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The global surge in aging populations has intensified osteoporosis challenges, necessitating improved diagnostic methods. While dual X-ray absorptiometry (DXA) is the conventional standard in assessing bone mineral density (BMD), the exploration of quantitative computed tomography (QCT) has been proposed, particularly phantomless techniques. Challenges in single-energy CT, emphasizing internal calibration standards like subcutaneous fat, are discussed. Advances in PL-QCT, notably with automatic region of interest (ROI) selection, show improved accuracy. Dual-energy CT (DECT) introduces new dimensions for musculoskeletal analysis. Despite advancements, challenges persist, including interindividual variability and patient-specific factors. Evolving single-energy CT and DECT techniques show promise in refining BMD assessment and osteoporosis diagnosis, enhancing patient care. Continued research and integration into clinical practice are vital for realizing these advancements' full benefits. In this review, we evaluate and summarize current evidence on the feasibility and different approaches to achieve analysis of BMD with phantomless QCT. [ABSTRACT FROM AUTHOR]

Simple Summary: The biggest obstacle to curing cancer is the fact that cancers often harbor mutant cells, called resistant cells, that are unaffected by cancer drugs. We tested a strategy for maintaining control over resistant cells called adaptive therapy. We tested this strategy on mice that had human breast cancer. In adaptive therapy, we aim to keep alive many cancer cells that are sensitive to cancer drugs and use them to compete with the resistant cells. We can prevent the sensitive cells from growing out of control using occasional low doses of a cancer drug. Competition with the sensitive cells prevents the resistant cells from growing out of control, resulting in long-term control of the cancer. Thus, we turn cancer into a chronic, nonlethal disease. Our experiment showed the effectiveness of this approach and how we might make it even better by switching between two drugs. Adaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number of cancer cells. In preparation for a clinical trial, we used endocrine-resistant MCF7 breast cancer to stimulate second-line therapy and tested adaptive therapy using capecitabine, gemcitabine, or their combination in a mouse xenograft model. Dose modulation adaptive therapy with capecitabine alone increased survival time relative to MTD but not statistically significantly (HR = 0.22, 95% CI = 0.043–1.1, p = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI = 0.024–0.55, p = 0.007) and intermittent adaptive therapies, the survival time was significantly increased compared to high-dose combination therapy (HR = 0.07, 95% CI = 0.013–0.42, p = 0.003). Overall, the survival time increased with reduced dose for both single drugs (p < 0.01) and combined drugs (p < 0.001), resulting in tumors with fewer proliferation cells (p = 0.0026) and more apoptotic cells (p = 0.045) compared to high-dose therapy. Adaptive therapy favors slower-growing tumors and shows promise in two-drug alternating regimens instead of being combined. [ABSTRACT FROM AUTHOR]

Chemoresistance to standard neoadjuvant treatment commonly occurs in locally advanced breast cancer, particularly in the luminal subtype, which is hormone receptor-positive and represents the most common subtype of breast cancer associated with the worst outcomes. Identifying the genes associated with chemoresistance is crucial for understanding the underlying mechanisms and discovering effective treatments. In this study, we aimed to identify genes linked to neoadjuvant chemotherapy resistance in 62 retrospectively included patients with luminal breast cancer. Whole RNA sequencing of 12 patient biopsies revealed 269 differentially expressed genes in chemoresistant patients. We further validated eight highly correlated genes associated with resistance. Among these, solute carrier family 12 member 1 (SLC12A1) and glutamate ionotropic AMPA type subunit 4 (GRIA4), both implicated in ion transport, showed the strongest association with chemoresistance. Notably, SLC12A1 expression was downregulated, while protein levels of glutamate receptor 4 (GLUR4), encoded by GRIA4, were elevated in patients with a worse prognosis. Our results suggest a potential link between SLC12A1 gene expression and GLUR4 protein levels with chemoresistance in luminal breast cancer. In particular, GLUR4 protein could serve as a potential target for drug intervention to overcome chemoresistance. [ABSTRACT FROM AUTHOR]

Simple Summary: We introduce GUST-mouse (Genes Under Selection in Tumors for mouse), a novel computational method designed to identify cancer driver genes within mouse tumor exomes. As the first method of its kind, GUST-mouse transcends conventional frequency-based rules. It incorporates molecular evolutionary theories and leverages transfer learning techniques to effectively differentiate between oncogenes, tumor suppressor genes, and passenger genes. When applied to mouse models of breast cancer, leukemia, and lung cancer, GUST-mouse unveiled that the emergence of somatic driver mutations is profoundly influenced by the genetically engineered background of the mouse models. A comparative analysis with human cancer drivers illuminated both shared and distinct patterns, casting new light on the intricate process of tumorigenesis. The pioneering framework of the GUST-mouse method opens a new avenue for identifying driver genes in non-human cancers. The mouse is a widely used model organism in cancer research. However, no computational methods exist to identify cancer driver genes in mice due to a lack of labeled training data. To address this knowledge gap, we adapted the GUST (Genes Under Selection in Tumors) model, originally trained on human exomes, to mouse exomes via transfer learning. The resulting tool, called GUST-mouse, can estimate long-term and short-term evolutionary selection in mouse tumors, and distinguish between oncogenes, tumor suppressor genes, and passenger genes using high-throughput sequencing data. We applied GUST-mouse to analyze 65 exomes of mouse primary breast cancer models and 17 exomes of mouse leukemia models. Comparing the predictions between cancer types and between human and mouse tumors revealed common and unique driver genes. The GUST-mouse method is available as an open-source R package on github. [ABSTRACT FROM AUTHOR]

Oxidative stress is a condition caused by an imbalance in the occurrence of reactive oxygen species in the cells and tissues of organisms. An ultra-performance liquid chromatography–electrospray ionization tandem mass spectrometry (UPLC–ESI–MS/MS) method was developed for the simultaneous determination of two oxidative stress biomarkers, 8-hydroxydeoxyguanosine (8OHDG) and dityrosine (DIY), in the gills, skin, dorsal fin, and liver tissue of Atlantic salmon (Salmo salar) parr. The use of target analyte-specific 13C and 15N internal standards allowed quantification of each target analyte to be performed through the standard solvent calibration curve. The relative recoveries [mean ± (relative standard deviation%)] of 8OHDG and DIY were 101 ± 11 and 104 ± 13% at a fortified concentration of 10 ng/mL (8OHDG) and 500 ng/mL (DIY), respectively, ensuring the accuracy of the extraction and quantification. The chromatographic separation was carried out using a gradient elution program with a total run time of 5 min. The limits of detection (LODs) were 0.11 and 1.37 ng/g wet weight (w.w.) for 8OHDG and DIY, respectively. To demonstrate the applicability of the developed method, it was applied in 907 tissue samples that were collected from Atlantic salmon parr individuals reared in an experimental land-based recirculating aquaculture system (RAS) treated with peracetic acid. Moreover, the possibility of using the dorsal fin as an alternative matrix for the minimally invasive assessment of oxidative stress in Atlantic salmon parr was introduced. To our knowledge, 8OHDG and DIY were used for the first time as biomarkers for biomonitoring the fish health (oxidative stress) of Atlantic salmon parr in RAS. [ABSTRACT FROM AUTHOR]

