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The proper development of an offshore oil and gas field relies on a project's ability to deliver the maximum economic benefits while maintaining safety and environmental targets. In this sense, offshore oil and gas companies have continually evaluated ways to optimize system designs and streamline operations to ensure the achievement of these objectives. A set of technological alternatives that have been highlighted is subsea processing, which requires moving a processing system from the topsides to the seabed. The assessment of subsea processing systems has become an important step during the field development strategy definition, especially in terms of flow assurance by mitigating hydrate and wax formation. When combined with mature subsea production technologies, the potential benefits of deploying subsea processing include enhanced reservoir recovery improved facilities availability, reduced topsides processing requirements, and reduced overall field development cost resulting in improvement of project economics. In addition, depending on the subsea architecture chosen, subsea processing can contribute to reducing the carbon footprint, which is in line with the industry's decarbonization goals. Due to the potential benefits of the subsea processing architectures, new technologies are emerging to overcome the technical challenges to enable this transfer of strategic processes from the topsides to the subsea. The objective of this paper is to present and discuss the mapped subsea processing system archetypes that may significantly increase hydrocarbon production in a cost-optimized way for new fields, tiebacks, and operating facilities. The mapped archetypes are implemented in an Expert System that integrates all technical areas for offshore field development, providing hundreds of conceptual alternatives to understand the impact of using subsea processing systems. This paper provides an overview of promising technologies that have the potential to increase the scope of subsea processing, leading to the identification of the most favorable architectures for each project. This study incorporates a detailed analysis of 27 different subsea archetypes, combining processes such as liquid boosting to host, gas compression to host, two-phase and three-phase separation, produced water reinjection or disposal, seawater injection with sulphate removal, dense phase (natural gas or CO2) boosting to reinjection, gas dehydration, and gas compression. Such analysis indicated that equipment with different technological maturity levels can be combined to create a subsea processing arrangement that meets the project requirements.

In this study, we evaluated the biological role of miRNA-31-5p in papillary thyroid cancer (PTC).By using the real-time PCR, we measured miRNA-31-5p expression levels in 25 PTC tissues and in two human PTC cell lines (K1 and TPC-1). Then, K1 cells were transiently transfected with mirVana inhibitor or mirVana mimic to miRNA-31-5-p. Cell proliferation was determined by MTT and colony formation assays. The in vitro metastatic ability of thyroid cancer cells was evaluated by adhesion, migration and invasion assays. Epithelial mesenchymal transition (EMT) and Hippo pathway related gene and protein levels were evaluated by using the TaqMan™ Gene Expression Assays and western blot analysis, respectively.We found a significant increase of miR-31-5-p expression in tumor tissue and in K1 cells harboring the BRAF p.V600E mutation. Knockdown of miR-31-5p determined a reduction of cell proliferation, associated with a significant decrease in cell adhesion, migration and invasion properties. A downregulation of EMT markers and YAP/β-catenin axis was also observed.Our findings suggest that miRNA-31-5p acts as oncogenic miRNA in human thyrocytes and its overexpression may be involved in the BRAF-related tumorigenesis in PTCs, providing new understanding into its pathological role in PTC progression and invasiveness.

Aberrant activation of the RET proto-oncogene is implicated in a plethora of cancers. RET gain-of-function point mutations are driver events in multiple endocrine neoplasia 2 (MEN2) syndrome and in sporadic medullary thyroid cancer, while RET rearrangements are driver events in several non-medullary thyroid cancers. Drugs able to inhibit RET have been used to treat RET-mutated cancers. Multikinase inhibitors were initially used, though they showed modest efficacy and significant toxicity. However, new RET selective inhibitors, such as selpercatinib and pralsetinib, have recently been tested and have shown good efficacy and tolerability, even if no direct comparison is yet available between multikinase and selective inhibitors. The advent of high-throughput technology has identified cancers with rare RET alterations beyond point mutations and fusions, including RET deletions, raising questions about whether these alterations have a functional effect and can be targeted by RET inhibitors. In this mini review, we focus on tumors with RET deletions, including deletions/insertions (indels), and their response to RET inhibitors.

Manufacturing molds for plastic parts injection are a particular machining domain, where challenging materials, like AISI P20 steel, are forced to satisfy the highest surface quality requirements. Before mirror polishing, milling operation is a common and challenging task due to drilling and milling with the same tool. Thus, special cutting tools, like asymmetric indexable type, are often used. This tool presents two geometrically equal positive inserts – one placed horizontally and the other vertically – for the flexible machining of holes, cavities, floors, and walls. Rough-medium milling operations lead to a complicated relationship between cutting conditions and geometrical tool parameters, making it challenging to balance the tool life of both inserts. The novelty of this work is to propose a model for cutting force prediction with an asymmetric tool to explain the separated behavior of both inserts and determine a better compromise between cutting conditions and tool life. The experimental tests were done for model validation and then wear cutting tests for testing improved cutting conditions. The results predicted by the model proved that by changing the depth of cut from 0.3 mm to 0.8 mm, the wear in both inserts was more balanced, increasing chip volume up to 1.7 times.

In the search for novel effective compounds to use in thyroid cancer (TC) unresponsive to current treatment, attention has recently focused on plant-derived compounds with anticancer activity. In this review, we discuss the preclinical studies demonstrating phytochemical activity against thyroid cancer cells. In particular, we describe their antiproliferative properties or ability to re-induce iodine retention, thus supporting their potential use as single agents or adjuvants in radioiodine-resistant thyroid cancer treatment.

