While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and FOXA1, rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner.

while composting of organic wastes is increasingly adopted in sustainable agriculture, continued interest on biochar application, dark soils, and compost, showed morphological aspects and functionality of biochar as a challenge to solve the CO2 aspects related to climatic change, and carbon stability in sustainable soils, as Black carbon presents long chemical permanency due to incomplete combustion of biomass. The objective of this work was to study the characteristics of soil amendments and to review the state of the art of biochar, showing differences in composition and main microorganisms with relevant presence in the soils. Arbuscular mycorrhizal spores (Scutellospora sp., Glomus like, Funneliformis geosporus, Glomus crenatum, and Acaulospora excavata, obtained from TPI soil samples are shown. New strategies are highlighted such as nutrient supplementation of compost, which can constitute the basis for improved compost-based biofertilizers in the future. Thus, the most important strategies for C sequestration are underlined to diminish substantial organic agro- and municipal wastes, increasingly disposed in the fields, landfills or either released by burning or discarding.

Diffusion magnetic resonance imaging (dMRI) is an imaging technique that provides information on the microstructural organization of biological tissue. dMRI allows for non-invasive visualization and quantitative assessment of white matter architecture in the brain by characterizing restrictions on the random motion of water molecules. Ultra-high field MRI scanners, such as those operating at 7 Tesla (7T) or higher, can boost signal-to-noise ratio (SNR) to improve dMRI compared with what is attainable at conventional field strengths such as 3T or 1.5T. However, at 7T wavelength effects cause lower transmit magnetic field efficiency in the human brain, mainly in the posterior fossa region, manifesting as signal dropouts in this region. Recently, we reported a simple approach of using a wireless radiofrequency (RF) surface array to improve transmit efficiency and signal sensitivity at 7T. Here we demonstrate the feasibility and effectiveness of using this RF enhancer for in-vivo dMRI at 7T. The use of the RF enhancer can effectively recover signal dropouts in the regions with intrinsically lower SNR such as cerebellum, leading to a better depiction of principal fiber orientations and enhanced visualization of extended tracts to the brainstem and pons enabling more comprehensive delineation of the full white matter architecture.

Blueberries are rich in a variety of functional substances and have high nutritional and health values, but they are not resistant to decline during fresh storage. Here, the effects of six Bacillus species on storage quality of, and antioxidant levels in, the southern highbush blueberry ‘O'Neal’ fruit were investigated. Bacillus treatments reduced the fruit decay rate, slowed fruit quality decline, inhibited malondialdehyde accumulation, and increased superoxide dismutase and peroxidase activity levels. Bacillus altitudinis Y-14 had the best effect overall. Further, the effects of 1-methylcyclopropene (1-MCP), B. altitudinis Y-14, and 1-MCP+B. altitudinis Y-14 treatments on the storage quality and antioxidant of rabbiteye blueberry ‘Brightwell’ fruit were investigated, and each treatment effectively reduced the decay rate and weight loss of fruit. When stored for 25 days, the decay rate of the 1-MCP+B. altitudinis Y-14 group was only 8.33%, significantly lower than that of the control. The three treatments delayed the fruit quality decline, inhibited malondialdehyde accumulation, and increased superoxide dismutase and peroxidase activity levels. The 1-MCP+B. altitudinis Y-14 treatment had the best effect. Thus, the combined 1-MCP and B. altitudinis Y-14 treatment may be an effective way to improve the storage quality and extend the storage period of blueberries.

New strategies for enhancing drug delivery to the blood–brain barrier (BBB) represents a major challenge in treating cerebral diseases. Nano-emulsion based nanocarriers represent an ideal candidate to improve drug delivery thanks to their versatility in functionalization and cargo protection. In this work, a paclitaxel loaded nano-emulsion has been firstly functionalized and stabilized with two layers constituted of chitosan and hyaluronic acid, and, secondly, the latter has been conjugated to the CRT peptide. CRT is a bioactive peptide that selectively recognizes bEnd.3 cells, model of the BBB, thanks to its interactions with transferrin (Tf) and its receptor (TfR). Cytotoxic results showed a higher uptake of CRT functionalized nano-emulsion 41.5 % more than the negative control, demonstrating the ability of this novel tool to be accumulated on the brain endothelium tissue. Thanks to these results, our approach can be fully generalizable to the design of multifunctional nanocarriers for delivery of therapeutic agents to the central nervous systems.

Objective To explore the endoscopic anatomical structures of lumbar surgery. Methods A total of 290 patients who underwent lumbar endoscopic surgery due to lumbar intervertebral disc (IVD) herniation from September 2020 to September 2022 were retrospectively reviewed in our hospital,179 patients had complete surgical video recordings, including 108 males and 71 females, aged from 19 to 65 years, with an average age of 41±16 years. The endoscopic structures through the intervertebral foramen and interlaminar space were independently identified by 3 doctors with more than 3 years of related surgery experience. When there were differences of opinions, the three doctors would discuss and come to a consensus. The probability, location, and neighboring structures of each specific structures were statistically analyzed. Results The anatomical structures observed through the lumbar foramen under endoscopy include muscles and ligaments attached to the superior articular process (SAP), main blood vessels inside the intervertebral foramen, blood vessels on the surface of IVD, and blood vessels on the surface of the dural sac and nerve root. The major anatomical structures observed through interlaminar space are multifidus, the conjugated ligament of ligament flavum and capsule ligament (capsule part of flavum ligaments), edges of the lamina, specific vessel bundle to facet with exit nerve root. Conclusion The anatomical structures under spinal endoscopy have certain characteristics, which are grossly different from those under open surgery. Familiarity with these anatomical structures has important clinical significance.

Background: The safety and effectiveness of factor-Xa (FXa) inhibitors for nonvalvular atrial fibrillation (NVAF) remains inconclusive. We investigated the current dosing of rivaroxaban, apixaban and edoxaban by monitoring drug plasma concentration (PC) and coagulation activity. Methods and Results: This multicenter clinical study monitored the drug PC levels and two coagulation biomarkers (fibrinogen: FIB, and fibrin monomer complex: FMC) at peak and trough timing in 268 outpatients receiving rivaroxaban (n = 72), apixaban (n = 71), and edoxaban (n = 125) for NVAF. Doses were adjusted according to the dose adjustment criteria of each drug. Based on our previous study, each peak drug PC remained below the cut-off level for predicting bleeding events except in eight patients (three on rivaroxaban, two on apixaban and three on edoxaban) in whom bleeding events occurred; among them, two (one each on rivaroxaban and edoxaban) had a peak drug PC below the cut-off level. Drug PCs widely varied from peak to trough, whereas FMC levels remained within the normal range (< 6.1 µg/ml) regardless of PC variation. These finding suggested that the anticoagulant effects of these drugs persisted throughout the day regardless of the drug PC levels, dosage, and frequency of dosing. Regarding the change in peak drug PC levels over time, rivaroxaban tended to accumulate more than edoxaban (p

The growing deforestation of tropical forests requires the implementation of restoration actions capable of assisting the recovery of biodiversity and functioning of these ecosystems. This research aimed to identify the environmental factors that influence woody plant recruitment abundance and diversity in an Andean forest restoration project in Medellin (Colombia). Data from all individuals taller than 80 cm was collected in 22 plots of 200 m2. The environmental factors selected were edaphic variables, plantation structure, slope, elevation, prior land use and landscape forest cover. A generalized linear model was adjusted for recruitment density, and linear mixed models were built for recruited species richness, diversity and dominance. Woody plant recruitment attributes in our study area were similar to a typical secondary succession in an Andean forest, but planted trees contributed little to these attributes. While recruitment density was affected by slope, canopy closure and landscape forest cover, recruitment diversity was influenced by physical (bulk density) and chemical (pH, aluminum, CEC) edaphic factors, planted trees diversity (species richness and composition), canopy closure and mortality rate of planted trees. We conclude that a good development of planted trees enhances both recruitment attributes, indicating a synergy between active restoration and passive regeneration processes.

Plastics, once regarded as a revolutionary material shaping modern society, now poses an unprecedented threat to our environment. Household solid waste sorting stations produce several fractions, one of which contains a high concentration of Low-Density Polyethylene (LDPE) film waste (packaging, sunscreen film, etc.). This fraction is difficult to recycle because it contains quite a lot of impurities. Usually, it is sent to the cement factories that burn it together with other fuels. However, with some processing techniques such catalytic pyrolysis this fraction could be valorized. In this paper the experiments which were carried out at a laboratory scale installation, in batches with a processing capacity of 1-3 kg of waste. The pyrolysis reactor is connected to a distillation column giving the possibility to separate the fractions. The gaseous and liquid fractions were characterized by GC-FID-TCD (gases) and GC-MS (liquids) analysis. Natural catalysts such as bentonite or clinoptilolite were studied and used in the melting of plastic mass to simplify the process as much as possible. To test the activity of the catalysts, the pyrolysis of LDPE granules was initially studied. It was found that natural zeolites are much more active than bentonite and that a minimum concentration of 5-10% is needed to have a positive effect on the composition of the fractions (increasing the weight of the light fractions C1-C6, C6-C10 and C11-C13) in relation to the heavy fractions C13-C20 and C20+. Catalytic pyrolysis gives a completely different distribution of light hydrocarbons. The best catalyst selected from LDPE lab experiments, was then tested upon the pyrolysis of plastic film waste obtained by a waste treatment plant. The research objective reported in this paper was to obtain a fraction of combustible gases in the largest possible proportion, which can be much easier exploited by burning in an engine that drives an electric generator.

Academic procrastination, more than merely postponing tasks, represents a significant failure in the self-regulation process of learning. Research on study skills highlights academic time management as one of the crucial elements of learning strategies and sustainable education. These abilities will help achieve the Sustainable Development Goals fourth goal. Therefore, this study aimed to understand how students plan time management in school activities and its influence on study procrastination, analyzing differences between genders and the hours students spend studying. The Time Management Planning Inventory, the Study Procrastination Questionnaire, and a personal and school data sheet were used. A sample of 506 students from elementary schools in northern Portugal was utilized. The results revealed that gender and study hours significantly influence how students plan time management for school tasks in the short and long term. This variable also showed a significant impact on the procrastination of study activities. The practical implications of this study are substantial, as they provide educators and researchers insights into the factors influencing academic procrastination and the role of time management planning and study hours. These insights can be applied to develop effective strategies to reduce academic procrastination and promote sustainable education.

This study investigates anomaly detection of IoT device traffic using Convolutional Neural Networks (CNN) and Variational Autoencoders (VAE) to enhance the detection capability of security threats in IoT environments. A series of hardware configurations, software environments, and hyperparameters were utilized to optimize the training and testing processes of the models. The CNN model demonstrates robust classification performance, achieving an accuracy rate of 95.85% on the test dataset, effectively distinguishing between different types of IoT device traffic. Meanwhile, the VAE model exhibits proficient anomaly detection capabilities by effectively capturing abnormal patterns in the data using reconstruction loss and KL divergence. The combined use of CNN and VAE models offers a comprehensive solution to cybersecurity challenges in IoT environments. Future research directions include exploring diverse IoT traffic data, practical deployment for validation, and further optimization of model structures and parameters to improve performance and applicability.

Introduction: Transportation logistics play a pivotal role in facilitating both individual mobility and supply chain operations on a global scale. However, conventional transportation systems have contributed significantly to urban congestion and environmental degradation. In response to these challenges, there is a growing momentum towards the adoption of intelligent transportation systems (ITS) and sustainable transportation solutions. This research aims to explore the potential of renewable energy sources to power electric vehicles (EVs) and flying automobiles, thereby accelerating the transition towards a low-carbon future. Objectives: The primary objectives of this research are as follows: - Investigate the role of renewable fuels in powering both EVs and flying cars to reduce reliance on fossil fuels and mitigate carbon emissions. - Analyze the dynamic growth and sustainability implications of advancements in battery technology and alternative renewable energy sources, such as Hydrogen Fuel Cells. - Evaluate the challenges and opportunities associated with the integration of flying vehicles into existing transportation infrastructure, focusing on safety, airspace control, and infrastructure development. - Review insights and guidance to stakeholders on promoting sustainable transportation solutions for EVs and flying cars through the utilization of renewable energy sources and the reduction of carbon emissions from the literature. Methodology: This research employs a mixed-method approach, combining literature review, and causal loop diagram analysis. The literature review provides a comprehensive understanding of current trends, challenges, and opportunities in sustainable transportation and renewable energy technologies. A causal loop diagram is utilized to visualize the dynamic interactions between various factors influencing the adoption of EVs and flying cars, including technological advancements, policy interventions, and market dynamics. Results and Discussion: The findings of this research highlight the significant potential of renewable energy sources, such as solar, wind, and hydrogen, in powering both EVs and flying cars. Advances in battery technology and hydrogen fuel cells are identified as key drivers in accelerating the transition towards sustainable transportation systems. However, challenges remain in terms of infrastructure development, safety regulations, and airspace management for flying vehicles. Nevertheless, there is a noticeable advancement in reducing carbon emissions and reliance on fossil fuels with the widespread adoption of EVs. By harnessing renewable energy and implementing effective policy measures, stakeholders might able to promote the widespread adoption of sustainable transportation solutions, thereby contributing to environmental protection and societal well-being. Conclusion: Literally, this research underscores the importance of sustainable transportation solutions in addressing urban congestion, environmental pollution, and energy security concerns. By leveraging renewable energy sources and embracing technological advancements, such as EVs and flying cars, stakeholders pave the way for a more sustainable and resilient transportation system. However, concerted efforts are needed to overcome existing challenges and ensure the successful integration of these technologies into existing infrastructure. Through collaborative partnerships and innovative initiatives, a low-carbon future for transportation logistics can be achieved, benefiting both the environment and society as a whole.

