47 research outputs found
Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma
No full textDanilo Cucchi,1,* Maria Anna Occhione,2,* Alberto Gulino,2,3 Enrico De Smaele1 1Department of Experimental Medicine, 2Department of Molecular Medicine, Sapienza University of Rome, Rome, 3Center of Life NanoScience @ La Sapienza, Istituto Italiano di Tecnologia, Rome, Italy*These authors contributed equally to this workAbstract: Basal cell carcinoma (BCC) of the skin is the most common type of cancer and accounts for up to 40% of all cancers in the US, with a growing incidence rate over recent decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutic approaches. Furthermore, patients with BCC present a high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render primary interest in the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, the critical role of the morphogenetic Hedgehog (Hh) pathway has become evident. This pathway is found altered and activated in almost all BCCs, both sporadic and inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hh components. Several Hh inhibitors have been so far identified – from the first identified natural cyclopamine to the recently Food and Drug Administration-approved synthetic vismodegib – most of which target the Hh receptor Smoothened (either its function or its translocation to the primary cilium). Other molecules await further characterization (bisamide compounds), while drugs currently approved for other diseases such as itraconazole (an antimicotic agent) and vitamin D3 have been tested on BCC with encouraging results. The outcomes of the numerous ongoing clinical trials are expected to expand the field in the very near future. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg, Gli) or to exploit combinatorial therapies (eg, with phosphatidylinositol 3-kinase inhibitors or retinoids) in order to overcome potential drug resistance.Keywords: BCC, Hedgehog, vismodegib, Smo inhibitors, Gli antagonists, retinoids, itraconazole, vitamin D
Lactate transporters as therapeutic targets in cancer and inflammatory disease
No full textIntroduction: Inflammation is associated with the accumulation of lactate at sites of tumour growth and inflammation. Lactate initiates tissue responses contributing to disease. We discuss the potential of targeting lactate transporters in the treatment of cancer and inflammatory conditions. Areas covered: Lactate is the product of glycolysis, which is considered to be a waste metabolite and a fuel for oxidative cells. It is also an active signalling molecule with immunomodulatory and angiogenic properties. They are the consequence of lactate binding to membrane receptor(s) or being transported through specific carrier-mediated transporters across the cellular membrane. Carriers are distinct in proton-linked monocarboxylate transporters (MCTs) and Na+-coupled electrogenic transporters (SMTCs), expressed by several tissues including immune system, endothelium and epithelium. Several tumours and inflammatory sites (i.e., arthritic synovium, atherosclerotic plaque) show accumulation of lactate and altered expression of its transporters, thus suggesting a role of this metabolite in cancer and inflammatory disorders. We review the most recent evidence on lactate biology, focusing on transporter expression and function in health and disease. Expert opinion: Lactate-initiated signalling is gaining attention for its implications in cancer and inflammation. This review deals with the therapeutic potential of targeting lactate transporters and drugs that are already in clinical use for cancer and discusses the opportunity to develop new therapeutics for inflammatory disease based on recent findings.</p
Non-native English within the European Parliament
No full textIl volume tratta dell’inglese non nativo parlato entro il Parlamento Europeo, un dominio in cui i parlanti hanno il diritto di esprimersi in una qualsiasi tra le lingue europee ufficiali. Il fatto che alcuni parlanti preferiscano l’inglese alla loro lingua materna è indicativo dell’uso crescente dell’inglese in Europa e presso le istituzioni europee, un fenomeno che viene esaminato nel volume con riferimento all’emergere del termine ‘Euro-English’. L’analisi linguistica del discorso europarlamentare non nativo si basa sul corpus EU-Parl allestito dall’autrice, che comprende i discorsi effettivamente pronunciati durante le sedute parlamentari e i loro rispettivi resoconti ufficiali. I risultati rivelano che il discorso dei non nativi è caratterizzato da deviazioni dalle norme dello Standard English e da tratti informali forse inaspettati, se si considera la formalità del contesto. Al contempo, si chiariscono le pratiche dei revisori di madrelingua che redigono i resoconti ufficiali. L’uso dei sostantivi ‘thing’ e ‘stuff’, tradizionalmente associati con l’informalità tipica dei parlanti nativi in contesti conversazionali, viene poi studiata nel contesto istituzionale del Parlamento Europeo e nei resoconti ufficiali.The volume focuses on non-native English as spoken within the European Parliament, a setting where