Miracle-dz/UniFAR-FTUs huggingface dataset:
The Value of Real-World Data in Understanding Prostate Cancer Risk and Improving Clinical Care: Examples from Swedish Registries

Simple Summary Real-world data (RWD), i.e., data reflecting normal clinical practice collected outside the constraints of randomised controlled trials, provide important insights into our understanding of prostate cancer and its management. Clinical cancer registries are an important source of RWD. Depending on their scope and the potential linkage to other data sources, registry-based data can be utilised to address a variety of questions including risk factors, healthcare utilisation, treatment effectiveness, adverse effects, disparities in healthcare access, quality of care and healthcare economics. This review describes the various registry-based RWD sources for prostate cancer research in Sweden (namely the National Prostate Cancer Register, the Prostate Cancer data Base Sweden (PCBaSe) and the Patient-overview Prostate Cancer) and documents their utility for better understanding prostate cancer aetiology and improving clinical care. Abstract Real-world data (RWD), that is, data from sources other than controlled clinical trials, play an increasingly important role in medical research. The development of quality clinical registers, increasing access to administrative data sources, growing computing power and data linkage capacities have contributed to greater availability of RWD. Evidence derived from RWD increases our understanding of prostate cancer (PCa) aetiology, natural history and effective management. While randomised controlled trials offer the best level of evidence for establishing the efficacy of medical interventions and making causal inferences, studies using RWD offer complementary evidence about the effectiveness, long-term outcomes and safety of interventions in real-world settings. RWD provide the only means of addressing questions about risk factors and exposures that cannot be “controlled”, or when assessing rare outcomes. This review provides examples of the value of RWD for generating evidence about PCa, focusing on studies using data from a quality clinical register, namely the National Prostate Cancer Register (NPCR) Sweden, with longitudinal data on advanced PCa in Patient-overview Prostate Cancer (PPC) and data linkages to other sources in Prostate Cancer data Base Sweden (PCBaSe).
Immune Checkpoint Inhibitor-Induced Diabetes Mellitus: Potential Role of T Cells in the Underlying Mechanism

Immunotherapy is now a recognized treatment option for several types of cancer. However, some cancer patients treated with immune checkpoint inhibitors (ICIs) are subject to immune-related adverse events, including induced diabetes mellitus. The exact role and molecular/genetic action of ICIs in diabetes are still not well understood. Elucidating the underlying mechanisms in a proper fashion would allow better refining of biomarkers that would help diagnose patients at risk of altered immune system homeostasis, but would also hold the potential of new therapeutic options for diabetes. In the present narrative review, we propose to discuss the case of autoimmune diabetes following treatment with ICIs and the role of ICIs in the pathophysiology of diabetes. We also present some scarce available data on interesting potential immune therapies for diabetes.
Health Potential of Aloe vera against Oxidative Stress Induced Corneal Damage: An “In Vitro” Study

Fuchs endothelial corneal dystrophy (FECD) is characterized by the gradual deterioration of corneal endothelial cells (CECs) and is the most common cause of corneal transplantation worldwide. CECs apoptosis caused by oxidative stress plays a pivotal role in the pathogenesis of FECD. Antioxidant compounds have been of considerable significance as a candidate treatment in the management of corneal diseases. Based on these findings, the objective of this study was to evaluate the effects of an aloe extract with antioxidant properties, in an “in vitro” model of FECD. Human corneal epithelial (HCE) cells were preincubated with aloe extract 100 μg/mL, two hours before hydrogen peroxide (H2O2) stimulus. H2O2 challenge significantly reduced the cell viability, increased the generation of Reactive Oxygen Species (ROS) and malondialdehyde levels. Moreover, m-RNA expression and activity of Nrf-2, Catalase and Superoxide dismutase (SOD) were reduced together with an enhanced expression of IL-1β, tumor necrosis factor-α (TNF-α), IL-6, and cyclooxygenase 2 (COX-2). Furthermore, Bcl-2, Caspase-3 and Caspase-8 expression were down-regulated while Bax was up-regulated by H2O2 stimulus. Aloe extract blunted the oxidative stress-induced inflammatory cascade triggered by H2O2 and modulated apoptosis. Aloe extract defends HCE cells from H2O2-induced injury possibly due its antioxidant and anti-inflammatory activity, indicating that eye drops containing aloe extract may be used as an adjunctive treatment for FECD.
Oligomeric Aβ1-42 Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function

Alzheimer’s disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ1-42, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.
Physico-Chemical Characterization and Biological Activities of a Digestate and a More Stabilized Digestate-Derived Compost from Agro-Waste

