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This study examines public estates in Tuscany's Maremma region from the 9th to 11th centuries, identifying material markers of royal properties. It explores the role of public lands, local aristocracies, landscape transformations, production, exchange, and rural economic growth before the 12th century.

There is growing awareness that tumour cells build up a \"self-advantageous\" microenvironment that reduces effectiveness of anti-tumour immune response. While many different immunosuppressive mechanisms are likely to come into play, recent evidence suggests that extracellular adenosine acting at A2A receptors may have a major role in down-modulating the immune response as cancerous tissues contain elevated levels of adenosine and adenosine break-down products. While there is no doubt that all cells possess plasma membrane adenosine transporters that mediate adenosine uptake and may also allow its release, it is now clear that most of extracellularly-generated adenosine originates from the catabolism of extracellular ATP. Measurement of extracellular ATP is generally performed in cell supernatants by HPLC or soluble luciferin-luciferase assay, thus it generally turns out to be laborious and inaccurate. We have engineered a chimeric plasma membrane-targeted luciferase that allows in vivo real-time imaging of extracellular ATP. With this novel probe we have measured the ATP concentration within the tumour microenvironment of several experimentally-induced tumours. Our results show that ATP in the tumour interstitium is in the hundreds micromolar range, while it is basically undetectable in healthy tissues. Here we show that a chimeric plasma membrane-targeted luciferase allows in vivo detection of high extracellular ATP concentration at tumour sites. On the contrary, tumour-free tissues show undetectable extracellular ATP levels. Extracellular ATP may be crucial for the tumour not only as a stimulus for growth but also as a source of an immunosuppressive agent such as adenosine. Our approach offers a new tool for the investigation of the biochemical composition of tumour milieu and for development of novel therapies based on the modulation of extracellular purine-based signalling.

Maria Teresa Landi and colleagues identify a rare missense variant in POT1 shared by five melanoma-prone families from Italy and associated with increased telomere length and telomere fragility. They also identify additional familial melanoma cases with rare missense variants in POT1 and find a significant excess of rare exonic POT1 variants in melanoma cases compared to controls, implicating POT1 variants in melanoma susceptibility. Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Nel primo paragrafo dell’articolo si procede ad una sintetica rassegna delle indagini che hanno riguardato i paesaggi costieri della Toscana altomedievale, necessaria ad inquadrare il caso studio preso in esame. Quest’ultimo è relativo all’analisi multidisciplinare delle evidenze materiali di una corte regia identificata con quella di Valli, citata nel dotario di Ugo di Arles del 937 a favore della futura moglie Berta e di sua figlia Adelaide. Nel secondo, terzo e quarto paragrafo si illustrano in dettaglio i risultati delle ricerche per il caso studio: da quelle svolte nel centro della corte regia, ovvero nel sito dell’attuale Vetricella (Grosseto), ai survey multidisciplinari nel territorio circostante, originariamente interno alla stessa corte. Il paesaggio antropico e le modifiche del paesaggio naturale e forestale sono ricostruite dalle prime fasi di occupazione altomedievale sino all’abbandono, nel corso dell’XI-XII secolo. Nell’ultimo paragrafo i dati esposti sono comparati con quelli desumibili dalle indagini svolte nei territori circostanti, con l’obiettivo di arricchire il quadro delineato nel noto modello toscano elaborato da Riccardo Francovich, tramite il concetto di polarizzazione, a cui si legherebbe la trama dell’articolazione di queste comunità costiere rispetto a luoghi topici e dominanti.

Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2val¹⁹. Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.

Prognosis for pediatric sarcoma (pSC)-affected patients, especially those with relapsed/refractory disease, is dismal. The available treatment options are unsatisfactory, challenging researchers to address this unmet need. The investigational B7-H3 targeted ADC vobramitamab duocarmazine (vobra duo) showed clinical effectiveness towards several B7-H3-positive adult tumors and pre-clinical efficacy in pediatric neuroblastoma models. Cytotoxicity of vobra duo was evaluated in 2D and 3D models toward pSC cell lines expressing B7-H3, showing a dose-dependent cell viability reduction. Proliferation was assessed by time-lapse single-cell segmentation. Compared to controls, vobra duo resulted in a significant increase in the cell doubling time. AKT/mTOR master effectors of cell proliferation were investigated by phospho-specific western blot assays. A down-modulation of phospho-AKT/ -P70 S6K and -4E-BP1 protein expression was detected in both A204 (rhabdomyosarcoma) and U-2-OS (osteosarcoma) cells, the most treatment-sensitive and resistant cell lines, respectively, suggesting their involvement in vobra duo-mediated anti-proliferative effect. In response to treatment, all cell lines underwent apoptotic cell death. A significant increase in the executioner cleaved caspase-3 was detected, and a partial but significant reversion of apoptotic cell death was noted following pre-treatment with the pan-caspase inhibitor, Q-VD-OP-h. Vobra duo also triggered caspase-independent apoptotic events: i) increased AIF nuclear translocation, ii) increased mitochondrial superoxide production, and iii) the depolarization of mitochondrial membrane potential. In vivo, the effectiveness of vobra duo was assayed by single and repeated intravenous administration in the mouse rhabdomyosarcoma model. The single injection of 3 mg/Kg of vobra duo induced a significant tumor growth delay. Repeated vobra duo doses ameliorated this outcome, reverting rhabdomyosarcorma to rhabdomyoma tumor, by increasing Desmin and Myogenin/Myf-4 differentiation markers expression, and reducing both Ki-67 and CD133. In conclusion, the in vitro and in vivo anti-tumor effects towards pSC highlight the need to extend the investigation to patient-derived preclinical models, to pave the way for clinical translation.

