Search Results (821)

Background: Colorectal liver metastasis (CRLM) represents a major clinical challenge in oncology, affecting 25–50% of colorectal cancer patients and significantly impacting survival. While multimodal therapies—including surgical resection, systemic chemotherapy, and local ablative techniques—have improved outcomes, prognosis remains heterogeneous due to variations in tumor biology, patient factors, and institutional practices. Methods: This review synthesizes current evidence on prognostic factors influencing CRLM management, encompassing clinical (e.g., tumor burden, anatomic distribution, timing of metastases), biological (e.g., CEA levels, inflammatory markers), and molecular (e.g., RAS/BRAF mutations, MSI status, HER2 alterations) determinants. Results: Key findings highlight the critical role of molecular profiling in guiding therapeutic decisions, with RAS/BRAF mutations predicting resistance to anti-EGFR therapies and MSI-H status indicating potential responsiveness to immunotherapy. Emerging tools like circulating tumor DNA (ctDNA) and radiomics offer promise for dynamic risk stratification and early recurrence detection, while the gut microbiome is increasingly recognized as a modulator of treatment response. Conclusions: Despite advancements, challenges persist in standardizing resectability criteria and integrating multidisciplinary approaches. Current guidelines (NCCN, ESMO, ASCO) emphasize personalized strategies but lack granularity in terms of incorporating novel biomarkers. This exhaustive review underscores the imperative for the development of a unified, biomarker-integrated framework to refine CRLM management and improve long-term outcomes. Full article

This article utilises Max-Neef’s Human Scale Development (HSD) framework (1991) to answer two research questions: what impact does government and community-based social protection (SP) have on UK asylum-seeker wellbeing; how are interactions with all forms of SP, both as giver and receiver, supporting or harming the satisfaction of asylum-seekers’ fundamental human needs at this time? The research study utilised a mixed-methods, collaborative, case study design situated within a refugee and asylum-seeker (RAS) support charity in Southwest England. Methods included peer-led Qualitative Impact Protocol interviews, Photovoice, surveys, and staff interviews. Data were subjected to an inductive, bottom-up process on Causal Map software (version 2, Causal Map Ltd., 39 Apsley Rd., Bath BA1 3LP, UK) and the analysis used the HSD framework. We found eight over-arching themes. The four main needs-violators/destroyers of asylum-seeker wellbeing were dehumanisation, unfreedoms, enforced ignorance, and (re)traumatisation, and the four main needs-satisfiers were common humanity, autonomy and resistance, exerting agency through knowledge exchange, and healing. Five policy and practice-focused bridging satisfiers are recommended to help move individual and collective experience from a negative to a positive state in the research population. Policy and practice should be transparent and evidence-based, efficient and equitable, supportive of participation and productivity, trauma-informed, and multi-agency. Full article

Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking. We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC₅₀ and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC₅₀). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient. In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment. A comparison with known RAS showed that S759A, located in the active site of nsp12, conferred the highest remdesivir resistance (106.1-fold increase in replication). Nsp12-RAS V166A/L, V792I, E796D or C799F, all adjacent to the active site, caused intermediate resistance (2.0- to 11.5-fold), whereas N198S, D484Y, or E802D, located farther from the active site, showed no resistance (≤2.0-fold). In conclusion, our classification system, correlating replication under remdesivir treatment with RAS location in nsp12, shows that most nsp12-RAS cause moderate resistance. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

The increasing complexity of modern control systems highlights the need for reliable and robust fault detection, isolation, and identification (FDII) methods, particularly in safety-critical and industrial applications. The study focuses on the FDII of multiplicative faults in a DC motor and its electronic amplifier. To simulate such scenarios, a complete laboratory platform was developed for real-time FDII, using relay-based switching and custom LabVIEW software 2009. This platform enables real-time experimentation and represents an important component of the study. Two estimation-based fault detection (FD) algorithms were implemented: the Sliding Window Algorithm (SWA) for discrete-time models and a modified Sliding Integral Algorithm (SIA) for continuous-time models. The modification introduced to the SIA limits the data length used in least squares estimation, thereby reducing the impact of transient effects on parameter accuracy. Both algorithms achieved high model output-to-measured signal agreement, up to 98.6% under nominal conditions and above 95% during almost all fault scenarios. Moreover, the proposed fault isolation and identification methods, including a decision algorithm and an indirect estimation approach, successfully isolated and identified faults in key components such as amplifier resistors (R₁, R₉, R₁₂), capacitor (C₈), and motor parameters, including armature resistance (R_a), inertia (J), and friction coefficient (B). The decision algorithm, based on continuous-time model coefficients, demonstrated reliable fault isolation and identification, while the reduced Jacobian-based approach in the discrete model enhanced fault magnitude estimation, with deviations typically below 10%. Additionally, the platform supports remote experimentation, offering a valuable resource for advancing model-based FDII research and engineering education. Full article