The excessive use of agricultural soils and the reduction in their organic matter, following circular economy and environmental sustainability concepts, determined a strong attention in considering composting as a preferred method for municipalities and industries to recycle organic by-products. Microorganisms degrade organic matter for producing CO2, water and energy, originating stable humus named compost. The current study analyzed the chemical composition of a cow slurry on-farm digestate and a more stabilized digestate-derived compost (DdC), along with their phytotoxic, genotoxic and antifungal activities. The chemical analysis showed that digestate cannot be an ideal amendment due to some non-acceptable characteristics. Biological assays showed that the digestate had phytotoxicity on the tested plants, whereas DdC did not induce a phytotoxic effect in both plants at the lowest dilution; hence, the latter was considered in subsequent analyses. The digestate and DdC induced significant antifungal activity against some tested fungi. DdC did not show genotoxic effect on Vicia faba using a micronuclei test. Soil treated with DdC (5 and 10%) induced damping-off suppression caused by Fusarium solani in tomato plants. The eco-physiological data indicated that DdC at 5–10% could increase the growth of tomato plants. In conclusion, DdC is eligible as a soil amendment and to strengthen the natural soil suppressiveness against F. solani.
Role of Constitutive STAR in Leydig Cells

Leydig cells contain significant amounts of constitutively produced steroidogenic acute regulatory protein (STAR; STARD1). Hormone-induced STAR plays an essential role in inducing the transfer of cholesterol into the mitochondria for hormone-dependent steroidogenesis. STAR acts at the outer mitochondrial membrane, where it interacts with a protein complex, which includes the translocator protein (TSPO). Mutations in STAR cause lipoid congenital adrenal hyperplasia (lipoid CAH), a disorder characterized by severe defects in adrenal and gonadal steroid production; in Leydig cells, the defects are seen mainly after the onset of hormone-dependent androgen formation. The function of constitutive STAR in Leydig cells is unknown. We generated STAR knockout (KO) MA-10 mouse tumor Leydig cells and showed that STAR KO cells failed to form progesterone in response to dibutyryl-cAMP and to TSPO drug ligands, but not to 22(R)-hydroxycholesterol, which is a membrane-permeable intermediate of the CYP11A1 reaction. Electron microscopy of STAR KO cells revealed that the number and size of lipid droplets were similar to those in wild-type (WT) MA-10 cells. However, the density of lipid droplets in STAR KO cells was drastically different than that seen in WT cells. We isolated the lipid droplets and analyzed their content by liquid chromatography–mass spectrometry. There was a significant increase in cholesteryl ester and phosphatidylcholine content in STAR KO cell lipid droplets, but the most abundant increase was in the amount of diacylglycerol (DAG); DAG 38:1 was the predominantly affected species. Lastly, we identified genes involved in DAG signaling and lipid metabolism which were differentially expressed between WT MA-10 and STAR KO cells. These results suggest that constitutive STAR in Leydig cells is involved in DAG accumulation in lipid droplets, in addition to cholesterol transport. The former event may affect cell functions mediated by DAG signaling.
Refining the marine reptile turnover at the Early–Middle Jurassic transition

Even though a handful of long-lived reptilian clades dominated Mesozoic marine ecosystems, several biotic turnovers drastically changed the taxonomic composition of these communities. A seemingly slow paced, within-geological period turnover took place across the Early–Middle Jurassic transition. This turnover saw the demise of early neoichthyosaurians, rhomaleosaurid plesiosaurians and early plesiosauroids in favour of ophthalmosaurid ichthyosaurians and cryptoclidid and pliosaurid plesiosaurians, clades that will dominate the Late Jurassic and, for two of them, the entire Early Cretaceous as well. The fossil record of this turnover is however extremely poor and this change of dominance appears to be spread across the entire middle Toarcian–Bathonian interval. We describe a series of ichthyosaurian and plesiosaurian specimens from successive geological formations in Luxembourg and Belgium that detail the evolution of marine reptile assemblages across the Early–Middle Jurassic transition within a single area, the Belgo–Luxembourgian sub-basin. These fossils reveal the continuing dominance of large rhomaleosaurid plesiosaurians, microcleidid plesiosaurians and Temnodontosaurus-like ichthyosaurians up to the latest Toarcian, indicating that the structuration of the upper tier of Western Europe marine ecosystems remained essentially constant up to the very end of the Early Jurassic. These fossils also suddenly record ophthalmosaurid ichthyosaurians and cryptoclidid plesiosaurians by the early Bajocian. These results from a geographically-restricted area provide a clearer picture of the shape of the marine reptile turnover occurring at the early–Middle Jurassic transition. This event appears restricted to the sole Aalenian stage, reducing the uncertainty of its duration, at least for ichthyosaurians and plesiosaurians, to 4 instead of 14 million years.
Vaccine Hesitancy among Italian Patients Recovered from COVID-19 Infection towards Influenza and Sars-Cov-2 Vaccination

