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Personal care products (PCPs) are increasingly studied worldwide to understand better their ecotoxicological effects on different aquatic species. However, studies assessing their ecotoxicological effects on tropical marine aquatic organisms are still scarce. To address this information gap, this study aimed to evaluate the acute and chronic toxicity of three PCPs, methylparaben (MP), propylparaben (PP) and butylhydroxytoluene (BHT), on the tropical sea urchin Echinometra lucunter. The procedures were based on the protocols established by the US Environmental Protection Agency and the Brazilian national standard (ABNT NBR 15350). Predictive computational tools (Opera Qsar and Vega Qsar) were used to evaluate the persistence/biodegradability, bioaccumulation and mobility of PCPs. Acute exposure results showed the following ranking of toxicity: BHT (IC50= 38.14 mg/l) > PP (IC50= 73.20 mg/l) > MP (IC50= 74.47 mg/l). Chronic toxicity tests indicated that BHT presented the lowest IC50(6.85 mg/l), followed by PP (IC50= 15.57 mg/l) and MP (IC50= 20.09 mg/l). Additionally, in silico predictions support the findings related to the potential risks of these PCPs in aquatic ecosystems. The data obtained in this study can support future analyses of environmental risk concerning PCPs and support the establishment of concentration limits in relevant legislation.

Abstract: Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. Study registration: This protocol was registered in clinicaltriasl.gov (NCT04282083).

Purpose: The aim of this study is to describe the clinical management of an Italian series of patients with advanced gastro-entero-pancreatic (GEP) MiNENs treated in clinical practice. Methods: Clinical records of patients from four Italian referral Centers were retrospectively analyzed to correlate clinical/biological data with clinical outcomes. All the surgical specimens were centrally reviewed. Results: Clinical data and surgical samples of 51 patients during 1995–2015 were analyzed. Sites of origin were: 32 colorectal, 14 gastro-esophageal, and 5 pancreatobiliary. Twenty-one out of fifty-one (42.2%) developed metachronous distant metastases. Only 5/51 (9.8%) patients received peri-operative therapy, and 23/51 (45.1%) first-line chemotherapy, mostly fluoropyrimidines/oxaliplatin. The NEN component was poorly differentiated in the whole population. Patients with Ki67 index < 55% in the NEC component had a significantly longer median overall survival (OS) (35.3 months; 95% CI 27.1–41.0) than those with Ki67 ≥ 55% (11.9 months; 95% CI 9.1–14.0) P= 0.0005. The median OS was 14 months (95% CI 10.1–19.1) in the whole cohort, with 11.4 months (95% CI 6.2–20.2) in patients who received a first-line therapy. Conclusion: This study confirms that GEP-MiNENs represent a complex disease and that over the past years the clinical management has been predominantly guided by the subjective judgment of the clinicians. Although, in this series, the NEC component appeared mostly responsible for the systemic spread and prognosis on the whole neoplasm, the lack of strong prognostic and predictive factors universally recognized seems to condition their management so far. Future prospective clinical and biomolecular studies could help clinicians to improve clinical management of GEP-MiNENs.

Background The optimal management of patients with acute ischemic stroke (AIS) due to tandem occlusion (TO) and underlying carotid dissection (CD) remains unclear.Objective We present our multicenter-experience of endovascular treatment (EVT) approach used and outcomes for AIS patients with CD-related TO (CD-TO).Methods Consecutive AIS patients underwent EVT for CD-TO at five Italian Neuro-interventional Tertiary Stroke Centers were retrospectively identified. TO from atherosclerosis and other causes of, were excluded from the final analysis. Primary outcome was successful (mTICI 2b-3) and complete reperfusion (mTICI 3); secondary outcome was patients’ 3-months functional independence (mRS≤2).Results Among 214 AIS patients with TO, 45 presented CD-TO. Median age was 54 years (range 29–86), 82.2% were male. Age <65 years (p< 0.0001), lower baseline NIHSS score (p= 0.0002), and complete circle of Willis (p= 0.0422) were associated with mRS ≤ 2 at the multivariate analysis. Comparisons between antegrade and retrograde approaches resulted in differences for baseline NIHSS scores (p= 0.001) and number of EVT attempts per-procedure (p= 0.001). No differences in terms of recanalization rates were observed between antegrade and retrograde EVT approaches (p= 0.811) but higher rates of mTICI3 revascularization was observed with the retrograde compared to the antegrade approach (78.6% vs 73.3%), anyway not statistically significant. CD management technique (angioplasty vs aspiration vs emergent stenting) did not correlate with 3-months mRS≤2.Conclusion AIS patients with CD-TO were mostly treated with the retrograde approach with lower number of attempts per-procedure but it offered similar recanalization rates compared with the antegrade approach. Emergent carotid artery stenting (CAS) proved to be safe for CD management but it does not influence 3-months patients’ clinical outcomes.

