Acidic microenvironment plays a key role in human melanoma progression through a sustained exosome mediated transfer of clinically relevant metastatic molecules

Background: Microenvironment cues involved in melanoma progression are largely unknown. Melanoma is highly influenced in its aggressive phenotype by the changes it determinates in its microenvironment, such as pH decrease, in turn influencing cancer cell invasiveness, progression and tissue remodelling through an abundant secretion of exosomes, dictating cancer strategy to the whole host. A role of exosomes in driving melanoma progression under microenvironmental acidity was never described. Methods: We studied four differently staged human melanoma lines, reflecting melanoma progression, under microenvironmental acidic pHs pressure ranging between pH 6.0-6.7. To estimate exosome secretion as a function of tumor stage and environmental pH, we applied a technique to generate native fluorescent exosomes characterized by vesicles integrity, size, density, markers expression, and quantifiable by direct FACS analysis. Functional roles of exosomes were tested in migration and invasion tests. Then we performed a comparative proteomic analysis of acid versus control exosomes to elucidate a specific signature involved in melanoma progression. Results: We found that metastatic melanoma secretes a higher exosome amount than primary melanoma, and that acidic pH increases exosome secretion when melanoma is in an intermediate stage, i.e. metastatic non-invasive. We were thus able to show that acidic pH influences the intercellular cross-talk mediated by exosomes. In fact when exposed to exosomes produced in an acidic medium, pH naïve melanoma cells acquire migratory and invasive capacities likely due to transfer of metastatic exosomal proteins, favoring cell motility and angiogenesis. A Prognoscan-based meta-analysis study of proteins enriched in acidic exosomes, identified 11 genes (HRAS, GANAB, CFL2, HSP90B1, HSP90AB1, GSN, HSPA1L, NRAS, HSPA5, TIMP3, HYOU1), significantly correlating with poor prognosis, whose high expression was in part confirmed in bioptic samples of lymph node metastases. Conclusions: A crucial step of melanoma progression does occur at melanoma intermediate -stage, when extracellular acidic pH induces an abundant release and intra-tumoral uptake of exosomes. Such exosomes are endowed with pro-invasive molecules of clinical relevance, which may provide a signature of melanoma advancement

Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research

Status of the ARGO-YBJ experiment

The ARGO-YBJ experiment, under construction at the Yangbaijing Laboratory (P.R. China, 4300 m a.s.l.), is a full coverage detector of dimension 7478 m2 made by a single layer of Resistive Plate Counters. About 10% of the final active area ( 700 m2) is in stable operation to check the detector performance and the reconstruction algorithms. In this paper the status of the experiment and the analysis of the first data are presented

Status of the ARGO-YBJ experiment

The ARGO-YBJ esperiment is devoted to the study of may issues in gamma-astronomy and cosmic ray physics. The apparatus design is based on Resistive Plate Chambers operated in streamer mode and assembled in a single layer, fully covering a surface of 78 x 74 square meters (the surface beccomes 110 x 110 square meters taking into account a partially instrumented ring). The mounting of the detector is going on in the YangBaJing Laboratory (Tibet, China) at 4300 m above the sea level. The present status of the experiment, the performances of the detector and some preliminary analysis of data will be presented

Status of the ARGO-YBJ experiment

The ARGO-YBJ experiment, under construction at the Yangbaijing Laboratory (P.R. China, 4300 m a.s.l.), is a full coverage detector of dimension 7478 m2 made by a single layer of Resistive Plate Counters. About 10% of the final active area ( 700 m2) is in stable operation to check the detector performance and the reconstruction algorithms. In this paper the status of the experiment and the analysis of the first data are presented

A new multianodic large area photomultiplier to be used in underwater neutrino detectors

In this article we describe the properties of a new 10-in. hemispherical photomultiplier manufactured by Hamamatsu. The prototype has a segmented photocathode and four independent amplification stages. The photomultiplier is one of the main components of a newly designed direction-sensitive optical module to be employed in large-scale underwater neutrino telescopes. The R&D activity has been co-funded by the INFN and the KM3NeT Consortium. The prototype performance fully meets with the design specifications

Deep seawater inherent optical properties in the Southern Ionian Sea

The NEMO (NEutrino Mediterranean Observatory) Collaboration has been carrying out since 1998 an evaluation programme of deep sea sites suitable for the construction of the future Mediterranean km(3) Cerenkov neutrino telescope. We investigated the seawater optical and oceanographic properties of several deep sea marine areas close to the Italian Coast. Inherent optical properties (light absorption and attenuation coefficients) have been measured as a function of depth using an experimental apparatus equipped with standard oceanographic probes and the commercial transmissometer AC9 manufactured by WETLabs. This paper reports on the visible light absorption and attenuation coefficients measured in deep seawater of a marine region located in the Southern Ionian Sea, 60-100 km SE of Cape, Passero (Sicily). Data show that blue light absorption coefficient is about 0.015 m(-1) (corresponding to an absorption length of 67 m) close to the one of optically pure water and it does not show seasonal variation