We aimed to assess the attitude towards influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations among coronavirus disease 2019 (COVID-19) recovered patients. We performed a cross-sectional study consisting of a standardized telephone interview carried out between September and November 2020 targeting a cohort of adult in- and out-patients that had recovered from COVID-19 after the first wave (March–May 2020) at Udine Hospital (Italy). Overall, 599 people participated (320 female, median age 53 years) and most had experienced an acute COVID-19 with mild illness (409, 68.3%). The majority were hesitant or undecided towards influenza (327, 54.6%) and SARS-CoV-2 (353, 59.2%) vaccines. Older age, public work exposure, and previous 2019 flu shots were the main factors associated with a positive attitude toward both vaccinations (p < 0.05). Being hospitalized during the acute COVID-19 phase was associated with the willingness to get a flu shot (94/272, 34.5%) but not SARS-CoV-2 vaccine (70/244, 28.7%). Vaccine hesitancy is diffuse and multifactorial also among COVID-19 recovered.
Optimisation of the Extrusion Process through a Response Surface Methodology for Improvement of the Physical Properties and Nutritional Components of Whole Black-Grained Wheat Flour

Chronic undernourishment affects billions of people. The development of whole-grain food with high nutritional quality may provide a valuable solution to nutritional security. Black-grained wheat (BGW), as a rich source of protein and micronutrients, is a good raw material for value-added products. The objectives of this study were to investigate the effects of barrel temperature, feed moisture content, and feed rate on the physical properties and nutritional components of whole BGW flour extrudates and to optimise their processing conditions by using the response surface methodology. The increasing barrel temperature, feed moisture content, and feed rate affected the specific volume, expansion ratio, hardness, fracturability, water absorption index (WAI), water solubility index (WSI), and total starch content of the extrudates, but did not significantly affect the content of protein, ash, iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn). The extruded wheat flour had a significantly higher content of Fe and Cu, and a lower total starch content than the unextruded flour under extrusion conditions. A significantly higher content of protein, ash, Zn, Cu, and Mn, and a significantly lower total starch content were found in the extruded and unextruded flours made of whole BGW than in those made of whole white-grained wheat. According to the significance of the regression coefficients of the quadratic polynomial model, the optimum extrusion parameters were as follows: a barrel temperature of 145.63 °C, feed moisture content of 19.56%, and feed rate of 40.64 g·min−1 in terms of the maximum specific volume, expansion ratio, fracturability, WAI and WSI, and the minimum hardness. These results may be used by food manufacturers to successfully develop extruded products from whole BGW flour, meeting consumer demands and needs.
Antioxidant Activity and Bio-Accessibility of Polyphenols in Black Carrot (Daucus carota L. ssp. sativus var. atrorubens Alef.) and Two Derived Products during Simulated Gastrointestinal Digestion and Colonic Fermentation

Black carrot has been attracting increasing thanks to its high bioactive compound content. This study presents the polyphenol bio-accessibility of black carrot and two derived products (black carrot snack (BC snack) and black carrot seasoning (BC seasoning)) after in vitro gastrointestinal digestion and colonic fermentation. Additionally, antioxidant activity was measured by 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS), 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) assays. Nine flavonoids and eight anthocyanins were determined by ultra high-performance liquid chromatography high resolution mass spectrometry (UHPLC-HRMS) analysis, the predominant compounds being the hydroxycinnamic acids 3-O-feruloylquinic acid, 4-O-feruloylquinic acid and chlorogenic acid. The BC snack (108 µmol/g DW) presented the highest total polyphenol content, followed by BC seasoning (53 µmol/g DW) and black carrot (11.4 µmol/g DW). The main polyphenols still bio-accessible after in vitro digestion were the hydroxycinnamic acids, with mean recovery rates of 113 % for black carrot, 69% for BC snack and 81% for BC seasoning. The incubation of black carrot and its derived products with human faecal bacterial resulted in the complete degradation of anthocyanins and in the formation of mainly 3-(4′-hydroxyphenyl)propanoic acid as the major catabolic event. In conclusion, our results suggest that the black carrot matrix impacts significantly affects the bio-accessibility of polyphenols and, therefore, their potential health benefits.
Atomic Layer Deposition of ZrO2 on Titanium Inhibits Bacterial Adhesion and Enhances Osteoblast Viability