Simple Summary: Modern "adaptive therapy" approaches to cancer therapy rely on adjusting the dose of drugs as the size of the tumor changes. They hold the promise of transforming cancer from an acute lethal disease to a chronic disease we could live with, but not die from. Previous adaptive therapy experiments have used a single drug. We set out to explore how to best combine multiple drugs in these strategies. Unfortunately, there are far too many possible ways we might combine drugs in adaptive therapies to be evaluated with clinical trials. Instead, we used computer simulations of how cancers evolve in response to therapies to identify the most promising strategies that should be tested in mouse experiments and in clinical trials in the future. These promising strategies were not specific to any particular drug or particular type of cancer, and so may have general applicability for virtually all cancers. The standard of care for cancer patients aims to eradicate the tumor by killing the maximum number of cancer cells using the maximum tolerated dose (MTD) of a drug. MTD causes significant toxicity and selects for resistant cells, eventually making the tumor refractory to treatment. Adaptive therapy aims to maximize time to progression (TTP), by maintaining sensitive cells to compete with resistant cells. We explored both dose modulation (DM) protocols and fixed dose (FD) interspersed with drug holiday protocols. In contrast to previous single drug protocols, we explored the determinants of success of two-drug adaptive therapy protocols, using an agent-based model. In almost all cases, DM protocols (but not FD protocols) increased TTP relative to MTD. DM protocols worked well when there was more competition, with a higher cost of resistance, greater cell turnover, and when crowded proliferating cells could replace their neighbors. The amount that the drug dose was changed, mattered less. The more sensitive the protocol was to tumor burden changes, the better. In general, protocols that used as little drug as possible, worked best. Preclinical experiments should test these predictions, especially dose modulation protocols, with the goal of generating successful clinical trials for greater cancer control. [ABSTRACT FROM AUTHOR]

We review and synthesize key findings and limitations of mathematical models for prostate cancer, both from theoretical work and data-validated approaches, especially concerning clinical applications. Our focus is on models of prostate cancer dynamics under treatment, particularly with a view toward optimizing hormone-based treatment schedules and estimating the onset of treatment resistance under various assumptions. Population models suggest that intermittent or adaptive therapy is more beneficial to delay cancer relapse as compared to the standard continuous therapy if treatment resistance comes at a competitive cost for cancer cells. Another consensus among existing work is that the standard biomarker for cancer growth, prostate-specific antigen, may not always correlate well with cancer progression. Instead, its doubling rate appears to be a better indicator of tumor growth. Much of the existing work utilizes simple ordinary differential equations due to difficulty in collecting spatial data and due to the early success of using prostate-specific antigen in mathematical modeling. However, a shift toward more complex and realistic models is taking place, which leaves many of the theoretical and mathematical questions unexplored. Furthermore, as adaptive therapy displays better potential than existing treatment protocols, an increasing number of studies incorporate this treatment into modeling efforts. Although existing modeling work has explored and yielded useful insights on the treatment of prostate cancer, the road to clinical application is still elusive. Among the pertinent issues needed to be addressed to bridge the gap from modeling work to clinical application are (1) real-time data validation and model identification, (2) sensitivity analysis and uncertainty quantification for model prediction, and (3) optimal treatment/schedule while considering drug properties, interactions, and toxicity. To address these issues, we suggest in-depth studies on various aspects of the parameters in dynamical models such as the evolution of parameters over time. We hope this review will assist future attempts at studying prostate cancer. [ABSTRACT FROM AUTHOR]

Reaching the Sustainable Development Goals requires a fundamental socio-economic transformation accompanied by substantial investment in low-carbon infrastructure. Such a sustainability transition represents a non-marginal change, driven by behavioral factors and systemic interactions. However, typical economic models used to assess a sustainability transition focus on marginal changes around a local optimum, which--by construction--lead to negative effects. Thus, these models do not allow evaluating a sustainability transition that might have substantial positive effects. This paper examines which mechanisms need to be included in a standard computable general equilibrium model to overcome these limitations and to give a more comprehensive view of the effects of climate change mitigation. Simulation results show that, given an ambitious greenhouse gas emission constraint and a price of carbon, positive economic effects are possible if (1) technical progress results (partly) endogenously from the model and (2) a policy intervention triggering an increase of investment is introduced. Additionally, if (3) the investment behavior of firms is influenced by their sales expectations, the effects are amplified. The results provide suggestions for policy-makers, because the outcome indicates that investment-oriented climate policies can lead to more desirable outcomes in economic, social and environmental terms. [ABSTRACT FROM AUTHOR]

The UN sustainable development goals contain environmental, economic, and social objectives. They may only be reached, or at least it would be easier to reach them, if instead of a trade-off between these objectives that implies a need for balancing them, there are synergies to be reaped. This paper discusses how the structures of economic models typically used in policy analysis influence whether win-win strategies for the environment and the economy can be conceptualised and analysed. With a focus on climate policy modelling, the paper points out how, by construction, commonly used model structures find mitigation costs rather than benefits. This paper describes mechanisms that, when added to these model structures, can bring win-win options into a model's solution horizon, and which provide a spectrum of alternative modelling approaches that allow for the identification of such options. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) is one of the leading causes of disability worldwide, with a significant socioeconomic burden on healthcare systems. It is mainly caused by degenerative disc disease (DDD), a progressive, chronic, and age-related process. With its capacity to accurately characterize intervertebral disc (IVD) and spinal morphology, magnetic resonance imaging (MRI) has been established as one of the most valuable tools in diagnosing DDD. However, existing technology cannot detect subtle changes in IVD tissue composition and cell metabolism. In this review, we summarized the state of the art regarding innovative quantitative MRI modalities that have shown the capacity to discriminate and quantify changes in matrix composition and integrity, as well as biomechanical changes in the early stages of DDD. Validation and implementation of this new technology in the clinical setting will allow for an early diagnosis of DDD and ideally guide conservative and regenerative treatments that may prevent the progression of the degenerative process rather than intervene at the latest stages of the disease. [ABSTRACT FROM AUTHOR]

Environmental contamination from toxic metals and pesticides is an issue of great concern due to their harmful effects to human health and the ecosystems. In this framework, we assessed the adverse effects when aquatic organisms are exposed to toxicants such as deltamethrin (DM) and lead (Pb), alone or in combination, using zebrafish as a model. Moreover, we likewise evaluated the possible protective effect of vitamin C (VC) supplementation against the combined acute toxic effects of the two toxicants. Juvenile zebrafish were exposed to DM (2 μg L−1) and Pb (60 μg L−1) alone and in combination with VC (100 μg L−1) and responses were assessed by quantifying acetylcholinesterase (AChE) activity, lipid peroxidation (MDA), some antioxidant enzyme activities (SOD and GPx), three-dimension locomotion responses and changes of elements concentrations in the zebrafish body. Our results show that VC has mitigative effects against behavioral and biochemical alterations induced by a mixture of contaminants, demonstrating that it can be used as an effective antioxidant. Moreover, the observations in the study demonstrate zebrafish as a promising in vivo model for assessing the neuroprotective actions of bioactive compounds. [ABSTRACT FROM AUTHOR]

