Search Results (54)

Background: Medulloblastoma is the childhood tumor with the highest morbidity and mortality worldwide. This type of cancer is characterized by a high degree of heterogeneity that gives rise to different molecular groups with disparities in the clinical presentation and prognosis. Among the molecular differences, one of the most relevant factors is alternative splicing, as it is responsible for transcriptomic diversity. EZH2 is a gene processed by alternative splicing that functions as an epigenetic regulator. In cancer, certain EZH2 mRNA variants are associated with tumorigenesis; however, in medulloblastoma, the alternative splicing pattern of EZH2 has not been studied. Currently, the best tool for identifying alternative splicing variants is long-read sequencing. Methods: We amplified the most variable region of EZH2 alternative splicing and used nanopore sequencing to obtain the transcriptional profile of the gene in patients with medulloblastoma. We verified the variants identified with Sanger sequencing and digital RT–PCR. Finally, we studied the relationship between the expression levels and the clinical–biological characteristics of the patients. Results: We identified seven mRNA variants of EZH2 expressed in medulloblastoma patients, five of which had not been reported previously. In addition, high expression of the novel variant EZH2_RetI8 was associated with patient mortality (p < 0.05). Conclusions: This is the first evidence of the EZH2 mRNA variant profile in medulloblastoma, revealing seven alternative transcripts, one of which is associated with patient mortality. This is a clear example of the complexity of the transcriptome and how long-read sequencing can resolve alternative splicing patterns. Full article

Dynamic comparators play an important role in electronic systems, requiring high accuracy, low power consumption, and minimal offset voltage. This work proposes an accurate and low-complexity offset calibration design based on a capacitive load approach. It was designed using a 65 nm CMOS technology and comprehensively evaluated under Monte Carlo simulations and PVT variations. The proposed scheme was built using MIM capacitors and transistor-based capacitors, and it includes Verilog-based calibration algorithms. The proposed offset calibration is benchmarked, in terms of precision, calibration time, energy consumption, delay, and area, against prior calibration techniques: current injection via gate biasing by a charge pump circuit and current injection via parallel transistors. The evaluation of the offset calibration schemes relies on Analog/Mixed-Signal (AMS) simulations, ensuring accurate evaluation of digital and analog domains. The charge pump method achieved the best Energy-Delay Product (EDP) at the cost of lower long-term accuracy, mainly because of its capacitor leakage. The proposed scheme demonstrated superior performance in offset reduction, achieving a one-sigma offset of 0.223 mV while maintaining precise calibration. Among the calibration algorithms, the window algorithm performs better than the accelerated calibration. This is mainly because the window algorithm considers noise-induced output oscillations, ensuring consistent calibration across all designs. This work provides insights into the trade-offs between energy, precision, and area in dynamic comparator designs, offering strategies to enhance offset calibration. Full article

Background: The “fast track” addition (within 48 h) of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) to the optimized oral lipid-lowering therapy (LLT) during hospitalization for acute coronary syndrome (ACS) has been shown to rapidly achieve the low-density lipoprotein cholesterol (LDL-C) therapeutic targets. However, so far, its efficacy in real-world settings remains understudied. Methods: We retrospectively analyzed 128 ACS patients treated at our center, comparing “PCSK9i fast track” use within 48 h to standard “stepwise” LLT. Lipid levels and incidence of major adverse cardiovascular events (MACEs) were evaluated at 30 and 180 days. Results: The “PCSK9i fast track” group achieved significantly lower LDL-C levels at 30 days (41.5 ± 27.5 vs. 85.6 ± 35.9 mg/dL, p < 0.001) and 180 days (29.6 ± 21.0 vs. 59.0 ± 32.4 mg/dL, p < 0.001). Recommended LDL-C targets (<55 mg/dL) were met by 88.3% of the “PCSK9i fast track” group at 180 days, compared with 61.9% of controls (p < 0.001). No significant differences in MACEs were observed between groups. No adverse effects from PCSK9i use were noted. Conclusions: The “PCSK9i fast track” strategy was safe and effective in achieving LDL-C targets more rapidly than conventional approaches in real-world ACS patients. Full article

Renewable energy technology innovation (RETI) is an effective means of reducing emissions without sacrificing productivity, making it a key driver of carbon productivity (CP) improvement. This study employs a dataset covering 30 Chinese provinces from 2010 to 2021 to empirically examine the impact of RETI on CP. Additionally, it explores the non-linear effects of environmental regulation (ER) and R&D investment (RD) in this relationship. The findings indicate that RETI significantly enhances CP, a result that remain robust across multiple robustness and endogeneity tests. The heterogeneity analysis reveals that RETI has the strongest impact on CP in the eastern region, followed by the central region, but has a negligible effect in the western region. Among the different types of RETI, the positive effects of solar, wind, and energy storage technology innovations on CP are more evident. Moreover, the impact of RETI on CP is stronger in economically developed provinces than in less developed ones. The mechanism analysis shows that RETI indirectly enhances CP by optimizing industrial structure, increasing renewable energy generation, and improving energy efficiency. The threshold effect analysis suggests that as ER intensifies, the positive effect of RETI on CP follows a non-linear relationship that strengthens initially but then diminishes. In contrast, as RD rises, the marginal benefits of RETI on CP are continually strengthened. Full article

