frequently prescribed drug in 2nd line (28.9\%) and imatinib in later lines (26.4\%). With progressing lines of treat-ment, healthcare consumption showed a trend towards increased non-TKI prescriptions per patient (8 for 2nd line and 9.7 for &gt; 3rd line). The management of patients with CML in later lines resulted in increased overall healthcare burden, with hospitalizations accounting for about half of total expenditure, whatever the treatment line and type of TKI.Conclusions: This analysis in Italian real-life clinical practice reported economic expenditure for patients with CML in 2nd or &gt; 3rd lines with TKIs, mostly burdened by hospitalizations. Such clinical complexity suggests that further efforts are needed to improve the therapeutic management of later lines of CML