Although chemotherapeutics are used to treat infections in farmed fish, knowledge on how they alter host physiology is limited. Here, we elucidated the physiological consequences of repeated exposure to the potent oxidative chemotherapeutic peracetic acid (PAA) in Atlantic salmon (Salmo salar) smolts. Fish were exposed to the oxidant for 15 (short exposure) or 30 (long exposure) minutes every 15 days over 45 days. Unexposed fish served as the control. Thereafter, the ability of the remaining fish to handle a secondary stressor was investigated. Periodic chemotherapeutic exposure did not affect production performance, though survival was lower in the PAA-treated groups than in the control. Increased ventilation, erratic swimming, and a loss of balance were common behavioural manifestations during the oxidant exposure. The plasma reactive oxygen species levels increased in the PAA-treated groups, particularly after the third exposure, suggesting an alteration in the systemic oxidative stress status. Plasma indicators for internal organ health were affected to a certain degree, with the changes mainly observed after the second and third exposures. Metabolomics disclosed that the oxidant altered several circulating metabolites. Inosine and guanosine were the two metabolites significantly affected by the oxidative stressor, regardless of exposure time. A microarray analysis revealed that the gills and liver were more responsive to the oxidant than the skin, with the gills being the most sensitive. Moreover, the magnitude of the transcriptomic modifications depended on the exposure duration. A functional analysis showed that genes involved in immunity and ribosomal functions were significantly affected in the gills. In contrast, genes crucial for the oxidation-reduction process were mainly targeted in the liver. Skin mucus proteomics uncovered that the changes in the mucosal proteome were dependent on exposure duration and that the oxidant interfered with ribosome-related processes. Mucosal mapping revealed gill mucous cell hypertrophy after the second and third exposures, although the skin morphological parameters remained unaltered. Lastly, repeated oxidant exposures did not impede the ability of the fish to mount a response to a secondary stressor. This study provides insights into how a chemical oxidative stressor alters salmon physiology at both the systemic and mucosal levels. This knowledge will be pivotal in developing an evidence-driven approach to the use of oxidative therapeutics in fish, with some of the molecules and pathways identified as potential biomarkers and targets for assessing the physiological cost of these treatments. [ABSTRACT FROM AUTHOR]

Membrane trafficking is all about time. Automation in such a biological process is crucial to ensure management and delivery of cellular cargoes with spatiotemporal precision. Shared molecular regulators and differential engagement of trafficking components improve robustness of molecular sorting. Sequential recruitment of low affinity protein complexes ensures directionality of the process and, concomitantly, serves as a kinetic proofreading mechanism to discriminate cargoes from the whole endocytosed material. This strategy helps cells to minimize losses and operating errors in membrane trafficking, thereby matching the appealed deadline. Here, we summarize the molecular pathways of molecular sorting, focusing on their timing and efficacy. We also highlight experimental procedures and genetic approaches to robustly probe these pathways, in order to guide mechanistic studies at the interface between biochemistry and quantitative biology. [ABSTRACT FROM AUTHOR]

Our body composition is enormously influenced by our lifestyle choices, which affect our health and longevity. Nutrition and physical activities both impact overall metabolic condition, thus, a positive energy balance causes oxidative stress and inflammation, hastening the development of metabolic syndrome. With this knowledge, boosting endogenous and exogenous antioxidants has emerged as a therapeutic strategy for combating metabolic disorders. One of the promising therapeutic inventions is the use of alkaline reduced water (ARW). Aside from its hydrating and non-caloric properties, ARW has demonstrated strong antioxidant and anti-inflammatory properties that can help stabilize physiologic turmoil caused by oxidative stress and inflammation. This review article is a synthesis of studies where we elaborate on the intra- and extracellular effects of drinking ARW, and relate these to the pathophysiology of common metabolic disorders, such as obesity, diabetes mellitus, non-alcoholic fatty liver disease, and some cancers. Highlighting the health-promoting benefits of ARW, we also emphasize the importance of maintaining a healthy lifestyle by incorporating exercise and practicing a balanced diet as forms of habit. [ABSTRACT FROM AUTHOR]

In jawed vertebrates, adaptive immune responses are enabled by T cells. Two lineages were characterized based on their T cell receptor (TcR) heterodimers, namely αβ or γδ peptide chains, which display an Ig domain-type sequence that is somatically rearranged. γδ T cells have been less extensively characterized than αβ and teleost fish, in particular, suffer from a severe scarcity of data. In this paper, we worked on the well-known model, the European sea bass Dicentrarchus labrax, to broaden the understanding of teleost γδ-T cells. The T cell receptor chain (TR) γ transcript was expressed at a later developmental stage than TRβ, suggesting a layered appearance of fish immune cells, and the thymus displayed statistically-significant higher mRNA levels than any other organ or lymphoid tissue investigated. The polyclonal antibody developed against the TRγ allowed the localization of TRγ-expressing cells in lymphoid organs along the ontogeny. Cell positivity was investigated through flow cytometry and the highest percentage was found in peripheral blood leukocytes, followed by thymus, gut, gills, spleen and head kidney. Numerous TRγ-expressing cells were localized in the gut mucosa, and the immunogold labelling revealed ultrastructural features that are typical of T cells. At last, microalgae-based diet formulations significantly modulated the abundance of TRγ+ cells in the posterior intestine, hinting at a putative involvement in nutritional immunity. From a comparative immunological perspective, our results contribute to the comprehension of the diversity and functionalities of γδ T cells during the development of a commercially relevant marine teleost model. [ABSTRACT FROM AUTHOR]

The widespread presence of heavy metals in drinking water sources arises as a major health concern, particularly in developing countries. The development of low-cost and reliable detection techniques is identified as a societal need to provide affordable water quality control. Herein, a bismuth film-coated gold ultramicroelectrode array (BF-UMEA) was used for the detection of Pb(II) and Cd(II) in water samples via square wave anodic stripping voltammetry (SWASV). Experimental parameters such as deposition time, Bi(III) concentration, acetate buffer concentration, pH, square wave frequency, amplitude, and step potential were all varied to determine their effects on the current peak intensities of the target metal ions. Ten-fold excess in the concentration of interferences was found to cause a decrease in the stripping peak areas of Cd(II) and Pb(II) in the following order of magnitude: benzene < NaCl < Ni(II) < Cu(II). Using Box–Behnken design, the optimum SWASV parameters that provided maximum current peak areas were 14.76 Hz (frequency), 50.10 mV (amplitude), and 8.76 mV (step potential). The limits of detection of the as-prepared BF-UMEA were 5 and 7 µg L−1 for Pb(II) and Cd(II), respectively. These results demonstrate the potential use of a BF-UMEA in SWASV for the trace quantification of Pb(II) and Cd(II) in water samples. [ABSTRACT FROM AUTHOR]

A reduction in daily caloric or nutrient intake has been observed to promote health benefits in mammals and other vertebrates. Feed Restriction (FR), whereby the overall food intake of the organism is reduced, has been explored as a method to improve metabolic and immune health, as well as to optimize productivity in farming. However, less is known regarding the molecular and physiological consequences of FR. Using the model organism, Danio rerio, we investigated the impact of a short-term (month-long) FR on growth, gut morphology and gene expression. Our data suggest that FR has minimal effects on the average growth rates, but it may affect weight and size heterogeneity in a sex-dependent manner. In the gut, we observed a significant reduction in gut circumference and generally lower mucosal heights, whereas other parameters remained unchanged. Gene Ontology (GO), EuKaryotic Orthologous Groups (KOG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified numerous metabolic, reproductive, and immune response pathways that were affected by FR. These results broaden our understanding of FR and contribute towards growing knowledge of its effects on vertebrate health. [ABSTRACT FROM AUTHOR]

Epidermal club cells (ECCs), along with mucus cells, are present in the skin of many fishes, particularly in the well-studied Ostariophysan family Cyprinidae. Most ECC-associated literature has focused on the potential role of ECCs as a component of chemical alarm cues released passively when a predator damages the skin of its prey, alerting nearby prey to the presence of an active predator. Because this warning system is maintained by receiver-side selection (senders are eaten), there is want of a mechanism to confer fitness benefits to the individual that invests in ECCs to explain their evolutionary origin and maintenance in this speciose group of fishes. In an attempt to understand the fitness benefits that accrue from investment in ECCs, we reviewed the phylogenetic distribution of ECCs and their histochemical properties. ECCs are found in various forms in all teleost superorders and in the chondrostei inferring either early or multiple independent origins over evolutionary time. We noted that ECCs respond to several environmental stressors/immunomodulators including parasites and pathogens, are suppressed by immunomodulators such as testosterone and cortisol, and their density covaries with food ration, demonstrating a dynamic metabolic cost to maintaining these cells. ECC density varies widely among and within fish populations, suggesting that ECCs may be a convenient tool with which to assay ecoimmunological tradeoffs between immune stress and foraging activity, reproductive state, and predator–prey interactions. Here, we review the case for ECC immune function, immune functions in fishes generally, and encourage future work describing the precise role of ECCs in the immune system and life history evolution in fishes. [ABSTRACT FROM AUTHOR]