(1) Background: The lateral arm flap has been the very useful choice in the reconstruction of small- to medium-sized defects like hand, extremity, oral head and neck area reconstructions. Its versatile characteristics and surgical feasibility allow this flap to be widely applied, but the reconstructive potential in facial subunit after tumor ablative procedures has never been reported. In this study, we aimed to utilize the advantages of the flap to treat facial temple subunit defect reconstruction. (2) Methods: Between 2020 and 2023, 12 patients underwent temple reconstruction with lateral arm free flaps after malignant tumor wide excision. There were 7 women and 5 men, and the mean patient age was 60.6 years old. Among the patients with cancer, 6 had squamous cell carcinoma, 5 had basal cell carcinoma and 1 had myxofibrosarcoma. All the flaps were elevated under general anesthesia. Aloprostadil(PGE1, Eglandin®) were administered postoperatively. (3) Results: All the flap types were fasciocutaneous type with varied sizes from 3 × 4 to 5 × 7 cm (Average size of flap 22.7cm2) were utilized. The average pedicle length was 6.1cm. The versatility of the lateral arm flap enabled successful coverage of all cases with no specific complications. Good functional outcome and range of motion in the recipient arm were obtained after surgery. (4) Conclusion: The authors successfully verified the advantages of lateral arm flaps in the treatment of medium sized facial subunt temple defect reconstruction.

Background: Self-harm (SH) refers to self-injury or intentional self-poisoning with varying degrees of suicidal intent and is a major public health issue for children and adolescents (C&A) worldwide. Given significant gaps exist in our understanding of the associated psychopathology in C&A, this paper outlines the protocol for a prospective clinical study examining risk factors of SH and additional candidate parameters (not routinely assessed) during an acute SH episode. Methods: The EXPAAND (EXploring Psychiatric and Attentional risk-factors in Adolescents Needing intervention for Deliberate self-harm) is a randomised control trial to assess additional novel candidate risk factors for SH in C&A and to evaluate the effectiveness of SH-targeted brief psychological intervention (Therapeutic Assessment (TA)), within a real-world acute clinical setting, as we include neurodiversity and gender diversity in this study. EXPAAND is conducted in 4 phases: (i) recruitment & randomisation; (ii) extended assessment; (iii) randomised intervention; and (iv) follow-up observational period to ascertain clinical outcomes for comparison. Expected Results: We envisage that by diagnosing and treating attentional disorders when detected will mitigate potential confounding effects of these conditions. We also expect that SH-focused TA will be effective in reducing subsequent SH and in improving engagement in follow-up and subsequent treatments.

This study provides a comprehensive comparison of the Peter Chew Sum method and Newton's Sum in Quadratic Root Function Computations. Both methods offer significant advancements by alleviating the need for memorization of multiple formulas. However, when confronted with higher-order quadratic root functions such as the calculation of power 33. Newton's Sum method proves cumbersome due to its requirement of all previous answers for final computation, leading to increased steps and error risks. In contrast, the Peter Chew Sum method simplifies the computational process by requiring only a few previous answers, resulting in a more straightforward series of operations. We contextualize our analysis within the historical progression of mathematical techniques, highlighting the transformative leap represented by the Peter Chew Sum method in quadratic root function computations. Peter Chew Sum addressing the limitations of Newton's Sum , especially concerning higher-order functions such as the calculation of power 256. Furthermore, study demonstrates that the innovative approach of the Peter Chew Sum method not only simplifies complex computations but also fosters enhanced conceptual understanding among students. In conclusion, study findings underscore the profound impact of the Peter Chew Sum method on quadratic root function computations.

This research follows the publication of recent scoping and systematic reviews of existing literature on vaccine literacy (VL), its relationship to vaccine hesitancy (VH), and associated variables, such as vaccination beliefs, attitudes, and behaviors towards immunization. In this review, 17 articles were selected, published between December 2022 and November 2023, in which VL tools were used, most of which support the notion of a negative association between VL and VH, although not confirmed by others. Moreover, the definitions of the variables under consideration were not homogeneous between studies, some aimed to evaluate the association of VL with vaccine confidence, while others were more focused on outcomes such as willingness to be vaccinated or vaccine uptake. The complexity of the factors underlying VL, and the heterogeneity of the methods applied in the studies, in particular the limitations of cross-sectional surveys, still make it difficult to have a comprehensive understanding of the role of VL. Therefore, it is important to develop future assessment tools that consider not just the measurement of psychological factors connected to the motivational aspect of VL, but also those related to knowledge and competencies. For this purpose, a theoretical framework is proposed, where the positioning of VL at the intersection between antecedents and beliefs/attitudes leading to behaviors explains why and how VL serves as a tool and a critical, direct, or mediating driver of vaccination choices, overcoming VH and increasing vaccination rates, operating at personal, as well as at organizational and community level.

The Yellow-legged Hornet (Vespa velutina nigrithorax) (YLH) is an invasive insect that arrived in Europe in 2004 and is now spread across nine countries. It is a threat to the native entomofauna and harmful to beekeeping and agriculture, as it is a ravenous predator of the European Honey Bee (Apis mellifera) and other pollinating species. Its expansion has been unstoppable and all resources are needed to fight against it, including native vertebrate predators. Among these, the European Bee-eater (Merops apiaster) (EBE) is a potential one, but little is known about its predation on YLH. In a study carried out in Portugal, remains of YHL were detected in EBE nesting sites, which to the best of our knowledge is the first such report. This means that this bird could be one more agent in the biological control of this pest (although research on predation intensity is still needed), in conjunction with other natural predators and other strategies. In the Iberian Peninsula both species are allopatric in vast regions, so the role of EBE may be more limited. However, in the rest of Europe, at a country or continent scale, the scenario may be different and sympatry may occur to a greater extent.

This study uses the social impact theory to analyse consumer behaviour amidst Covid-19. Fear of scarcity has changed consumer buying behaviour in crisis times such as the now abating global health crisis – i.e., Covid-19. The study asserts that the existing five-stage model of consumer purchasing decisions does not fit neatly in turbulent times. It proposes a shortened four-stage process of need recognition, purchase, ownership and satisfaction as a better and more adaptable fit. Cutting out information search and evaluation of alternatives in the old model, and replacing these with ownership, is where the main contribution of the study lies. The study has implications for managing the marketing mix as we know it. It asserts that not all the 4Ps of the marketing mix are important in crisis times.

The ErbB/HER family of protein-tyrosine kinases (ErbB) and the phosphatidylinositol 3-kinase (PI3K) represent crucial targets in the treatment of head and neck squamous cell carcinoma (HNSCC). We previously reported that a combination therapy using Afatinib (ErbB inhibitor) and Copanlisib (PI3K inhibitor), both FDA-approved kinase inhibitors, suppressed the growth of HPV-positive HNSCC. In our current study, we further evaluated the efficacy and clinical potential of this combination therapy for treating HPV-negative HNSCC in vitro and in animal model. We found that the combination treatment of Afatinib and Copanlisib dramatically enhanced inhibition of cell proliferation and reduced cell survival when compared to treatment with either inhibitor in two HPV negative HNSCC cell lines. Notably, this combination led to significant inhibition of xenograft tumor growth in mice, without any apparent effects on body weight. Copanlisib alone effectively blocked PI3K/Akt signaling, but caused up-regulation of HER2 and HER3 phosphorylation as previously reported in other types of cancer. However, the combination treatment with Copanlisib and Afatinib completely blocked phosphorylation of the ErbB family (including HER3) and Akt, while also remarkedly increasing apoptosis. These results suggest that co-targeting the ErbB family and PI3K kinases by a combination treatment of Afatinib and Copanlisib can have clinical potential for patients.

Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest into the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed the CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials that evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are undergoing. In this review, we summarize the current status of knowledge regarding the changes of CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biologic mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.

Background/Aims: Conflicting results have been reported regarding the interaction between proton pump inhibitors (PPIs) and clopidogrel. We investigated whether concomitant PPI use influenced the risk of recurrence in patients with stroke and myocardial infarction (MI). Methods: This study used two databases for different designs, the Korean National Health Insurance Service (NHIS) database for a self-controlled case series design, and the national sample cohort of the NHIS database converted to the Observational Medical Outcomes Partnership-Common Data Model version for a cohort study. Results: In the PPI co-prescription group, recurrent hospitalization with stroke occurred in 17.6% of the 8,201 patients with history of stroke, and recurrent MI occurred in 17.1% of the 1,216 patients with history of MI during 1 year. According to the self-controlled case series, the overall relative risk (RR) of recurrent stroke was 2.09 [95% confidence interval (CI); 1.83-2.38], and the RR showed an increasing trend with PPI duration. In the cohort study, there was a higher incidence of recurrent stroke in the PPI co-prescription group [Hazard ratio (HR): 1.34, 95% CI: 1.01-1.76, P=0.04]. The overall RR of recurrent MI was 1.47 (95% CI; 1.02-2.11) in the self-controlled case series; however, there was no statistically significant difference in recurrent MI in the cohort study (HR:1.42, 95% CI:0.79-2.49, P=0.23). The impact of individual PPIs on stroke and MI showed different patterns. Conclusions: PPI co-prescription with clopidogrel was associated with recurrent stroke; however, its association with recurrent MI remains inconclusive. The influence of individual PPIs should be clarified in the future.

The possibility of treating more patients for a longer time, has exploded the concept of anticipation in the systemic treatment of metastatic prostate cancer (mPC). The genetic analysis of Damage DNA Repair (DDR) mutations in pathogenetic variants (PV) and the development of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors led to the first valid precision medicine option tailored for mPC. PARP inhibitors are repeating the same evolutionary path experienced for androgen receptor signaling inhibitors (ARSI), starting from the late stage of second line mCRPC in a limited population and time frame. Inevitably also PARP inhibitors will be absorbed by the concept of anticipation and intensification of care. The anticipation of PARP inhibitors in the first line mCRPC therapy is already underway and further one in mHSPC will soon be verified. According to the crosstalk between androgen receptors (AR) and DNA repair, the new message that is emerging is that the combination of PARP inhibitors with ARSI, disconnects PARP from the genetic analysis. Most of the recent trials analyzing PARP inhibitors plus abiraterone or enzalutamide, enrolled first line mCRPC irrespectively to gene PV. The conclusion of the PROPEL trial was that the advantage was independent to PV status, however the highest advantage was reported in BRCA1/2 mutated subgroup. The conclusion of the MAGNITUDE trial was different, with a significant advantage only in the DDR mutated subgroup and the DDR non-mutated was closed for further enrollment. The combination of PARP inhibitors with ARSI represents a significant strategy in the concept of anticipation and intensification of care in mPC. However, it should not nullify the advantages of precision medicine linked to the genetic analysis of DDR.

Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most of the pivotal phase III studies; this precludes the generalization of the ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common “special” NSCLC subpopulations.

Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival and other cellular processes and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to develop new therapeutic agents for human diseases. Macrocyclization has emerged as an effective drug discovery strategy over the past decade to improve target selectivity and potency of small molecules. Small compounds with linear structures upon macrocyclization can lead to changes in their physicochemical and biological properties by firmly reducing conformational flexibility. A number of distinct protein kinases exhibit similar binding sites. Comparison of protein binding site provides crucial insights for the drug discovery and development. Binding site similarities are helpful to understand polypharmacology, identifying potential off-targets and repurposing of known drugs. In this review, we focused on comparing binding sites of those kinases for which macrocyclic inhibitors are available/studied so far. Furthermore, we calculated the volume of binding site pocket for each targeted kinase and then compared it with the binding site pocket of the kinase for which only acyclic inhibitors were designed till date. Our review and analysis of several explored kinases might be useful to target new protein kinases for macrocyclic drug discovery.