Background: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. Purpose: To evaluate gender differences in clinical presentation and outcome of CaS. Methods: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. Results: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p= 0.002, and 3.7%, p= 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p= 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p= 0.044; 6.7% vs 31.5%, p= 0.001; 50.9% vs. 26.7%, p= 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p= 0.04), but no differences in terms of PFS (p= 0.51) and OS (p= 0.64) were found between gender. Conclusions: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

Pheochromocytomas and paragangliomas (PPGLs) can metastasize in approximately 15–20% of cases. This review discusses the available evidence on the biology and treatment of metastatic PPGLs. Chemotherapy is the first-line treatment option for this evolving and symptomatic disease. In patients with high MIBG uptake and positive PETGa-68, radiometabolic treatment may be considered. The efficacy of sunitinib has been shown in observational studies, and pembrolizumab has been evaluated in phase II clinical studies, while other agents investigated in this setting are anti-angiogenic drugs cabozantinib, dovitinib, axitinib and lenvatinib. As these agents' efficacy and safety data, alone or in combination, are scant and based on few treated patients, enrollment in clinical trials is mandatory. Future therapeutic options may be represented by DNA repair system inhibitors (such as olaparib), HIF2 inhibitors and immunotherapy.

Introduction: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2.Methods: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable.Results: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p= 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p= 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months (p= 0.03).Conclusions: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.

ABSTRACTIntroductionDespite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients.Areas coveredIn this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: ‘pancreatic ductal adenocarcinoma,’ ‘immunotherapy,’ ‘immunotherapy resistance,’ ‘immune escape,’ ‘biomarkers.’ Papers published between 2000 and 2021 were selected.Expert opinionThe tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.

In recent decades, the concept of the gut microbiota as a potential novel therapeutic strategy for mental health has emerged. The tiny microbes inhabiting our gut communicate through a bidirectional communication signaling with the brain that influences gut physiology, brain function and behavior. Accumulating evidence suggests that perturbation of the gut microbiota contributes to the pathophysiology of mental illnesses including autism, depression and anxiety as well as neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. This review will highlight recent findings in both human and animal studies indicating how changes in the gut microbiota can impact the pathophysiology of such diseases. The current work will also provide an understanding of the efficacy of microbiota-targeted therapies on psychiatric disorders.

Microplastics (MPs) are ubiquitous contaminants of the marine environment, and the deep seafloor is their ultimate sink compartment. Manipulative and field experiments provided evidence of the ingestion of MPs by deep-sea fauna, but knowledge of MPs’ fate once ingested still remains scant. We provide evidence of MP partial retention and fragmentation mediated by digestion activity of a Norwegian langoustine, a good bioindicator for MP contamination of the deep sea. We report here that MPs in the intestines were more abundant and significantly smaller (up to 1 order of magnitude in surface) than those in the stomachs. Our results show that the stomach can act as a size-bottleneck for ingested MPs, enhancing the retention of larger particles within the stomach and promoting fragmentation into smaller plastic debris, which is then released in the intestine. Our results provide evidence that the langoustine is responsible for the fragmentation of MPs already accumulated in sediments through its scavenging activity and digestion. These findings highlight the existence of a new peculiar kind of “secondary” MPs, introduced in the environment by biological activities, which could represent a significant pathway of plastic degradation in a secluded and stable environment such as the deep sea.

IMPORTANCE: The addition of oxaliplatin to the standard 6-month fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been reported to reduce the risk of relapse although it does not increase survival. The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with stage III colon cancer. The utility remains unknown. OBJECTIVE: To assess the noninferiority and toxic effects of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjunct chemotherapy among patients with high-risk stage II resected colorectal cancer enrolled in the TOSCA trial. DESIGN, SETTING, AND PARTICIPANTS: The TOSCA study was a noninferiority phase 3 randomized clinical trial conducted from June 2007 to March 2013 in 130 Italian centers. Included patients had resected colorectal cancer located 12 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. In this preplanned study assessing the per-protocol population, 5-year relapse-free survival was evaluated in 1254 patients with high-risk stage II resected colorectal cancer who had received adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). INTERVENTIONS: Patients were originally randomized (1:1) in the TOSCA trial to receive 3 months (experimental group) or 6 months (control) of standard doses of FOLFOX or CAPOX at the discretion of the treating physician. MAIN OUTCOME AND MEASURES: A hazard ratio of at least 1.2 between the 3-month and 6-month chemotherapy groups was set to reject the null hypothesis of noninferiority. RESULTS: Overall, 1254 patients (mean [SD] age, 62.4 [9.8] years; 565 women [45.1%]) with clinical high-risk stage II resected colorectal cancer were analyzed at a median follow-up of 62 months (interquartile range, 53-71) months. Of them, 301 patients (24.0%) had pT4N0M0 tumors, and the remaining 953 patients (76.0%) had high-risk pT3N0M0 tumors; 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm, with an estimated hazard ratio of 1.41 (95% CI, 1.05-1.89; P = .86 for noninferiority). For CAPOX, the 5-year relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 6-month arm; 95% CI, −6.28% to 7.80%), whereas for FOLFOX, the difference was pronounced: 8.56% in favor of the longer-duration arm (95% CI, 3.45%-13.67%). Nevertheless, the test for an interaction between duration and regimen was not statistically significant. Neurotoxicity was approximately 5 times lower in the shorter duration arm than in the longer duration arm. CONCLUSIONS AND RELEVANCE: In the 3-month arm, the treatment was significantly less toxic than in the 6-month arm. Noninferiority was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0064660