Proto-oncogenes in the RAS superfamily play dual roles in maintaining cellular homeostasis, such as regulating growth signals and contributing to cancer development through proliferation and deregulation. Activating proto-oncogenes in vitro transforms cells, underscoring their centrality in gene regulation and cellular networks. Despite decades of research, poor outcomes in advanced cancers reveal gaps in understanding Ras-driven mechanisms or therapeutic strategies. This narrative review examines RAS genes and Ras proteins in both housekeeping functions, such as cell growth, apoptosis, and protein trafficking, as well as in tumorigenesis, integrating insights from human (HRAS, KRAS, NRAS), mouse (Hras, Kras, Nras), and Drosophila melanogaster (ras) models. While RAS mutations are tightly linked to human tumors, the interplay between their standard and oncogenic functions remains complex. Even within the same tissue, distinct cancer pathways—such as the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways—can drive varied disease courses, complicating treatment. Advanced-stage cancers add further challenges, including heterogeneity, protective microenvironments, drug resistance, and adaptive progression. This synthesis organizes current knowledge of RAS gene regulation and Ras protein function from genomic alterations and intracellular signaling to membrane dynamics and extracellular interactions, offering a layered perspective on the Ras pathway’s role in both housekeeping and tumorigenic contexts. Full article

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC. Full article

The RasGAP SH3 domain binding protein (G3BP) is a highly conserved family of proteins in eukaryotic organisms that coordinates signal transduction and post-transcriptional gene regulation and functions in the formation of stress granules. G3BPs have important roles in abiotic/biotic stresses in mammals, and recent research suggests that they have similar functions in higher plants. Brassica contains many important oilseeds, vegetables, and ornamental plants, but there are no reports on the G3BP family in Brassica species. In this study, we identified G3BP family genes from six species of the U’s triangle (B. rapa, B. oleracea, B. nigra, B. napus, B. juncea, and B. carinata) at the genome-wide level. We then analyzed their gene structure, protein motifs, gene duplication type, phylogeny, subcellular localization, SSR loci, and upstream miRNAs. Based on transcriptome data, we analyzed the expression patterns of B. napus G3BP (BnaG3BP) genes in various tissues/organs in response to Sclerotinia disease, blackleg disease, powdery mildew, dehydration, drought, heat, cold, and ABA treatments, and its involvement in seed traits including germination, α-linolenic acid content, oil content, and yellow seed. Several BnaG3BP DEGs might be regulated by BnaTT1. The qRT-PCR assay validated the inducibility of two cold-responsive BnaG3BP DEGs. This study will enrich the systematic understanding of Brassica G3BP family genes and lay a molecular basis for the application of BnaG3BP genes in stress tolerance, disease resistance, and quality improvement in rapeseed. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD), a recently proposed term to replace non-alcoholic fatty liver disease (NAFLD), emphasizes the critical role of metabolic dysfunction and applies broader diagnostic criteria. Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin–angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems. Full article

Electrochemical treatment by means of direct current (DC) is usually used as a measure for steel rebar corrosion protection, e.g., cathodic protection (CP), electrochemical chloride extraction (ECE), and re-alkalization (RA). However, the passage of an electrical charge through the pore system of concrete or mortar, coupled with the migration of ions, concentration changes, and resulting phase changes, may alter its chloride penetration resistance and, subsequently, the time until rebar corrosion activation. Porosity changes in hardened Portland cement mortar were studied by means of mercury intrusion porosimetry (MIP) and electrochemical impedance spectroscopy (EIS), and alterations in the mortar surface phase composition were observed by means of X-ray diffraction (XRD). In order to innovatively investigate the impact of DC treatment on the properties of the mortar–electrolyte interface, the cathode-facing mortar surface and the anode-facing mortar surface were analyzed separately. The corrosion of steel coupons embedded in DC-treated hardened mortar was monitored by means of the free corrosion potential (E_oc) and polarization resistance (R_p). The results showed that the DC treatment affected the surface porosity of the hardened Portland cement mortar at the nanoscale. Up to two-thirds of the small pores (0.001–0.01 µm) were replaced by medium-sized pores (0.01–0.06 µm), which may be significant for chloride ingress. Although the porosity and phase composition alterations were confirmed using other techniques (EIS and XRD), corrosion tests revealed that they did not significantly affect the time until the corrosion activation of the steel coupons in the mortar. Full article