Simple Summary: The small GTPase RAB11 is a master regulator of both vesicular trafficking and membrane dynamic defining the surface proteome of cellular membranes. As a consequence, the alteration of RAB11 activity induces changes in both the sensory and the transduction apparatuses of cancer cells leading to tumor progression and invasion. Here, we show that this strictly depends on RAB11′s ability to control the sorting of signaling receptors from endosomes. Therefore, RAB11 is a potential therapeutic target over which to develop future therapies aimed at dampening the acquisition of aggressive traits by cancer cells. Many disorders block and subvert basic cellular processes in order to boost their progression. One protein family that is prone to be altered in human cancers is the small GTPase RAB11 family, the master regulator of vesicular trafficking. RAB11 isoforms function as membrane organizers connecting the transport of cargoes towards the plasma membrane with the assembly of autophagic precursors and the generation of cellular protrusions. These processes dramatically impact normal cell physiology and their alteration significantly affects the survival, progression and metastatization as well as the accumulation of toxic materials of cancer cells. In this review, we discuss biological mechanisms ensuring cargo recognition and sorting through a RAB11-dependent pathway, a prerequisite to understand the effect of RAB11 alterations in human cancers. [ABSTRACT FROM AUTHOR]

The olfactory organs of fish have vital functions for chemosensory and defence. Though there have been some ground-breaking discoveries of their involvement in immunity against pathogens in recent years, little is known about how they respond to non-infectious agents, such as exogenous oxidants, which fish encounter regularly. To this end, we employed Atlantic salmon (Salmo salar) as a model to study the molecular responses at the nasal olfactory mucosa of a teleost fish when challenged with oxidants. Microarray analysis was employed to unravel the transcriptional changes at the nasal olfactory mucosa following two types of in vivo exposure to peracetic acid (PAA), a highly potent oxidative agent commonly used in aquaculture: Trial 1: periodic and low dose (1 ppm, every 3 days over 45 days) to simulate a routine disinfection; and Trial 2: less frequent and high dose (10 ppm for 30 min, every 15 days, 3 times) to mimic a bath treatment. Furthermore, leukocytes from the olfactory organ were isolated and exposed to PAA, as well as to hydrogen peroxide (H2O2) and acetic acid (AA)—the two other components of PAA trade products—to perform targeted cellular and molecular response profiling. In the first trial, microarrays identified 32 differentially expressed genes (DEG) after a 45-day oxidant exposure. Erythrocyte-specific genes were overly represented and substantially upregulated following exogenous oxidant exposure. In Trial 2, in which a higher dose was administered, 62 DEGs were identified, over 80% of which were significantly upregulated after exposure. Genes involved in immune response, redox balance and stress, maintenance of cellular integrity and extracellular matrix were markedly affected by the oxidant. All chemical stimuli (i.e., PAA, H2O2, AA) significantly affected the proliferation of nasal leukocytes, with indications of recovery observed in PAA- and H2O2-exposed cells. The migration of nasal leukocytes was promoted by H2O2, but not much by PAA and AA. The three chemical oxidative stressors triggered oxidative stress in nasal leukocytes as indicated by an increase in the intracellular reactive oxygen species level. This resulted in the mobilisation of antioxidant defences in the nasal leukocytes as shown by the upregulation of crucial genes for this response network. Though qPCR revealed changes in the expression of selected cytokines and heat shock protein genes following in vitro challenge, the responses were stochastic. The results from the study advance our understanding of the role that the nasal olfactory mucosa plays in host defence, particularly towards oxidative chemical stressors. [ABSTRACT FROM AUTHOR]

Ozone is a strong oxidant, and its use in aquaculture has been shown to improve water quality and fish health. At present, it is predominantly used in freshwater systems due to the high risk of toxic residual oxidant exposure in brackish water and seawater. Here, we report the effects of ozone on Atlantic salmon (Salmo salar) post-smolts (~100 g), in a brackish water (12 ppt) flow-through system. Salmon were exposed to oxidation reduction potential concentrations of 250 mV (control), 280 mV (low), 350 mV (medium), 425 mV (high) and 500 mV (very high). The physiological impacts of ozone were characterized by blood biochemical profiling, histopathologic examination and gene expression analysis in skin and gills. Fish exposed to 425 mV and higher showed ≥33% cumulative mortality in less than 10 days. No significant mortalities were recorded in the remaining groups. The skin surface quality and the thickness of the dermal and epidermal layers were not significantly affected by the treatments. On the other hand, gill histopathology showed the adverse effects of increasing ozone doses and the changes were more pronounced in the group exposed to 350 mV and higher. Cases of gill damages such as necrosis, lamellar fusion and hypertrophy were prevalent in the high and very high groups. Expression profiling of key biomarkers for mucosal health supported the histology results, showing that gills were significantly more affected by higher ozone doses compared to the skin. Increasing ozone doses triggered anti-oxidative stress and inflammatory responses in the gills, where transcript levels of glutathione reductase, copper/zinc superoxide dismutase, interleukin 1β and interleukin were significantly elevated. Heat shock protein 70 was significantly upregulated in the skin of fish exposed to 350 mV and higher. Bcl-2 associated x protein was the only gene marker that was significantly upregulated by increasing ozone doses in both mucosal tissues. In conclusion, the study revealed that short-term exposure to ozone at concentrations higher than 350 mV in salmon in brackish water resulted in significant health and welfare consequences, including mortality and gill damages. The results of the study will be valuable in developing water treatment protocols for salmon farming. [ABSTRACT FROM AUTHOR]

Bladder cancer, which has a rising incidence, is the 10th most common cancer. The transitional cell carcinoma histotype is aggressive and often current therapies are ineffective. We investigated the anti-proliferative effect of quercetin, a natural flavonoid, in combination with the alkylating agent mafosfamide (MFA) on two human bladder cancer cell lines, namely RT112 and J82, representing the progression from low-grade to high-grade tumors, respectively. In both cell types, the combined treatment led to a synergic reduction in cell viability confirmed by a combination index of less than one, though different biological responses were noted. In J82 cells, MFA alone and, to a lesser extent, with quercetin caused cell cycle arrest in the G2/M phase, but only the combined treatment triggered apoptotic cell death. In contrast, in RT112 cells, quercetin induced autophagy, evidenced by the autophagosome formation and the increase in LC-3 lipidation. Interestingly, the synergistic effect was observed only when cells were pre-treated with MFA for 24 h before adding quercetin, not in the reverse order. This suggests that quercetin may help overcome MFA resistance to apoptosis. Although further studies are needed, investigating the combined effects of quercetin and MFA could help elucidate the mechanisms of drug resistance in bladder cancer treatment.