Seagrass meadows are an important organic matter (OM) reservoir but, are currently being lost due to global and regional stressors. Yet, there is limited research investigating the cumulative impacts of anthropogenic stressors on the structure and functioning of seagrass benthic assemblages, key drivers of OM mineralization and burial. Here, using a 16‐month field experiment, we assessed how meiobenthic assemblages and extracellular enzymatic activities (as a proxy of OM degradation) in Posidonia oceanicasediments responded to ocean acidification (OA) and nutrient loadings, at CO2vents. P. oceanicameadows were exposed to three nutrient levels (control, moderate, and high) at both ambient and low pH sites. OA altered meiobenthic assemblage structure, resulting in increased abundance of annelids and crustaceans, along with a decline in foraminifera. In addition, low pH enhanced OM degradation rates in seagrass sediments by enhancing extracellular enzymatic activities, potentially decreasing the sediment carbon storage capacity of seagrasses. Nutrient enrichment had no effect on the response variables analyzed, suggesting that, under nutrient concentration unlikely to cause N or P imitation, a moderate increase of dissolved nutrients in the water column had limited influence on meiobenthic assemblages. These findings show that OA can significantly alter meiobenthic assemblage structure and enhance OM degradation rates in seagrass sediments. As meiofauna are ubiquitous key actors in the functioning of benthic ecosystems, we postulated that OA, altering the structure of meiobenthic assemblages and OM degradation, could affect organic carbon sequestration over large spatial scales.

Infestations of the ectoparasitic mite Varroa destructorcause significant honey bee colony weakening, due to both host-feeding and virus transmission effects. In addition to the natural (i.e., behavioral) and innate (i.e., cellular and humoral response) mechanisms of defense against pathogens and parasites, contribution to maintain good colony health may derive from the resident microbial community. The present study investigated variation in immune-related gene expression levels and in the relative abundance of representative bacterial taxa of the core honey bee microbiota in colonies infested by Varroamites in comparison with honey bees from non-infested colonies. Significant changes in the target bacterial taxa (Gammaproteobacteria, Betaproteobacteria, Lactobacillusspp., Bifidobacteriumspp., Brevibacillus laterosporus) were detected in immune-suppressed adults emerging from Varroa-infested colonies. Insect stages randomly sampled from infested and non-infested hives were characterized by high variability. Emerging adults bearing sucking Varroamites on their body showed a considerably higher deformed wing virus titer and a greater immune gene downregulation compared with adults without mites. Further, the abundance of the overall bacterial community and of specific bacterial taxa increased significantly in parasitized adults. A possible compensation mechanism involving the core bacterial community in Varroa-infested hives is discussed.

Gastroenteropancreatic neuroendocrine tumors (NETs) are a relatively rare group of heterogeneous neoplasms. The most significant advance in therapy of NETs has been the advent of the somatostatin analog octreotide, which represents a cornerstone in their management and dramatically changed the therapeutic landscape. Octreotide long-acting release (LAR) was developed to overcome some of the limitations of octreotide. Several clinical studies, including PROMID and RADIANT-2, have validated the clinical benefits of octreotide LAR in NETs, with tumor shrinkage in about 10% of patients and tumor stabilization in roughly half of cases. While the use of octreotide LAR is well-consolidated in NETs, some open questions remain. These include the use of high-dose octreotide LAR, as there is evidence that higher dose may provide longer disease control, and nonstandard treatment schedules, with administration every 21 days instead of 28 days, as well as their use in combination with targeted agents or peptide receptor radiotherapy in clinical practice. After 3 decades of clinical experience with octreotide LAR, the drug has a well-established safety profile. It is well-tolerated and treatment discontinuations due to adverse events are uncommon. One exception is cholelithiasis, which may increase with longer duration of treatment. According to the literature data, octreotide LAR is currently recommended in both functioning and nonfunctioning advanced NETs. This review summarizes the available clinical data with octreotide LAR and also provides future perspectives on its possible uses in patients with NETs.

The Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP or TPP11) is a trade agreement between Australia, Brunei Darussalam, Canada, Chile, Japan, Malaysia, Mexico, New Zealand, Peru, Singapore and Vietnam. CPTPP negotiations started after the Trans-Pacific Partnership Agreement reached a stalemate due to the withdrawal of the United States on 23 January 2017. This paper’s aim is to provide an appraisal of some sensitive provisions of the CPTPP, and their impact on access to affordable medicines. As access to medicines is mainly related to the protection of intellectual property rights and in particular patents, a first part of the paper will focus on the international regulatory framework for patents, considering the main international conventions, the TRIPS Agreement and its relation with preferential trade agreements. The narration will then focus on the provision of the CPTPP relating to patents and pharmaceuticals, and those relating to investment. The discussion will revolve around whether said provisions significantly depart from the framework set by TRIPS, for instance, including TRIPS-plus provisions, notably criticised for their adverse repercussions on the fundamental right to health. As regards the provisions in the investment chapter, the analysis will focus on whether the wording of said chapter is equipped to strike a balance between protection of foreign investors and health regulation. A conclusion will follow, summarising the main findings of the paper.