Aberrant activation of the

As an offshore asset approaches its designed life, and hydrocarbon production tends to decrease to a non-economic level, the operators have two options: extend the field's life or decommissioning. Decommissioning is the removal or abandonment of the field's assets. The process is complex and can be divided into five main pillars: wells’ plugging and abandonment, subsea structure decommissioning, umbilical/risers/flowlines decommissioning, topside removal, and jacket/hull decommissioning. The processes and alternatives depend on the field's characteristics, such as water depth, distance to coast, the weight of subsea equipment, wells’ history and condition, type of hull, as well as local legislation. All these nuances require comprehension regarding the decommissioning processes to target the most cost- effective alternative. Decommissioning is a costly process. It is necessary to understand the whole development, calculate time for each step and map the daily rate of the infrastructures (boats and equipment) required to estimate the cost by its availability. Depending on the equipment's integrity assessment, the field's life extension can be feasible and should be considered a viable alternative. Based on that, the development of an integrated model based computational system can help abstract the enormous complexity faced in real life, allowing operators to choose the most economically attractive option for a brownfield. This study aims to propose a methodology developed as a digital solution for analyzing alternatives of decommissioning based on user's input. The methodology consists of gathering the possibilities for decommissioning or life extension, applied to each of the main pillars. Based on the results, it is expected that the present work will deliver an important contribution to the industry regarding the adoption of integrated design practices for the technical and economic analysis of brownfields.

The objective of this paper is to present and discuss the philosophy behind the integration of "Model-Based Systems Engineering" (MBSE) with metaheuristic algorithms, referred to as "Model-Based Systems Metaheuristic Engineering" (MBSME), which has demonstrated high potential of techno-economic optimization of large capital projects in oil and gas industry, notably in the automatic and integrated conceptual design and selection of offshore systems architectures. Virtual modeling has always been an important part of systems engineering to support functional, performance and other engineering analysis. The so-called MBSME allows the simulation of several specific System-of-Systems physically addressed in offshore field development, bringing all the benefits of the traditional MBSE approach, and set a stochastic characteristic in the analysis, allowing the project team to focus on a Model-Centric approach, as well as to quickly understand the influence of several combined project strategies and application of different technologies, communicated through a Tradespace exploration map. Due to the characteristics associated with and the countless number of variables of the multidimensional problem addressed in an offshore field development, the integration of "Meta-Heuristic" algorithms with "Model-Based Systems Engineering" has demonstrated a remarkable efficiency and powerful applicability in the search for optimized design solutions in oil and gas industry, especially considering the processes of generation of conceptual alternatives of offshore production systems. This method leads to a reduction of more than 2/3 of the average time currently observed, with an increase in the number of conceptual alternatives evaluated in the order of tens to an order of thousands of options, in an automatic and integrated approach. Although the digital MBSME already developed addresses the combination of all technical disciplines associated with a complete offshore field development, the current work emphasizes the latest R&D achievements, addressing the automatic design and specification of Topside Facilities architecture, combined with the automatic selection of fitting for purpose Production Unit, based on internal requirements, such as the required capacity to support total weight and footprint imposed by the topside facilities’ modules, as well as external requirements, like water depth, surface metocean, type of well completion and oil storage requirements. An example of the MBSME application is presented, demonstrating a three-dimensional Tradespace exploration, relating Net Present Value (NPV), Capital Expenditure (CAPEX) and Breakeven Oil Price, through the application of a computational package in a hypothetical project, reflecting the design conditions of an offshore development in the Brazilian Pre-Salt region. The paper communicates an efficient method to increase the scope and accuracy of conceptual analyses, leading to the identification of the most favorable techno-economic conditions to the particularities of each project, supporting significant increases of return on investments.

As the environmental impact is critical for industry sustainability, early quantifying Greenhouse Gas (GHG) emissions of offshore units represents a central role and step-change improvement across the O&G value chain. Developing an overarching realistic model to estimate GHG emissions is a challenge due to the different methodologies available, the complexity of offshore installations, and the degree of uncertainty in the estimation of emission factors. The present work focuses on the earlier stages of new development, notably in Front End Loading-1 (FEL-1) and FEL-2, i.e., opportunity identification and conceptual engineering studies, respectively. The primary objective of this study is to propose an innovative modeling methodology to quantify Greenhouse Gas (GHG) emissions in offshore production facilities. Since E&P companies consider current and future carbon dioxide equivalents (CO2e) emissions as a factor into capital projects economics, this study additionally proposes a semi-empirical model for OPEX calculation considering the impact related to emissions (on a CO2e basis). Emissions of GHG in the O&G industry typically occur from one of the following general source classes: (i) combustion sources, including both stationary devices and mobile equipment; (ii) process emissions and vented sources; (iii) fugitive sources; and (iv) indirect sources. The projection of carbon emission costs along the asset life cycle is performed to simulate the economic impact of such emission on an OPEX perspective. After estimating the CO2e emissions, the procedure consists of using the "Carbon Emission Cost Projection" to calculate the cost of the CO2 emitted and penalize the OPEX of the evaluated alternative. The proposed model can be used to estimate Carbon Footprint for each one of the several conceptual engineering alternatives evaluated during the conceptual phase of the project, improving not only the techno-economic analysis but also the decision-making process of Capital Projects in the O&G Industry.

Radioiodine-refractory thyroid cancers represent the main cause of thyroid cancer-related death. At present, targeted therapies with multikinase inhibitors represent a unique therapeutic tool, though they have limited benefit on patient survival and severe drug-associated adverse events. This review summarizes current treatment strategies for radioiodine-refractory thyroid cancer and focuses on novel approaches to redifferentiate thyroid cancer cells to restore responsiveness to radioiodine administration.We summarize and discuss recent clinical trial findings and early data from real-life experiences with multikinase-inhibiting drugs. Possible alternative strategies to traditional redifferentiation are also discussed.The current review focuses primarily on the major advancements in the knowledge of the pathophysiology of iodine transport and metabolism and the genetic and epigenetic alterations occurring in thyroid neoplasia as described using preclinical models. Results of clinical studies employing new compounds to induce thyroid cancer cell redifferentiation by acting against specific molecular targets are also discussed. Finally, we describe the current scenario emerging from such findings as well as future perspectives.