The introduction of bio-based matrices in automotive applications would, in principle, increase their sustainability and, in case the use of secondary raw materials is also involved, even result in reduced resource depletion. The bio-based polymer composite matrix that has been mainly brought forward towards industrial application is poly(lactic acid) (PLA), which has often been proposed as the replacement for matrices based on polyolefins in fields such as packaging and short-term commodities since, in general, it matches the needs for conventional thermoplastic production processes. The passage to the automotive sector is not obvious, though: problems affecting durability, the relation with water and the environment, together with the requirement for outstanding mechanical and impact performance appear very stringent. On the other hand, PLA has obtained durable success in additive manufacturing as a competitor for acrylonitrile butadiene styrene (ABS). Also, the perspective for 3D and 4D printing does not appear to be confined to bare prototyping. These contrasting pieces of evidence indicate the necessity to provide more insight into the possible development of PLA use in the automotive industry, also considering the pressure for the combined use of more sustainable reinforcement types in automotive composites, such as natural fibers.

Alum is the most used vaccine adjuvant, due to its safety, low cost and adjuvanticity to various antigens. However, the mechanism of action of alum is complex and not yet fully understood, and the immune responses elicited can be weak and antigen-dependent. While several antigens rapidly desorb from alum upon exposure to serum, phosphorylated proteins remain tightly bound through a ligand-exchange reaction with surface hydroxyls on alum. Here, bacterial proteins and glycoconjugates have been modified with phosphoserines, aiming at enhancing the binding to alum and prolonging their bioavailability. Tetanus toxoid protein and Salmonella Typhi fragmented Vi-CRM conjugate were used. Both antigens rapidly and completely desorbed from alum after incubation with serum, verified via a competitive ELISA assay, and set up to rapidly evaluate in vitro antigen desorption from alum. After antigen modification with phosphoserines, desorption from alum was slowed down, and modified antigens demonstrated more prolonged retention at the injection sites through in vivo optical imaging in mice. Both modified antigens elicited stronger immune responses in mice, after a single injection only, compared to unmodified antigens. A stronger binding to alum could result in potent single-dose vaccine candidates and opens the possibility to design novel carrier proteins for glycoconjugates and improved versions of bacterial recombinant proteins.

Objective: This study aimed to evaluate the efficacy of a new biomarker, termed SIR-En, in identifying patients at risk of endometrial carcinoma among those presenting with abnormal uterine bleeding during menopause., Material and Methods: A retrospective case-control analysis was conducted on 242 women with menopausal abnormal uterine bleeding and endometrial thickness ≥ 4 mm. Peripheral blood samples were collected within 7 days before histological diagnosis. systemic inflammatory reaction (SIR) indices were calculated, including NLR, MLR, PLR, and SII. SIR-En was derived by multiplying SII and endometrial thickness. Statistical analyses, including multivariate linear regression and ROC curve analysis, were performed to assess the diagnostic capability of SIR-En., Results: Patients were categorized into endometrial hyperplasia (50 patients) and endometrial cancer (192 patients) groups. The SIR-En index was significantly higher in the carcinoma group (8710 vs. 6420; p = 0.003). The ROC curve for SIR-En had an AUC of 0.6351 (95% CI: 0.5579-0.7121). Using Youden's method, the optimal SIR-En cutoff was 13,806, showing a specificity of 0.940 and a positive predictive value of 0.957., Conclusions: Combining systemic inflammatory indices with endometrial thickness, the SIR-En index can effectively distinguish between endometrial hyperplasia and carcinoma in menopausal women with abnormal uterine bleeding. Despite the retrospective design, the identified cutoff's high specificity and positive predictive value support its potential utility in clinical practice. Further prospective studies are required to validate these findings and optimize clinical application.

Cancer patients, especially long cancer survivors, are exposed to several cardio-metabolic diseases, including diabetes, heart failure, and atherosclerosis, which increase their risk of cardiovascular mortality. Therapy with glucagon-like peptide 1 (GLP1) receptor agonists demonstrated several beneficial cardiovascular effects, including atherosclerosis and heart failure prevention. Cardiovascular outcome trials (CVOTs) suggest that GLP-1 RA could exert cardiorenal benefits and systemic anti-inflammatory effects in patients with type-2 diabetes through the activation of cAMP and PI3K/AkT pathways and the inhibition of NLRP-3 and MyD88. In this narrative review, we highlight the biochemical properties of GLP-1 RA through a deep analysis of the clinical and preclinical evidence of the primary prevention of cardiomyopathies. The overall picture of this review encourages the study of GLP-1 RA in cancer patients with type-2 diabetes, as a potential primary prevention strategy against heart failure and atherosclerosis.

Acetylsalicylic acid (ASA) represents a cornerstone of antiplatelet therapy for the treatment of atherosclerotic coronary artery disease (CAD). ASA is in fact indicated in case of an acute coronary syndrome or after a percutaneous coronary intervention with stent implantation. Aspirin hypersensitivity is frequently reported by patients, and this challenging situation requires a careful evaluation of the true nature of the presumed sensitivity and of its mechanisms, as well as to differentiate it from a more frequent (and more easily manageable) aspirin intolerance. Two main strategies are available to allow ASA administration for patients with CAD and suspected ASA hypersensitivity: a low-dose ASA challenge, aimed at assessing the tolerability of ASA at the antiplatelet dose of 100 mg, and desensitization, a therapeutic procedure which aims to induce tolerance to ASA. For those patients who cannot undergo ASA challenge and desensitization due to previous serious adverse reactions, or for those in whom desensitization was unsuccessful, a number of further alternative strategies are available, even if these have not been validated and approved by guidelines. The aim of this state-of-the-art review is therefore to summarize the established evidence regarding pathophysiology, clinical presentation, diagnosis, and management of aspirin hypersensitivity and to provide a practical guide for cardiologists (and clinicians) who have to face the not uncommon situation of a patient with concomitant coronary artery disease and aspirin hypersensitivity.

Hepatocellular carcinomas (HCCs) are highly heterogeneous malignancies. They are characterized by a peculiar tumor microenvironment and dense vascularization. The importance of signaling between immune cells, endothelial cells, and tumor cells leads to the difficult recapitulation of a reliable in vitro HCC model using the conventional two-dimensional cell cultures. The advent of three-dimensional organoid tumor technology has revolutionized our understanding of the pathogenesis and progression of several malignancies by faithfully replicating the original cancer genomic, epigenomic, and microenvironmental landscape. Organoids more closely mimic the in vivo environment and cell interactions, replicating factors such as the spatial organization of cell surface receptors and gene expression, and will probably become an important tool in the choice of therapies and the evaluation of tumor response to treatments. This review aimed to describe the ongoing and potential applications of organoids as an in vitro model for the study of HCC development, its interaction with the host's immunity, the analysis of drug sensitivity tests, and the current limits in this field.

Inflammatory bowel diseases (IBD) have a complex, poorly understood pathogenesis and lack long-lasting effective treatments. Recent research suggests that intestinal fungal dysbiosis may play a role in IBD development. This study investigates the effects of the glucocorticoid-induced leucine zipper protein (GILZp)", known for its protective role in gut mucosa, and a yeast extract (Py) with prebiotic properties, either alone or combined, in DSS-induced colitis. Both treatments alleviated symptoms via overlapping or distinct mechanisms. In particular, they reduced the transcription levels of pro-inflammatory cytokines IL-1β and TNF-α, as well as the expression of the tight junction protein Claudin-2. Additionally, GILZp increased MUC2 transcription, while Py reduced IL-12p40 and IL-6 levels. Notably, both treatments were effective in restoring the intestinal burden of clinically important Candida and related species. Intestinal mycobiome analysis revealed that they were able to reduce colitis-associated fungal dysbiosis, and this effect was mainly the result of a decreased abundance of the Meyerozima genus, which was dominant in colitic mice. Overall, our results suggest that combined treatment regimens with GILZp and Py could represent a new strategy for the treatment of IBD by targeting multiple mechanisms, including the fungal dysbiosis.