Temozolomide (TEM) based therapy has been reported being effective in the treatment of metastatic neuroendocrine neoplasms (NEN), with response rates ranging from 30 to 70%. Among patients affected by advanced glioblastoma or melanoma and treated with TEM, loss of tumoral O6-methylguanine DNA methyltransferase (MGMT) is correlated with improved survival. In NEN patients, the role of MGMT deficiency in predicting clinical outcomes of TEM treatment is still under debate. In this study we evaluated 95 patients with advanced NENs undergoing treatment with TEM-based therapy. MGMTpromoter methylation status was evaluated with two techniques: methylation specific-polymerase chain reaction or pyrosequencing. Treatment with TEM-based therapy was associated with an overall response rate of 27.4% according to RECIST criteria (51.8% of patients with and 17.7% without MGMTpromoter methylation). Response to therapy, progression free survival and overall survival was correlated to MGMT status at univariate and multivariate analysis. Methylation of MGMTpromoter could be a strong predictive factor of objective response and an important prognostic factor of a longer PFS and OS. According to our results, MGMTmethylation status, evaluated with methylation specific-polymerase chain reaction or pyrosequencing, should have an important role in patients with metastatic NENs, in order to guide therapeutic options. These results need further confirmation with prospective studies.

The objective response is an important endpoint to evaluate clinical activity of new anticancer drugs. Standardized criteria for evaluating response are needed for comparing results of different trials and represent the basis for advances in cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 are the most used in clinical practice and in clinical trials; however, they are not able to capture atypical responses seen with immunotherapy drugs. We describe the evolution of response criteria with a special focus on the immune-related criteria.

Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases. We collected ileal well-differentiated neuroendocrine tumors specimens from consecutive patients with prior primary resection and distant synchronous or metachronous liver metastases. We obtained 195 specimens from primary tumors (n= 106) and metastases (n= 89). The expression (E) of SDHB and the immunostaining intensity (I) were evaluated semiquantitatively and combined into a single score. SDHB score was evaluated in primitive tumor and metastatic specimens. SDHB was found in all tumor cells. Mean SDHB expression was 72.7 % ± 17.1 % in primitive specimens and 27.9 % ± 24.6 % in metastatic specimens (p< 0.0001). SDH intensity was higher in primitive specimens (p< 0.0001). SDHB score was 9–12 in 96 specimens of the primitive group and 2 metastatic specimens (p< 0.0001). None of the analyzed parameters was predictive of overall survival in the primitive subset. In the metastatic subset, loss of SDHB expression, intensity, and score were prognostic factors for survival. Lower expression and intensity of SDHB in metastatic lesions were associated with longer overall survival. When combining SDHB score and Ki-67 % in the metastatic subset, a lower SDHB score was associated with prolonged overall survival, independently from Ki-67 %. SDHB score was different in primitive and metastatic specimens. The combination of SDHB score and Ki-67 % was a stronger predictor of overall survival than Ki-67 % alone. This stratification might help predict survival.

Purpose: This paper aims to report on a study to investigate the feasibility of thermal reflective multi-layer system (TRMS) as support for disaster resilience. Design/methodology/approach: It is an innovative insulation system, developed from space engineering studies, is lightweight and is characterised by a thermal conductivity of 0.038 W/mK, making it a strong candidate for inexpensive shelter after disaster design. Findings: One of the results of this study is a proposal for the air shelter house, a new concept design of a shelter based on TRMS. Originality/value: The combined use of TRMS with the low cost of building materials and a 3D printer system for the construction joints provides a good compromise between building cost and energy efficiency performance. Such an innovative design supports disaster resilience during response, reconstruction and mitigation phases, and it is suitable for a wide variety of cultural and environmental situations where energy efficiency is important.

Introduction:Although epidermal growth factor receptor (EGFR) inhibitors have progressively become a relevant therapeutic arm in the treatment of patients with advanced colorectal cancer, the responses achieved are not durable and resistance invariably occurs. The advances in sequencing technology have allowed not only a more profound molecular tumor characterization but also the identification of the different molecular pathways involved in drug resistance and disease progression. These biological improvements have encouraged researchers to design clinical studies testing novel target therapies.Areas covered:After discussing the results of key Phase III randomized trials and providing commentary on the most promising novel agents (Sym004, MM-151, GA201 and MEHD7945A), the authors present the future steps ahead toward a real tailored treatment.Expert opinion:EGFR inhibitors are highly effective in the advanced disease setting. Although the negative predictive role of RAS and possibly BRAF mutations has already been established, more comprehensive efforts are needed to optimize the use of these drugs. At the same time, understanding the underlying biology will help basic scientists to develop new compounds able to overcome both primary and acquired resistance and help clinical researchers to test novel drugs within adequately designed trials whose results eventually are expected to reshape the overall treatment strategy.

Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1–2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017.