This work empirically analyzes the drivers of RETI from a financial perspective, using panel data from China’s provincial-level regions from 2013 to 2022. The results indicate that green financial development can significantly promote renewable energy innovation, which still holds after a series of robustness tests. Analysis of the mechanisms shows that green finance drives renewable energy technological innovation (RETI) by easing financing limitations and promoting the green transformation of industrial sectors. Furthermore, threshold effect analysis indicates a significant threshold effect regarding the influence of green finance on technological innovation within the renewable energy sector. Specifically, when the level of technological innovation in renewable energy surpasses a certain threshold value, the facilitating effect of green finance on this innovation becomes markedly stronger. Further analysis also reveals that technological innovation in renewable energy can significantly drive the low-carbon transformation of the energy consumption structure. Full article

The stability of slopes is influenced by seasonal variations in thermal, hydrological, and mechanical processes. This study investigates the role of snowmelt in triggering shallow landslides through controlled laboratory experiments simulating winter, spring, and summer conditions. Snowpack dynamics and water movement were analyzed to understand filtration, infiltration, and runoff mechanisms. The results show that during winter, snow acts as a protective layer, slowing infiltration through its insulating and loading effects. In spring, rising temperatures melt snow, increasing water infiltration and filtration, accelerating soil saturation, and triggering slope failures. Summer rainfall-induced landslides exhibit distinct mechanisms, driven by progressive saturation. The transition from winter to spring highlights a critical phase where snowmelt interacts with warmer soils, intensifying slope instability risks. Numerical simulations using HYDRUS 1D validated the experimental findings, demonstrating its utility in modeling infiltration under varying thermal gradients. This study underscores the importance of incorporating snowmelt dynamics into landslide risk assessments and early warning systems, particularly as climate change accelerates snowmelt cycles in mountainous regions. These findings provide essential insights into seasonal variations in collapse mechanisms, emphasizing the need for further research to address the increasing impact of snowmelt in shallow landslides. Full article

Background: Thrombotic microangiopathy (TMA) is a potentially life-threatening complication associated with carfilzomib, a proteasome inhibitor approved for treating multiple myeloma. TMA typically presents within the initial months of treatment; however, delayed onset is rare and poses significant diagnostic challenges. Methods: We conducted a retrospective analysis of the medical records of a 47-year-old Caucasian woman diagnosed with IgA kappa myeloma who developed signs and symptoms consistent with TMA eleven months after the initiation of carfilzomib therapy and already in ongoing very good partial remission. Results: The clinical presentation included an acute onset of weakness, dizziness, somnolence, diffuse bruising, oliguria, jaundice, severe thrombocytopenia, and acute kidney injury. An immediate workup raised a strong suspicion for TMA, confirmed by laboratory findings of schistocytosis and complement activation. Following the immediate discontinuation of carfilzomib, the patient underwent 18 plasmapheresis (PEX) sessions and received supportive fresh frozen plasma transfusions, which resulted in the complete remission of TMA symptoms without the need for complement inhibitory therapy. Conclusions: The need for ongoing monitoring for TMA throughout carfilzomib therapy, regardless of treatment duration, is emphasized. Early diagnosis and intervention, including drug discontinuation and the timely initiation of PEX, are crucial for patient recovery. Full article