Background and Objectives: We aimed at evaluating the impact of Controlling Nutritional Status (CONUT) score on clinically significant decline in estimated glomerular filtration rate (eGFR) in patients with non-metastatic Clear Cell Renal Cell Carcinoma (ccRCC) undergoing radical nephrectomy (RN)., Materials and Methods: We retrospectively analyzed a multi-institutional cohort of 140 patients with ccRCC who underwent RN between 2016 and 2018 at three Urological Centers. The CONUT score was calculated with an algorithm including serum albumin, total lymphocyte count, and cholesterol. Clinical and pathologic features were analyzed using Fisher's exact test for categorical variables and a Mann-Whitney U test for continuous variables. To define the independent predictors of clinically significant eGFR decline, univariable (UVA) and multivariable (MVA) binomial logistic regression analyses were performed in order to assess the Odds Ratio (OR) with 95% Confidence Intervals (CIs)., Results: The optimal cut-off value to discriminate between a low and high CONUT score was assessed by calculating the ROC curve. The area under the curve (AUC) was 0.67 (95%CI 0.59-0.78) with the most appropriate cut-off value at 2 points. Overall, 46 patients (32.9%) had a high CONUT score (>2). Statistically significant variables associated with eGFR decline at 24 months were age ≥ 70 (OR 2.01; 95%CI 1.17-3.09; p 0.05), stage II-III chronic kidney disease (CKD) (OR 6.05; 95%CI 1.79-28.3; p 0.001), and a high CONUT score (OR 3.98; 95%CI 1.58-10.4; p 0.004)., Conclusions: The CONUT score is a low-time-consuming, cost-effective, and promising tool able to preoperatively screen patients at risk of developing CKD after a RN.

Shigellosis represents a significant global health concern particularly affecting children under 5 years in low- and middle-income countries (LMICs) and is associated with stunting and antimicrobial resistance. There is a critical need for an effective vaccine offering broad protection against the different Shigella serotypes. A correlate of protection has not yet been established but there is a general consensus about the relevant role of anti-O-Antigen-specific IgG and its functionality evaluated by the Serum Bactericidal Assay (SBA). This study aims to characterize a high-throughput luminescence-based SBA (L-SBA) against seven widespread Shigella serotypes. The assay was previously developed and characterized for S. sonnei and S. flexneri 1b, 2a, and 3a and has now been refined and extended to an additional five serotypes ( S. flexneri 4a, 5b, 6, X, and Y). The characterization of the assay with human sera confirmed the repeatability, intermediate precision, and linearity of the assays; both homologous and heterologous specificity were verified as well; finally, limit of detection and quantification were established for all assays. Moreover, different sources of baby rabbit complement showed to have no impact on L-SBA output. The results obtained confirm the possibility of extending the L-SBA to multiple Shigella serotypes, thus enabling analysis of the functional response induced by natural exposure to Shigella in epidemiological studies and the ability of candidate vaccines to elicit cross-functional antibodies able to kill a broad panel of prevalent Shigella serotypes in a complement-mediated fashion.

The pathophysiology of pulmonary hypertension is complex and multifactorial. It is a disease characterized by increased pulmonary vascular resistance at the level due to sustained vasoconstriction and remodeling of the pulmonary arteries, which triggers an increase in the mean pulmonary artery pressure and subsequent right ventricular hypertrophy, which in some cases can cause right heart failure. Hypoxic pulmonary hypertension (HPH) is currently classified into Group 3 of the five different groups of pulmonary hypertensions, which are determined according to the cause of the disease. HPH mainly develops as a product of lung diseases, among the most prevalent causes of obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or hypobaric hypoxia due to exposure to high altitudes. Additionally, cardiometabolic risk factors converge on molecular mechanisms involving overactivation of the mammalian target of rapamycin (mTOR), which correspond to a central axis in the development of HPH. The aim of this review is to summarize the role of mTOR in the development of HPH associated with metabolic risk factors and its therapeutic alternatives, which will be discussed in this review.

Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients' care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders. This review aims at presenting the multimodal approach supported by the integration of multiple analyses and disciplines as a valuable solution to clarify complex genotype-phenotype correlations and promote an in-depth examination of rare disorders. Taking into account the literature from large-scale population studies and ongoing technological advancement, this review described some examples to show how a multi-skilled team can improve the complex diagnosis of rare diseases. In this regard, Facio-Scapulo-Humeral muscular Dystrophy (FSHD) represents a valuable example where a multimodal approach is essential for a more accurate and precise diagnosis, as well as for enhancing the management of patients and their families. Given their heterogeneity and complexity, rare diseases call for a distinctive multidisciplinary approach to enable diagnosis and clinical follow-up.

Septic arthritis (SA) represents an orthopedics urgency and mainly affects the knee joint. Due to its devastating effects on cartilage, immediate management is crucial. SA is characterized by an annual incidence of 2 to 10 cases per 100,000 individuals, with mortality rates fluctuating between 0.5% and 15%, with a substantially higher mortality rate observed in older people (15%) in contrast to younger cohorts (4%). The etiology of septic arthritis is multifactorial: a spectrum of Gram-positive and Gram-negative bacteria can contribute to the development of this condition, especially Staphylococcus aureus . The treatment involves urgent (arthroscopic or arthrotomic) debridement associated with adequate antibiotic therapy. Intra-articular antibiotic carriers can also be used to increase their local concentration and effectiveness. The case of a 67-year-old woman affected by knee SA from methicillin-susceptible S. aureus is presented. She was treated with an arthroscopic debridement enhanced by intra-articular antibiotic-loaded calcium sulphate beads, together with antibiotic therapy. At 2-year follow up, the infection had been eradicated and the patient fully recovered. This is the first description, to our knowledge, in the English literature, of the use of antibiotic-loaded calcium sulphate beads as an adjuvant in the surgical treatment of SA of a native knee joint.

Digital solutions in the field of restorative neurology offer significant assistance, enabling patients to engage in rehabilitation activities remotely. This research introduces ReMoVES, an Internet of Medical Things (IoMT) system delivering telemedicine services specifically tailored for multiple sclerosis rehabilitation, within the overarching framework of the STORMS project. The ReMoVES platform facilitates the provision of a rehabilitative exercise protocol, seamlessly integrated into the Individual Rehabilitation Project, curated by a multidimensional medical team operating remotely. This manuscript delves into the second phase of the STORMS pilot feasibility study, elucidating the technology employed, the outcomes achieved, and the practical, professional, and academic implications. The STORMS initiative, as the genesis of digital telerehabilitation solutions, aims to enhance the quality of life for multiple sclerosis patients.