Purpose The study was intended to create a uniform zirconia layer even on the surface of complex structures via atomic layer deposition (ALD). The impact of crystalline zirconia deposited by ALD on bacterial adhesion and osteoblast viability was assessed via surface treatment of dental implants. Methods Amorphous zirconia was deposited using an atomic layer deposition reactor (Atomic Classic, CN1, Hwaseong, Korea) on titanium discs. Heating the samples at 400°C resulted in crystallization. Samples were divided into three groups: the control group, the group carrying amorphous ALD-zirconia (Z group), and the heat-treated group following zirconia ALD deposition (ZH group). The surface of each sample was analyzed, followed by the assessment of adhesion of Streptococcus mutans and Porphyromonas gingivalis, and viability and differentiation of MC3T3-E1 cells. Results The adhesion of S. mutans and P. gingivalis was significantly reduced in the Z and ZH groups compared with the control group (P < 0.05). The viability of MC3T3-E1 cells was significantly increased in the ZH group compared with the control group (P < 0.001), while no significant differences were observed in the Z group (P > 0.05). Differentiation of MC3T3-E1 cells showed a marginally significant increase in the ZH group compared with the control group (P < 0.1), while no significant differences were found in the Z group (P > 0.1). Conclusion Compared with the pure titanium group, the groups that were coated with zirconia via ALD showed a decreased adhesion of S. mutans during the early stages of biofilm formation and P. gingivalis adhesion inducing peri-implantitis, and an increase in MC3T3-E1 cell viability and differentiation. The findings indicate the possibility of treating the implant surface to reduce peri-implantitis and improve osseointegration.
Homocysteine in Neurology: A Possible Contributing Factor to Small Vessel Disease

Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols/L is defined as hyperhomocysteinemia (HHcy). Hcy has many roles, the most important being the active participation in the transmethylation reactions, fundamental for the brain. Many studies focused on the role of homocysteine accumulation in vascular or degenerative neurological diseases, but the results are still undefined. More is known in cardiovascular disease. HHcy is a determinant for the development and progression of inflammation, atherosclerotic plaque formation, endothelium, arteriolar damage, smooth muscle cell proliferation, and altered-oxidative stress response. Conversely, few studies focused on the relationship between HHcy and small vessel disease (SVD), despite the evidence that mice with HHcy showed a significant end-feet disruption of astrocytes with a diffuse SVD. A severe reduction of vascular aquaporin-4-water channels, lower levels of high-functioning potassium channels, and higher metalloproteinases are also observed. HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control. HHcy also promotes a constant enhancement of microglia activation, inducing the sustained pro-inflammatory status observed in SVD. This review article addresses the possible role of HHcy in small-vessel disease and understands its pathogenic impact.
Modelling DCD effect on nitrate leaching under controlled conditions

Effects of nitrogen losses through nitrate leaching are one of the major environmental issues worldwide. To determine the potential effect of dicyandiamide (DCD), a nitrification inhibitor, on the transformation of urea nitrogen and subsequent nitrate leaching, incubation and column leaching experiments were performed. Tokomaru silt loam soil was treated with urea, DCD, or urea plus DCD. A control was also used. In the laboratory incubation experiment, the conversion of urea to ammonium (i.e. ammonification process or urea hydrolysis) occurred within a day, thereby increasing the soil pH from 5.8 to 6.9. DCD did not affect the ammonification process. However, DCD did slow down the subsequent oxidation of ammonium to nitrate (i.e. nitrification process). The half-life time of ammonium in this soil was increased from 9 days for the urea treatment to 31 days for the urea + DCD treatment. The production of nitrate was 5 times slower when DCD was added. In the leaching experiments, half the columns were leached after 1 day of incubation (Day 1), the other half 7 days later (Day 7). For Day 1, no significant differences in nitrate leaching could be seen between the treatments, as the nitrification had not yet taken place. For Day 7, DCD decreased nitrate leaching by 71% with a corresponding decrease in nitrate-induced cation leaching, including ammonium. Thus, DCD seems to be effective in decreasing both ammonium and nitrate leaching, but its high solubility and thus mobility could be a limitation to its use. The convection–dispersion equation, including source–sink terms for nitrogen transformations, ammonification, and nitrification rate constants, and a factor for nitrification inhibition by DCD, accounting for degradation and efficiency of DCD, could be used reasonably well to simulate nitrate leaching from the column leaching experiments. However, model parameter values for nitrification rate, and efficiency and decay rate for DCD, were different from those obtained from the incubation experiments, which was probably because of the difference in water content of soil between the incubation and leaching experiments.