The manuscript describes the development of zein nanoparticles containing paclitaxel (PTX) and the bromo-and extra-terminal domain inhibitor (S)-tertbutyl2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepin-6-yl)acetate (JQ1) together with their cytotoxicity on triple-negative breast cancer cells. The rationale of this association is that of exploiting different types of cancer cells as targets in order to obtain increased pharmacological activity with respect to that exerted by the single agents. Zein, a protein found in the endosperm of corn, was used as a biomaterial to obtain multidrug carriers characterized by mean sizes of ˂200 nm, a low polydispersity index (0.1–0.2) and a negative surface charge. An entrapment efficiency of ~35% of both the drugs was obtained when 0.3 mg/mL of the active compounds were used during the nanoprecipitation procedure. No adverse phenomena such as sedimentation, macro-aggregation or flocculation occurred when the nanosystems were heated to 37 °C. The multidrug nanoformulation demonstrated significant in vitro cytototoxic activity against MDA-MB-157 and MDA-MB-231 cancer cells by MTT-test and adhesion assay which was stronger than that of the compounds encapsulated as single agents. The results evidence the potential application of zein nanoparticles containing PTX and JQ1 as a novel nanomedicine.

Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer and is responsible for 20‑50% of thyroid cancer‑associated deaths. The absence of response to conventional treatments makes the search for novel therapeutics a clinical challenge. In the present study, the effects of 15,16‑dihydrotanshinone I (DHT), a tanshinone extracted from Salvia miltiorrhiza Bunge (Danshen), which has previously been shown to possess anticancer activity, were examined in two human ATC cell lines. DHT significantly reduced cell viability, which was coupled with an increase in apoptosis. DHT administration also reduced the colony‑forming ability and proliferation of these cells in soft agar and downregulated the expression of epithelial‑to‑mesenchymal transition‑related genes. In addition, DHT significantly reduced MAD2 expression, a target of HuR with a relevant role in ATC. Finally, cotreatment with cisplatin and DHT has a greater effect on cell viability than each compound alone. In conclusion, to the best of our knowledge, the present study is the first to demonstrate that DHT exerts antitumor effects on ATC cells by reducing MAD2 expression levels. Moreover, a synergistic effect of DHT with cisplatin was shown. Further in vivo studies are required to assess this phytochemical compound as a potential adjuvant for the treatment of ATC.

Introduction: Despite the low frequency of Covid-19-associated bacterial infections, empirical antibacterial treatment is as high as 70 to 90%. The primary goal of this study was to determine the impact of the implementation of an antimicrobial stewardship program to target Covid-19 patients (ASP-COVID). Materials and methods: Retrospective, descriptive, and analytic pre and post intervention study. Prevalence and adequacy of antibacterial treatment in hospitalized patients prior and after ASP-COVID implementation were assessed. Monthly antibiotic consumption in DDD/100 patients-day and costs related with inadequate usage were estimated. Results: One hundred and fifty three patients, 75 prior and 78 after ASP-COVID implementation, were included. No significant difference in population characteristics between both periods was observed. Moderate and severe clinical presentations were more frequent after the intervention (p=0,03). ASP implementation showed a significant reduction of antimicrobial treatment (64% vs 41%, p=0,004), with an increment of adequate usage (37,5% vs 46,8%, p=NS). Unnecessary usage was higher prior to ASP (80% vs 50%, p =0,03) and length of treatment post intervention (13,3% vs 43,7%%, p=0,02). Program implementation decreased beta lactam antibiotics + IBL and azithromycin consumption. After adjusting for severity, no significant difference was found in mortality, incidence of ICU admission nor combined antibacterial therapy with macrolides between both periods. Conclusions: ASP-COVID implementation was an effective strategy in reducing antimicrobial usage and in optimizing antibacterial treatment indications, highlighting the importance of its rapid and timely application.

For the first time, the 9% Ni steel is being used in CO2 injection units in floating production storage offloading vessels. Pipe joints welded with nickel-based superalloy 625 as the filler metal present difficulties in ultrasonic inspection owing to the sonic attenuation and deviation caused by the anisotropic and coarse-grained weld metal. This study aims to conduct a probability of detection (POD) to evaluate the discontinuity detection reliability in 9% Ni steel arc welded joints. The inspections were performed using ultrasonic phased array transducers with transversal and longitudinal waves, by using both a conventional wedge formed of Rexolite® and an adapted wedge filled with water to simulate the immersion inspection. POD curves were developed using the hit/miss and â vs a models. The inspection performed with transversal waves detected much fewer discontinuities than that performed with longitudinal waves. Furthermore, inspection performed with longitudinal waves after weld metal cap pass removal exhibited much more reliability in 9% Ni steel welded joints. The obtained POD curves were shown to be a suitable tool to evaluate the inspection of 9% Ni steel welded joints, as they confirmed that the best inspection procedure involves a combination of three different phased array ultrasonic testing configurations.

This paper presents the ongoing development and qualification program of a subsea sulphate removal and injection system and provides an overview of the system together with the features that enable its operation subsea. The ongoing development program has completed a dry piloting phase that focused on the design of the system, subsystems, assembly of the pilot and qualification of the process, including the modified operation of the filtration technologies. This development is in cooperation with 5 leading global oil companies. The pilot operation took place over a period of 6 months. Injection of seawater to provide reservoir pressure support is often the choice to increase oil recovery in a field. Traditionally, large and heavy topside processing systems are deployed to treat and inject seawater. This creates significant operational challenges, especially in brownfields, where topside space and weight capacity are constrained. Moving the system to the seabed will greatly reduce the capacity demand imposed on the floating facility and will eliminate the need for an expensive high-pressure riser and flowline system. The subsea system requires a different operational approach in which the conventional chemical cleaning is eliminated. Special design considerations must be made to maintain operational robustness without the chemical cleaning in place unit. Baker Hughes and its partners are proposing to move the seawater treatment system to the seabed to simplify and debottleneck the topside facilities and reduce the total cost of ownership. Seawater treatment systems for injection are conventionally topside units. Necessary operational modifications have to be implemented to enable its reliable operation in subsea conditions. These modifications are being validated through piloting.