Curcumin (Cur), the primary curcuminoid found in Curcuma longa L., has garnered significant attention for its potential anti-inflammatory and antibacterial properties. However, its hydrophobic nature significantly limits its bioavailability. Additionally, adipose-derived stem cells (ADSCs) possess immunomodulatory properties, making them useful for treating inflammatory and autoimmune conditions. This study aims to verify the efficacy of poly(ε-caprolactone) nanocapsules (NCs) in improving Cur's bioavailability, antibacterial, and immunomodulatory activities. The Cur-loaded nanocapsules (Cur-NCs) were characterized for their physicochemical properties (particle size, polydispersity index, Zeta potential, and encapsulation efficiency) and stability over time. A digestion test simulated the behavior of Cur-NCs in the gastrointestinal tract. Micellar phase analyses evaluated the Cur-NCs' bioaccessibility. The antibacterial activity of free Cur, NCs, and Cur-NCs against various Gram-positive and Gram-negative strains was determined using the microdilution method. ADSC viability, treated with Cur-NCs and Cur-NCs in the presence or absence of lipopolysaccharide, was analyzed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay. Additionally, ADSC survival was assessed through the Muse apoptotic assay. The expression of both pro-inflammatory (interleukin-1β and tumor necrosis factor-α) and anti-inflammatory (IL-10 and transforming growth factor-β) cytokines on ADSCs was evaluated by real-time polymerase chain reaction. The results demonstrated high stability post-gastric digestion of Cur-NCs and elevated bioaccessibility of Cur post-intestinal digestion. Moreover, Cur-NCs exhibited antibacterial activity against Escherichia coli without affecting Lactobacillus growth. No significant changes in the viability and survival of ADSCs were observed under the experimental conditions. Finally, Cur-NCs modulated the expression of both pro- and anti-inflammatory cytokines in ADSCs exposed to inflammatory stimuli. Collectively, these findings highlight the potential of Cur-NCs to enhance Cur's bioavailability and therapeutic efficacy, particularly in cell-based treatments for inflammatory diseases and intestinal dysbiosis.

Background: EUS-guided gastroenterostomy (EUS-GE) is a novel and effective procedure for the management of malignant gastric outlet obstruction (GOO) with more durable results when compared to enteral stenting (ES). However, data comparing EUS-GE to ES in patients already treated with EUS-guided choledocoduodenostomy (EUS-CDS) for distal malignant biliary obstruction (DMBO) are lacking. We aimed to compare outcomes of EUS-GE and ES for the palliation of GOO in this specific population of patients., Methods: A multicenter, retrospective analysis of patients with DMBO treated by EUS-CDS and subsequent GOO treated by EUS-GE or ES from 2016 to 2021 was conducted. Primary outcomes were overall AEs rate and dysfunction of the EUS-CDS after GOO treatment. Secondary outcomes included clinical success, technical success, procedure duration, length of hospital stay and relapse of GOO symptoms., Results: A total of 77 consecutive patients were included in the study: 25 patients underwent EUS-GE and 52 underwent ES. AEs rate and patency outcomes of the EUS-CDS after GOO treatment were comparable between the two groups (12.5% vs. 17.3%; p = 0.74). No recurrence of GOO symptoms was registered in the EUS-GE group while 11.5% of ES patients had symptoms recurrence, even if not statistically significant ( p = 0.16), after a mean follow-up period of 63.5 days., Conclusion: EUS-GE and ES are both effective and safe for the palliation of GOO in patients already treated by EUS-CDS for DMBO with no difference in the biliary stent dysfunction rate and overall AEs. EUS-GE is associated with less recurrence of GOO symptoms.

In this paper, we report the possibility of using the X-ray powder diffraction (XRPD) technique to detect gamma-hydroxybutyric acid (GHB) in the form of its sodium salt in different beverages, but because it is not possible to freely buy GHB, beta-hydroxybutyric acid (BHB) and its sodium salt (NaBHB) were used as a model to fine-tune an X-ray diffraction method for the qualitative analysis of the sodium salt of GHB. The method requires only a small quantity of beverage and an easy sample preparation that consists only of the addition of NaOH to the drink and a subsequent drying step. The dry residue obtained can be easily analyzed with XRPD using a single-crystal X-ray diffractometer, which exploits its high sensitivity and allows for very fast pattern collection. Several beverages with different NaBHB:NaOH molar ratios were tested, and the results showed that NaBHB was detected in all drinks analyzed when the NaBHB:NaOH molar ratio was 1:50, using a characteristic peak at very low 2θ values, which also permitted the detection of its presence in complex beverage matrices. Moreover, depending on the amount of NaOH added, shifting and/or splitting of the characteristic NaBHB salt peak was observed, and the origin of this behavior was investigated.

(1) Background: In 2018 FIGO reclassified tumors confined to the cervix larger than 4 cm as stage IB3. Although concurrent CTRT has been the standard of care and surgery the alternative, optimal management remains controversial due to the lack of direct comparison between surgery and CTRT. (2) Methods: This prospective observational study investigated the efficacy, safety and oncologic outcomes of nerve-sparing laparoscopic radical hysterectomy (nsLRH) for FIGO stage IB3 cervical cancer patients (IB3). From 2009 to 2023, IB3 patients underwent laparoscopic pelvic lymphadenectomies with frozen section analysis, followed by a nsLRH if the lymph nodes were tumor-free. No uterine manipulator was used and the vaginal cuff was sealed before retrieving the specimen. Intermediate-risk patients were under close observation without adjuvant therapy. Outcomes were monitored until 2023. (3) Results: During the study period, 74 IB3 patients were treated. Sixty-eight (91.9%) underwent a nsLRH. A complete resection with negative margins was achieved in all cases. At a median of 68 months of follow-up, the disease-free survival (DFS) rate was 89.7% and the overall survival (OS) rate was 93.1%. The overall complication rate was 23.5% and there were no grade 4-5 complications. (4) Conclusions: In patients with IB3 cervical cancer, a nsLRH is safe and effective. While awaiting the results from ongoing randomized trials, these findings support nsLRH as a viable treatment.

Background/objectives: Solitary fibrous tumors (SFTs) represent a rare mesenchymal malignancy that can occur anywhere in the body. Due to the low prevalence of the disease, there is a lack of contemporary data regarding patient demographics and cancer-control outcomes., Methods: Within the SEER database (2000-2019), we identified 1134 patients diagnosed with malignant SFTs. The distributions of patient demographics and tumor characteristics were tabulated. Cumulative incidence plots and competing risks analyses were used to estimate cancer-specific mortality (CSM) after adjustment for other-cause mortality., Results: Of 1134 SFT patients, 87% underwent surgical resection. Most of the tumors were in the chest (28%), central nervous system (22%), head and neck (11%), pelvis (11%), extremities (10%), abdomen (10%) and retroperitoneum (6%), in that order. Stage was distributed as follows: localized (42%) vs. locally advanced (35%) vs. metastatic (13%). In multivariable competing risks models, independent predictors of higher CSM were stage (locally advanced HR: 1.6; metastatic HR: 2.9), non-surgical management (HR: 3.6) and tumor size (9-15.9 cm HR: 1.6; ≥16 cm HR: 1.9)., Conclusions: We validated the importance of stage and surgical resection as independent predictors of CSM in malignant SFTs. Moreover, we provide novel observations regarding the independent importance of tumor size, regardless of the site of origin, stage and/or surgical resection status.

The industry of off-highway vehicles is one of the fields of major application of nodular cast irons, which guarantee the manufacture of complex geometries and ensure good mechanical properties. The present investigation deals with the fatigue design of off-highway axles made of EN-GJS-500-7. Typically, off-highway axles are weakened by stress risers which must be assessed against fatigue. In this investigation, laboratory specimens have been extracted from an off-highway axle to take into account the manufacturing process effects. Different specimens' geometries have been prepared, including plain, bluntly notched and sharply V-notched specimens, and constant amplitude, load-controlled axial fatigue tests were conducted using two nominal load ratios, namely push-pull and pulsating tension loading. As a result, both the notch and the mean stress effects on the fatigue behaviour of EN-GJS-500-7 have been experimentally investigated for the first time. A well-known local approach, which takes the strain energy density (SED) averaged over a properly defined structural volume as a fatigue damage parameter, has been applied both in the linear elastic and elastic plastic formulations. Since the SED correlated the geometrical notch effects of the specimens as well as the mean stress effects, a master curve based on the averaged SED has been defined for the first time, to the best of the authors' knowledge, for the fatigue design of off-highway axles made of EN-GJS-500-7.