Recently we observed a renewed interest in home hemodialysis for the treatment of chronic renal disease thanks to the latest technological innovations, which allow to undergo this treatment more easily than in the past. The revival of this method raises an interesting debate in the scientific community; this debate has shown some critical positions in Italy through the NephroMeet platform. In this paper we highlight the main clinical evidences and the psychological and social effects of home hemodialysis, through a revision of the most recent literature and the conversational analysis of a successful case. Our perspective starts from the concept of health as defined by the WHO. We show how home extracorporeal hemodialysis presents important advantages, both clinical and psychosocial, and why it should be considered as a valid alternative after transplantation and peritoneal dialysis.

The incidence of neuroendocrine tumors is rising, and this rise is explained by more than just better diagnostic procedures. About 85% of these neoplasms arise in gastrointestinal or pulmonary sites, but cases where the location is more unusual also occur in clinical practice. The tailgut cyst is a rare entity well described in the medical literature, but a neuroendocrine tumor within such a cyst is a very rare event, with about 30 cases described in the literature to date. In this report we present the case of a young woman with this unusual diagnosis. The characteristics of the case differ from most previous case reports in a few respects: the patient was a young rather than middle-aged female; she had a presacral mass with a significant solid component; at diagnosis, there was evidence of a lytic lesion in the coccyx. Despite this particular medical presentation, radical surgery was accomplished. In this disease the greatest risk is local relapse, but adjuvant radiotherapy may compromise the patient's fertility. We therefore opted for strict control only, but this decision might be debatable.

The aim of this article is to provide a discussion on the Mediterranean as a helpful framework for comparison. In order to illustrate what kind of comparison we have been thinking of, we will be dealing with two case studies that investigate the relationship between mobility and religious identities. The first case study focuses on mobility across Greek and Albanian border regions, whereas the second investigates migration from rural areas of Morocco to rural areas of central Sardinia (Italy). The theoretical ground in which the research is situated merges approaches on migration to southern Europe (, ), approaches on borderlands, and reflections on boundaries as analytical tools (), and finally focuses on the social meaning of religious identity.

On Monday, 6 April 2009 at 3:32 a.m. (local time), a moment magnitude 6.3 earthquake with an epicenter located near the city of L'Aquila, in central Italy, killed 308 people, injured 1,500, left 22,000 homeless, and temporarily displaced another 65,000. This study examines a sample of the affected population and finds that despite the long list of historical earthquakes that struck the region and the swarm of foreshocks occurring up to four months before the main shock of 6 April, the residents of L'Aquila had a rather low earthquake risk perception and an unjustified confidence in the seismic safety of their houses. This low perception of earthquake risk and ignorance of the real structural resistance of buildings appear to have inhibited the individual and collective propensity to develop emergency plans. This situation was further exacerbated by the lack of clear and forthright communication from the emergency management authorities about the impossibility of precisely predicting earthquakes and about the risks posed by many of the city's old buildings.

Although the prophylactic administration of indomethacin in extremely low-birth weight infants reduces the frequency of patent ductus arteriosus and severe intraventricular hemorrhage, it does not appear to provide any long-term benefit in terms of survival without neurosensory and cognitive outcomes. Considering the increased drug-induced reduction in renal, intestinal, and cerebral blood flow, the use of prophylaxis cannot be routinely recommended in preterm neonates. However, a better understanding of the genetic background of each infant may allow for individualized prophylaxis using NSAIDs and metabolomics.

Aims and background Neuroendocrine tumors of an unknown primary site are rarer than other neuroendocrine tumors (0.6–2% of all neuroendocrine tumors) and have a poor prognosis. The aim of the study was to review the cases of unknown primary site neuroendocrine tumors encountered at the Istituto Nazionale Tumori of Milan between 1984 and 2008 in order to verify their incidence and evaluate their characteristics and prognosis.Methods and study design During the study period, 750 neuroendocrine tumor patients attended our Institute, 82 of whom (10.9%) were diagnosed as having neuroendocrine tumors of an unknown primary site. The data from their medical records were analyzed descriptively, and survival probabilities were calculated using the Kaplan-Meier method and the logrank test, considering patient, tumor and treatment-related characteristics.Results The 82 patients with neuroendocrine tumors of an unknown primary site (34 males) had a median age of 60 years; 57 (69.5%) had histologically well-differentiated tumors, 3 (3.7%) poorly differentiated tumors, and 22 (26.8%) had tumors that could not be classified. Of the 52 patients (62.2%) who underwent Octreoscan(®)(Bykgulden Italia SpA), 40 (78.4%) showed a pathological uptake and 11 (21.6%) were negative. Thirty-one patients (37.8%) underwent metastatic site surgery, which was radical in 11 cases (35.4%). Forty-eight patients (58.5%) received somatostatin analogues, and 41 (50.0%) underwent chemotherapy. At the end of the study period, 59 patients (72.0%) had died, 31 (53.0%) because of disease progression, and 23 (28.0%) were still alive.Conclusions Neuroendocrine tumors of an unknown primary site are difficult to identify but their incidence is higher than previously reported, and the prognosis remains unfavorable.