The approval of monoclonal antibodies against programmed death-ligand 1 (PD-L1) and programmed cell death protein (PD1), has changed the landscape of cancer treatment. To date, many Immune Checkpoint Inhibitors (ICIs) have been approved by the FDA for the treatment of metastatic cancer as well as locally recurrent advanced cancer. However, immune-related adverse events (irAEs) of ICIs highlight the need for biomarker analysis with strong predictive value. Liquid biopsy is an important tool for clinical oncologists to monitor cancer patients and administer or change appropriate therapy. CTCs frequently express PD-L1 and this constitutes a clinically useful and non-invasive method to assess PD-L1 status in real time. This review summarizes all the latest findings about the clinical significance of CTC for the management of cancer patients during administration of immunotherapy and mainly focuses on the assessment of PD-L1 expression in CTCs.

Gap junctions (GJs) made of connexin-43 (Cx43) are important for the conduction of electrical impulses in the heart. Modulation of Cx43 activity may be useful in the treatment of cardiac arrhythmias and other dysfunctions. Search of novel GJ modulating agents using molecular docking approach allows to predict the binding affinities that often significantly differ from experimentally estimated their potencies. The objective of this study was to demonstrate that Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using the QSAR model and molecular docking, we evaluated the known Cx43 GJ inhibitors, suggested a new one, and tested it experimentally. Our QSAR model predicted the concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds and estimated the correlation between predicted and experimental IC50ies (pIC50 and eIC50). This led to suggestion of monocyclic monoterpene d-limonene as putative Cx43 inhibitor with pIC50 = 1.07. In turn, dual whole-cell patch-clamp measurements provided eIC50=1.41. The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR model well correlated with their eIC50ies (R = 0.88) in contrast to pIC50s obtained from molecular docking (R = 0.42). However, the molecular docking suggested that inhibitor potency may depend on their docking sites on Cx43.

Scale inhibitors are deployed as preventive and rejuvenation operation in oil and gas industry when production operations are under threat or menace of scale blockage. The application of scale inhibitors is carried out through a method known as squeezing. In general, the squeeze process is governed by inhibitor-rock interaction which is described by adsorption/desorption isotherm. Most reservoirs produce loose sand grains or fine sand which float and flow within the pore spaces along with the squeezed scale inhibitors. Hypothetical reports have shown that not all scale inhibitors pumped into the formation adsorb onto the formation rock. A number of factors (irreversible adsorption, pH changes, competing ions, concentration and temperature) have been considered to affect the adsorption and return profile of these scale inhibitors. This review work examines the performances of most common scale inhibitors used in the oil and gas production activities, theoretical application in reservoirs and how loose fine sand grains affect the adsorption and desorption characteristics of squeezed scale inhibitors. Additionally, presented were overviews of previous reports on fine sand production and migration of fine sands through formation pores in reservoirs.

The chemical investigation of the anti-yeast methanol extract from the stem bark of Terminalia mantaly led to the isolation of seven compounds: 3-O-methyl-4-O-α-rhamnopyranoside ellagic acid (1), 3-O-mehylellagic acid (2), arjungenin or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid (3), arjunglucoside or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid glucopyranoside (4), 2α,3α,24-trihydroxyolean-11,13(18)-dien-28-oïc acid (5), stigmasterol (6), stigmasterol 3-O-β-D-glucopyranoside (7). Their structures were established by means of spectroscopic analysis and comparison with published data. Compounds 1-5 were tested in vitro for activity against three pathogenic yeast isolates, Candida albicans, Candida parapsilosis and Candida krusei. The activity of compounds 1, 2 and 4 were comparable to that of the reference compound fluconazole (MIC values below 32 µg/ml) against the three tested yeast isolates. They were also tested for inhibitory properties against four enzymes of metabolic significance: Glucose-6-Phosphate Deshydrogenase (G6PD), human erythrocyte Carbonic anhydrase I and II (hCA I and hCA II), Glutathione S-transferase (GST). Compound 4 showed highly potent inhibitory property against the four tested enzymes with overall IC₅₀ values below 4 µM and inhibitory constant (Ki) <3 µM.

We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in overall survival (OS) and progression free survival (PFS) in gBRCA1/2m patients compared to both germinal BRCA1/2 wild type (gBRCA1/2wt) and to the untested population. Regarding the efficacy of PI3K inhibitors, there are no subgroup or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.

The aim of this study was to analyze the relationship between healthy vascular aging (HVA) and the Mediterranean diet alongside other lifestyles in a Spanish population aged 35 to 75 years without previous cardiovascular diseases. Methods: Cross-sectional descriptive study with 501 individuals aged 35 to 75 years recruited from five health centers by random sampling stratified by age and sex (55.90±14.24 years, 49.70% men). HVA was determined in two steps. Step 1: Subjects with vascular damage to the carotid arteries or peripheral arterial disease were classified as non-HVA. Step 2: The study population was classified by age and sex using the percentiles of the vascular aging index (VAI), with VAI ≤p25 considered HVA and >p25 considered non-HVA. The VAI was estimated using the following formula (VAI = (log (1.09) × 10 cIMT + log (1.14) cfPWV) × 39.1 + 4.76. Carotid-femoral pulse wave velocity (cfPWV) was measured with the SphygmoCor® device and carotid intima-media thickness using Sonosite Micromax® ultrasound. Mediterranean diet (MD) adherence, alcohol and tobacco use were recorded through validated questionnaires. Physical activity was assessed with the ActiGraph-GT3X® accelerometer. Results: The mean VAI value was 61.23±12.86; (Men 63.47±13.75 and women 59.04±11.54; p

The increasing adoption of student-centred learning environs by the institutions of higher education in business, has led to new mechanisms and methodologies such as the Simulation-Based Learning (SBL), Problem-Based Learning (PBL) and Challenge-Based Learning (CBL). Literature has shown evidence of raising interest in these methodologies towards a more experiential paradigm with regard to upcoming events from the surrounding real-world context. This paper presents a Systematic Bibliographic Literature Review (SBLR) with respect to the integration and application of these innovative and collaborative methodologies in higher education. It aimed to identify its relevant advantages, challenges, and consequences for the future of business education. Bibliographic databases were searched for documents published up to May 2024 to categorize key topics discussed in the literature on SBL, PBL and CBL. The review process identified 89 empirical and non-empirical papers on SBL, PBL and CBL, business related paperwork, which resulted from the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) method. PRISMA is a framework with evidence-based data designed to help authors perform a systematic literature review. Data analysis revealed diverse subthemes for those methodologies uses in business higher education institutions. The research questions “What are the advantages, challenges and implications of SBL, PBL and CBL altogether, in the training of business students?” guided the study. The central output of the research is the discovery of the varying uses of SBL, PBL and CBL overall, to cope with diverse demands arising within environmental context. Future research directions are suggested.

Introduction: The escalating morbidity, mortality, and healthcare costs associated with invasive candidiasis pose significant challenges in pediatric intensive care units (PICUs). Conventional diagnostic methods fall short in effectiveness, while various risk factors exacerbate the prevalence of these infections. This study introduces a novel model that amalgamates the Candida Score with key predictors to enhance the specificity and applicability of mortality risk assessments for pediatric patients with fungemia. Methods: This retrospective cohort study aimed to develop an integrated model for estimating mortality risk in children with fungemia in PICUs. We constructed and evaluated multiple predictive models using the Candida Score and other relevant clinical and laboratory variables. The discriminative abilities of the models were assessed using the area under the receiver operating characteristic curve (AUC). Results: The study cohort comprised 85 pediatric patients admitted between 2016 and 2020, with a median age of 6 months and a male predominance of 62.4%. The mortality rate was 45.9%. Candida albicans was the most prevalent causative agent, accounting for 37.55% of fungemia cases. Multivariable Logistic regression revealed the duration of mechanical ventilation, and the Candida Score were significant predictors of mortality. Each additional day of ventilation increased mortality odds by 11.5% (OR = 1.115, 95% CI: 1.025-1.212, p = 0.011), while a higher Candida Score more than doubled the odds (OR = 2.205, 95% CI: 1.359-3.578, p = 0.001).The Random Forest predictive model demonstrated superior discriminative performance, with an AUC of 0.838 (95% CI: 0.738-0.917), outperforming Gradient Boosting and Logistic Regression models, which had AUCs of 0.7759 (95% CI: 0.667-0.877) and 0.7085 (95% CI: 0.589-0.813), respectively. Although the internal validation yielded satisfactory results, external validation is warranted. Conclusion: This study presents an innovative approach for accurately assessing the risk of mortality due to fungemia in PICU patients by integrating the Candida Score with critical predictors. The Random Forest model emerged as the most effective predictive tool due to its exceptional discriminative ability.

Habenaria, a member of Orchidaceae family is the cosmopolitan distributions, which has significant medicinal and ornamental values. Regardless of morphology and molecular data that have been studied in recent times, the phylogenetic relationship is still under debate. Here, we sequenced, assembled, and annotated the whole chloroplast (cp) genome of two species (Habenaria aitchisonii Rchb.f. and Habenaria tibetica Schltr.ex Limpricht) of Habenaria grown on the Qinghai-Tibetan Plateau (QTP), and combined with seven already published cp genomes which may assist to uncover their genomic profiling. The two genomes ranged from 155259-155269 bp in length and both encoded 132 genes, including 86 protein, 38 tRNA and 8 rRNA. In the cp genomes, the tandem repeats (797), SSRs (2195) and diverse loci (3214) were identified. Comparative analyses of codon usage, amino frequency, microsatellite, oligo repeats and transition and transversion substitutions showed similarities among the species. Moreover, we identified 16 highly polymorphic regions with nucleotide diversity above 0.02, which may be suitable for robust authentic barcoding and inferring in the phylogeny of Habenaria species. Among the polymorphic regions, positive selection was significantly exerted on the several genes such as cemA, petA, and ycf1. This may suggest that the important adaptation stratagem for two Habenaria species on the QTP. The phylogenetic relationship displayed that H.aitchisonii and H. tibetica have closer relationship than others and the rest seven species clustered in the other three groups. Our findings also supported the idea that Habenaria could be divided into different sections. This study enriched the genomics resources of Habenaria, which may be helpful for the conservation efforts of these endangered species.

Surface water plays a crucial role in climate change, human production, and life, making accurate monitoring and observation of surface water particularly important. However, due to the significant diversity and complexity of water distribution in surface space, accurate mapping of surface water faces considerable challenges. When extracting water bodies from medium-resolution satellite remote sensing images, CNN methods may suffer from limitations in receptive fields and insufficient context modeling capabilities, leading to the loss of water body boundary details and poor fusion of multiscale features. Currently, there is relatively little research on this issue; therefore, it is necessary to explore new combinations of deep learning networks to address these challenges. The purpose of this study is to address the above issues. We propose a new combination of deep learning networks that fully utilize multiscale information to enhance water features. Specifically, we first combine deformable convolutions with the Swin Transformer to increase effective receptive fields while better integrating global semantic information. This combination can capture features of water bodies at different scales, improve the accuracy and integrity of water extraction, and provide reliable technical support for detailed water body extraction. We tested the newly constructed model using Sentinel-2 satellite images. Our model achieved results of over 90%, with an average accuracy of 97.89%, average precision of 94.98%, average recall of 90.05%, and an average F1 score of 92.33%. In addition, our model achieved an accuracy of 98.03% in mountainous areas. Our experiments and results validate the potential of combining the Swin Transformer and deformable convolutions in detailed water body extraction.

Hydrogels have gained significant attention as vehicles for transdermal delivery systems. These polymeric-structured substances have been implemented in pharmaceutical and cosmetic applications. Many factors are employed in their preparation. Light, pH, temperature and specific molecules ligands are commonly used in the production of hydrogels. The Transdermal delivery system (TDD) is a widely used route, used to deliver actives/drugs via the skin. Hydrogels as a TDD have been shown to be efficient in enhancing the efficacy in delivering the actives and drugs. The aim of this review is to discuss the hydrogels application in both dermatological therapeutic and cosmetic applications, covering the types, and properties of hydrogel polymer networks. Furthermore, this review presents one of the most extensively used polymers (Hyaluronic acid HA) in this field and discusses the properties, preparation methods and applications of HA hydrogel patches as a delivery system, including methods of loading the actives and the releasing of these actives from them.

The deaf-mute and individuals with hearing disabilities who communicate through sign language should not be overlooked or excluded. It is a social responsibility to strive for an inclusive world without inequality. Advances in technology offer various solutions to address the communication gap, one of which is the use of computer-based sign language recognition systems. This project proposes a Malaysian Sign Language recognition model utilizing MobileNetV1, a convolutional neural network-based algorithm, to interpret sign language in real-time settings through a website application using Streamlit. The outcome of the model test shows that it has achieved a recognition rate of 96 percent. Although the proposed model has demonstrated the ability to recognize sign language, it is suggested that further improvement can be achieved by enhancing the quality and diversity of the dataset. The implementation of a more comprehensive dataset would lead to improved performance and increased accuracy of the model. This project underscores the importance of considering and accommodating the needs of the deaf-mute and individuals with hearing disabilities and highlights the potential of technology to bridge communication barriers and achieve a more inclusive society.

