Search Results (67)

Background: The optimal extent of lymphadenectomy in colon cancer (CC) remains controversial. While Complete Mesocolic Excision (CME)/D3 dissection may improve oncological outcomes, the survival benefit appears limited to patients with central lymph node metastases (LNMs). Molecular profiling could help identify patients who may benefit from extended lymphadenectomy. Methods: This prospective cohort sub-study of the international T-REX trial included 97 patients with stage I–III CC who underwent curative resection at the National Cancer Centre, Vilnius, Lithuania (2015–2018). Lymph node mapping was performed by anatomical zones, and BRAF and KRAS mutation status in primary tumors was determined by quantitative PCR. Associations between genetic mutations, LNM distribution, and survival outcomes were analyzed. Results: A total of 2710 lymph nodes were retrieved from 97 patients, of which 100 (3.7%) were metastatic, and identified in 33 (34.0%) patients. Central LNMs were observed in 5 (5.2%) patients overall but were significantly more frequent among those with BRAF-mutated tumors (30.8%) compared to KRAS-mutated (2.4%) or wild-type (0%) cases (p < 0.001). BRAF mutations were associated with increased odds of intermediate (OR 8.1, 95% CI 1.4–45.6) and central (OR 36.8, 95% CI 3.7–366.7) LNMs. Mutation status did not impact overall or disease-free survival. Conclusions: BRAF mutations in primary CC are linked to higher rates of intermediate and central LNMs. Patients with BRAF-mutated tumors may benefit from extended lymphadenectomy. Future randomized trials should evaluate biomarker-driven surgical strategies in CC. Full article

The continuous-flow technologies in organic synthesis for the production of active pharmaceutical ingredients (APIs) are nowadays more and more applied. In-silico process design is a powerful tool able to support organic synthesis in the field of scale-up and process development. Process design feasibility and reliability depend on the availability of a well-defined chemical reaction kinetic scheme, information which is usually derived from experimental datasets collected on purpose. The latter approach is time-consuming and demanding in terms of resources. Different possibilities are here proposed to valorize widely available experimental data from explorative works with different approaches, depending on the nature, richness, and structure of the datasets. The kinetic parameters (i.e., reaction order, kinetic constant, and activation energy) of some interesting organic reactions have been approximately estimated by applying different computational methodologies, thanks to built-in experimental databases. The numerical algebra approach dealing with linear and non-linear regression analysis for the kinetic parameters has been initially considered and related to the database information for oseltamivir synthesis. The Bayesian statistic was applied to the ibuprofen case through the application of the Markov Chain Monte Carlo (MCMC) method for reaction order estimation. At last, a Machine Learning (ML) approach has been applied to the Rolipram and Pregabalin case study. The in-house developed T-ReX experimental kinetic constant database was exploited, with application of the k-Nearest neighbor algorithm for classification and regular expression pattern recognition. Advantages and limitations of the three approaches are discussed. Full article

Background: The efficacy and safety of tivozanib for the treatment of advanced or metastatic renal cell carcinoma (mRCC) have been established in the first-line setting in the Phase III trial TIVO-1. Methods: The prospective T-Rex study conducted in German clinical practice evaluated the safety, effectiveness and impact on quality of life (QoL) of first-line treatment with tivozanib in 32 patients with mRCC recruited between May 2019 and April 2021. Results: Recruited patients were predominantly elderly, with 53.1% aged over 75 years. Patients received a median of 6.5 tivozanib treatment cycles and the median time on treatment was 5.7 months. Overall, 78.1% of patients experienced treatment-related adverse events, including diarrhea, nausea and hypotension/hypertension. A clinical (i.e., complete or partial) response was observed in 46.9% of patients. Patients’ QoL remained stable from baseline to the end of treatment and most symptomatic toxicities resolved by the final treatment cycle, with the exclusion of dry skin, itching, and hand–foot syndrome. Conclusions: These data demonstrate that first-line treatment with tivozanib was associated with clinical activity, favorable tolerability, and stable QoL in patients with mRCC treated in everyday clinical practice across Germany, including those with advanced age. Full article