The acidic soluble fraction of whole saliva of type 1 diabetic children was analyzed by reversed phase (RP)11The abbreviations used are:aPRPssalivary acidic proline-rich phosphoproteinsbPRPsbasic salivary proline-rich proteinsP-Bproline-rich peptide P-BRPreversed phaseIgimmunoglobulinXICextracted ion currentPRPproline-rich proteinsHst-1histatin-1.–HPLC-ESI-MS and compared with that of sex- and age-matched control subjects. Salivary acidic proline-rich phosphoproteins (aPRP), histatins, α-defensins, salivary cystatins, statherin, proline-rich peptide P-B (P-B), beta-thymosins, S100A8 and S100A9*(S100A9* corresponds to S100A9 vairant lacking the first four amino acids), as well some naturally occurring peptides derived from salivary acidic proline-rich phosphoproteins, histatins, statherin, and P-B peptide, were detected and quantified on the basis of the extracted ion current peak area. The level of phosphorylation of salivary acidic proline-rich phosphoproteins, histatin-1 (Hst-1), statherin and S100A9* and the percentage of truncated forms of salivary acidic proline-rich phosphoproteins was also determined in the two groups. The study revealed that statherin, proline-rich peptide P-B, P-C peptide, and histatins, were significantly less concentrated in saliva of diabetic subjects than in controls, while concentration of α-defensins 1, 2 and 4 and S100A9* was higher. The low concentration of P-C peptide was paralleled by high levels of some of its fragments. On the whole, the study highlighted the severe impairment of the repertoire of peptides involved in the safeguard of the oral cavity in children who have diabetes, as well as an higher concentration of the proinflammatory mediator S100A9* with respect to healthy children.

The acidic soluble fraction of whole saliva of type 1 diabetic children was analyzed by reversed phase (RP)1–HPLC-ESI-MS and compared with that of sex- and age-matched control subjects. Salivary acidic proline-rich phosphoproteins (aPRP), histatins, α-defensins, salivary cystatins, statherin, proline-rich peptide P-B (P-B), beta-thymosins, S100A8 and S100A9*(S100A9* corresponds to S100A9 vairant lacking the first four amino acids), as well some naturally occurring peptides derived from salivary acidic proline-rich phosphoproteins, histatins, statherin, and P-B peptide, were detected and quantified on the basis of the extracted ion current peak area. The level of phosphorylation of salivary acidic proline-rich phosphoproteins, histatin-1 (Hst-1), statherin and S100A9* and the percentage of truncated forms of salivary acidic proline-rich phosphoproteins was also determined in the two groups. The study revealed that statherin, proline-rich peptide P-B, P-C peptide, and histatins, were significantly less concentrated in saliva of diabetic subjects than in controls, while concentration of α-defensins 1, 2 and 4 and S100A9* was higher. The low concentration of P-C peptide was paralleled by high levels of some of its fragments. On the whole, the study highlighted the severe impairment of the repertoire of peptides involved in the safeguard of the oral cavity in children who have diabetes, as well as an higher concentration of the proinflammatory mediator S100A9* with respect to healthy children.

Differential diagnosis NETs may be highly challenging. In order to exclude conditions that may mimic a neuroendocrine neoplasms, a deep knowledge of all the aspects of the disease, together with an adequate capacity to interpret clinical data and imaging findings and to put them in right correlation, are strongly warranted. Patients which suspected neuroendocrine neoplasms should be referred to reference centers to receive optimal multidisciplinary care. Free full text available at www.tumorionline.it

Aims and background Carcinoids are infrequent neoplasms arising from neuroendocrine cells. Due to blurred symptoms and the presence of equivocal diagnostic findings, these tumors are sometimes misdiagnosed. Therefore, increased rates of false neuroendocrine tumors represent an emerging problem in clinical practice. Our aim is to alert clinicians on this matter by supplying them with useful warnings.Methods In the specialized neuroendocrine tumor study Center Centro di Riferimento per lo Studio e la Cura dei Carcinoidi e dei Tumori Neuroendocrini (Ce.Ri.Ca), some patients highly suspected to have a neuroendocrine tumor have been recognized as having false neuroendocrine tumors. The related clinical and instrumental findings leading to a previous wrong neuroendocrine tumor diagnosis are reported.Results From July 2006 to December 2008, 88 consecutive cases of neuroendocrine tumors (Nets) were referred at Ce.Ri.Ca. In the former group, 8 cases of false Nets were discovered while in the remaining 80 cases a correct Net diagnosis was carried out. Watchful differential diagnoses and skill appraisal of laboratory investigations resulted in: chronic atrophic gastritis with enterochromaffin-like cell hyperplasia (4 cases), estrogen-deprivation syndrome (1), hypochondriac disorder (1), metabolic syndrome (1), and sarcoidosis (1).Conclusions Neuroendocrine tumors are still relatively known clinical entities. To discriminate false neuroendocrine tumors from neuroendocrine tumors requires a good expertise and a large daily practice with the disease. Good knowledge and skillfulness in identifying biochemical alterations and false radiological positive results could avoid both patient inconvenience and very expensive workup. The importance of a multidisciplinary approach in specialized centers is emphasized.