speakers have the right to express themselves in any of the European official languages. The fact that some speakers opt for English rather than their own mother tongue indicates the increasing use of English in Europe and within the European institutions, a phenomenon which is examined in the volume with reference to the emergence of the term 'Euro-English'. The linguistic analysis of non-native europarliamentary discourse is based on the EU-Parl corpus compiled by the author, which comprises actual speeches delivered by non-native speakers during parliamentary sittings and their corresponding official written proceedings. Findings reveal that non-native speaker discourse is characterised by deviations from Standard English norms and informal traits which one would perhaps not expect, given the formality of the setting. Simultaneously, light is shed on the practice of English mother tongue revisers who draw up the written proceedings. The use of the vague nouns ‘thing’ and ‘stuff’, traditionally associated with the informality expected by native speakers in conversational settings, is then studied in the institutional setting of the European Parliament and in the written proceedings
The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability
No full textUSP21 is a centrosome-associated deubiquitylase (DUB) that has been implicated in the formation of primary cilia - crucial organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here, we identify KCTD6 - a cullin-3 E3-ligase substrate adapter that has been previously linked to Hh signaling - as well as Gli1, the key transcription factor responsible for Hh signal amplification, as new interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to have a similar fold to Smr domains. Importantly, we show that both depletion and overexpression of catalytically active USP21 suppress Gli1-dependent transcription. Gli proteins are negatively regulated through protein kinase A (PKA)-dependent phosphorylation. We provide evidence that USP21 recruits and stabilises Gli1 at the centrosome where it promotes its phosphorylation by PKA. By revealing an intriguing functional pairing between a spatially restricted deubiquitylase and a kinase, our study highlights the centrosome as an important hub for signal coordination
Patient-reported outcomes and complication rates after lateral maxillary sinus floor elevation: a prospective study
No full textObjectives Oral surgery morbidity is highly variable based on patients' characteristics and kind of surgical intervention. However, poor data are available in the literature regarding patient outcomes after oral surgery. The aim of this retrospective study was to evaluate patient-reported outcome and complication rates after maxillary sinus floor elevation. Materials and methods Data from the records of patients undergoing maxillary sinus elevation have been collected from a private dental office. Patient-reported outcome has been assessed using a 100-mm visual analog scale to evaluate the post-operative pain (VAS(pain)) experienced in the first week following surgery and visual rating scales to evaluate discomfort level (VRSdiscomfort: 0 to 4) and willingness to repeat the same surgical procedure (VRSwillingness: 0 to 3). Analgesics intake, swelling onset and duration, and ecchymosis have been also recorded. Results VAS(pain) showed moderate values in the first 2 days (< 50) post-surgery, with a tendency to progressively decrease over the next 2 days. Average assumption of painkillers was 3.93 +/- 3.03. Discomfort level (VRSdiscomfort) after surgery was low (median: 1; IR: 1-0), while willingness to undergo the same surgical procedure was very high (77.63% of patients). Swelling and ecchymosis were experienced by 97.36% and 51.32% of patients, respectively, with a mean duration of 4.09 +/- 1.43 and 2.21 +/- 2.31 days, respectively. Membrane perforation occurred in 4 cases. Other post-operative complications were not observed. Conclusions Maxillary sinus grafting is a safe procedure, with a low complication rate and moderate morbidity that is well tolerated by patients. Particular attention is needed in case selection, surgical planning and operator expertise. © 2021, The Author(s)
Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4(+) T Cell Differentiation via PI3K p110 delta-Akt-Mediated Signals
No full textThis work was supported by the British Heart Foundation (Fellowship FS/12/38/29640 and Project Grant PG/15/105/31906 to CM) and the Fondazione Cariplo (a Project Grant to CM and GDN), and forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institutes of Health Research. D Cucchi was supported in part by a Fellowship from the Istituto Pasteur, Fondazione Cenci-Bolognetti. GDN was supported by the Telethon Foundation (GGP13002) and the Italian Ministero della Salute (WFR GR-2011-02346974).This work was supported by the British Heart Foundation (fellowship FS/12/38/29640 and project grant PG/15/105/31906 to C.M.) and the Fondazione Cariplo (a project grant 2015-0552 to C.M. and G.D.N.) and forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institutes of Health Research. D.Cucchi was supported in part by a fellowship from the Istituto Pasteur, Fondazione Cenci-Bolognetti. G.D.N. was supported by the Telethon Foundation (GGP13002) and the Italian Ministero della Salute (WFR GR-2011-02346974). F.M.M.-B. is a recipient of the British Heart Foundation Chair of Cardiovascular Immunology (CH/15/2/32064)