Immunotherapy, particularly Immune Checkpoint Blockade (ICB), has demonstrated significant efficacy in treating melanoma in recent years. However, accurately predicting treatment success and avoiding ineffective therapies remains an unresolved challenge. Therefore, this study aims to develop statistical models utilizing neural networks to forecast the effectiveness of immune checkpoint therapies for melanoma patients. Our models primarily rely on Artificial Neural Networks (ANN) to anticipate both Overall Survival (OS) and Progression-Free Survival (PFS) among melanoma patients undergoing anti-CTLA4 and anti-PD1/anti-PDL1 therapy. We incorporate gene expression data, measured in Transcripts per Million (TPM), derived from bulk tumor RNA-sequencing datasets. Additionally, clinical variables such as gender, age, and treatment type are factored into our analysis. The ANN underwent optimization to attain the highest feasible precision in anticipating the predetermined survival outcome. Issues stemming from high-dimensional data, such as overfitting, were tackled through regularization and feature selection methods. Consequently, the ANN-based model incorporating feature selection exhibited the capacity to forecast survival (PFS) in response to ICB therapy with a maximal precision of 86%. Conversely, the ANN lacking feature selection but incorporating regularization achieved accuracies of up to 72% for PFS and 71% for OS, correspondingly. In order to confront the challenge posed by limited patient samples and to assess replicability, the model underwent training and validation based on the amalgamation of all five datasets. However, this amalgamation failed to enhance predictive performance, necessitating further investigations.

The institutionalization of people with intellectual disabilities has been a common international response across cultures and generations that persists to this day. This chapter recounts its inheritance and manifestation in modern service provision. An institutional mind-set persists among clinicians and managers despite policies that emphasise the rights of persons with intellectual disability and anti-discriminatory practice. Alternative provision is rooted in person-centred practice; with a growing body of evidence for the improved quality of life that results from it. A reflective activity encourages readers to examine a recent case when they were associated with an institutional placement and what alternatives might have been sought. Yet alliances with other professionals, self-advocates and family carers will be needed to effect real and lasting changes in our service cultures and even then, the long shadows of institutional care may still persist.

Objective To investigate nailfold capillary parameters in community-dwelling individuals aged over 60 years who have hypertension and do not exercise regularly. Furthermore, the study examined the correlations between capillary function and other health-related indicators. Design A single- center pilot trial Setting Faculty of Health, Tsukuba University of Technology, Japan Participants hypertensive community-dwelling elderly people Intervention Microcirculation was observed before and 1 min after arm-curl exercise by means microscopy of capillary with non-exercised limb. Additionally, we examined other health-related indicators. Outcome measures: Acute effects of reperfusion on nailfold density, flow, and diameters. Secondary outcomes included the correlations between microvascular parameters and other health-related indicators. We hypothesized that brief exercise could enhance microcirculation reperfusion and correlate with other health-related parameters.　 Results: There were 20 participants with a mean (SD) age of 67.1 (5.8) years. The capillary flow rate changed from 2.3±6.7 to 2.7±0.2 log µm/s (P

The main proteinase (Mpro), or 3CLpro, is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle and is responsible for breaking down and releasing vital functional viral proteins crucial for virus development and transmission. As a catalytically active dimer, its dimerization interface has become an attractive target for antiviral drug development. Recent research has extensively investigated the enzymatic activity of Mpro, focusing on its role in regulating the coronavirus replication complex and its significance in virus maturation and infectivity. Computational investigations have identified four druggable pockets, suggesting potential allosteric sites beyond the substrate-binding region. Empirical validation through site-directed alanine mutagenesis targeted residues in both the active and allosteric regions corroborated these predictions. Structural studies of drug target proteins can inform therapeutic approaches, with metadynamics simulations shedding light on the role of H163 in regulating Mpro function and providing insights into its dynamic equilibrium to the wild-type enzyme. Despite the efficacy of vaccines and drugs in mitigating SARS-CoV-2 spread, ongoing viral evolution, selective pressures, and continued transmission pose challenges, potentially leading to resistance mutations. Phylogenetic analyses indicated the existence of several resistance variations predating drug introduction to the human population, emphasizing the likelihood of drug spread. Hydrogen/deuterium-exchange mass spectrometry reveals the structural influence of the mutation, while clinical trials on 3CLPro inhibitors underscore the clinical significance of reduced enzymatic activity and offer avenues for future therapeutic exploration. Understanding the implications of 3CLPro mutations holds promise for shaping forthcoming therapeutic strategies against COVID-19. This review delves into factors influencing mutation rates and identifies areas warranting further investigation, providing a comprehensive overview of Mpro mutations, their categorization, and terminology. Moreover, we examined their associations with clinical outcomes, illness severity, unresolved issues, and future research prospects, including their impact on vaccine efficacy and potential therapeutic targeting.

Limited research has been conducted on the metabolites present in the essential oils (EOs) of Phlomoides rotata (Benth. ex Hook. f.) Mathiesen (PR, syn. Lamiophlomis rotata (Benth.) Kudô), and their potential pharmacological activities, such as antioxidant properties, are often overlooked. We conducted a metabolomics-based screening to identify the characteristic metabolites (CMs) in the EOs extracted from PR. Meanwhile, we evaluated their in vitro antioxidant activities (AOAs). The EOs obtained through hydro-distillation are characterized by a light yellow color and a fresh, elegant fragrance. Cryoprecipitation was used to separate the crystals (Crs) from the EOs, resulting in the crystal-free EOs (CFs). A total of 121 components are identified and quantified in the EOs, Crs, and CFs. Among them, 84 were reported for the first time from such EOs. The major compounds include long-chain fatty acids (LCFAs) and their esters, such as palmitic acid (PA), myristic acid (MA), linoleic acid (LA), oleic acid (OA), stearic acid, and methyl palmitate (MP). Furthermore, 11 kinds of apocarotenoids (also called norisoprenoids) were first systematically investigated. Among them, eight C13-norisoprenoids, with trans-β-damascenone (DN) being particularly notable for its flavor, were identified. A sum of 11 CMs are screened , including PA, MA, LA, OA, MP, hexahydrofarnesyl acetone, phytol (PT), DN, stearic acid, linalool, and hexanal. These CMs are biosynthesized through FAs and 2-C-Methyl-D-erythritol 4-phosphate/1-Deoxy-D-xylulose 5-phosphate pathways. The in vitro AOAs of EOs, Crs, CFs, and seven selected CMs (PA, MA, LA, OA, MP, PT, and DN) were evaluated. Generally, PA and MA exhibited pro-oxidant activities (POAs) or weak AOAs. LA and OA demonstrated POAs or weak AOAs at lower concentrations, but at higher concentrations, they displayed medium to strong AOAs. Importantly, the CFs typically exhibited stronger AOAs compared to the corresponding EOs and Crs, potentially due to variations in their PA content. Overall, this study provides valuable insights into the potential utilization of EOs from PR.

Aim To perform a comprehensive analysis of discordances between contrast-enhanced CT (ceCT) and 18F-FDG PET/CT in the evaluation of the extra-cerebral treatment monitoring in patients with stage IV melanoma. Materials and methods We conducted a retrospective monocentric observational study over a 3 years period in patients referred for 18F-FDG PET/CT and ceCT in the framework of therapy monitoring of immune checkpoint or tyrosine kinase inhibitors (ICIs or TKIs) as of January-2017. Imaging reports were analysed by two physicians in consensus. Anatomical site responsible for discordances, as well as induced changes in treatment were noted. Results Eighty patients were included and 195 couples of scans analysed. Overall, discordances occurred in 65 cases (33%). Eighty percent of the discordances (52/65) were due to 18F-FDG PET/CT scans upstaging the patient. Amongst these discordances, 17/52 (33%) led to change in patient’s management, the most frequent being radiotherapy of a progressing site. ceCT represented 13/65 (20%) of discordances and induced changes in patients’ management in 2/13 cases (15%). The more frequent anatomical site involved was subcutaneous for 18F-FDG PET/CT findings and lung or liver for ceCT. Conclusions Treatment monitoring with 18F-FDG

Aim To perform a comprehensive analysis of discordances between contrast-enhanced CT (ceCT) and 18F-FDG PET/CT in the evaluation of the extra-cerebral treatment monitoring in patients with stage IV melanoma. Materials and methods We conducted a retrospective monocentric observational study over a 3 years period in patients referred for 18F-FDG PET/CT and ceCT in the framework of therapy monitoring of immune checkpoint or tyrosine kinase inhibitors (ICIs or TKIs) as of January-2017. Imaging reports were analysed by two physicians in consensus. Anatomical site responsible for discordances, as well as induced changes in treatment were noted. Results Eighty patients were included and 195 couples of scans analysed. Overall, discordances occurred in 65 cases (33%). Eighty percent of the discordances (52/65) were due to 18F-FDG PET/CT scans upstaging the patient. Amongst these discordances, 17/52 (33%) led to change in patient’s management, the most frequent being radiotherapy of a progressing site. ceCT represented 13/65 (20%) of discordances and induced changes in patients’ management in 2/13 cases (15%). The more frequent anatomical site involved was subcutaneous for 18F-FDG PET/CT findings and lung or liver for ceCT. Conclusions Treatment monitoring with 18F-FDG

Fluorinated cytokinins have emerged as promising alternatives to traditional cytokinins in plant tissue culture, offering enhanced stability and bioactivity. However, their metabolic fate and impact on endogenous cytokinin profiles remain largely unexplored. This study investigated the cytokinin metabolism of Phalaenopsis orchids under varying exogenous cytokinin treatments (BA, FmT, FmTR) and culture conditions (open vs. closed containers). The results reveal distinct metabolic profiles associated with each treatment, highlighting the complex interplay between exogenous and endogenous cytokinin levels. Additionally, we proposed an alternative inactivation pathway involving the conversion of FmTR and BA to pT and pTR. These findings provide valuable insights into the intricate relationship between cytokinin metabolism and plant growth under in vitro conditions, with implications for optimizing micropropagation protocols

The increasing focus on sustainability and the adoption of green practices across industries underscore the necessity of equipping future professionals with competencies in implementing sustainable solutions. This study explores the perceptions of former students from two departments within the technological sector towards sustainability practices. A cross-sectional online survey was carried out among alumni from two programs at the University of Thessaly, a university recognized for its commitment to sustainability and green initiatives as a member of the INVEST European University alliance. The survey questionnaire included background inquiries and 16 statements designed to gauge alumni perspectives towards sustainability practices. Specifically, it aims to assess their views through self-assessment and compare differences between the two alumni groups. Responses were collected on a 5-point Likert scale ranging from strongly disagree to strongly agree. A total of 300 graduates from the Computer Science and Telecommunications as well as Electrical Engineering undergraduate programs were encouraged to take part in the survey, achieving a response rate of 69%. Of those who responded, 61% (n = 126) represented the Computer Science and Telecommunications group, while 39% (n = 81) were from the Electrical Engineering program. Our findings indicate a generally positive attitude towards sustainability, with statistically significant differences in perspectives on the implementation of sustainable technologies and stakeholder engagement. These results underscore the necessity of integrating sustainability education deeply within the curricula of technological programs to cultivate a workforce capable of addressing future environmental challenges. This study illuminates the critical role of educational frameworks in shaping the sustainability competencies of technology professionals.

Introduction: Glomerulopathy is a term used to describe a broad spectrum of renal diseases, character-ized by dysfunction of glomerular filtration barrier, especially of podocytes. Several podocyte-associated proteins have been found and proved their usefulness as urine markers of podocyte dysfunction. Two of them are nephrin (NEP) and prodocalyxin (PDC). Purpose: This study aims to evaluate the association of podocyte damage, as it is demonstrated via the concentrations of urinary proteins, with clinical and histological data from patients with several types of glomerulonephritis. Methods: We measured urine levels of two podocyte-specific markers, NEP and PDC (corrected for urine creatinine levels), in patients with a wide range of glomerulopathies. Serum and urine parameters as well as histological parameters from renal biopsy were recorded. Results: In total, data from 37 patients with glomerulonephritis and 5 healthy controls were analyzed. PDC and NEP concentrations correlated between them and with serum creatinine levels (p=0.001 and p=0.013 respectively), and with histological lesions associated with chronicity index of renal cortex, such as severe interstitial fibrosis, severe tubular atrophy and hyalinosis (for PDC/NEP, all p3gr/24h with diffuse fusion of podocyte foot processes (p=0.016) was identified. Conclusions: Podocalyxin and nephrin concentrations in urine represent markers of podocyte dysfunction and in our study they were associated both with serum creatinine and histological chronicity indices.