Background: The sesquiterpene lactone cynaropicrin, a major constituent of the artichoke leaves extracts, has shown several biologic activities in many preclinical experimental models, including anti-proliferative effects. Objective: Herein we evaluated the effects of cynaropicrin on the growth of three human anaplastic thyroid carcinoma cell lines, investigating the molecular mechanism underlying its action. Method: MTT assay was used to evaluate the viability of CAL-62, 8505C and SW1736 cells, and flow cytometry to analyse cell cycle distribution. Western blot was performed to detect the levels of STAT3 phosphorylation and NFkB activation. Antioxidant effects were analyzed by measuring the reactive oxygen species and malonyldialdehyde dosage was used to check the presence of lipid peroxidation. Results: Viability of CAL-62, 8505C and SW1736 cells was significantly reduced by cynaropicrin in a dose- and time-dependent way, with an EC50 of about 5 µM observed after 48 h of treatment with the compound. Cellular growth inhibition was accompanied both by an arrest of the cell cycle, mainly in the G2/M phase, and the presence of a significant percentage of necrotic cells. After 48 h of treatment with 10 µM of cynaropicrin, a reduced nuclear expression of NFkB and STAT3 phosphorylation were also revealed. Moreover, we observed an increase in lipid peroxidation, without any significant effect on the reactive oxygen species production. Conclusion: These results demonstrate that cynaropicrin reduces the viability and promotes cytotoxic effects in anaplastic thyroid cancer cells associated with reduced NFkB expression, STAT3 phosphorylation and increased lipid peroxidation. Further characterization of the properties of this natural compound may open the way for using cynaropicrin as an adjuvant in the treatment of thyroid cancer.

Aim of this study was to evaluate the association between body mass index (BMI) and aggressive features of differentiated thyroid cancer (DTC) in a prospective cohort. Patients with DTC were prospectively enrolled at a tertiary referral center and grouped according to their BMI. Aggressive clinic-pathological features were analyzed following the American Thyroid Association Initial Risk Stratification System score. The cohort was composed of 432 patients: 5 (1.2%) were underweight, 187 (43.3%) normal weight, 154 (35.6%) overweight, 68 (15.7%) grade 1 obese, 11 (2.5%) grade 2 obese and 7 (1.6%) grade 3 obese. No single feature of advanced thyroid cancer was more frequent in obese patients than in others. No significant correlation was found between BMI, primary tumor size (Spearman’s ρ − 0.02; p = 0.71) and ATA Initial Risk Stratification System score (ρ 0.03; p = 0.49), after adjustment for age. According to the multivariate logistic regression analysis, male gender and pre-surgical diagnosis of cancer were significant predictors of cancer with high or intermediate–high recurrence risk according to the ATA system (OR 2.06 and 2.51, respectively), while older age at diagnosis was a protective factor (OR 0.98), and BMI was not a predictor. BMI was a predictor of microscopic extrathyroidal extension only (OR 1.06). Obesity was not associated with aggressive features in this prospective, European cohort of patients with DTC.

Modern forwarders are an effective extraction option for timber harvesting operations that provide the opportunity for higher levels of mechanization. With their ability to carry logs from the forest to the roadside or processing areas, they have an established lower environmental impact in comparison to tree-length skidding options. However, little is published regarding their productivity potential or the factors that influence productivity. Three case studies were carried out; (1) a selective harvest in Calabria, Italy, with a smaller 12 t capacity John Deere 1110E, (2) a clear-cut on the West Coast of New Zealand, with a larger 19 t capacity John Deere 1910E and (3) a larger clear-cut operation in Canterbury, New Zealand, with two John Deere 1910E forwarders. An elemental time and motion study was used resulting in 73.4 h of detailed data, with 159 cycles extracting 2241 m3 of timber. Productivity models were created for all three sites as well as one combined model. Average cycle time was 33.2, 24.2 and 22.8 min, and average productivity 24.6, 37.1 and 42.7 t per productive machine hour, respectively. Cycle time was the fastest, and consequently productivity the highest, at the Canterbury site where the terrain roughness was low, overcoming any effect of the average small piece size (0.59 m3). Travel speed was slowest at the West Coast site showing the effect of wet and difficult terrain, with travel empty speed being just 3.8 km/h, compared to 6.7 and 6.9 km/h at the other two sites. Productivity at the two clear-cut operations was significantly higher than the selective cut, compounded by the use of the larger capacity forwarders. Distance and payload were significant factors for each cycle time model; in the combined model the sites were also significant. The calculated unit cost of forwarder extraction in the sites ranged from €2.55 to €4.70/m3. For regions such as southern Italy that have relatively low levels of forest mechanization, this information can be used to help design and improve more traditional labor-intensive harvesting systems.

Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor.

Most timber harvesting operations in the southern Mediterranean area of Italy can be considered to be in an early stage of mechanization. It is mainly based on agricultural tractors that are sometimes equipped with specific forest-related accessories such as winches, hydraulic cranes, or log grapples. In recent years, there has been an increase of specialized forestry machines working in Calabria, southern Italy, including forwarders, skidders and cable yarders. This study assesses the efficiency and costs of extraction using forwarders, as a mechanized alternative to agricultural tractors and horse logging. Time studies were conducted to quantify the productivity and operational cost of log forwarding for two John Deere forwarders in two different coniferous stands: (A) Calabrian pine and (B) silver fir. The empirical time study included 100 forwarding cycles (i.e., 50 for each site) that were broken down into four different work phase elements. Models for cycle time, total productivity and individual work phases were calculated. The average load per cycle was 11.8 m3 in stand A and 9.97 m3 in stand B and the average one-way forwarding distance was 306 m in A and 597 m in B. The average productivity per scheduled machine hour (SMH) was 14.4 m3 in A and 15.7 m3 in B, while the costs, calculated to be 3.60 €/m3 in A and 4.90 €/m3 in B, were considered lower respect traditional methods.