Erratum to: Evidence-based indications for hindfoot endoscopy
No full textThe author would like to correct the following errors in the online publication of the article: In the “Hindfoot periarticular area” section, under the sub-heading “Posterior ankle impingement”, the seventh and eighth paragraph should read as: The AOFAS score was the most frequently used clinical outcome score; where used, cumulative results showed average post-operative score of 90.6 points [1, 2, 11, 22, 24, 27, 32, 42, 50, 56, 64, 68] and pre- to post-operative increase by an average of 24.0 points [1, 2, 24, 27, 32, 42, 50, 56, 64]. Six studies reported results of isolated os trigonum excision in 99 ankles [2, 18, 22, 24, 33, 46]: the pre- to postoperative increase in AOFAS was available for 22 patients and reached 33.7 points [2, 24], while pre- to post-operative VAS decrease was available for 62 patients and was >6 points [18, 24, 33]. In the “Articular joint spaces” section, under the subheading “Subtalar joint articular space”, the first paragraph should read as follows: Osteoarthritis Level of evidence IV and V Degenerative changes of the subtalar joint are reported in the literature as indications for hindfoot endoscopy in prone position, eitherby means of talocalcaneal arthrodesis [3-5, 10, 29, 30, 38,39, 57] or arthroscopic osteophyte resection and debridement [39, 42]. Seven retrospective case series adequately documented the clinical results of 73 procedures of posterior arthroscopic subtalar arthrodesis (PASTA) [3, 4, 10, 29, 30, 38, 57]. Over these studies, post-traumatic or primary osteoarthritis were the preoperative indications for PASTA in more than 90 % of the cases. In five cases, subtalar arthropathy was related to a tarsal coalition [3, 4]. Five of the seven series evaluated post-operative clinical outcome with the AOFAS score: the cumulative results showed average post-operative score by 80.3 points and pre- to postoperative increase by an average of 40.4 points [3, 4, 29, 38, 57] The original article has been updated accordingly
In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors
No full textAberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog (Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using immunohistochemistry. We found a positive correlation between nuclear GLI1 expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining significantly correlated with a lower tumor grade. Next, the in vitro effects of two Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61. GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21-Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT-61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of TUBO cells in BALB/c mice to different extents. These findings suggest that targeting the Hh pathway using antagonists that act downstream of SMO is a more efficient strategy than using antagonists that act upstream of SMO for interrupting Hh signaling in breast cancer
β-arrestin1-mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renewal of SHH medulloblastoma cancer stem cells
No full textBackground
Aberrant Sonic Hedgehog/Gli (Hh/Gli) signaling pathway is a critical regulator of Sonic hedgehog medulloblastoma (SHH-MB). Cancer stem cells (CSCs), thought to be largely responsible for tumor initiation, maintenance, dissemination and relapse, have been identified in SHH-MB. Since we previously demonstrated that Hh/Gli signaling controls CSCs features in SHH-MB and that in these tumors miR-326 is down regulated, here we investigated whether there is a functional link between Hh/Gli signaling and miR-326.
Methods
We evaluated β-arrestin1 (Arrb1) and its intragenic miR-326 levels in CSCs derived from SHH-MB. Subsequently, we modulated the expression of Arrb1 and miR-326 in CSCs in order to gain insight into their biological role. We also analyzed the mechanism by which Arrb1 and miR-326 control Hh/Gli signaling and self-renewal, using luciferase and protein immunoprecipitation assays.
Results
Low levels of Arrb1 and miR-326 represent a feature of CSCs derived from SHH-MB. We observed that re-expression of Arrb1 and miR-326 inhibits Hh/Gli signaling pathway at multiple levels, which cause impaired proliferation and self-renewal, accompanied by down regulation of Nanog levels. In detail, miR-326 negatively regulates two components of the Hh/Gli pathway the receptor Smoothened (Smo) and the transcription factor Gli2, whereas Arrb1 suppresses the transcriptional activity of Gli1, by potentiating its p300-mediated acetylation.
Conclusions
Our results identify a new molecular mechanism involving miR-326 and Arrb1 as regulators of SHH-MB CSCs. Specifically, low levels of Arrb1 and miR-326 trigger and maintain Hh/Gli signaling and self-renewal