Renewable energy technology innovation (RETI) plays a vital role in transforming economic growth models and promoting urban green development (GD). This paper examines 13 cities at the prefectural level and above in the Beijing-Tianjin-Hebei region from 2008 to 2022, assessing the GD levels of these cities using the entropy weight TOPSIS method. The study investigates the effects and mechanisms of RETI on urban GD through fixed effect models, mediation effect models, and threshold effect models. The results indicate that (1) RETI significantly promotes urban GD in the Beijing-Tianjin-Hebei region, a conclusion that remains valid after conducting several robustness tests. (2) The promoting effect of RETI on urban GD exhibits heterogeneity based on urban resource endowments and spatial layouts, with a more pronounced positive impact in non-resource-based cities and core cities. (3) Mechanism analyses demonstrate that RETI indirectly promotes urban GD in the Beijing-Tianjin-Hebei region by facilitating the low-carbon upgrading of industrial structures and the transition to cleaner energy systems. (4) When R&D investment (RD) is lower than 0.0097, RETI has a clear inhibitory effect on urban GD, meaning that for every unit increase in RETI, the level of urban GD decreases by 0.355 units; when RD is between 0.0097 and 0.0375, RETI exerts a clear positive effect on urban GD, meaning that for every unit increase in RETI, the level of urban GD rises by 0.606 units; however, once RD exceeds 0.0375, the positive effect of RETI on urban GD begins to diminish. In this range, for every unit increase in RETI, the level of urban GD increases by only 0.170 units. When the green policy support index (GPSI) is lower than 0.0427, RETI has a clear promotion effect on urban GD, meaning that for every unit increase in RETI, the level of urban GD rises by 0.171 units; when the GPSI exceeds 0.0427, the promotion effect of RETI on urban GD is further strengthened, meaning that for every unit increase in RETI, the level of urban GD rises by 0.221 units. Full article

Modern ICT infrastructures, i.e., cyber-physical systems and critical infrastructures relying on interconnected IT (Information Technology)- and OT (Operational Technology)-based components and (sub-)systems, raise complex challenges in tackling security and safety issues. Nowadays, many security controls and mechanisms have been made available and exploitable to solve specific security needs, but, when dealing with very complex and multifaceted heterogeneous systems, a methodology is needed on top of the selection of each security control that will allow the designer/maintainer to drive her/his choices to build and keep the system secure as a whole, leaving the choice of the security controls to the last step of the system design/development. This paper aims at providing a comprehensive methodological approach to design and preliminarily implement an Open Platform Architecture (OPA) to secure the cyber-physical systems of critical infrastructures. Here, the Open Platform Architecture (OPA) depicts how an already existing or under-design target system (TS) can be equipped with technologies that are modern or currently under development, to monitor and timely detect possibly dangerous situations and to react in an automatic way by putting in place suitable countermeasures. A multifaceted use case (UC) that is able to show the OPA, starting from the security and safety requirements to the fully designed system, will be developed step by step to show the feasibility and the effectiveness of the proposed methodology. Full article

Thromboinflammation/immunothrombosis plays a role in several diseases including thrombotic thrombocytopenic purpura (TTP) and COVID-19. Unlike the extensive research that has been conducted on COVID-19 cytokine storms, the baseline and acute phase cytokine profiles of TTP are poorly characterized. Moreover, we compared the cytokine profiles of TTP and COVID-19 to identify the disease-specific/general characteristics of thromboinflammation/immunothrombosis. Plasma concentrations of 33 soluble mediators (SMs: cytokines, chemokines, soluble receptors, and growth factors) were measured by multiplex bead-based LEGENDplex™ immunoassay from 32 COVID-19 patients (32 non-vaccinated patients in three severity groups), 32 TTP patients (remission/acute phase pairs of 16 patients), and 15 control samples. Mainly, the levels of innate immunity-related SMs changed in both diseases. In TTP, ten SMs decreased in both remission and acute phases compared to the control, one decreased, and two increased only in the acute phase compared to remission, indicating mostly anti-inflammatory changes. In COVID-19, ten pro-inflammatory SMs increased, whereas one decreased with increasing severity compared to the control. In severe COVID-19, sixteen SMs exceeded acute TTP levels, with only one higher in TTP. PCA identified CXCL10, IL-1RA, and VEGF as the main discriminators among their cytokine profiles. The innate immune response is altered in both diseases. The cytokine profile of TTP suggests a distinct pathomechanism from COVID-19 and supports referring to TTP as thromboinflammatory rather than immunothrombotic, emphasizing thrombosis over inflammation as the driving force of the acute phase. Full article

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the ‘old’ multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events. Full article

Leukemia is the most common childhood cancer and its etiology could be related to various environmental contaminants such as particulate matter (PM). The objective of our study is to evaluate the potential association between exposure to PM during pregnancy and the incidence of childhood leukemia. We established a population-based nationwide cohort using the Spanish Birth Registry Statistics database of the National Statistics Institute. We used spatiotemporal land use random forest models to estimate the concentrations of PM₁₀ and PM_2.5 for the entire pregnancy and by trimesters. We conducted logistic regression analyses adjusted for various covariates. In addition, we fitted generalized additive models (GAMs) to estimate the non-linear relationship between PM levels and leukemia incidence. The study included 3,112,123 children and 1066 cases of leukemia. The results for the continuous variable of PM₁₀ exposure levels suggested an increased risk of childhood leukemia to be associated with higher exposure. The results for the categorized PM₁₀ variable suggest an increased risk of childhood leukemia among pregnant women whose exposure levels were higher than the median (third and fourth quartiles). The results for PM_2.5 were weaker. We found association between exposure to PM₁₀ during pregnancy and an increased risk of childhood leukemia. Our findings indicate that public health interventions should aim to reduce air pollution to lower the incidence of childhood leukemia. Full article