C-peptide has been shown to exert several, previously unknown, biological effects. A recent cross-sectional study demonstrated an association between low C-peptide serum levels and low lumbar bone density of postmenopausal women not affected by diabetes. To date, very little research attention has been directed toward the association between C-peptide and osteoporotic fractures. To contribute toward filling this gap, we investigated the association between C-peptide and fractures in postmenopausal women. A cohort of 133 non-diabetic postmenopausal women with and without a history of fractures was evaluated in this cross-sectional investigation. Standardized interviews were performed to gather information on the patients’ fracture history. All of the participants underwent a bone mineral density assessment by DXA, radiographs, and a serum C-peptide measurement. Thirty-four women presented fractures. Bivariate analysis revealed an inverse correlation between C-peptide and fractures (r = −0.27, p = 0.002). A significant difference in mean C-peptide levels was also found between women with vs. without fractures (p = 0.01, adjusted for age, BMI and glucose). Logistic regression analysis showed that C-peptide levels, femoral and vertebral BMD were all negatively associated with fracture status (B = −1.097, ES = 0.401, p = 0.006, 95% CI 0.15–0.73; B = −15.6, SE = 4.17, p

Several studies published in the last decade suggest that the beneficial role of extra-virgin olive oil (EVOO) in human health is mostly attributable to the main secoiridoid derivatives (oleuropein, oleocanthal, and oleacein). Anti-cancer properties have also been demonstrated for certain compounds present in small quantities in EVOO, including oleuropein and hydroxytyrosol, which have been extensively studied, while minor attention has been given to the most abundant secoiridoid oleacein. The aim of our research was to study the molecular mechanisms underlying the anti-proliferative and anti-metastatic capacity of oleacein in the SH-SY5Y human neuroblastoma cell line. Our results demonstrate that oleacein is able to reduce the proliferation of the SH-SY5Y cells by blocking the cell cycle in the S phase and inducing apoptotic cell death through the increase in both Bax and p53 as well as a reduction in the Bcl-2 expression and STAT3 phosphorylation. Moreover, oleacein caused reduction in the SH-SY5Y cell adhesion and migration. Overall, these findings indicate that oleacein exerts anti-cancer effects against neuroblastoma cells, suggesting a promising role as a candidate against this type of cancer.

This work aims to compare the ultrasonic inspection of 9%Ni steel joints welded with the Gas Metal Arc Welding (GMAW) process and Shielded Metal Arc Welding (SMAW) process. These are the two most widely used processes used to weld pipes for CO2 injection units for floating production storage and offloading (FPSO) in the Brazilian oil and gas industry. The SMAW equipment is simple and portable, which is convenient for the FPSO, however, the GMAW process has the advantage of welding with high productivity. In this study we performed a numerical simulation using the software CIVA, 11th version, to analyze the behavior of ultrasonic longitudinal wave beams through GMAW and SMAW dissimilar weld joints. Ultrasonic tests were performed on calibration blocks drawn from both welded joints to evaluate the simulation results. The results are discussed with regard to the microstructure of the weld metal via electron backscatter diffraction (EBSD) analyses. The SMAW process presented better inspection performance than the GMAW process in terms of attenuation and dispersion effects. Although the SMAW had a better outcome, for both processes the configuration of 16 active elements and a scanning angle of 48&deg, resulted in an optimized inspection of the entire joint.

Various natural compounds have been successfully tested for preventing or counteracting the toxic effects of exposure to heavy metals. In this study, we analyzed the effects of cadmium chloride (CdCl2) on immortalized, non-tumorigenic thyroid cells Nthy-ori-3-1. We investigated the molecular mechanism underlying its toxic action as well as the potential protective effect of quercetin against CdCl2-induced damage. CdCl2 suppressed cell growth in a dose- and time-dependent manner (IC50 value ~10 μM) associated with a decrease in levels of phospho-ERK. In addition, CdCl2 elicited an increase in reactive oxygen species (ROS) production and lipid peroxidation. A significant increase in GRP78, an endoplasmic reticulum (ER) stress-related protein, was also observed. Supplementation of quercetin counteracted the growth-inhibiting action of CdCl2 by recovering ERK protein phosphorylation levels, attenuating ROS overproduction, decreasing MDA content and reducing the expression of GRP78 in cells exposed to CdCl2. Thus, in addition to revealing the molecular effects involved in cadmium-induced toxicity, the present study demonstrated, for the first time, a protective effect of quercetin against cadmium-induced damages to normal thyroid cells.

Optimal management of patients with thyroid cancer requires the use of sensitive and specific biomarkers. For early diagnosis and effective follow-up, the currently available cytological and serum biomarkers, thyroglobulin and calcitonin, present severe limitations. Research on microRNA expression in thyroid tumors is providing new insights for the development of novel biomarkers that can be used to diagnose thyroid cancer and optimize its management. In this review, we will examine some of the methods commonly used to detect and quantify microRNA in biospecimens from patients with thyroid tumor, as well as the potential applications of these techniques for developing microRNA-based biomarkers for the diagnosis and prognostic evaluation of thyroid cancers.