The advancement of Internet of Things (IoT) technology has enabled battery-powered devices to be deployed across a wide range of applications; however, it also introduces challenges such as high energy consumption and security vulnerabilities. To address these issues, adiabatic logic circuits offer a promising solution for achieving energy efficiency and enhancing the security of IoT devices. Adiabatic logic circuits are well suited for energy harvesting systems, especially in applications such as sensor nodes, RFID tags, and other IoT implementations. In these systems, the harvested bipolar sinusoidal RF power is directly used as the power supply for the adiabatic logic circuit. However, adiabatic circuits require a peak detector to provide bulk biasing for pMOS transistors. To meet this requirement, a diode-connected MOS transistor-based voltage doubler circuit is used to convert the sinusoidal input into a usable DC signal. In this paper, we propose a novel adiabatic logic design that maintains low power consumption while optimizing energy and current fluctuations across various input transitions. By ensuring uniform and complementary current flow in each transition within the logic circuit’s functional blocks, the design reduces energy variation and enhances resistance against power analysis attacks. Evaluation under different clock frequencies and load capacitances demonstrates that the proposed adiabatic logic circuit exhibits lower fluctuation and improved security, particularly at load capacitances of 50 fF and 100 fF. The results show that the proposed circuit achieves lower power dissipation compared to conventional designs. As an application example, we implemented an ultrasonic transmitter circuit within a LoRaWAN network at the end-node sensor level, which serves as both a communication protocol and system architecture for long-range communication systems. Full article

Background/objective: Mucosal melanoma (MM) is a poorly responsive, rare and aggressive subtype with few cases having targetable recurrent driver mutations, although Ras/MAPK and PI3K/AKT/mTOR signaling pathway activations are common. Eventual tumor evasion of targeted therapy continues to limit treatment success. Adequate models are necessary to address therapeutic resistance. The relatively greater incidence of naturally occurring MM in dogs, as well as its comparable clinical and pathological characteristics to human MM, represents an opportunity for study as a human MM patient surrogate. Resistance-promoting crosstalk between Ras/MAPK and PI3K/AKT/mTOR signaling under trametinib inhibition of MEK was studied in canine MM. Emphasis was placed on the suppressive effect of trametinib on cell cycle entry and its potential role in drug resistance. Methods: D-type cyclins were investigated following trametinib treatment of five MM cell lines exhibiting differential drug sensitivities. Signaling pathway activation, proliferation, survival, cell death, and cell cycle were analyzed in the context of D-type cyclin expression. Cyclin D2 expression was manipulated using siRNA knockdown or inducible recombinant overexpression. Results: Trametinib diminished cyclin D1 in all cell lines. While relatively trametinib-resistant MM cells exhibited capacity to upregulate cyclin D2, which promoted proliferation, sensitive MM cells lacked similar cyclin D2 compensation. Inhibition of the compensatory cyclin D2 in resistant cells conferred sensitivity. Induced cyclin D2 overexpression in otherwise trametinib-sensitive MM cells promoted survival. Upregulated PI3K/AKT/mTOR signaling under trametinib treatment was suppressed by mTORC1/2 inhibition, which similarly diminished cyclin D2 response. Conclusions: The compensatory switch from preferential reliance on cyclin D1 to D2 plays a role in MM resistance to MEK inhibition. Full article

