NSCLC as the Paradigm of Precision Medicine at Its Finest: The Rise of New Druggable Molecular Targets for Advanced Disease

Standard treatment for advanced non-small cell lung cancer (NSCLC) historically consisted of systemic cytotoxic chemotherapy until the early 2000s, when precision medicine led to a revolutionary change in the therapeutic scenario. The identification of oncogenic driver mutations in EGFR, ALK and ROS1 rearrangements identified a subset of patients who largely benefit from targeted agents. However, since the proportion of patients with druggable alterations represents a minority, the discovery of new potential driver mutations is still an urgent clinical need. We provide a comprehensive review of the emerging molecular targets in NSCLC and their applications in the advanced setting.     

Chronic Hyperkaliemia in Chronic Kidney Disease: An Old Concern with New Answers

Increasing potassium intake ameliorates blood pressure (BP) and cardiovascular (CV) prognoses in the general population; therefore the World Health Organization recommends a high-potassium diet (90–120 mEq/day). Hyperkalaemia is a rare condition in healthy individuals due to the ability of the kidneys to effectively excrete dietary potassium load in urine, while an increase in serum K⁺ is prevalent in patients with chronic kidney disease (CKD). Hyperkalaemia prevalence increases in more advanced CKD stages, and is associated with a poor prognosis. This scenario generates controversy on the correct nutritional approach to hyperkalaemia in CKD patients, considering the unproven link between potassium intake and serum K⁺ levels. Another concern is that drug-induced hyperkalaemia leads to the down-titration or withdrawal of renin-angiotensin system inhibitors (RASI) and mineralocorticoids receptors antagonists (MRA) in patients with CKD, depriving these patients of central therapeutic interventions aimed at delaying CKD progression and decreasing CV mortality. The new K⁺-binder drugs (Patiromer and Sodium-Zirconium Cyclosilicate) have proven to be adequate and safe therapeutic options to control serum K⁺ in CKD patients, enabling RASI and MRA therapy, and possibly, a more liberal intake of fruit and vegetables.     

Lipidomic Approaches to Study HDL Metabolism in Patients with Central Obesity Diagnosed with Metabolic Syndrome

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated “omics” approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (vs. controls). Compared with healthy subjects, MetS patients showed higher free fatty acids, diglycerides, phosphatidylcholines, and triglycerides, particularly those enriched in products of de novo lipogenesis. On the other hand, the “lysophosphatidylcholines to phosphatidylcholines” and “cholesteryl ester to free cholesterol” ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated “omics” approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.     

达涅利薄板坯连铸连轧设备最新技术成果

给出达涅利薄板坯连铸连轧技术的最新应用成果.这些成果表明,达涅利技术不仅用于生产普通钢种,还可用于生产质量要求严格的优质钢种和高附加值产品.由达涅利在尼兹尼.诺夫戈罗德区Vyksa建设1套CRC(连铸连轧)设备.这是在俄罗斯建设的第1套薄板坯连铸连轧设备,也是世界上第1套利用薄板坯连铸连轧工艺路线生产北极高寒地区用API管线钢的生产设备.另外2套设备已在中国唐山钢铁集团有限公司和本溪钢铁集团有限公司进入满负荷生产阶段,前者一直保持着设备生产能力世界纪录,后者则成为中国第一家利用薄板坯连铸连轧工艺生产硅钢的厂家.     

达涅利厚板坯连铸新技术和样板生产厂

达涅利戴维·迪斯汀顿是达涅利集团中负责板坯连铸机设备设计和供货的一家专业公司,通过与用户密切合作,开发了许多创新设备,如获得专利的INMO结晶器和OPTIMUM最优化扇形段,推出许多先进的连铸技术,如动态轻压下等,极大地促进了连铸技术的发展.正是由于这些先进技术,才有可能使达涅利在近些年来为世界上最先进的连铸板坯生产厂家提供连铸设备,其中包括韩国浦项、德国蒂森克虏伯、中国宝钢和法国阿赛洛米塔尔.介绍了达涅利的这些创新设备和它们在2006年12月份几乎同时试车投产的两家著名钢厂,宝钢(中国)和阿赛洛米塔尔(法国敦克尔克)的使用情况.     

Cytokines from Bench to Bedside: A Retrospective Study Identifies a Definite Panel of Biomarkers to Early Assess the Risk of Negative Outcome in COVID-19 Patients

The main aim of this study was to identify the most relevant cytokines which, when assessed in the earliest stages from hospital admission, may help to select COVID-19 patients with worse prognosis. A retrospective observational study was conducted in 415 COVID-19 patients (272 males; mean age 68 ± 14 years) hospitalized between May 2020 and March 2021. Within the first 72 h from hospital admission, patients were tested for a large panel of biomarkers, including C-reactive protein (CRP), Mid-regional proadrenomedullin (MR-proADM), Interferon-γ, interleukin 6 (IL-6), IL-1β, IL-8, IL-10, soluble IL2-receptor-α (sIL2Rα), IP10 and TNFα. Extensive statistical analyses were performed (correlations, t-tests, ranking tests and tree modeling). The mortality rate was 65/415 (15.7%) and a negative outcome (death and/or orotracheal intubation) affected 98/415 (23.6%) of cases. Univariate tests showed the majority of biomarkers increased in severe patients, but ranking tests helped to select the best variables to put on decisional tree modeling which identified IL-6 as the first dichotomic marker with a cut-off of 114 pg/mL. Then, a good synergy was found between IL-10, MR-proADM, sIL2Rα, IP10 and CRP in increasing the predictive value in classifying patients at risk or not for a negative outcome. In conclusion, beside IL-6, a panel of other cytokines representing the degree of immunoparalysis and the anti-inflammatory response (IP10, sIL2Rα and IL-10) showed synergic role when combined to biomarkers of systemic inflammation and endothelial dysfunction (CRP, MR-proADM) and may also better explain disease pathogenesis and suggests targeted intervention.     

Analyzing the relationship between car generation and severity of motor-vehicle crashes in Denmark

While the number of fatalities on Danish roads has decreased in the last 40 years, research has not investigated the contribution of legislation changes, enforcement measures, technological enhancements, infrastructural improvements and human factors to this reduction. In the context of a Danish car market with remarkably high registration tax that causes potential buyers to hold longer onto old cars, the relationship between technological enhancements of vehicles and severity of crashes requires particular attention.     

Single crystal silicon nanopillars, nanoneedles and nanoblades with precise positioning for massively parallel nanoscale device integration

Arrays of precisely positioned single crystal silicon nanopillars, nanoneedles, and nanoblades with minimum feature sizes as small as 30 nm are fabricated using entirely scalable top-down fabrication techniques. Using the same scalable technologies, devices consisting of electrically connected silicon nanopillars with multiple addressable electrodes for each nanostructure are realized. The arrays of nanopillars, nanoneedles, and nanoblades are shown to exhibit Raman signal enhancement on 1,2-benzenedithiol monolayers, opening a path to nanodevices that manipulate, position, detect and analyze molecules.