In the last years public and scientific debate about the reduction of CO2 and polluting emissions has intensified and the importance of renewable energies and fuel has increased. Scientific researches on the economic possibility to use wood and biomass to obtain electric and thermal energy has shown contrasting results. Jatropha curcas is a multipurpose plant with many attributes and considerable potential . This species is considered of a great interest for plant oil production purposes in the last years, also for its ability to grow on ‘marginal lands’, not suitable for food crops. In these conditions, prohibitive for other species, it may be also utilized to prevent and/or control soil erosion and to reclaim abandoned lands because of its widespread root apparatus development. This approach requires strategic and spatial planning for the land use. The present study shows preliminary results froma research project, funded by the Calabria Region, aimed to promote the cultivation of Jatropha in Calabrian marginal areas, for agriculture and bioenergy purposes. Several experimental fields with Jatropha plants, performed last winter in Calabria, produced positive results, and first processes for biodiesel extraction have been started. In conclusion, the considerable potential of this plant, the low input requirements and its lower CO 2 footprint in comparison with other oil-bearing crops, as well as the ability to prevent soil erosion problems, are the main advantages and the main reasons to promote J. curcas L. cultivation in Calabrian marginal soils.

Concerns about climate change and food productivity have spurred interest in biochar, a form of charred organic material, typically applied in agriculture to improve soil productivity and as mean of carbon sequestration. An innovative approach in agriculture is the use of agro-industrial waste for the production of soil fertilizers for agricultural purposes and as a source of energy. A common agricultural practice is to burn crop residues in the field to produce ashes that can be used as soil fertilizers. This approach is able to supply plants with certain nutrients such as Ca, Na, K, Mg, B, S and Mo. However the lack of N and P in the ashes, together with the occasional presence of heavy metals (Ni, Pb, Cd, Se, Al, etc.), has a negative effect on soil and therefore crop productivity. This work describes the opportunity to create an innovative supply chain from agricultural waste biomass. Olive ( Olea europaea L.) and hazelnut ( Corylus avellana L.) pruning residues represent a major component of biomass waste in the area of Viterbo (Italy). In this study, we evaluated the production of biochar from these residues. Furthermore, a physico-chemical characterization of the produced biochar was performed to assess the quality of the two biochars according to the standards of the European Biochar Certificate (EBC). The results of this study indicate the cost-effective production of high- quality biochars from olive and hazelnuts biomass residues.

Growing evidence shows that dietary composition has a marked impact on the risk of developing obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), certain types of endocrine cancer and many other intertwined metabolic and reproductive disorders, all featured by insulin resistance (IR) [...]

Aging is a risk factor for the development of multiple chronic diseases, including cardiovascular disease, cancer and dementia. Life expectancy has increased in certain countries but this phenomenon is associated with a reduction of years of healthy life. Aging is associated with a number of physical and functional changes, especially sarcopenia. Sarcopenia is a clinical condition associated with a decrease in skeletal muscle and muscle strength, however, sarcopenia is a reversible condition. On the basis of the current scientific literature, sarcopenia could more appropriately capture an individual’s vulnerability to negative health-related outcomes since it represents an early form of the chronic diseases. Recognition of this clinical condition can improve the management of older individuals in many different clinical settings. Despite the limitations of the indirect methods used to study body composition, the Italian College of the Academic Nutritionists ME/49 recommends that health authorities and health professionals around the world should make a greater effort to diagnose sarcopenia earlier and to manage it more effectively. In line with the development of cancer screening, the use of two diagnostic tools for sarcopenia (BIA and DXA) should be implemented.

H&uuml, rthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. In both cases, metastatic tissues harbored a mutation of SETD2, each resulting in loss of the SRI and WW domains of SETD2, a methyltransferase that trimethylates H3K36 (H3K36me3) and also interacts with p53 to promote its stability. Functional studies of the novel p.D1890fs6* mutation (case 1) revealed significantly reduced H3K36me3 levels in SETD2-mutated tissue and primary cell cultures and decreased levels of the active form of p53. Restoration of SETD2-wildtype expression in the SETD2-mutant cells significantly reduced the expression of four well-known stemness markers (OCT-4, SOX2, IPF1, Goosecoid). These findings suggest potential roles for SETD2 loss-of-function mutations in HCC progression, possibly involving p53 destabilization and promotion of stemness. Their prevalence and potential treatment implications in thyroid cancer, especially HCC, require further study.

Phenolic secoiridoids from olive, including oleocanthal, oleuropein and related derivatives, are bioactive natural products with documented anticancer activities, that have mainly been attributed to their antioxidant, anti-inflammatory and antiproliferative effects. This review summarizes the results of the preclinical studies on the natural secoiridoids of olive used as single agents or in combination with other chemotherapeutics against cancer cells. The molecular targets of their action are described. A critical analysis of the importance of the experimental studies in view of the possible use in humans is also discussed.

Mutations in TERT promoter have been detected in the more aggressive papillary thyroid cancers (PTCs). To elucidate the role of TERT as an eligible molecular target in these tumors, the expression of hTERT was analyzed in a series of PTCs and the effects of both pharmacological and RNA-interference-induced hTERT silencing were investigated in two human PTC cell lines (K1 and BCPAP). The expression levels of hTERT mRNA and protein were evaluated by real-time PCR and western blot assays, respectively. Effects of hTERT silencing on PTC cell lines were analyzed by MTT, migration and western blot assays. Pharmacological inhibition of hTERT was performed using two bromodomain and extra-terminal (BET) inhibitors, JQ1 and I-BET762. hTERT expression results increased in 20 out of 48 PTCs, including tumors either positive or negative for the presence of hTERT promoter and/or BRAF mutations. In K1 and BCPAP cells, hTERT silencing determined a reduction in cell viability (~50% for K1 and ~70%, for BCPAP, vs control) and migration properties that were associated with a decrease of AKT phosphorylation and β-Catenin expression. Moreover, hTERT mRNA levels were down-regulated by two BET inhibitors, JQ1 and I-BET762, which at the same dosage (0.5 and 5 µM) reduced the growth of these thyroid cancer cells. These findings demonstrate that hTERT may represent an excellent therapeutic target in subgroups of aggressive PTCs.