Composite materials, particularly carbon fiber-reinforced polymers (CFRPs), have become a cornerstone in industries requiring high-performance materials due to their exceptional mechanical properties, such as high strength-to-weight ratios, and their inherent lightweight nature. These attributes make CFRPs highly desirable in aerospace, automotive, and other advanced engineering applications. However, the compressive behavior of CFRP structures remains a challenge, primarily due to the material sensitivity to structural instability, leading to matrix cracking and premature failure under compressive loads. Isogrid structures, characterized by their unique geometric patterns, have shown promise in enhancing the compressive behavior of CFRP panels by providing additional support that mitigates these issues. Traditionally, these structures are manufactured using automated techniques like automated fiber placement (AFP) and automated tape laying (ATL), which, despite their efficacy, are often cost-prohibitive for small-scale or custom applications. Recent advancements in 3D-printing technology, particularly those involving continuous fiber reinforcement, present a cost-effective and flexible alternative for producing complex CFRP structures. This study investigates the compressive behavior of 3D-printed isogrid structures, fabricated using continuous carbon fiber reinforcement via an Anisoprint Composer A3 printer equipped with towpreg coextrusion technology. A total of eight isogrid panels with varying infill percentages were produced and subjected to buckling tests to assess their performance. The experimental results indicate a direct correlation between infill density and buckling resistance, with higher infill densities leading to increased buckling loads. Additionally, the failure modes were observed to shift from local to global buckling as the infill density increased, suggesting a more uniform distribution of compressive stresses. Post-test analyses using optical microscopy and scanning electron microscopy (SEM) revealed the presence of voids within the 3D-printed structures, which were found to negatively impact the mechanical performance of the isogrid panels. The findings of this study demonstrate that 3D-printed isogrid CFRP structures can achieve significant buckling resistance, making them a viable option for high-performance applications. However, the presence of voids remains a critical issue, highlighting the need for process optimizations in 3D-printing techniques to enhance the overall performance and reliability of these structures.

(1) Background: Endometrial carcinoma (EC) classified as no specific molecular profile (NSMP) represents a heterogeneous group with variable prognoses. This retrospective, single-center study aims to further stratify NSMP ECs to tailor treatment strategies and improve outcomes. (2) Methods: From 2020 to 2023, we collected data on 51 patients diagnosed with NSMP EC following the introduction of molecular profiling at our institution. Patients were retrospectively analyzed for estrogen receptor (ER) status, histotype, and grade to identify potential prognostic subgroups. (3) Results: Our analysis identified two distinct subgroups within NSMP EC: low-risk and high-risk, based on ER status, histotype, and grade. The low-risk NSMP group demonstrated significantly better survival outcomes compared to the high-risk group. With a median follow-up time of 16 moths (IQR 13.0-29.7), the disease-free survival (DFS) and overall survival (OS) for the low-risk group were 100%. For the high-risk group, the DFS and OS were 71.4% and 78.6%, respectively, which showed a statistically significantly difference (Log-Rank Mantel-Cox < 0.001). In the high-risk group, four patients experienced recurrence, and three of these patients died. (4) Conclusions: Stratifying NSMP EC into low-risk and high-risk categories based on ER status, histotype, and grade can lead to more accurate prognostic assessments. In time, it may require tailored adjuvant therapies and a personalized treatment.

Objectives: This study aims to demonstrate the role of case-level American College of Medical Genetics (ACMG) criteria, such as familial segregation and pathology data, in providing conclusive evidence for the pathogenicity of ultrarare GLA variants causing Anderson-Fabry disease when gene-level and variant-level criteria provide ambiguous or discrepant results. Case/family description: A 52-year-old woman presented with new-onset shortness of breath, chest pain, and palpitations. Echocardiography revealed mild left ventricular wall thickening (14 mm) and mild diastolic dysfunction. She was the second of three siblings born to unrelated parents, both of whom died from malignancies. Family screening identified brothers, one affected 55-year-old with hypertension and asthma and one unaffected 47-year-old. The 15-year-old son of the proband complained of exercise-induced burning feet acral pain his electrocardiogram showed a short PR interval and signs of early hypertrophy., Results: Endomyocardial biopsies of the proband and the affected sibling demonstrated substrate accumulation (globotriaosylceramide). The anti-α-galactosidase-A immunostain showed a total loss of the enzyme in the hemizygous male and a mosaic pattern in the heterozygous female. The next-generation sequencing short-read multigene panel identified the c.547+3A>G variant in the GLA gene and excluded variants in other genes; Oxford-Nanopore long-read sequencing excluded known pathogenic deep intronic variants. A Multiplex-Ligation-dependent-Probe-Amplification assay excluded copy number variations. Based on the variant-level and gene-level ACMG criteria, the variant was classified as a Variant of Uncertain Significance or Likely Benign using different bioinformatic tools. By adding case-level functional data (endomyocardial biopsy, PS3&#95;VeryStrong) and familial data (segregation of genotype with phenotype, PP2&#95;Moderate), the variant was classified as Likely Pathogenic/Pathogenic., Conclusion: ACMG case-level data can unambiguously resolve uncertain interpretations of GLA variants.

This work investigated the gelation kinetics and mechanical properties of agarose hydrogels studied at different concentrations (in the range 1-5 g/L) and temperatures. Rheological measurements were performed by diffusing wave spectroscopy (DWS) using polystyrene and titanium dioxide particles as probes. The study emphasized the influence of gelation kinetics on the mechanical behavior of the hydrogels. The results showed that the gel properties were closely related to the thermal history and aging time of the samples. The insights gained from this study are critical for optimizing the performance of agarose hydrogels in specific applications and highlight the importance of controlling the concentration and thermal conditions during hydrogel preparation.

The rising incidence of metabolic diseases is linked to elevated blood glucose levels, contributing to conditions such as diabetes and promoting the accumulation of advanced glycation end products (AGEs). AGEs, formed by non-enzymatic reactions between sugars and proteins, build up in tissues and are implicated in various diseases. This article explores the relationship between glycemic control and AGE accumulation, focusing on fertility implications. A computational model using network theory was developed, featuring a molecular database and a network with 145 nodes and 262 links, categorized as a Barabasi-Albert scale-free network. Three main subsets of nodes emerged, centered on glycemic control, fertility, and immunity, with AGEs playing a critical role. The transient receptor potential vanilloid 1 (TRPV1), a receptor expressed in several tissues including sperm, was identified as a key hub, suggesting that the modulation of TRPV1 in sperm by AGEs may influence fertility. Additionally, a novel link between glycemic control and immunity was found, indicating that immune cells may play a role in endocytosing specific AGEs. This discovery underscores the complex interplay between glycemic control and immune function, with significant implications for metabolic, immune health, and fertility.

In recent years, several strategies have been developed for the treatment of transthyretin-related amyloidosis, whose complex clinical manifestations involve cardiomyopathy and polyneuropathy. In view of this, transthyretin stabilizers represent a major cornerstone in treatment thanks to the introduction of tafamidis into therapy and the entry of acoramidis into clinical trials. However, the clinical treatment of transthyretin-related amyloidosis still presents several challenges, urging the development of new and improved therapeutics. Bearing this in mind, in this paper, the most promising among the recently published transthyretin stabilizers were reviewed. Their activity was described to provide some insights into their clinical potential, and crystallographic data were provided to explain their modes of action. Finally, structure-activity relationship studies were performed to give some guidance to future researchers aiming to synthesize new transthyretin stabilizers. Interestingly, some new details emerged with respect to the previously known general rules that guided the design of new compounds.