Abstract: GRIDA3 (Shared Resources Manager for Environmental Data Analysis and Applications) is a multidisciplinary project designed to deliver an integrated system to forge solutions to some environmental challenges such as the constant increase of polluted sites, the sustainability of natural resources usage and the forecast of extreme meteorological events. The GRIDA3 portal is mainly based on Web 2.0 technologies and EnginFrame framework. The portal, now at an advanced stage of development, provides end-users with intuitive Web-interfaces and tools that simplify job submission to the underneath computing resources. The framework manages the user authentication and authorization, then controls the action and job execution into the grid computing environment, collects the results and transforms them into an useful format on the client side. The GRIDA3 Portal framework will provide a problem-solving platform allowing, through appropriate access policies, the integration and the sharing of skills, resources and tools located at multiple sites across federated domains.

Abstract: Neuroendocrine tumours (NETs) represent a group of neoplasias characterized by significant histopathological and biological heterogeneity. Diagnosis of neuroendocrine tumours relies upon histological examination augmented by newer techniques, such as pet-dotatoc scan. Surgery represents the only curative therapeutic approach. In advanced unresectable disease, medical treatment is the best choice. Somatostatin analogues allow adequate control of the carcinoid syndrome with a low effect on tumour cell growth. Chemotherapy has a good activity only in poor prognosis patients. According to the clinical course of the disease, a multimodal approach could be evaluated in selected cases. New target therapy including multikinase inhibitors, monoclonal antibody and m-tor inhibitors is now under clinical investigation for the treatment of advanced NETs. Preliminary results demonstrated a good activity in terms of disease control rate and tumour shrinkage.

A rare variant of malignant melanoma (MM) of the uterine cervix that mimics a malignant peripheral nerve sheath tumor (MPNST) is described. A 43-year-old white woman was admitted to the hospital complaining of genital discharge and vaginal bleeding. Neoadjuvant chemotherapy and total abdominal hysterectomy and bilateral salpingo-ovariectomy plus pelvic lymphadenectomy were performed, and the diagnosis was MPNST, FIGO IIB. Pathological examination showed a diffuse proliferation of amelanotic spindle cells and large, highly atypical, frequently multinucleated, bizarre, and S100-, HMB-45−, vimentin-positive cells. The patient remained disease-free for 43 months, when an abdominal computed tomographic scan showed local polypoid vaginal lesions, with histological features of typical MM. A pathological review was obtained in our institution by a gynecological pathologist, who defined the primary neoplasm in the cervix as an MM, with a pattern of growth histologically simulating an MPNST, metastatic to the vagina. To our knowledge, this is the first report in literature of MM of the uterine cervix resembling MPNST. Despite its rarity, this variant of MM should be considered when a diagnosis of cervix MPNST is made. The histological and immunohistochemical features of these different entities should be considered in the differential diagnosis.

We report on a child with Filippi syndrome who shows syndactyly of fingers and toes, severe pre and postnatal growth retardation, postnatal microcephaly, epilepsy, and severe mental retardation with speech impairment. Standard cytogenetics, CGH microarray, and molecular analysis of the GJA1Cx43 gene coding region were normal. We review the literature and provide additional information delineating the genetic and neurological aspects of the syndrome. © 2008 WileyLiss, Inc.

No relevant conflicts of interest to declare.

Acute leukemias (AL) is a major cause of cancer death in young age. Extensive research is being conducted to identify novel and innovative approaches for leukemia treatment. Transcriptomic and epigenetic studies might help to discover potential targets, paving the way for molecular-targeted therapies.

α1-Antitrypsin deficiency is an autosomal codominant inherited disorder, with increased risk of developing lung and liver disease. The large majority of subjects affected by α1-antitrypsin deficiency carry the PIZZ or PISZ genotypes, which can be easily detected using several molecular methods. Another pathologic allele, the M-Malton variant (also known as Mnichinan and Mcagliari), can mimic the Pi Z clinical phenotype, but this α1-antitrypsin deficiency variant is not easily recognizable and, therefore, seems to be more underrecognized than the Z or S alleles. We report the development of a rapid qualitative fluorescent real-time PCR assay designed for the detection of the M-Malton α1-antitrypsin deficiency alleles using 2 specific molecular beacons. The assay is able to detect in a single tube the homozygous as well the heterozygous genotypes. The procedure combines the great sensitivity of the polymerase chain reaction, the specificity provided by allele-specific molecular beacons, and the throughput of a multicolour fluorescence detection procedure. This technique will be useful for research and molecular diagnostic laboratories involved in the study of α1-antitrypsin deficiency-related diseases.

ABSTRACTReactivities of human sera against selected recombinant Mycobacterium tuberculosisantigens were assessed by enzyme-linked immunosorbent assay. The results obtained indicate that patients with tuberculosis (TB) do not develop a strong humoral response against PE_PGRS and PPE proteins or against the Ag85B and heparin-binding hemagglutinin (HBHA) recombinant antigens. Conversely, purified methylated HBHA was strongly recognized by sera obtained from TB patients compared to controls.