Background. Obesity has been hypothesized to contribute to the aggressiveness of thyroid cancer through the production of abnormal levels of serum adipokines. Leptin receptor (OB-R) expression has also been documented in papillary thyroid cancer (PTC). Aim. In this translational study, we analyzed in vitro the effects of leptin on the growth and migration of thyroid cancer cells (TPC-1 and K1), the molecular mechanisms underlying leptin’s action, and the influence of prolonged leptin exposure on cell response to a protein kinase inhibitor lenvatinib. The expression levels of OB-R mRNA and protein were also investigated in vivo in a series of aggressive PTCs divided into two groups based on the presence of the BRAF mutation. Results. In TPC-1 and K1 cells, prolonged treatment with leptin (500 ng/ml for 96 h) resulted in a mild increase in the proliferation (about 20% over control only in K1 cells, p<0.05) and in the migration of both cancer cell lines. Immunoblot analysis revealed a slight increase in the phosphorylation of AKT, but no effect on β-catenin and phospho-ERK expressions. The inhibitory effects of lenvatinib on the viability of both cell lines were not influenced by the leptin treatment. OB-R transcript (in fresh tissues) and proteins (in formalin-fixed and paraffin-embedded specimens) were expressed in all PTC tissues examined, with no significant differences between BRAF-mutated and BRAF-wild-type tumors. Conclusions. These results demonstrate leptin’s role in mildly increasing the aggressive phenotype of PTC cells but without influencing the action of lenvatinib. Further studies will clarify whether it is possible to target OB-R, expressed in all aggressive PTCs, as an adjuvant treatment approach for these malignancies.

Many reports indicate that the protective action of nutraceuticals in the Mediterranean diet, against metabolic and cardiovascular diseases, can be attributed to the action of polyphenolic components of extra-virgin olive oil (EVOO). Here, we evaluated the protective effects of oleacein, one of the most abundant secoiridoids in EVOO, on the damages/metabolic alterations caused by high-fat diet (HFD) in male C57BL/6JolaHsd mice. After 5 weeks of treatment with 20 mg/kg of oleacein, body weight, glycemia, insulinemia, serum lipids, and histologic examination of liver tissue indicated a protective action of oleacein against abdominal fat accumulation, weight gain, and liver steatosis, with improvement of insulin-dependent glucose and lipid metabolism. Both serum parameters and hepatic histologic examination were altered in mice fed with HFD. By contrast, in the animals that received oleacein, plasma glucose, cholesterol and triglyceride serum levels, and liver histology were similar to controls fed with normocaloric diet. In addition, protein levels of FAS, SREBP-1, and phospho-ERK in liver were positively modulated by oleacein, indicating an improvement in liver insulin sensitivity. In a group of obese mice, treatment with oleacein determined a light, but still significant reduction of the increase in body weight, mainly due to lesser liver steatosis enlargement, associated with reduced levels of SREBP-1 and phospho-ERK and lower levels of total serum cholesterol; in these animals, altered plasma glucose and triglyceride serum levels were not reverted by oleacein. These results indicate that HFD-related hepatic insulin resistance may be partially prevented by oral administration of oleacein, suggesting a protective role of this nutraceutical against diet-dependent metabolic alterations. Additional studies are necessary to check whether oleacein can be used as an adjuvant to improve insulin sensitivity in humans.

A substantial proportion of patients with advanced thyroid carcinoma fail to respond to or at some point become refractory to conventional therapies. This resistance and the phenomena of thyroid cancer progression and metastasis themselves are thought to be related to tumor-cell sub-populations with stem-like properties. We isolated thyrospheres from four advanced thyroid carcinomas that were resistant to radioiodine therapy and analyzed their molecular profiles. ALDH activity and proteomic profile of main stem cell markers were used to assess stem cell properties. The TaqMan Low Density Array approach was used to evaluate the expression of several genes involved in the EMT process. The phosphorylation status of tyrosine kinase receptors (RTKs) was analyzed to identify potential markers for targeted therapies. We then investigated the effects of the EMT-inhibitor crizotinib on both cell proliferation and phosphorylation status of RTK targets. The cancer stem-like properties of a subset of cells from primary cultures of each tumor were demonstrated. A wide variability among thyrospheres arising from the four thyroid cancers in terms of ALDH activity, stem cell marker expression, and phosphoproteome profiling was present. Dysregulated expression of genes involved in the EMT was observed in all four thyrosphere lines. Treatment with crizotinib was ineffective in cancer stem-like cells, suggesting the presence of a mechanism of resistance in thyrospheres. Collectively, our data indicate that thyroid cancer stem-like populations vary markedly from tumor to tumor and require detailed molecular and biological characterization if they are to be used as the basis of "personalized" treatment of aggressive disease.

Effects of flavonoids extracted from Citrus reticulata (mandarin) juice on proliferation and migration of 3 human anaplastic thyroid carcinoma (ATC) cell lines were evaluated. Flavonoid components of Mandarin juice extract (MJe) were analyzed by uHPLC. Proliferation of CAL-62, C-643, and 8505C cells, measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, was significantly reduced by MJe in a concentration- and time-dependent way, with maximal effect elicited at 0.5 mg/ml concentration after 48 h. Cytofluorimetric analysis showed a block in the G2/M phase of the cell cycle, accompanied by low cell mortality owed to autophagic death. The extract caused also a reduction of cell migration, associated with decreased activity of the metalloproteinase MMP-2. These findings demonstrate that the flavonoid fraction of mandarin juice exerts in vitro antiproliferative effects on ATC cells, associated with a reduction of migration, suggesting for such a functional food a potential use as adjuvant in the treatment of thyroid cancer.

