The emerging role of cancer nanotechnology in the panorama of sarcoma

In the field of nanomedicine a multitude of nanovectors have been developed for cancer application. In this regard, a less exploited target is represented by connective tissue. Sarcoma lesions encompass a wide range of rare entities of mesenchymal origin affecting connective tissues. The extraordinary diversity and rarity of these mesenchymal tumors is reflected in their classification, grading and management which are still challenging. Although they include more than 70 histologic subtypes, the first line-treatment for advanced and metastatic sarcoma has remained unchanged in the last fifty years, excluding specific histotypes in which targeted therapy has emerged. The role of chemotherapy has not been completely elucidated and the outcomes are still very limited. At the beginning of the century, nano-sized particles clinically approved for other solid lesions were tested in these neoplasms but the results were anecdotal and the clinical benefit was not substantial. Recently, a new nanosystem formulation NBTXR3 for the treatment of sarcoma has landed in a phase 2-3 trial. The preliminary results are encouraging and could open new avenues for research in nanotechnology. This review provides an update on the recent advancements in the field of nanomedicine for sarcoma. In this regard, preclinical evidence especially focusing on the development of smart materials and drug delivery systems will be summarized. Moreover, the sarcoma patient management exploiting nanotechnology products will be summed up. Finally, an overlook on future perspectives will be provided

Vivere lo Spazio Urbano: Progetto di riqualificazione per il quartiere di Vallemiano

A cavallo dei due versanti collinari del promontorio di Ancona si presenta un punto di snodo di grande rilevanza: il quartiere di Vallemiano. La sua particolare posizione geografica, lungo il tratto mediano della valle del torrente Miano, posta lontano dal nucleo storico ma non ancora definibile come zona periferica, rende il quartiere Vallemiano un punto di raccordo tra lo sviluppo urbano delle due parti della città (Prima Ancona e Seconda Ancona). Il forte paesaggio infrastrutturale, caratterizzato da passaggi sottoelevati, sopraelevati, linea ferroviaria e arteria principale di distribuzione, definisce il confine preciso dell’area e lo portano, contemporaneamente, ad essere delimitato e chiuso in sé stesso. Da qui l’area si predispone ad essere vista e vissuta come semplice luogo di passaggio e quindi ad essere poco valorizzato. Per questa ragione il quartiere è da sempre stato oggetto di progetti di riqualificazione per la definizione di una propria immagine e per il rilancio della convivialità. La fondazione di questo rione risale ai primi decenni del ‘900 a seguito dell’edificazione del sito del mattatoio, considerato uno dei primi esempi di architettura industriale in Italia e ad oggi classificato come bene appartenente all’archeologia industriale ma sin dalla sua edificazione fino ai giorni nostri questo rione è sempre stato privo di una sua identità Un luogo, quello di Vallemiano, che nasce ed è definibile ancora oggi come quartiere popolare e che è da sempre privo di un centro di aggregazione sociale. L’obietto del progetto è quello di: - ricostruire il tessuto sociale e l’anima del quartiere, attraverso una rigenerazione urbana che restituisca il dialogo e l’integrazione di cui il sito necessita. - Favorire l’integrazione tra il vecchio e il nuovo, mantenendo viva la sua storia e riappropriandolo del lato naturale che gli interventi di speculazione edilizia avvenuti in seguito al boom economico hanno deturpato

Use of an Outdoor Swimming Pool as Seasonal Heat Source in Heat Pump Applications

The improvement of energy efficiency in the building sector is one of the most promising actions for achieving the energy and environmental goals of the European Community. The deep retrofit of buildings is obviously the best solution in terms of energy performance result. When the deep retrofit is not allowed or possible, the simple maintenance of the building envelope and plant is usually done to assure the operation over time. This type of intervention could require the installation of new HVAC systems that could include a HP, which nowadays represents one of the key devices for the energy saving and the sustainable development. This work regards the study of the energy performance of a swimming Pool Centre in North-East Italy. The objective of this work is the exploitation of an outdoor swimming pool as a heat source for a HP system. The HP system uses two different heat sources, the air and the water. The final SCOP of the double source HP system has been calculated and compared with an air source HP solution. This analysis has been carried out by means of dynamic energy simulations in TRNSYS environment

Hippo and rassf1a Pathways: A Growing Affair

First discovered in Drosophila, the Hippo pathway regulates the size and shape of organ development. Its discovery and study have helped to address longstanding questions in developmental biology. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the Yki protein (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation, survival, and apoptosis. A dysfunction of the Hippo pathway activity is frequently detected in human cancers. Recent studies have highlighted that the Hippo pathway may play an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation, and tissue regeneration. Recently, the impact of RASSF proteins on Hippo signaling potentiating its proapoptotic activity has been addressed, thus, providing further evidence for Hippo's key role in mammalian tumorigenesis as well as other important diseases

Which model of stroke unit is better for stroke patient management?

