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User behaviour can significantly affect indoor thermal comfort conditions, as well as energy consumption, especially in existing buildings with high thermal masses where natural cross ventilation is the main strategy to reduce cooling loads. The aims of this paper were: (i) to compare how behavioural changes evaluated by means of rule-based and stochastic models lead to changes in indoor thermal comfort levels, and (ii) to define the patterns of indoor thermal comfort in historic residential buildings in future scenarios. To this end, a historic building located in Molfetta (Southern Italy) was analysed using a dynamic energy simulation engine in five weather scenarios (Typical Meteorological Year, current extreme weather file 2018, predicted weather files for 2020, 2050, and 2080 generated by morphing method), and stochastic and rule-based models for window openings were adopted and compared. The results showed that the stochastic model was more accurate than the rule-based one, resulting in a reduction of discomfort conditions during the summer period between 30% and 50% in all climate scenarios. However, although the differences between predicted discomfort levels using rule-based and stochastic models tended to increase, discomfort levels still appeared to be not acceptable in the 2050 and 2080 scenarios due to the rising temperature driven by climate change.

Objective: We previously reported that the olfactory receptor OR51E2, overexpressed in LNCaP prostate cancer cells, promotes cell invasiveness upon stimulation of its agonist β-ionone, and this phenomenon increases metastatic spread. Furthermore, we showed that the induced cell invasiveness involves a PI3 kinase dependent signalling pathway. We report here the results of a new investigation to address whether gallein, a small inhibitor of G protein βγ subunit interaction with PI3 kinase, can inhibit β-ionone effects both in vitro and in vivo., Results: We demonstrate that gallein can inhibit the β-ionone-induced cell invasiveness in vitro, as well as the spread of metastases in vivo. LNCaP cell invasiveness, assessed using spheroid cultures in collagen gels in vitro, was increased by β-ionone and the effect was reversed by co-administration of gallein. LNCaP tumour cells, subcutaneously inoculated to immunodeficient mice, generated more metastases in vivo when β-ionone was applied through the skin. Furthermore, the intraperitoneal injection of gallein inhibited this increased metastasis spread. Our results thus support the role of OR51E2 in the β-ionone observed effects, and suggest that gallein could be a potential new agent in personalized medicine of the tumours expressing OR51E2.

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3β activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients., Competing Interests: The authors have declared that no conflict of interest exists.

Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET). AdVince includes the gene promoter from human chromogranin A for selective replication in neuroendocrine cells, miR122 target sequences for reduced liver toxicity, and a cell-penetrating peptide in the capsid for increased infectivity of tumor cells and optimized spread within tumors. This paper describes the preclinical evaluation of AdVince on freshly isolated human gastrointestinal NET cells resected from liver metastases and freshly isolated human hepatocytes as well as in fresh human blood. AdVince selectively replicates in and kills NET cells. Approximately 73-fold higher concentration of AdVince is needed to induce a similar level of cytotoxicity in NET cells as in hepatocytes. AdVince did not activate complement or induce considerable amount of proinflammatory cytokines or chemokines in human blood. The data presented herein indicate that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET., (© 2016 S. Karger AG, Basel.)

This study aims at investigating miR-196a roles using in vitro models. miR-196a was detected in small intestinal neuroendocrine tumors (SI-NETs) and lung NETs. miR-196a target prediction analysis suggested HOXA9, HOXB7, LRP4 and RSPO2 genes for further investigation. The level of these four genes is detectable in SI-NET tissue specimens at different disease stages and serum samples of untreated and somatostatin analogs treated patients with liver metastases. A miR-196a inhibitor was used to silence its effects in NET cells. We show that the four target genes were significantly upregulated at transcriptional level in silenced NET cells. HOXA9, HOXB7, LRP4 and RSPO2 encoded proteins are also upregulated at translational level in miR-196a silenced NET cells. miR-196a downstream genes BMP4, ETS1, CTNNB1, FZD5, LRP5 and LRP6 were significantly upregulated at transcriptional level in miR-196a silenced CNDT2.5 and NCI-H727 cells. In addition, miR-196a clearly does not play a role in NET cell growth control., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We previously detected and investigated nine altered microRNAs in small intestinal neuroendocrine tumor (SI-NET) tissues at different stages of disease. The aims of this study are to: 1) analyze whether SI-NET tissue microRNAs can be also detected in patient serum samples, 2) investigate a potential somatostatin analogs (SSAs) role on microRNA levels regulation in SSA-treated patient samples and 3) elucidate whether the serum microRNA levels in samples collected in different hospitals are predictable and steady. Our results show that tissue microRNAs are detectable in patient serum samples, and miR-96, -182, -183, -196a and -200a levels are lower in SI-NET untreated patients than in SSA-treated patients at all different stages. Conversely, miR-31, -129-5p, -133a and -215 levels do not show any difference in untreated SI-NET patients and SSA-treated patients at all different stages. Our findings also show that miR-200a exhibits an atypical behavior with high levels in both untreated and SSA-treated patients at liver metastasis stage, and unequivocally never at the earlier stages. Serum samples collected in two hospitals keep alike microRNA level pattern, elucidating that the results are not dependent on samples handling. In conclusion, SI-NET tissue microRNAs are always detectable in untreated and SSA-treated patient serum samples, SSAs play an unknown role in eliciting SSA-treated patients' microRNA levels higher than in untreated patients, and this study enlightens that miR-200a might be involved in the liver metastasis during SI-NET progression.

Neuroendocrine tumors (NETs) consist of heterogeneous neoplasms. The neuroendocrine cells of the human body are confined to certain organs, such as the thyroid, pancreas and adrenals, or they are dispersed throughout the body in the respiratory tract and in the intestinal mucosa. The cells belong to the diffuse endocrine cell system, share a neuroendocrine phenotype, and accumulate precursor molecules which are then processed into hormones, peptides or amines. The tightly controlled release on stimulation is either to the blood stream or adjacent cells or neurons. Neuroendocrine cells regulate various processes in the human body, such as gastrointestinal secretion, blood pressure and response to stress. NETs present a wide spectrum of malignant diseases from rather benign to very malignant and lethal variants. NETs may occur in any organ, but are mainly detected in the gastroenteropancreatic system and in the lungs. The understanding of NET biology and treatments has changed dramatically during the last decade. Today, the main problems that clinicians and translational scientists face in overcoming these malignancies relate to various aspects within the molecular pathogenesis of NETs. This chapter focuses on the importance of novel biomarkers: microRNA and microRNA inhibitors; DNA methylation and epigenetics, and immunotherapy and virotherapy to develop novel treatments for NETs., (© 2015 S. Karger AG, Basel.)