The rise of the Internet has enabled people to express their opinions on various subjects through social media, blogs, and website comments. As a result, there has been a significant increase in research on sentiment analysis. However, most of the research efforts have focused on analyzing sentiment in English-language data, neglecting the wealth of information available in other languages. In this paper, we provide a comprehensive review of the current state-of-the-art in multilingual sentiment analysis. The survey investigates techniques for data preprocessing, representation learning, and feature extraction in multilingual sentiment analysis. It explores cross-lingual transfer learning, domain adaptation, and data augmentation methods that enhance the performance of sentiment analysis models, particularly in low-resource languages and domains. It provides insights into the state-of-the-art approaches, challenges, and opportunities in this evolving field and encourages further advancements in multilingual sentiment analysis research.

The paper presents the observational, remote sensing and model simulation to analyze Southern Brazil Antarctic Ozone Hole influence (SBAOHI) events occurred between 2005 and 2014. To an-alyze it we use Total Ozone Column (TOC) data provide by Brewer Spectrophotometer (BS) and OMI (Ozone Monitoring Instrument) instrument satellite, besides the AURA/MLS (Microwave Limb Sounder) instrument satellite ozone profiles was utilized with DYBAL (Dynamical Barrier Localization) code in MIMOSA (Modélisation Isentrope du transport Mésoéchelle de l’Ozone Stratosphérique par Advection) model Potential Vorticity (PV) fields. TOC has 7.0 ± 2.9 DU re-ductions average in 62 events. October have more events (30.7%). Polar Tongue events are 19.3% of total, being in October more frequently observed (50% of cases), with medium intensity (58.2%) and in stratosphere medium levels (55.0%). Already Polar Filament events (80.7%) are more frequent in September (32.0%), medium intensity (42.0%) and in stratosphere medium lev-els (40.7%). ENSO index positive phase influenced 61.3% of events, having dominance in all in-tensity categories (minor 57.9%, medium 51.6%, major 58.3%), while the equilibrium dominate the QBO influence with 50% of total cases in positive phase and 50 % in negative phase.

In the evolving landscape of digital marketing, cross-channel attribution modeling plays a crucial role in understanding and optimizing the customer journey across various touchpoints. As consumers interact with brands through multiple channels—such as social media, email, search engines, and display ads—accurately attributing conversions to the right channels is vital for optimizing marketing strategies and budgets. However, the advent of stringent privacy regulations, such as the General Data Protection Regulation (GDPR) and the California Consumer Privacy Act (CCPA), has significantly impacted the data collection and analysis processes in digital marketing. This paper explores the challenges and opportunities presented by cross-channel attribution modeling in the age of heightened privacy awareness. It examines how traditional data-driven attribution models, which often rely on tracking individual user behavior, are being adapted or replaced in response to privacy concerns and regulatory requirements. The paper discusses the emergence of privacy-preserving techniques, such as aggregated data analysis, differential privacy, and the use of anonymized data, which aim to balance the need for accurate attribution with the protection of consumer privacy. Furthermore, the paper highlights the role of first-party data and the growing importance of consent management in the collection and utilization of consumer information. It also investigates how marketers are leveraging advancements in artificial intelligence and machine learning to enhance attribution models in a privacy-conscious world. The study concludes by offering best practices for businesses seeking to navigate the complexities of cross-channel attribution in the context of evolving privacy regulations, emphasizing the need for transparency, compliance, and ethical data handling. This research provides valuable insights for marketers, data scientists, and policymakers on how to effectively manage the interplay between accurate attribution and privacy, ensuring that marketing efforts remain effective while respecting consumer rights.

Treating central giant cell granuloma (CGCG) is challenging due to high recurrence rates and variable therapy responses. This study examines the efficacy of various treatments in reducing CGCG recurrence. A literature review explored outcomes of surgical excision, curettage, intralesional corticosteroid injection, and adjuvant therapy, considering factors like lesion location, size, and histological features. Aggressive surgical techniques such as en bloc resection were found to potentially lower recurrence rates compared to conservative approaches. However, treatment should be tailored to individual patient needs. Further research is needed to confirm these findings and improve treatment strategies. A concise literature review was conducted using PubMed, MEDLINE, and Google Scholar, focusing on papers published from 1986 to 2024. Search terms included "central giant cell granuloma," "recurrence," "treatment modalities," and "surgical excision". Studies reporting recurrence rates and treatment outcomes for CGCG were analyzed. Twenty-nine studies were reviewed, including six studies on surgical excision and curettage, eight studies on intralesional corticosteroid injections, six studies on calcitonin therapy, five studies on interferon alpha therapy and four studies on the therapy with denosumab. Analysis indicated that aggressive surgical treatments like en bloc resection were associated with lower recurrence rates compared to conservative methods. Predictors of recurrence included lesion size (&gt;3 cm), location (mandible), and aggressive histopathological features. Aggressive surgical excision combined with nonsurgical methods may lower recurrence rates, while conservative techniques remain viable in some cases. Further prospective research is needed to validate these findings and enhance CGCG treatment options.

The clothing industry is a hotbed for exploitative working conditions and environmental damages, of which affluent global North countries remain a substantial driver. The circular economy is a potential solution to these issues, but its social implications remain unclear. Using the UK as a case study, this article analyses the global social impacts of a transition to circular clothing economies in the global North, finding these to be (almost) entirely dependent upon the intentions and design of the associated politics. Some aspects of a transition will be unambiguously good for some people; others will only be beneficial with careful governance. Moreover, entrenched global economic inequalities leave trade-offs borne largely by the global South, highlighting the need for circular economy research – its drive for localisation notwithstanding – to look globally to consider how a fair transition can be achieved.

This research aims to explore the adoption and impact of green supply chain practices (GSCP) on sustainable development in Bangladesh. The study seeks to understand the current state of GSCP adoption across various industries, identify key drivers and barriers, assess the perceived benefits and challenges, and evaluate the overall impact on environmental sustainability, economic performance, and social well-being. The research employs a qualitative approach, utilizing interviews with key stakeholders, document analysis, and literature review to gather data and insights. Interviews were conducted with representatives from government agencies, businesses, civil society organizations, and academia to obtain diverse perspectives on GSCP adoption and its implications for sustainable development in Bangladesh. The findings reveal a mixed scenario of GSCP adoption across different industries in Bangladesh, with sectors such as textiles leading the way. Key drivers of GSCP adoption include regulatory pressures, market forces, corporate social responsibility initiatives, and financial incentives. However, organizations face significant barriers such as high upfront costs, lack of awareness and expertise, regulatory uncertainty, and supply chain complexity. Despite these challenges, GSCP offer various benefits, including environmental sustainability, economic performance, and social well-being. Successful initiatives demonstrate tangible impacts, highlighting the potential of GSCP to contribute to sustainable development. The research is limited by its qualitative nature and focus on selected industries and stakeholders. Future studies could employ quantitative methods and broader sampling to provide a more comprehensive understanding of GSCP adoption and its implications in Bangladesh. The findings provide actionable insights for policymakers, industry leaders, and other stakeholders to promote GSCP adoption and enhance sustainable development in Bangladesh. Strategies for overcoming barriers and maximizing benefits are outlined, emphasizing the importance of collaboration and capacity-building initiatives. GSCP adoption can have positive social implications by promoting ethical labor practices, improving working conditions, and fostering community engagement. By prioritizing sustainability, businesses can contribute to social well-being and inclusive growth. This research contributes to the literature on GSCP adoption and sustainable development in Bangladesh by providing empirical insights and practical recommendations. The study adds to the understanding of the drivers, barriers, benefits, and challenges associated with GSCP adoption, highlighting the importance of integrating environmental, economic, and social considerations in supply chain management.

The Diaphorina citri Kuwayama (D. citri) is one of the major pests in the citrus industry, which spreads Citrus Huanglongbing disease. It has developed resistance to chemical insecticides. Therefore, searching for greener solutions for pest management is critically important. The main aim of this study was to evaluate the repellent and insecticidal efficacy of essential oils (EOs) from four species of Myrtaceae plants: Psidium guajava (PG), Eucalyptus robusta (ER), Eucalyptus tereticornis (ET), and Baeckea frutescens (BF) against D. citri and to analyze their chemical composition. GC-MS analysis was performed, and the results indicated that the EOs of PG, ER, ET, and BF were rich in terpenoids, ketones, esters, and alcohol compounds. The repellent rate of all four EOs showed that it decreased with exposure time but increased with concentrations of EOs. Repellent rates ranged from 80.50% to 100.00% after treating D. citri for 6 hours with four EOs at 100% concentration and decreased to 67.71% to 85.49% after 24 hours of exposure. Among the compounds from the EOs tested, eucalyptol had the strongest repellent activity, with a 24-hour repellency rate of 100%. The contact toxicity bioassay results showed that all EOs have insecticidal toxicity to D. citri; the LC50 for nymphs was 36.47-93.15 mL/L, and for adults, it was 60.72-111.00 mL/L. These results show that when PG is used as the reference material, both ER, ET, and BF EOs have strong biological activity against D. citri, which provides a scientific basis for the further development of plant-derived agrochemicals.

The purpose of this research is to examine the benefits and limitations of implementation of novel digital academic advising systems using automated collection and reporting processes for ABET student outcomes data based on principles of authentic OBE for effective developmental advising. We examine digital developmental advising models of undergraduate engineering programs in two universities that employ customized features of the web-based software EvalTools® - Advising Module based on assessment methodology incorporating the Faculty Course Assessment Report, Performance Indicators and hybrid rubrics classified according to the affective, cognitive and psychomotor domains of Bloom’s learning model. A case study approach over a six-year period is adopted for this research. The two case studies present results of samples of developmental advising activity employing sequential explanatory mixed methods models using a combination of quantitative and qualitative analyses of a) detailed students’ outcomes and Performance Indicators information; and b) self-evaluation of their professional development and lifelong learning skills. The findings of this study show that digital advising systems employing the Faculty Course Assessment Report using Performance Indicators and hybrid rubrics can provide comprehensive and realistic outcomes data to help both developmental advisors and students easily identify the specific cause of performance failures, implement practical recommendations for remedial actions and track improvements. Inherent strong skills can also be identified in academically weak students by observing patterns or trends of relatively better performing outcomes to reinforce natural affinity for learning specialized competencies and pursue related and successful career paths.

Medical image segmentation is a critical step in various healthcare applications, aiding in diagnosis, treatment planning, and disease monitoring. In this study, we investigate the efficacy of a segmentation approach based on the 2D wavelet transform. Leveraging a dataset comprising 10 diverse medical images, we evaluate the performance of our segmentation method using three key metrics: accuracy, precision, and recall. Our findings demonstrate that the proposed approach enhances segmentation accuracy, offering promising results compared to existing methods. By harnessing the multi-resolution feature extraction capabilities of the 2D wavelet transform, our method achieves improved delineation of medical image structures, paving the way for more accurate and efficient healthcare interventions.

This study presents a groundbreaking approach in the field of gaming AI, focusing on the classic game” Pacman” through the lens of DRL integrated with advanced optimization techniques. The core of the research involves adapting DRL models for” Pacman”, utilizing the ESO for hyper- parameter tuning. These novel adaptations significantly enhance the AI agent’s performance, demonstrating a remarkable improvement in adaptability, responsiveness, and efficiency within the game environment. A pivotal aspect of this research is the innovative integration of metaheuristic optimization techniques into the DRL framework, a first in the domain of Atari gaming AI. This integration has proven essential in fine-tuning the DRL models, leading to a more effective and dynamic gaming experience. The study thoroughly evaluates and compares the performance of these algorithms, providing empirical support for their effectiveness and setting a new benchmark in AI-driven game development. The implications of this research extend beyond gaming AI, opening up possibilities for future exploration in several directions. Expanding DRL models to other complex gaming environments, continuous algorithmic enhancements, real-time learning adaptations, and applying these principles to robotics and autonomous vehicles are examples. The research also emphasizes ethical and responsible AI use in gaming to address fairness and addiction issues.

Epilepsy is one of the most prevalent and serious brain disorders, affecting 70 million people worldwide. Antiseizure medications (ASMs) though relieve symptoms and prevent the occurrence of future seizures in epileptic patients have limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms for development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made and challenges facing in the development of NLRP3 inhibitors for the treatment of epilepsy.