Prostate cancer, a malignancy of significant prevalence, affects approximately half a million men in Europe, with one in twelve males receiving a diagnosis before reaching the age of 75. Radiotheranostics represents a paradigm shift in prostate cancer treatment, leveraging radionuclides for diagnostic and therapeutic applications, with PSMA emerging as the primary molecular target. Regulatory bodies have approved various PSMA-targeted radiodiagnostic agents, such as [¹⁸F]DCFPyL (PYLARIFY^®, Lantheus Holdings), [¹⁸F]rhPSMA-7.3 (POSLUMA^®, Blue Earth Diagnostics), and [⁶⁸Ga]Ga-PSMA-11 (LOCAMETZ^®, Novartis/ILLUCCIX^®, Telix Pharmaceuticals), as well as therapeutic agents like [¹⁷⁷Lu]Lu-PSMA-617 (PLUVICTO^®, 15 Novartis). The approval of PLUVICTO^® in March 2022 for patients with metastatic castration-resistant prostate cancer who have undergone prior treatments, including androgen receptor pathway-targeting agents and taxane-based chemotherapy, represents a significant advancement. Other radionuclides like ¹⁶¹Tb, ¹⁴⁹Tb, ²²⁵Ac, ²²⁷Th, ²²³Ra, ²¹¹At, ²¹³ Bi, ²¹²Pb, ⁸⁹Zr, and ¹²⁵I are presented, emphasizing their clinical implementation or the stage of clinical trial they are in in the flow to biomedical implementation. Three clinically wise used radionuclides ¹⁷⁷Lu, ²²⁵Ac, ²²³Ra are shown along with their characteristics. This review aims to elucidate the molecular mechanisms underpinning PSMA, explore the clinical applications of PSMA-targeted radiotheranostics, and critically examine the diverse challenges these therapies encounter in the treatment of prostate cancer. Full article

Significant progress has been made in the low-temperature toughness and crack resistance of polypropylene fiber-reinforced composites. However, there is still a gap in the research on damage evolution under freeze–thaw cycles and complex stress ratios. To solve the problem of durability degradation of traditional rubble masonry in cold regions, this paper focuses on the study of polypropylene fiber-mortar-masonry blocks with different fiber contents. Using acoustic emission and digital image technology, the paper conducts a series of tests on the scaled-down polypropylene fiber-mortar-masonry structure, including uniaxial compressive tests, three-point bending tests, freeze–thaw cycle tests, and tests with different stress ratios. Based on the Kupfer criterion, a biaxial failure criterion for polypropylene fiber mortar-masonry stone (PPF-MMS) was established under different freeze–thaw cycles. A freeze–thaw damage evolution model was also developed under different stress ratios. The failure mechanism of PPF-MMS structures was analyzed using normalized average deviation (NAD), RA-AF, and other parameters. The results show that when the dosage of PPF is 0.9–1.1 kg/m³, it is the optimal content. The vertical stress shows a trend of increasing first and then decreasing with the increase in the stress ratio, and when α = 0.5, the degree of strength increase reaches the maximum. However, the freeze–thaw cycle has an adverse effect on the internal structure of the specimens. Under the same number of freeze–thaw cycles, the strength of the specimens without fiber addition decreases more rapidly than that with fiber addition. The NAD evolution rate exhibits significant fluctuations during the middle loading period and near the damage failure, which can be considered precursors to specimen cracking and failure. RA-AF results showed that the specimens mainly exhibited tensile failure, but the occurrence of tensile failure gradually decreased as the stress ratio increased. Full article

Introduction: Renal artery stenosis can significantly impact long-term graft survival rates following kidney transplant. Early recognition and management can improve the longevity of the kidney allograft. We aimed to evaluate the clinical role of duplex ultrasound in the diagnosis of renal artery stenosis (RAS). We also wanted to evaluate the current incidence of renal artery stenosis at our institute. Methods: A retrospective, consecutive series of 367 patients who underwent renal transplantation between 1 January 2020 and 30 December 2024 was conducted. We collected data regarding the recipients’ age, body mass index, and comorbidities. All patients diagnosed with renal artery stenosis were identified. The incidence of kidney transplant artery stenosis and presentation were recorded. All general physical parameters and laboratory data were collected and analyzed. Results: A total of 28 patients had initial suspicion of renal artery stenosis, documented via initial dedicated duplex ultrasound of the transplanted kidney. The initial mean systolic BP at initial US was 151 (99–213) mmHg, and mean creatinine was 2.43 (1.28–6.38) mg/dL. However, on repeat duplex ultrasound, three patients showed no features of renal artery stenosis and had no physical parameters consistent with RAS. A total of 25 patients diagnosed with RAS on initial duplex ultrasound underwent angiography. Twenty-four patients were confirmed with RAS on angiography, while one patient had a normal angiogram. Among patients diagnosed with TRAS, the mean resistive index was 0.71 ± 0.17 at the upper pole, 0.73 ± 0.19 at the mid pole, and 0.71 ± 0.21 at the lower pole. The mean peak systolic velocity was 462.57 ± 166.28 cm/s. Conclusions: Duplex ultrasound is an important initial tool for diagnosing transplant renal artery stenosis. An increase in peak systolic velocity was observed in our cohort; however, resistive indices were largely within acceptable limits. Management should be guided by clinical parameters (e.g., elevated systolic BP and rising creatinine) alongside imaging findings. Full article