In the following we present a new non-invasive methodology aimed at the diagnosis of stone building materials used in historical buildings and architectural elements. This methodology consists of the integrated sequential application of in situ proximal sensing methodologies such as the 3D Terrestrial Laser Scanner for the 3D modelling of investigated objects together with laboratory and in situ non-invasive multi-techniques acoustic data, preceded by an accurate petrographical study of the investigated stone materials by optical and scanning electron microscopy. The increasing necessity to integrate different types of techniques in the safeguard of the Cultural Heritage is the result of the following two interdependent factors: 1) The diagnostic process on the building stone materials of monuments is increasingly focused on difficult targets in critical situations. In these cases, the diagnosis using only one type of non-invasive technique may not be sufficient to investigate the conservation status of the stone materials of the superficial and inner parts of the studied structures 2) Recent technological and scientific developments in the field of non-invasive diagnostic techniques for different types of materials favors and supports the acquisition, processing and interpretation of huge multidisciplinary datasets.

This paper presents a 1:20,000 scale Geoarchaeological map of the Cornia river coastal plain in southern Tuscany. The Geoarchaeological map integrates a comprehensive dataset of geomorphological and archaeological features. The spatial relationships between landforms and archaeological records show that the settlement pattern from the VII century BC to the V century AD was mostly influenced by the presence of several depositional landforms which formed before the period under consideration. Integrating the outputs of geomorphological and topographical analyses with archaeological databases is also helpful for land planning, especially in areas where present-day anthropic exploitation needs predictive and valid tools to assess the archaeological hazard.

Cancer metabolism is characterized by an accelerated glycolytic rate facing reduced activity of oxidative phosphorylation. This “Warburg effect” represents a standard to diagnose and monitor tumor aggressiveness with 18 F-fluorodeoxyglucose whose uptake is currently regarded as an accurate index of total glucose consumption. Studying cancer metabolic response to respiratory chain inhibition by metformin, we repeatedly observed a reduction of tracer uptake facing a marked increase in glucose consumption. This puzzling discordance brought us to discover that 18 F-fluorodeoxyglucose preferentially accumulates within endoplasmic reticulum by exploiting the catalytic function of hexose-6-phosphate-dehydrogenase. Silencing enzyme expression and activity decreased both tracer uptake and glucose consumption, caused severe energy depletion and decreased NADPH content without altering mitochondrial function. These data document the existence of an unknown glucose metabolism triggered by hexose-6-phosphate-dehydrogenase within endoplasmic reticulum of cancer cells. Besides its basic relevance, this finding can improve clinical cancer diagnosis and might represent potential target for therapy.

Today, the integrated study of historic buildings and their associated artifacts through three-dimensional modelling has become essential. Non-destructive diagnostic techniques are crucial for thorough understanding of the state of conservation of artifacts and stone construction materials used in ancient times. Therefore, it is extremely important to create digital copies that preserve the memory of the analysed forms while also allowing an understanding of the deterioration phenomena that affect historic artifacts, thus guiding restoration efforts. In this paper, the authors present the integrated application of non-destructive geomatic techniques such as terrestrial laser scanning (TLS) in synergy with close-range photogrammetry (CRP) methods, and their integration with non-destructive geophysical diagnostic methods such as ultrasonic indirect tests, ultrasonic transmission tomography, and electrical resistivity. These methods have been further enhanced by complementary petrographic analyses of the investigated building stone materials. The integrated and coordinated application of these non-destructive techniques allowed the creation of high-precision models of both the surface and interior of several artifacts from the Basilica of San Saturnino, the oldest church in Cagliari (Italy), dedicated to the city’s patron saint. Finally, this integrated study highlighted areas of deterioration of these artifacts due to atmospheric elements such as wind and rain, and anthropogenic phenomena such as atmospheric particulate matter from traffic and other manufacturing activities.