The present study explored whether exposure to complex childhood trauma (CCT) is reflected in the resting-state electroencephalography (EEG) temporal alpha power of complex trauma-exposed adolescents, given the association of temporal alpha with fear circuitry (learning and conditioning) in a sample of 25 adolescents and similar controls, ages 12-17 years. Both trauma and psychopathology were screened or assessed, and resting-state EEG was recorded, following a preregistered protocol for data collection. Temporal alpha power, corresponding to T5 and T6 electrode location (10-20 international system), was extracted from resting-state EEG in both eyes-open and eyes-closed conditions. We found that in the eyes-open condition, right, but not left, temporal alpha was significantly higher in adolescents exposed to CCT, relative to healthy controls, suggesting that childhood trauma exposure may have a measurable impact on alpha oscillatory patterns, specifically in the right temporal region. Our study highlights the importance of considering neural markers, such as temporal alpha power, in understanding the long-term consequences of CCT exposure in developmental samples, with possible important clinical implications in guiding neuroregulation interventions.

Verification of inclusivity of molecular detection methods gives indications on the reliability of viral infections diagnosis because of the tendency of viral pathogens to undergo sequence variation. This study was aimed to select inclusive probe based reverse transcription quantitative PCR (RT-qPCR) assays for the diagnosis of the most widespread and detrimental viruses infecting honeybees, namely the acute bee paralysis virus (ABPV), the black queen cell virus (BQCV), the chronic paralysis bee virus (CBPV), the deformed wing virus variants A (DWVA) and B (DWVB), and the sacbrood virus (SBV). Therefore, detection methods previously described were re-evaluated in silico for specificity and inclusivity. Based on this evaluation, selected methods were modified or new ones were designed and tested in duplex RT-qPCR reactions. The limits of detection (LODs), effect of multiplexing on sensitivity and viral RNA quantification potential in bees and hive debris were assessed. This study made available diagnostic assays able to detect an increased number of virus variants compared to previously described tests and two viral pathogens in a single PCR reaction.

Background This study aimed to identify the prominent risk factors that may trigger danger signals of early onset of vascular deregulation in T1D. The risk factors we have identified may serve as dual-purpose biomarkers of rapid diagnosis that offer prospective tailor-made resolution therapeutics. Methods The healthy control (HC) was compared with individuals diagnosed with T1D for the risk factors of vascular deregulation in published research studies from year 2013 to 2023. The PubMed, Web of Science and Google Scholar databases were searched from 1/1/2013 to 1/9/2023. The risk of bias was assessed with the Cochrane (ROBINS-I ) tool, which is relevant to clinical subjects. A random effect model for continuous data was followed and analysed by RevMan 5.4 and GraphPad Prism software. Results 80 relevant case-control studies having 5293 HC and 7492 T1D patients were included. The age and sex-matched HC consisted of persons free of disease and not under any medication while clinical subjects of all age groups were included. 28 risk factors were grouped into six primary outcome models, all of which favoured the T1D synonymous with a high risk of CVD. Conclusions Our findings have strong implications for improving the quality of life and health economics related to vascular disease in T1D. HbA1c% is the most effective biomarker, followed by FBG, LDL-C, and AI% which the clinicians could evaluate using a simple blood test or non-invasive techniques. (Protocol registered at https://www.crd.york.ac.uk/prospero/ CRD42022384636).

Coal bottom ash (CBA) is a byproduct of coal-burning power plants. This material can be used as a fine aggregate replacement in concrete to reduce global natural material depletion. Concrete usage is increasing rapidly; subsequently, the industry’s carbon footprint is increasing. Using CBA in the construction industry will reduce the technical and economic problems associated with power plants by reducing solid waste. This project aimed to determine if adding new sustainable materials, such as CBA, to concrete will reduce natural raw material usage, energy consumption, and greenhouse gas emissions while improving performance. This study included two projects: comparing increased CBA content to the two-control project and determining the optimum content based on the compressive strength. The optimum CBA content is 50%, which reduces fine aggregate usage in a concrete mix by 50% while maintaining equivalent or better concrete strength than a pure Portland concrete mix without CBA. The air content of the concrete mix containing % CBA decreased with increased CBA content and compressive strength, possibly due to the spacing factor of the voids in the mix and CBA’s porous and fineness behavior. The CBA optimum content had a unit weight lower than the controls for both projects, which makes the CBA mix a lightweight concrete. Using this material can significantly reduce natural material usage and environmental harm by reducing CBA waste disposal and improving concrete performance.

To facilitate the promotion and application of the whole process engineering consulting (WPEC) model, the transmission mechanism of influencing factors in WPEC's promotion and application is investigated. It identifies and categorizes the influencing factors within the framework of "external environment-project factors-stakeholders", systematically organizing and summarizing ten primary categories and thirty-eight secondary influencing factors of WPEC's promotion and ap-plication. Utilizing the complex network analysis method, a network of influencing factors in the promotion and application of WPEC is constructed. The network is then converted into three binary networks based on weight, which are subjected to structural analysis and motif analysis. On this basis, the transmission mechanism of influencing factors in WPEC's promotion and applica-tion and its causations are explored.

Thrombosis after severe acute respiratory syndrome coronavirus 2 vaccination is a serious complication in patients who have a thrombophilic predisposition. In this case, a female patient with no family history of thrombophilia who had pediatric antiphospholipid syndrome (APS) developed deep vein thrombosis (DVT) when she was 6 years old; 6 months after receiving a second dose of the BNT162b2 vaccine, DVT reoccurred. The original thrombi were found in the right common iliac vein and the inferior vena cava, with concomitant left pulmonary infarction. The patient was treated with anticoagulants for 6 years after DVT onset, with subsequent treatment cessation for 5 years without recurrence. She received the BNT162b2 vaccine at 17 years of age, 1 week before a routine outpatient visit. Platelet factor 4 elevation was detected 14 days after the first vaccination, persisting for 5 months without thrombotic symptoms. Six months after the second vaccine dose, the DVT recurred and was treated with a direct oral anticoagulant. The vaccine exacerbated the patient’s APS by activating coagulation, causing thrombosis recurrence. Platelet factor 4 levels may indicate coagulation status. When patients predisposed to thrombosis are vaccinated, coagulation status and platelet activation markers should be monitored to prevent DVT development.

Physical exercise is the greatest stress on the cardiovascular system, not only in humans but also in all vertebrates. Consequently, the cardiovascular response cannot be thought of as having only one "anthropocentric" interpretation. The modulation of cardiac output (Q) in response to exercise in the five major groups of vertebrates exhibits considerable variability. Moreover, the response of the heart rate (HR) and the stroke volume (SV), the fundamental factors that cause the rise in Q, is also highly variable. The difference in the range of HR is difficult to determine in many vertebrates, both at rest and at maximal effort. Additionally, the increase in SV varies among vertebrates. For example, while rainbow trout and leopards increase their SV by increasing end diastolic volume (EDV), humans do so at the expense of both increasing EDV and reducing end systolic volume (ESV). The variation in arterial pressure that arises during exercise varies notably among vertebrates, such as amphibians, whose blood pressure values do not increase as significantly as in mammals. Such differences in cardiovascular response among vertebrates may be linked to their habitat or living environment. This review aims to analyze the cardiovascular response of vertebrates to physical exercise as the most common stressor.

HIV incidence remains alarmingly high among female sex workers (FSWs) in low- and middle-income countries, with Uganda being no exception. The elevated risk of HIV transmission among this vulnerable population can be attributed to a complex interplay of factors, including engaging in sexual activities with multiple partners, inconsistent condom usage, substance use, and structural barriers, such as legal criminalization and pervasive stigmatization by healthcare providers. To combat this epidemic, various HIV prevention interventions have been devised, targeting these multi-faceted challenges. This study involved conducting focus groups among FSWs and healthcare providers in Uganda, with the overarching objective of informing the development of a tailored HIV prevention intervention aimed squarely at FSWs. Through these discussions, valuable insights were gained into FSWs’ perceptions of their HIV risk, their attitudes regarding HIV prevention strategies, and their recommendations regarding the content and delivery of future interventions.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the genetic and clinical features among the CTCL subtypes. JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB are those signalling pathways that are found altered in CTCL and that are responsible for promoting both T-cell malignancy and the pro-tumorigenic microenvironment. Thus, targeting key players of these pathways can be an advantageous therapeutic option for CTCL. In this review, we aim to summarise the different approaches that precisely inhibit the kinases of each cited signalling. JAK inhibitors seem to be the most promising kinase inhibitors for CTCL. However, adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. More studies are needed, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas.

Immune checkpoint inhibitors (ICI’s) are in the forefront of advanced Non Small Cell Lung Cancer (NSCLC) treatment. Still, only 27- 46% of patients respond to initial therapy with ICI’s and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4%-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post-hoc analyses of several clinical trials. Future research of ICI rechallenge for NSCLC should focus on better patient stratification, to reflect the underlying biology of immunotherapy resistance more accurately.

Ras homolog enriched in brain (Rheb1 and Rheb2), a small GTPase, regulates neuronal activity and has drawn attention for its implications in cancer development, especially breast cancer. This study explores the multifaceted role of Rheb1 in cancer, elucidating its involvement in crucial cel-lular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses. Despite these acknowledged connections, a comprehensive understanding of the intricate interplay between Rheb1 and cancer remains elusive. This review consolidates cur-rent knowledge on the impact of Rheb1 on cancer hallmarks and examines the potential of Rheb1 as a therapeutic target in cancer treatment. The review underscores the need for a more profound comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes. Furthermore, the review emphasizes the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. This study, by bringing to light the complex associations between Rheb1/Rheb2 and cancer, delivers valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeu-tic strategies for treating cancer.

In advanced Parkinson’s disease (PD), and especially in PD related dementia (PDD), psychotic symptoms are common. One of the manifestations of psychosis in PD is delusional misidentification syndrome, a phenomenon in which the patient believes the identity of a person, object or location has been duplicated or altered. Our patient, a 75-year-old female, was diagnosed with idiopathic Parkinson’s disease at the age of 68. Recently, her cognition deteriorated and she developed the believe that she lived in a replica of her real home. The delusion resolved completely with rivastigmine patches. Also visual hallucinations improved on treatment. This suggests that the dysfunctional connections were likely to be cholinergic.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we synthesized usnic acid derivatives, which are hybrids of its known derivatives - tumor sensitizers to topotecan. New compounds inhibit Tdp1 in the micromolar and submicromolar concentration range; some of them enhance the effect of topotecan on the metabolic activity of cells of various lines according to the MTT test. One of the new compounds (compound 7) not only sensitizes Krebs-2 and Lewis carcinomas of mice to the action of topotecan, but also normalizes the state of the peripheral blood of mice, which is disturbed in the presence of a tumor. Thus, the synthesized substances may be the prototype of a new class of additional therapy for cancer.

An analysis of the relationship between plasma cytokines and the effectiveness of treatment with TNFαinhibitors was performed in 81 patients with moderate-to-severe psoriasis. Treatment efficacy was assessed by PASI score, and patients were classified into a positive effect (PASI≥75) and no effect group (PASI≤50). A positive effect was reached in 11 (41%) patients for etanercept, 14 (52%) for adalimumab, and 26 (96%) for infliximab. Data analysis did not show  differences in baseline TNFα levels and subsequent treatment effectiveness. The CART algorithm showed that at the baseline level of VEGF ≥ 32 pg/ml and IL17F &lt; 26 pg/ml, there was an 83% probability of a positive effect. Random forest analysis showed the importance of VEGF, ICAM1, sCD40L, IL17F and IL31 baseline levels in the prediction of treatment effectiveness.   Significant differences between the groups before/after the treatment were found only for TNFα: the median values were more than 50 times higher in no effect compared with positive effect group. There were differences before/after therapy in the levels of IL20, ICAM1, IL22, IL23 in the no effect group. The treatment affected the cytokine profile in most cases regardless of the effectiveness of therapy.

Small molecule kinase inhibitors (SMKIs) are one of the heightened concerns in the field of drug research and development. There are seventy-nine (up to July 2023) small molecule kinase inhibitors have been approved by FDA and hundreds kinase inhibitors candidates in clinical trials, which shed light on the treatment of some major diseases. As an important strategy of drug design, computer-aided drug design (CADD) plays an indispensable role in the discovery of SMKIs. CADD methods, such as docking, molecular dynamic, pharmacophore have been applied to the design and optimization of small molecule kinase inhibitors. In the review, we provide an overview of recent advances in CADD and SMKIs; and the application of CADD for discovery of SMKIs.

