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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.

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.

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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.

In this study, we investigated the profile of microRNAs (miRNAs) contained in exosomes secreted in the serum of patients with papillary thyroid cancer (PTC). Exosome were isolated by adding ExoQuick Exosome Precipitation Solution. Dynamic light scattering (DLS) and western blotting analysis were used to ensure the quality of exosomes. The expression levels of miRNAs were investigated using custom-designed TaqMan Advanced miRNA Array Cards in the screening cohort and using specific TaqMan Advanced MicroRNA Assays in the validation cohort. We identified miR24-3p, miR146a-5p, miR181a-5p and miR382-5p with different expression levels in two different series of 56 and 58 PTC patients as compared with healthy controls. Significant differences in the expression of three PTC exosomal miRNAs, depending on the presence of lymph node metastasis, were detected in only one PTC series. When comparing the expression levels of some PTC-specific exosomal miRNAs with those of the same miRNAs circulating free of any encapsulation, we found a significant correlation for only miR24-3p, suggesting that only select miRNAs are secreted in exosomes. Our findings demonstrate that four miRNAs are differently secreted in the exosomes of PTC patients, whereas no conclusive results were found to characterize PTCs with lymph node metastasis, suggesting caution in the use of circulating exosomal miRNA expression levels as lymph node metastasis biomarkers. Further investigation into the mechanisms governing miRNA secretion in tumor cells are required.

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.

Hu antigen R (HuR) is indeed one of the most studied RNA-binding protein (RBP) since its fundamental role both in tumorigenesis and cancer progression. For this reason, downregulation in HuR protein levels or inhibition of HuR biological function are, nowadays, attractive goals in cancer research. Here, we examined the antitumor effects of CMLD-2 in four thyroid cancer cell lines (SW1736, 8505 C, BCPAP and K1). Indeed, CMLD-2 competitively binds HuR protein disrupting its interaction with RNA-targets. 35 μM CLMD-2 produced a significant downregulation in thyroid cancer cell viability, coupled to an increase in apoptosis. Moreover, CMLD-2 treatment hindered both migration and colony formation ability. MAD2 is a microtubules-associated protein known to be greatly overexpressed in cancer and correlating with tumor aggressiveness. Furthermore, MAD2 is known to be a HuR target. CMLD-2 treatment induced a strong MAD2 downregulation and rescue experiments depicted it as a key effector in HuR-mediated in cancer. Altogether, these data contributed to foster HuR inhibition as valid antineoplastic treatment in thyroid cancer, highlighting MAD2 as a novel therapeutic target.

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.

Epidemiological evidence has confirmed the potential causal relationship between specific dietary factors and non-communicable diseases. However, currently nutrition was shown to be insufficiently integrated into medical education, regardless of the country. Without an adequate nutrition education, it is reasonable to assume that future physicians, as well as other health care professionals, will be not able to provide the highest quality care to patients in preventing and treating non-communicable diseases. Furthermore, the insufficient availability of physicians with specializations in nutrition has posed the basis for the development of non-medical careers in the field of nutrition. The present document was drafting by the Italian College of Academic Nutritionists, MED-49 (ICAN-49), with the aim to provide an overview on the nutritional competency standards covered by several health care professionals (Physicians Clinical Nutrition Specialists, Clinical Dietitians, Professional Clinical Nutrition Specialists, etc) for the prevention of diseases and/or support of pharmacological therapies. The aim of the ICAN 49 is to suggest a major shift in practice opportunities and roles for many nutritionists, especially for the management of the metabolic diseases, and promote a paradigm change: a clinical and educational leadership role for Physician Clinical Nutrition Specialists in the hospital setting.

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.

Insulin resistance (IR), defined as an attenuated biological response to circulating insulin, is a fundamental defect in obesity and type 2 diabetes (T2D), and is also linked to a wide spectrum of pathological conditions, such as non-alcoholic fatty liver disease (NAFLD), cognitive impairment, endothelial dysfunction, chronic kidney disease (CKD), polycystic ovary syndrome (PCOS), and some endocrine tumors, including breast cancer. In obesity, the unbalanced production of pro- and anti-inflammatory adipocytokines can lead to the development of IR and its related metabolic complications, which are potentially reversible through weight-loss programs. The Mediterranean diet (MedDiet), characterized by high consumption of extra-virgin olive oil (EVOO), nuts, red wine, vegetables and other polyphenol-rich elements, has proved to be associated with greater improvement of IR in obese individuals, when compared to other nutritional interventions. Also, recent studies in either experimental animal models or in humans, have shown encouraging results for insulin-sensitizing nutritional supplements derived from MedDiet food sources in the modulation of pathognomonic traits of certain IR-related conditions, including polyunsaturated fatty acids from olive oil and seeds, anthocyanins from purple vegetables and fruits, resveratrol from grapes, and the EVOO-derived, oleacein. Although the pharmacological properties and clinical uses of these functional nutrients are still under investigation, the molecular mechanism(s) underlying the metabolic benefits appear to be compound-specific and, in some cases, point to a role in gene expression through an involvement of the nuclear high-mobility group A1 (HMGA1) protein.

Exposure to environmental endocrine disruptors has been associated with an increased frequency of thyroid pathology. In this study, we evaluated the effects of various concentrations of methylmercury (MeHg) on immortalized, non-tumorigenic thyroid cells (Nthy-ori-3-1). Exposure to MeHg at 2.5 and 5 &micro, M for 24 h caused a reduction in cell viability with a decrease of the cell population in sub-G0 phase, as detected by MTT and flow cytometry. Conversely, MeHg at the lower concentration of 0.1 &micro, M increased the cell viability with a rise of G2/M phase. An immunoblot analysis showed higher expression levels of phospho-ERK and not of phospho-Akt. Further enhancement of the cell growth rate was observed after a prolonged exposure of the cells up to 18 days to MeHg 0.1 &micro, M. The present findings demonstrate the toxicity of high concentrations of MeHg on thyroid cells, while showing that treatment with lower doses of Hg, as may occur after prolonged exposure to this environmental contaminant, exerts a promoting effect on thyroid cell proliferation, by acting on the ERK-mediated pro-oncogenic signal transduction pathway.

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.