Conservation, characterization and exploitation of agrobiodiversity are key factors to guarantee food security and face future challenges such as climate changes. These issues are the subject of a series of international agreements, such as the Convention of Biological Diversity, with its Nagoya Protocol, and the International Treaty on Plant Genetic Resources for Food and Agriculture (ITPGRFA) adopted in 2001 and entered into force in 2004. Italy ratified the Treaty in 2004 and instituted a long-lasting program, RGV-FAO, to implement it. CREA is one of the three organizations involved in the RGV-FAO Program, together with the National Research Council (CNR) and Reti Semi Rurali. CREA maintains a total of 40,186 accessions including cereals, vegetables, fruits, forages, industrial crops, forest and woody crops, medicinal and aromatic plants, and their wild relatives. Accessions are conserved using different ex situ conservation systems (seeds, in vivo plants, vegetative organs and in vitro plantlets), and characterized using genetic, morpho-phenological and/or biochemical methods. Herein, we will present the CREA long-lasting program RGV-FAO with some examples of the use of plant genetic resources in breeding programs, including molecular approaches. Some critical issues related to access and benefit sharing in PGRFA, such as the Nagoya Protocol and the Digital Sequence Information, will be discussed, highlighting their potential impact on food security and on the advancement of knowledge. Full article

Background: Myopia management contact lenses have been shown to successfully decrease the rate of eye elongation in children by changing the peripheral refractive profile of the retina. Despite the efforts of the scientific community, the retinal response mechanism to defocus is still unknown. The purpose of this study was to evaluate the local electrophysiological response of the retina with a myopia control contact lens (CL) compared to a single-vision CL of the same material. Methods: The retinal electrical activity and peripheral refraction of 16 eyes (16 subjects, 27.5 ± 5.7 years, 13 females and 3 males) with myopia between −0.75 D and −6.00 D (astigmatism < 1.00 D) were assessed with two CLs (Filcon 5B): a single-vision (SV) CL and an extended-depth-of-focus (EDOF) CL used for myopia management. The peripheral refraction was assessed with an open-field WAM-5500 auto-refractometer/keratometer in four meridians separated by 45° at 2.50 m distance. The global-flash multifocal electroretinogram (gf-mfERG) was recorded with the Reti-port/scan21 (Roland Consult) using a stimulus of 61 hexagons. The implicit time (in milliseconds) and response density (RD, in nV/deg²) of the direct (DC) and induced (IC) components were used for comparison between lenses in physiological pupil conditions. Results: Although the EDOF decreased both the HCVA and the LCVA (one and two lines, respectively; p < 0.003), it still allowed a good VA. The EDOF lens induced a myopic shift in most retinal areas, with a higher and statistically significant effect on the nasal retina. No differences in the implicit times of the DC and IC components were observed between SV and EDOF. Compared with the SV, the EDOF lens showed a higher RD in the IC component in the foveal region (p = 0.032). In the remaining retinal areas, the EDOF evoked lower, non-statistically significant RD in both the DC and IC components. Conclusions: The EDOF myopia control CL enhanced the response of the inner layers of the fovea. This might suggest that, besides other mechanisms potentially involved, the central foveal retinal activity might be involved in the mechanism of myopia control with these lenses. Full article

Background: To evaluate changes in pattern electroretinogram (pERG) and pattern visual evoked potentials (pVEP) in patients with long-lasting type 1 diabetes without diabetic retinopathy (DR). Methods: Prospective study involving 92 eyes divided into two groups. The diabetic group included 46 eyes of 23 patients with type 1 diabetes (T1DM); the control group included 23 age-matched healthy subjects. pERG and pVEP were assessed using the RETI-port/scan21 recording software (version 1021.3.0.0). Results: Mean age was 48 ± 9.77 years for the diabetic group and 51.7 ± 4.75 years for the control group. The mean duration of diabetes was 28.88 ± 8.04 years. The mean HbA1c value was 7.29 ± 0.89%. There were no differences in the age or sex distribution. Regarding the pERG, T1DM patients exhibited a significant decrease in the amplitude of the P50 and N95 waves compared to the control group (p = 0.018 and p = 0.035, respectively), with no differences in the peak time of each component. pVEP showed no significant changes in either peak time or amplitude of the different components. Conclusions: Long-term T1DM patients without DR showed changes in the amplitude of pERG waves with preserved peak times. We did not observe modifications in pVEP. pERG may serve as a subclinical marker of ganglion cell damage in long-term T1DM patients. Full article