Evinacumab, a human monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3), has recently been approved by U.S. Food and Drug Administration as an add-on therapy for homozygous familial hypercholesterolemia (HoFH) in patients of 12 years and older. Its role as a triglyceride-lowering drug is also emerging in the literature. However, it has not been approved for this indication yet, neither in the adult nor in the pediatric population. We describe the case of a 10-year-old boy who underwent an allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia complicated by chronic graft–versus–host disease (GVHD) and presented life-threatening refractory hypertriglyceridemia due to the concomitant use of ruxolitinib and sirolimus. After the failure of the insulin treatment and due to the technical impossibility of performing lipid apheresis, we underwent the child to evinacumab treatment, obtaining a dramatic rapid reduction in triglyceride and cholesterol levels. This is the first report of a pediatric patient younger than 12 years in Europa receiving evinacumab to treat severe hypertriglyceridemia. The therapy with angiopoietin-like proteins inhibitors has been effective, safe, and well-tolerated in our patient, suggesting that evinacumab may be used in the pediatric population when other therapeutic strategies are ineffective or contraindicated.

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. Current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities – immune checkpoint inhibitors, cancer vaccines, oncolytic viruses, chimeric antigen receptor T cells and NK cells have shown promise. Clinical trials incorporating combination therapies of the above have overcome the microenvironment resistance and yielded survival and prognostic benefit. Rolling these new therapies out in the real-world scenario in a low cost, high throughput manner is the unmet need of the hour. These will bring practice changing implications to the glioma treatment landscape. In this review article, we focus on describing the hallmarks of the glioma microenvironment and its interplay with the different emerging modalities of immunotherapy.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a proteolytic enzyme that indirectly regulates serum LDL cholesterol by destroying LDL receptors. In clinical studies, the main role of the proprotein convertase subtilisin/Kexin type9 (PCSK9) inhibitor in cholesterol regulation was elucidated. It is produced in the liver but is also present in the kidney and intestine. It prevents HMGCo from synthesizing cholesterol. SREBP-2 is a reductase that is induced by statins. In a dose-dependent manner, increasing SREBP-2 levels enhanced LDL-R and PCSK9 gene expression. At the minimum, two procedures have been developed to overcome the plasma level of PCSK9. This is the LDLR test, polyclonal antibodies, and sentience oligonucleotide. Lower dosage statin treatment with a proprotein convertase subtilisin/Kexin type9 inhibitor will be most efficient in lowering LDL and avoiding statin adverse effects. In multiple long-term trials, statins have been found to reduce cardiovascular mortality by 30% and stroke incidence by 20%. In this way, we conclude the role of PCSK9 in hypercholesterolemia.

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease that increasingly become a global threat for the elder people's health and life. Although there are some drugs in clinic for treating PD, these treatments only can alleviate the symptoms of PD patients but fail in curative therapies. Therefore, seeking other potential mechanisms to develop more effective treatments that can modify the course of PD is still highly desirable. In the last two decades, histone deacetylases as an important group of epigenetic targets in drug discovery have attracted much attention. This review is focused on the current knowledge about histone deacetylases involved in PD pathophysiology and their inhibitors used in PD study. Further perspectives related to small molecules that can inhibit or degrade histone deacetylases to treat PD are also discussed.

Phytoene is a colourless natural carotenoid that absorbs UV light and provides antioxidant and anti-inflammatory activities as well as protection against photodamage. It is therefore valued for its skin health and aesthetic benefits by the cosmetic industry, as well as by the health food sector. The halotolerant green microalga Dunaliella salina is one of the richest sources of natural carotenoids. We have previously investigated over-production of phytoene in D. salina after cultivation with the well-characterised mitosis inhibitor, chlorpropham. In this study, 15 herbicides with different modes of action were tested for their potential to promote phytoene accumulation. All herbicides showed different levels of capabilities to support phytoene over-production in D. salina. Most significantly, the two mitosis inhibitors tested in this study, propyzamide and chlorpropham, showed similar capacities to support over-production of phytoene by D. salina cultures, as phytoene desaturase inhibitors. The cellular content of phytoene increased by over 10-fold within 48 h after treatment with the mitosis inhibitors compared to untreated cultures. Results indicate a general effect of mitosis inhibitors on phytoene accumulation in D. salina. Furthermore, red light was found to significantly enhance the phytoene yield when used in combination with effective inhibitor treatments. Red light can be applied to maximize the production of phytoene from D. salina.

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from ethyl acetate soluble fraction of Acacia auriculiformis stem bark. Column chromatography, gel filtration and NMR spectroscopy were used to purified and characterized betulin from the extract. Betulin which is a known inducer of apoptosis was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1epsilon (CK1epsilon), glycogen synthase kinase 3alpha/β (GSK-3alpha/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6) and vascular endothelial growth factor receptor 2 kinase (VEGFR2) and with activity in µM range. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to underline its putative use as anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway similarly to imatinib mesylate, a well-known inhibitor of ABL1 kinase. The interaction of betulin and ABL1 was studied by molecular docking showing an interaction of the inhibitor with the ATP binding pocket. Altogether, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and notably for treatment of leukemia.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the road for the emerging nanomedicine as a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 was reported in lung, colon, metastatic breast cancers and bladder squamous carcinoma. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. Sildenafil had been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the expression of Bad and Bax proapoptotic proteins. It was also reported that the use of sildenafil prior to the administration of Doxorubicin (DOX) increased its EPR-related concentration in breast cancer tissues by 2 folds. Further, a substantial reason of anticancer chemotherapeutic failure is due to multidrug resistance (MDR), exacerbated by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCCs. Sildenafil has demonstrated inhibitory effects on the efflux activity of ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing MDR caused by these transporters. In this review, we critically examine the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery pointing up the outcome of the most important related preclinical and clinical studies.

Tumor microenvironment (TME) represents a complex network between tumor cells and a variety of components including immune, stromal and vascular endothelial cells as well as extracellular matrix. A wide panel of signals and interactions here take place, resulting in a bi-directional modulation of cellular functions. Many stimuli, on one hand, induce tumor growth and spread of metastatic cells and, on the other hand, contribute to the establishment of an immunosuppressive environment. The latter feature is achieved by soothing immune effector cells, mainly cytotoxic T lymphocytes, B and NK cells, and/or through expansion of regulatory cell populations, including regulatory T and B cells, tumor-associated macrophages and myeloid-derived suppressor cells. In this context, immune checkpoints (IC) are key players in the control of T cell activation and anti-cancer activities, leading to the inhibition of tumor cell lysis and of pro-inflammatory cytokine production. Thus, these pathways represent promising targets for the development of effective and innovative therapies both in adults and childhood. Here we address the role of different cell populations homing the TME and of well-known and recently characterized IC in the context of pediatric solid tumors. We also discuss preclinical and clinical data available using IC inhibitors alone, in combination each other or administered with standard therapies.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for translating amino acids for protein synthesis. Their function in pathogen-derived infectious diseases has been well established, which has led to development of small molecule therapeutics. The applicability of ARS inhibitors for other human diseases such as fibrosis has recently been explored in the clinical setting. There are active studies to find small molecule therapeutics for cancers. Studies on central nervous system (CNS) disorders are burgeoning as well. In this regard, we present a concise analysis of the recent development of ARS inhibitors based on small molecules from the discovery research stage to clinical studies as well as a recent patent analysis from the medicinal chemistry point of view.

Necroptosis is a caspases-independent form of programmed cell death exhibiting intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development, tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis has been associated to chronic inflammatory diseases and cancer. Drugs that inhibit necroptosis could, therefore, be used therapeutically for the treatment of these diseases, and researches to develop such inhibitors are already underway. In this Review, we outline pathways for necroptosis and its role in chronic inflammation and cancer. We also discuss current and developing therapies that target necroptosis machinery.

Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumors treated with ICIs. PubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with a worse outcome in ABs users compared to no-ABs users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis (n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51–2.84; P<.01). Similarly, PFS was inferior in ABs users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22–1.93; p<.01). In cancer patients treated with ICIs, AB use significantly reduces OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed.

Androgen receptor signaling is crucial for prostate cancer growth and is positively regulated in part by intratumoral CYP3A5. As African American (AA) men often carry the wild type CYP3A5 and express high level of CYP3A5 protein, we blocked the wild type CYP3A5 in AA origin prostate cancer cells and tested its effect on androgen receptor signaling. q-PCR based profiler assay identified several AR regulated genes known to regulate AR nuclear translocation, cell cycle progression and cell growth. CYP3A5 processes several commonly prescribed drugs and many of these are CYP3A5 inducers or inhibitors. In this study, we test the effect of these commonly prescribed CYP3A5 inducers/inhibitors on AR signaling. The results show that the CYP3A5 inducers promoted AR nuclear translocation, downstream signaling and cell growth whereas CYP3A5 inhibitors abrogated them. The observed changes in AR activity is specific to alterations in CYP3A5 activity. Both the inducers tested demonstrated increased cell growth of prostate cancer cells, whereas the inhibitors showed reduced cell growth. Further, characterization and utilization of the observation that CYP3A5 inducers and inhibitors alter AR signaling may provide guidance to physicians prescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT, particularly AA.

Poor survival of human pluripotent stem cells (hPSCs) following freezing, thawing, or passaging hinders maintenance and differentiation in stem cell research. Rho-associated kinases (ROCKs) play a crucial role in hPSC survival. To date, a typical ROCK inhibitor, Y-27632, has been the primary agent used in hPSC research. Here, we report that another ROCK inhibitor, fasudil, can be used as an alternative. Fasudil increased hPSC growth due to survival rather than proliferation following thawing and passaging, similar to Y-27632. It did not affect pluripotency and genetic integrity including mitochondrial genome (mtDNA). Notably, the genes related to metabolism, mTORC1, and TP53 have mainly displayed a faster recovery pattern with ROCK inhibitors than control. Furthermore, fasudil was confirmed as useful for the single dissociation of hPSCs and for aggregation. It also increased retinal pigment epithelium (RPE) differentiation and the survival of neural crest cells during differentiation. These findings suggest that fasudil can replace Y-27632 for use in stem cell research.

Nipah virus (NiV) is responsible to cause various outbreaks in Asian countries, with latest from Kerala state of India. Till date there is no drug available despite its urgent requirement. In the current study, we have provided a computational one-stop solution for NiV inhibitors. We have developed “anti-Nipah” web resource, which comprised of a data repository, prediction method, and data visualization modules. The database comprised of 313 (181 unique) inhibitors from different strains and outbreaks of NiV extracted from research articles and patents. However, the quantitative structure–activity relationship (QSAR) based predictors were accomplished using classification approach employing 10-fold cross validation through support vector machine with 120 (68p + 52n) inhibitors. The overall predictor showed the accuracy and Matthew’s correlation coefficient of 88.89% and 0.77 on training/testing dataset respectively. The independent validation dataset also performed equally well. The data visualization modules from chemical clustering and principal component analyses displayed the diversity in the NiV inhibitors. Therefore, our web platform would be of immense help to the researchers working in developing effective inhibitors against NiV. The user-friendly webserver is freely available on URL: http://bioinfo.imtech.res.in/manojk/antinipah/

Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.

Prototypical functions of the chemokine receptor CCR6 include immune regulation by manoeuvring cell chemotaxis and selective delimiting of the pro-inflammatory TH17 and regulatory Treg subsets during chronic or acute systemic inflammation. Inhibition of CCR6 is proposed to attenuate disease symptoms and promote recuperation of multiple inflammatory and autoimmune disorders. Prescription medicines with pharmacodynamics involving the inhibition of the chemokine axis CCR6-CCL20 is very limited. Developing such therapeutics is still at an early experimental stage which has mostly utilized pre-clinical models and neutralizing mono or polyclonal antibodies against either partner, CCR6 or CCL20. Other methods have been constitutive use of small molecules as peptide inhibitors or small interfering ribonucleic acid (siRNA) to interfere with transcription at the nuclear level. We in our review aim at introducing the wide array of potential CCR6-CCL20 inhibitors that have been tried to date in the research field with accent on attendant immune-modulator capacity and which are immensely promising compounds as forerunners of future curatives. 16 different tractable inhibitors of the CCR6-CCL20 duo have been identified to possess high medicinal potential to the drug developers worldwide to treat autoimmune and inflammatory diseases. A multitude of antibody preparations are already available in the current pharmaceutical market as patented treatment for diseases in which the CCR6-CCL20 axis is operative, yet must be used only as supplements with existing routinely prescribed medication as they collectively produce adverse side effects. Novel inhibitors are needed to evaluate this invaluable therapeutic target which holds much promise in the research and development of complaisant remedies for inflammatory diseases.