Aims and background Carcinoma of the colon-rectum is an infrequent cause of brain metastases, constituting 1-5% of all metastatic lesions to the brain. We reviewed our experience in the treatment of brain metastases from colorectal cancer to define the efficacy of whole brain radiation therapy as a palliative measure in this setting of patients.Methods Twenty-three consecutive cases of brain metastasis from colorectal cancer treated between 1999 and 2004 were identified in the files of the Division of Radiotherapy of the A Businco Regional Oncological Hospital, Cagliari. Their records were reviewed for patient and tumor characteristics and categorized according to the RTOG RPA classes.Results Fifteen patients (65%) had multiple metastases. Twenty-one patients (91%) showed extracranial metastases. Fourteen patients were classified as RTOG RPA class II and 9 class III. The median radiation dose delivered was 2000 cGy in 5 fractions in one week (range, 20-36 Gy). In 14 of 20 assessable patients (70%), symptomatic improvement was observed. The median follow-up and survival time for all the patients, 12 females and 11 males, was 3 months. In 3 patients only the cause of death was the brain metastasis.Conclusions Despite the disappointing survival time, external radiation therapy to the whole brain proved to be an efficacious palliative treatment for patients with multiple or inoperable brain metastasis from colorectal cancer.

In order to classify the trophic state of detritus sink systems, instead of the conventional indicators based on inorganic nutrient availability and algal biomass and productivity in the water column, we used new biochemical descriptors based on the amount of sedimentary organic carbon (C) and nitrogen (N) potentially available to heterotrophs. We investigated spatial and temporal changes in microphytobenthic biomass, organic matter biochemical composition, and enzymatically hydrolyzable protein and carbohydrate pools along a north-south transect in the Marsala lagoon (Mediterranean Sea, Italy) at three stations characterized by different hydrodynamic conditions and organic matter content in the sediment. In the Marsala lagoon water currents decreased from north to south and this pattern was reflected by organic matter distribution and composition. Sediment organic matter concentrations were among the highest reported in the literature and, in the central area where large meadows of the seagrassPosidonia oceanicawere present, display a strong dominance of highly refractory carbohydrates. The protein to carbohydrate ratio was always < 1, indicating the dominance of aged organic detritus. Microphytobenthic biomass displayed an increasing pattern southward, and its contribution to the biopolymeric C pools ranged from negligible in the central sector of the lagoon to 50% in its northern part, indicating that sources of sediment organic C also changed along the hydrodynamic gradient. The percentage contribution of the enzymatically hydrolyzable fraction of proteins and carbohydrates was inversely related to total protein and total carbohydrate concentrations, respectively, suggesting that bioavailability of organic C and N increased with decreasing organic matter content in the sediment and with increasing hydrodynamic regime. Microphytobenthic contribution to biopolymeric C (as a proxy of autotrophic organic C) and the ratio of the enzymatically digestible fraction to biopolymeric C (as an indicator of organic matter liability) were significantly correlated, suggesting that chlorophyllasediment content might be used as an indicator of food promptly available to consumers. The present study also highlighted that the ratio of labile (i.e., enzymatically digestible) versus biopolymeric organic C in the sediments tends to decrease with increasing organic matter content, due to the increase of the refractory fraction of organic C.

A series of 18 1-[(1,2-diphenyl-1H-4-imidazolyl)methyl]-4-piperazines (1a−r) were designed and synthesized as possible ligands with mixed dopamine (DA) D2/serotonin 5-HT1A affinity, with the aim of identifying novel compounds with neurochemical and pharmacological properties similar to those of clozapine. The binding profile at D2 like, 5-HT1A, and 5-HT2A receptors of title compounds was determined. Modifications made in the phenyl rings of the parent compound (1a) produced congeners endowed with a broad range of binding affinities for DA D2 like, serotonin 5-HT1A, and 5-HT2A receptors, with IC50 values ranging from 25 to >10 000 nM. As for the modification of the piperazine N⁴-phenyl ring, the affinities for both D2 like and 5-HT1A receptors were progressively increased by introduction of ortho-methoxy and ethoxy groups (1b,o, respectively). Data revealed the presence of a para-chloro substituent in 1g to be associated with a relatively high affinity and substantial selectivity for D2 like receptors, whereas the meta-chloro analogue 1f exhibited preferential affinity for 5-HT1A receptors. A quantitative structure−affinity relationship analysis of the measured binding data resulted in regression equations that highlighted substituent physicochemical properties modulating the binding to subtypes 1A and 2A of serotonin 5-HT receptors but not to D2 like receptors. Thus, besides an electron-withdrawing field effect and ortho substitution, which both influence binding to serotonin 5-HT receptor subtypes, though to a different extent as revealed by regression coefficients in the multiparametric regression equations, the affinity of congeners 1a−r to 5-HT1A receptors proved to be linearly correlated with volume/polarizability descriptors, whereas their affinity to 5-HT2A receptors correlated with lipophilicity constants through a parabolic relationship. 1-[(1,2-Diphenyl-1H-4-imidazolyl)methyl]-4-(2-methoxyphenyl)piperazine (1b), with a D2/5-HT1A IC50 ratio of ~1, was selected for a further pharmacological study. In rats, the intraperitoneal administration of compound 1b, like that of clozapine, induced an increase in the extracellular concentration of DA measured in the medial prefrontal cortex. Furthermore, 1b and clozapine each inhibited GABA-evoked Cl^- currents at recombinant GABAA receptors expressed in Xenopus oocytes. These findings suggest that compound 1b may represent an interesting prototype of a novel class of drugs endowed with a neurochemical profile similar to that of atypical antipsychotics.