Recent studies have revealed in normal thyroid tissue the presence of the transcript of several phosphodiesterases (PDEs), enzymes responsible for the hydrolysis of cyclic nucleotides. In this work, we analyzed the expression of PDE5 in a series of human papillary thyroid carcinomas (PTCs) presenting or not BRAF V600E mutation and classified according to ATA risk criteria. Furthermore, we tested the effects of two PDE5 inhibitors (sildenafil, tadalafil) against human thyroid cancer cells. PDE5 gene and protein expression were analyzed in two different cohorts of PTCs by real-time PCR using a TaqMan micro-fluid card system and Western blot. MTT and migration assay were used to evaluate the effects of PDE5 inhibitors on proliferation and migration of TPC-1, BCPAP, and 8505C cells. In a first series of 36 PTCs, we found higher expression levels of PDE5A in tumors versus non-tumor (normal) tissues. PTCs with BRAF mutation showed higher levels of mRNA compared with those without mutation. No significant differences were detected between subgroups with low and intermediate ATA risk. Upregulation of PDE5 was also detected in tumor tissue proteins. Similar results were obtained analyzing the second cohort of 50 PTCs. Moreover, all tumor tissues with high PDE5 levels showed reduction of Thyroglobulin, TSH receptor, Thyroperoxidase, and NIS transcripts. In thyroid cancer cells in vitro, sildenafil and tadalafil determined a reduction of proliferation and cellular migration. Our findings demonstrate for the first time an overexpression of PDE5 in PTCs, and the ability of PDE5 inhibitors to block the proliferation of thyroid cancer cells in culture, therefore, suggesting that specific inhibition of PDE5 may be proposed for the treatment of these tumors.

The high consumption of olive tree products in the Mediterranean diet has been associated with a lower incidence of metabolic disorders and cardiovascular diseases. In particular, the protective effects of olive oil have been attributed to the presence of polyphenols such as oleuropein (Ole) and its derivatives. We have synthesized a peracetylated derivative of Ole (Ac-Ole) which has shownin vitroantioxidant and growth-inhibitory activity higher than the natural molecule. In this study, male C57BL/6JOlaHsd mice were fed with a standard (std), cafeteria (caf) diet, and caf diet supplemented with Ole (0.037 mmol/kg/day) and Ac-Ole (0.025 mmol/kg/day) for 15 weeks. We observed a significant reduction in the caf diet-induced body weight gain and increase of abdominal adipose tissue. Also, Ole and Ac-Ole prevented the development of hepatic steatosis. Finally, Ole and Ac-Ole determined a lower increase of HDL and LDL-cholesterol levels and corrected caf diet-induced elevation of plasma glucose concentrations by improving insulin sensitivity. The observed beneficial properties of Ole and Ac-Ole make these compounds and in particular Ac-Ole promising candidates for a potential pharmaceutic use in metabolic disorders.

Anaplastic thyroid cancer (ATC) constitutes one of the most aggressive types of human solid cancer, and is characterized by the absence of thyroid differentiation features and a marked degree of invasiveness. We have previously demonstrated that the RNA-binding protein Hu antigen R (HuR) is overexpressed in thyroid carcinoma; thus, the biological role of this RNA-binding protein was investigated in the present study using the ATC cell lines SW1736 and 8505C. In both cell lines, HuR protein levels were higher compared with in the non-tumorigenic thyroid cell line Nthy-ori-3.1. HuR silencing by RNA interference in both ATC cell lines decreased cell viability, increased apoptosis rates and reduced the capability to form colonies in soft agar. Thus, HuR plays an important role in the proliferation and aggressiveness of ATC cells. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) was able to reduce the viability of ATC cells. The results demonstrated that SAHA was able to decrease HuR expression in SW1736 and 8505C cells. Furthermore, since it is known that the transcription factor nuclear factor (NF)-κB modulates HuR expression, whether SAHA affects the nuclear (active) fraction of NF-κB in ATC cells was investigated. The data suggested that SAHA decreases ATC cell viability by reducing the active form of NF-κB, which, in turn, modulates HuR expression.

Application of distinct technologies of cancer genome analysis has provided important information for the molecular characterization of several human neoplasia, including follicular cell-derived thyroid carcinoma. Among them, comparative genomic hybridization (CGH)-based procedures have been extensively applied to evaluate genomic imbalances present in these tumours, obtaining data leading to an increase in the understanding of their complexity and diversity. In this review, after a brief overview of the most commonly used CGH-based technichs, we will describe the major results deriving from the most influential studies in the literature which used this approach to investigate the genomic aberrations of thyroid cancer cells. In most studies a small number of patients have been analyzed. Deletions and duplications at different chromosomal regions were detected in all investigated cohorts. A higher number of genomic imbalances has been detected in anaplastic or poorly differentiated thyroid carcinomas compared to well differentiated ones. Limitations in the interpretation of the results, as well the potential impact in the clinical practice are discussed. Though a quite heterogeneous picture arises from results so far available, CGH array, combined with other methodologies as well as an accurate clinical management, may offer novel opportunities for a better stratification of thyroid cancer patients.

The high frequency of

Histone post-translational modifications (HPTMs) play a major role in control of gene transcription. Among them, histone acetylation and methylation have been extensively investigated. Histone acetylation at different residues is generally associated to active gene transcription. In contrast, histone methylation can be associated either to transcriptional activation or repression, depending primarily on the histone residue that is subjected to the modification. Herein, effects of the histone deacetylase inhibitor SAHA on the sodium-iodide symporter (NIS) gene expression were investigated in breast cancer cells (MDA157 and MDA468). SAHA treatment induces high increase of NIS mRNA levels in MDA468 cells (300-fold), but moderate increase in MDA157 cells (fivefold). Histone H3 HPTMs (acetylation and methylations) on transcriptional units of NIS gene were investigated in these cell lines upon SAHA treatment. Our data indicate that HPTMs, particularly the H3 lysine 27 trimethylation, may operate in contrast to current models that relate epigenetic modifications with transcriptional activity.