Background: Most sepsis patients died during their first episode and the long-term survival post discharge was low. Major adverse cardiovascular events and repeated infections were regarded as the major causes in such conditions. No definite medications were proven to effectively improve the long-term outcome. We aimed to examine the benefit of statins on the long-term outcome of survived sepsis patients. Methods: Between 1999 and 2013, a total of 220,082 patients with the first episode of sepsis hospitalization were included and 134,448 ones (61.09%) survived to discharge. The survived patients who subsequently had statins use of >30 cumulative defined daily doses (cDDDs) post discharge were defined as the statin users. After propensity score matching of 1:5, a total of 7,356 and 36,780 survived patients were retrieved as the study (statin-users) and comparison cohort (non-statin users), respectively. The main outcome was the long term survival post discharge. HR with 95% CI was calculated using the Cox regression model to evaluate the effectiveness of statins with further stratification analyses according to cDDDs. Results: The study cohort, that is, the statin users had an adjusted HR of 0.29 (95% CI, 0.27-0.31) in long term mortality rate compared with the comparison cohort. For statin users with the cDDDs of 30–180, 180–365, and >365, the adjusted HRs were 0.32, 0.22, and 0.16, respectively, (95% CI, 0.30-0.34, 0.19-0.26, and 0.12-0.23, respectively) compared with the non-statin users (defined as statins use <30 cDDDs post discharge), and the P for trend <.0001. In the sensitivity analysis, after excluding the survived patients who died within three and six months post discharge, the adjusted HR of statins use remained significant (0.35, 95% CI 0.32-0.37 and 0.42, 95% CI 0.39-0.45, respectively). Conclusions: Statins decreased the long-term mortality post sepsis. Further randomized control trial deserved to be conducted to confirm this observation.

Conyza canadensis is a species invading large agricultural areas throughout the world, mainly to its ability to evolve herbicide resistance. Specifically, in Hungary, extensive areas have been infested by this species due to the difficulty in controlling it with glyphosate. To corroborate this fact as resistance and not as an incorrect herbicide application, eight suspicious glyphosate-resistant C. canadensis populations from different Hungarian regions were studied. In dose-response assays with glyphosate, the LD50 and GR50 values indicated that populations 1 to 5 were resistant to this herbicide (H-5 population the most resistant). Besides, the shikimic acid accumulation tests corroborated the results observed in the dose-response assays. 11 alternative herbicides from 6 different mode of action (MOA) were applied at field doses as control alternatives on populations H-5 and H-6 (both in the same regions). The H-5 population showed an unexpected resistance to flazasulfuron (ALS-inhibitor). The ALS enzyme activity studies indicated that the I50 for H-5 was 63.3 fold higher compared to its correspondent susceptible population (H-6). Therefore, the H-5 population exhibited multiple-resistance to flazasulfuron and glyphosate, being the first case reported in Europe for this two MOA. For that reason, the other herbicides with different MOA have to be tested here.

The use of the Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKIs are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib is the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in an early phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, drug-drug interactions associated with the treatment of CLL with BTK inhibitors, and examines its further implications.

This study fabricated piezoelectric fibers of polyvinylidene fluoride (PVDF) with graphene using near-field electrospinning (NFES) technology. A uniform experimental design table U*7 (7^4 ) was applied, considering weight percentage (1-13 wt%), distance between needle and disk collector (2.1-3.9 mm), and applied voltage (14.5-17.5 kV). We optimized the parameters using electrical property measurements and the Kriging response surface method. Adding 13 wt% graphene significantly improved electrical conductivity, increasing from 17.7 μS/cm for pure PVDF to 187.5 μS/cm. The fiber diameter decreased from 21.4 μm in PVDF/1% graphene to 9.1 μm in PVDF/13% graphene. Adding 5 wt% graphene increased the β-phase content by 6.9%, reaching 65.4% compared to pure PVDF fibers. Material characteristics were investigated using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD), contact angle measurements, and tensile testing. Optimal parameters included 3.47 wt% graphene, yielding 15.82 mV voltage at 5 Hz and 5 N force (2.04 times pure PVDF). Force testing showed a sensitivity (S) of 7.67493 log(mV/N). Fibers were attached to electrodes for piezoelectric sensor applications. Results affirmed enhanced electrical conductivity, piezoelectric performance, and mechanical strength. The optimized piezoelectric sensor could be applied to measure physiological signals, such as attaching it to the throat under different conditions to measure the output voltage. The force-to-voltage conversion facilitated subsequent analysis.

Age diversity in the workplace is a growing challenge. This study aimed to assess work ability among Family and Community Nurses (FCNs) in a large Local Health Authority (LHA) in Tuscany, Italy. The Work Ability Index (WAI) was administered to 178 FCNs, along with demographic and occupational data. Results showed a significant negative correlation between chronological age and WAI, indicating decreasing work ability with age. Moreover, work setting, educational attainment, and health conditions influenced work ability. Nurses working in home settings and those with higher educational levels reported better work ability. A high prevalence of health conditions, particularly musculoskeletal disorders, was observed. These findings highlight the need for targeted interventions to support FCNs' work ability and address age-related challenges. This study provides a foundation for developing strategies to optimize the nursing workforce and ensure high-quality care delivery.

Present experimental study assesses the mechanical properties of glass/carbon/glass hybrid composite laminates after exposure to moisture and elevated temperatures for extended periods. The top and bottom layers of the hybrid laminates are glass fiber reinforced and the middle layer is carbon fiber reinforced with the matrix specified as a polymer material. The hybrid laminates were manufactured using the resin transfer molding method and their compressive and tensile properties were determined using a tensile testing machine. The material parameters such as the storage modulus, the loss modulus, and the damping factors of the laminates were identified using dynamic mechanical analysis as a function of the temperature and the vibration frequency. The experimental results on compressive and tensile properties revealed slight variations when the hybrid laminates were kept at low temperatures for extended periods. This might occur due to the increasing molecular cross-linking of the polymer network. As the temperature increased, compressive, tensile, storage modules, loss modulus, and damping factors decreased. This might occur due to the increasing mobility of the binder material. Particularly, the highest stiffness parameters were obtained on -80°C/GCG (Glass/Carbon/Glass) laminates due to the presence of beta transition on the glassy region. The relationships between the glass transitions and the targeted frequencies were characterized. The values of the glass transition shift towards higher temperatures as the frequency increases. This might occur due to a reduction in the gaps between the crosslinking of the epoxy network when the frequency increases. The accuracy of the storage modulus results was compared with the empirical models. The model based on the Arrhenius law provided the closest correlation. Meanwhile, another model was observed that was not accurate enough to predict when gamma and beta relaxations occur under a glassy state.

With firm commitment to energy labelling, it is not a question of if but only of when the European Union will introduce an energy label for electric cars. To support such policy efforts, we conducted a scoping analysis of energy consumption and efficiency trade-offs for 342 electric car models sold in Europe. The results suggest that certified and real-world energy consumption average 19 ± 4 kWh/100 km and 21 ± 4 kWh/100 km, translating into drive ranges of 440 ± 120 km and 380 ± 110 km, respectively. Energy consumption is correlated with vehicle mass, frontal area, and battery capacity, but less so with rated power and vehicle price. Each 100 kg of vehicle mass and 0.1 m2 of frontal area tend to increase energy consumption by 0.20 ± 0.06 kWh/100 km and 0.72 ± 0.05 kWh/100 km. Raising battery capacity by 10 kWh increases vehicle mass by 145 kg, energy consumption by 0.6 kWh/100 km, and drive range by 45 km. Efficient vehicles are available at any price but drive range has a cost. Our findings point to considerable efficiency trade-offs that could be tapped by a dedicated energy label. We propose several options for categorizing vehicles on an efficiency scale from A to G, with and without additional utility parameters. Our analysis provides rationale for energy labelling of electric cars in Europe and could inspire similar analyses for other vehicle categories such as e-scooters, lightweight three- and four-wheelers, e-busses, e-trucks, and electric non-road machinery.

A novel scaffold design has been created to enhance tissue engineering and regenerative medicine by optimizing the controlled, prolonged release of hepatocyte growth factor (HGF), a powerful chemoattractant for endogenous mesenchymal stem cells. We present a new stacked scaffold that is made up of three different fibrin gel layers, each of which has HGF integrated into the matrix. The design attempts to preserve HGF's regenerative properties for long periods of time, which is necessary for complex tissue regeneration. These multi-layered fibrin gels have been mechanically evaluated using rheometry, and their degradation behavior has been studied using D-Dimer ELISA. Understanding the kinetics of HGF release from this novel scaffold configuration is essential for understanding HGF's long-term sustained bioactivity. A range of cell-based tests were carried out to verify the functionality of HGF following extended incorporation. These tests included 2-photon microscopy using phalloidin staining to examine cellular morphology, SEM analysis for scaffold-cell interactions, and scratch and scatter assays to assess migration and motility. The analyses show that the novel stacking scaffold promotes vital cellular processes for tissue regeneration in addition to supporting HGF's bioactivity. This scaffold design was developed for in situ tissue engineering. Using the body as a bioreactor, the scaffold should recruit mesenchymal stem cells from their niche thus combining the regenerative abilities of HGF and MSCs to promote tissue remodeling and wound repair.

Infrared thermography is a contactless imaging technique, useful to measure surface temperature at distance which has been widely applied in animal production. The possible applications within the pig husbandry include sow heat detection, reduction of the incidence of neonatal mortality, recognition of febrile state caused by pathogens, study of metabolic efficiency, evaluation of stress caused by heat, by constraints, or by aggressive interaction and meat quality prediction. Even if this technique could be easily influenced by environmental factors, the continuous improvement in the procedures and the decrease in the cost of the equipment will allow in the next future new and more applications in swine farming.

Introduction: Gastric cancer (GC) is one of the most common cancers in the world. It is a very aggressive and heterogeneous tumor. GC does not cause symptoms, so it is often diagnosed in an advanced stage and associated with poor prognosis. Despite new treatment options, it still remains a therapeutic problem. An important element determining the method of treatment of locally advanced gastric cancer (LAGC) is the assessment of lymph node metastases in preoperative and postoperative imaging and/or histopathological examination.Aim: The assessment of lymphovascular invasion (LVI) in histopathological examination in patients with LAGC after gastrectomy. The groups of patients were divided into patients who received preoperative chemotherapy, patients without preoperative chemotherapy, and all patients. Additionally, we assessed the correlation between the presence of LVI and the number of lymph nodes collected during gastrectomy.Material and method: We collected patients with histologically confirmed GC after gastrectomy. The collected samples were divided into three subgroups: patients with neoadjuvant chemotherapy (NAC), patients without NAC, and all patients. Histopathological examination assessed the presence of LVI infiltration. We then assessed the correlation between the presence of LVI and the presence of lymph node metastasis in GC. Additionally, we assessed the correlation between LVI and the number of lymph nodes evaluated in patients in each group. The statistical analyses were performed using Statistica v13.3 and Microsoft Excel 2021. The significance limit was set at p<0.05.Results:The presence of LVI strongly correlated with node involvement, and the result was statistically significant in all patients and the group of patients treated with NAC. The difference was not statistically significant in the group not treated by NAC. Additionally, we did not observe a correlation between the presence of LVI and the number of metastatic lymph nodes in GC.Summary and Conclusions: The presence of LVI in a patient with GC indicates a high probability of lymph node metastasis, which should translate into therapeutic procedures. Assessment of LVI may help identify potential patients with lymph node metastases, particularly in patients undergoing endoscopic resection without planned lymphadenectomy. It is advisable to expand research on a larger scale in order to establish clear standards in this area.

Reducing the carbon footprint of energy production is one of the most pressing challenges facing humanity today. Lignocellulosic biomass residues from fruit production industries show promise as a viable energy source. This paper presents a study of the Italian context concerning the utilization of orchard lignocellulosic residues for energy production as electricity or bioethanol. The potential of various orchard residues was assessed through chemical and physical analysis, and an equivalent electrical energy of about 6441.62 GWh or an amount of 0.48 Mt/y of bioethanol was obtained based on the average annual dry residue mass availability of about 3.04 Mt/y. These data represent the 9.30% of the national electrical energy production from renewable sources, as well as the 6.21% of the Italian demand for gasoline in 2022. Electricity generation from these residues shown its potential as a reliable and sustainable baseload power source, as well as source of renewable transportation fuel. The studied process could be a valuable reference to expand these concepts on global scale to achieve a greener and more sustainable energy future.

It has been empirically observed that the upper tail of the firm size distribution follows either the Pareto distribution or the Zipf distribution, with both patterns being explained by Gibrat’s law (Gabaix, 1999). This article analyzed firm revenue data from China, spanning from 2005 to 2013, to examine the whole range of the firm size distribution. Our empirical analysis revealed that firm revenue data over these years is well fitted by a three-parameter generalized Pareto distribution, with the fitted parameters indicating a dichotomy: The size distribution of large-sized firms, namely the upper tail, is asymptotically characterized by a Pareto distribution or a Zipf distribution, whereas the size distribution of smaller and medium-sized firms is approximated by an exponential distribution. This finding suggests that Gibrat’s law should be extended to account for the emergence of a generalized Pareto distribution.