The increasing prevalence of cerebrovascular diseases has made urgent the need to develop timely and effective treatment strategies to tackle this health problem. Stroke units (SUs) appear to be the ideal setting where the management of acute stroke patients, including specific treatments as thrombolysis, may be optimized. Which model of SU gives the best results is still an unsettled issue. The more intensive and timely multidisciplinary approach to the acute phase of stroke, the management of medical complications. and the earlier and more focused rehabilitation. are likely the most qualifying aspects of our Neurovascular treatment unit

A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences

Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular, the tumor stromal cells of these lesions are responsible for the recruiting of multinucleated giant cells which ultimately lead to bone disruption. In this regard, the underlying pathological mechanism of osteoclastogenesis processes in GCTB and DF is still poorly understood. Although current therapeutic strategy involves surgery, radiotherapy and chemotherapy, the benefit of the latter is still debated. Thus, in order to shed light on these poorly investigated diseases, we focused on the molecular biology of GCTB and DF. The expression of bone-vicious-cycle- and neoangiogenesis-related genes was investigated. Moreover, combining patient-derived primary cultures with 2D and 3D culture platforms, we investigated the role of denosumab and levantinib in these diseases. The results showed the upregulation of RANK-L, RANK, OPN, CXCR4, RUNX2 and FLT1 and the downregulation of OPG and CXCL12 genes, underlining their involvement and promising role in these neoplasms. Furthermore, in vitro analyses provided evidence for suggesting the combination of denosumab and lenvatinib as a promising therapeutic strategy in GCTB and DF compared to monoregimen chemotherapy. Furthermore, in vivo zebrafish analyses corroborated the obtained data. Finally, the clinical observation of retrospectively enrolled patients confirmed the usefulness of the reported results. In conclusion, here we report for the first time a molecular and pharmacological investigation of GCTB and DF combining the use of translational and clinical data. Taken together, these results represent a starting point for further analyses aimed at improving GCTB and DF management

Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple frequent local recurrences (50–60% of cases). On the other hand, UPS is an aggressive sarcoma prone to distant recurrence, which is correlated to a poor prognosis. Differential diagnosis is challenging due to their heterogeneous morphology, with UPS remaining a diagnosis of exclusion for sarcomas with unknown differentiation lineage. Moreover, both lesions suffer from the unavailability of diagnostic and prognostic biomarkers. In this context, a genomic approach combined with pharmacological profiling could allow the identification of new predictive biomarkers that may be exploited for differential diagnosis, prognosis and targeted therapy, with the aim to improve the management of STS patients. RNA-Seq analysis identified the up-regulation of MMP13 and WNT7B in UPS and the up-regulation of AKR1C2, AKR1C3, BMP7, and SGCG in MFS, which were confirmed by in silico analyses. Moreover, we identified the down-regulation of immunoglobulin genes in patient-derived primary cultures that responded to anthracycline treatment compared to non-responder cultures. Globally, the obtained data corroborated the clinical observation of UPS as an histotype refractory to chemotherapy and the key role of the immune system in determining chemosensitivity of these lesions. Moreover, our results confirmed the validity of genomic approaches for the identification of predictive biomarkers in poorly characterized neoplasms as well as the robustness of our patient-derived primary culture models in recapitulating the chemosensitivity features of STS. Taken as a whole, this body of evidence may pave the way toward an improvement of the prognosis of these rare diseases through a treatment modulation driven by a biomarker-based patient stratification

Systemic Inflammatory Indices in Second-Line Soft Tissue Sarcoma Patients: Focus on Lymphocyte/Monocyte Ratio and Trabectedin

A second-line standard of treatment has not yet been identified in patients with soft tissue sarcomas (STS), so identifying predictive markers could be a valuable tool. Recent studies have shown that the intratumoral and inflammatory systems significantly influence tumor aggressiveness. We aimed to investigate prognostic values of pre-therapy neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory index (SII), progression-free survival (PFS), and overall survival (OS) of STS patients receiving second-line treatment. In this single-center retrospective analysis, ninety-nine patients with STS were enrolled. All patients received second-line treatment after progressing to anthracycline. PFS and OS curves were calculated using the Kaplan–Meier method of RNA sequencing, and CIBERSORT analysis was performed on six surgical specimens of liposarcoma patients. A high NLR, PLR, and SII were significantly associated with worse PFS (p = 0.019; p = 0.004; p = 0.006). Low LMR was significantly associated with worse OS (p = 0.006). Patients treated with Trabectedin showed a better PFS when the LMR was low, while patients treated with other regimens showed a worse PFS when the LMR was low (p = 0.0154). The intratumoral immune infiltrates analysis seems to show a correlation between intratumoral macrophages and LMR. PS ECOG. The metastatic onset and tumor burden showed prognostic significance for PFS (p = 0.004; p = 0.041; p = 0.0086). According to the histologies, PFS was: 5.7 mo in liposarcoma patients vs. 3.8 mo in leiomyosarcoma patients vs. 3.1 months in patients with other histologies (p = 0.053). Our results confirm the prognostic role of systemic inflammatory markers in patients with STS. Moreover, we demonstrated that LMR is a specific predictor of Trabectedin efficacy and could be useful in daily clinical practice. We also highlighted a possible correlation between LMR levels and the percentage of intratumoral macrophages