Activation functions are fundamental to the representational capacity and optimization dynamics of deep neural networks. Although numerous nonlinearities have been proposed, ranging from classical sigmoid and tanh to modern smooth and trainable functions, no single activation is universally optimal, as each involves trade-offs among gradient flow, stability, computational cost, and expressiveness. This study introduces TRex, a novel activation function that combines the efficiency and linear growth of rectified units with the smooth gradient propagation of saturating functions. TRex features a non-zero, smoothed negative region inspired by tanh while maintaining near-linear behavior for positive inputs, preserving gradients and reducing neuron inactivation. We evaluate TRex against five widely used activation functions (ReLU, ELU, Swish, Mish, and GELU) across eight convolutional architectures (AlexNet, DenseNet-121, EfficientNet-B0, GoogLeNet, LeNet, MobileNet-V2, ResNet-18, and VGGNet) on two benchmark datasets (MNIST and Fashion-MNIST) and a real-world medical imaging dataset (SkinCancer). The results show that TRex achieves competitive accuracy, AUC, and convergence stability across most deep, connectivity-rich architectures while maintaining computational efficiency comparable to those of other smooth activations. These findings highlight TRex as a contextually efficient activation function that enhances gradient flow, generalization, and training stability, particularly in deeper or densely connected architectures, while offering comparable performance in lightweight and mobile-optimized models. Full article

Stress, workload, and uncertainty characterize occupational tasks across sports, healthcare, military, and transportation domains. Emerging theory and empirical research suggest that coordinated whole-body movements may reflect these transient mental states. Wearable sensors and optical motion capture offer opportunities to quantify such movement dynamics and classify mental states that influence occupational performance and human–machine interaction. We tested this possibility in a small pilot study (N = 10) designed to test feasibility and identify preliminary movement features linked to mental states. Participants performed a perceptual decision-making task involving facial emotion recognition (i.e., deciding whether depicted faces were happy versus angry) with variable levels of stress (via a risk of electric shock), workload (via time pressure), and uncertainty (via visual degradation of task stimuli). The time series of movement trajectories was analyzed both holistically (full trajectory) and by phase: lowered (early), raising (middle), aiming (late), and face-to-face (sequential). For each epoch, up to 3844 linear and non-linear features were extracted across temporal, spectral, probability, divergence, and fractal domains. Features were entered into a repeated 10-fold cross-validation procedure using 80/20 train/test splits. Feature selection was conducted with the T-Rex Selector, and selected features were used to train a scikit-learn pipeline with a Robust Scaler and a Logistic Regression classifier. Models achieved mean ROC AUC scores as high as 0.76 for stress classification, with the highest sensitivity during the full movement trajectory and middle (raise) phases. Classification of workload and uncertainty states was less successful. These findings demonstrate the potential of movement-based sensing to infer stress states in applied settings and inform future human–machine interface development. Full article

Long-duration space missions expose astronauts to galactic cosmic radiation (GCR), a complex spectrum of high-charge, high-energy (HZE) ions that pose significant risks of chronic tissue injury. To model these effects, we examined intestinal outcomes in wild-type mice 5 months after low-dose (50 cGy) 33-ion mixed-field GCR simulation (GCRsim). GCRsim induced sustained DNA double-strand breaks (DSBs) and oxidative stress, as shown by elevated γH2AX foci and 4-HNE staining. Intestinal epithelial cells (IECs) exhibited pronounced senescence, marked by increased SA-β-gal activity, p16 upregulation, LaminB1 loss, and induction of senescence-associated secretory phenotype (SASP) cytokines (Cxcl10, IL-6, IL-1β, Icam1). GCRsim also elevated circulating LINE-1 DNA and reduced expression of DNA-degrading nucleases (DNase2, TREX1), indicating impaired extracellular DNA clearance. Targeted molecular study revealed persistent activation of the cGAS–STING pathway, with elevated cGAS, STING, pTBK1, pIKKα/β, and nuclear pIRF3, pIRF7, and p65, consistent with chronic innate immune signaling. Functionally, GCRsim altered nutrient absorption gene expression—upregulating glucose transporters (Slc2a2, Slc2a5, Slc5a1) and gut hormones (Cck, Gip), while downregulating cholesterol/fat transporters (Npc1, Npc1l1). Biochemical markers supported intestinal injury, with decreased serum citrulline and increased intestinal fatty acid-binding protein (I-FABP), indicating barrier compromise. Collectively, these findings demonstrate that GCRsim drives sustained intestinal dysfunction, highlighting the need for countermeasures to protect GI health during deep-space missions. Full article

Gene duplication, a major source of new genes in evolution, often occurs via reverse transcription of mRNA, leading to the integration of a retrocopy into a new genomic locus. Here, we performed an in-depth analysis of the evolutionary history of the e(y)2 gene in Metazoa. The E(y)2 protein is a shared subunit of two highly conserved complexes involved in transcription regulation (the DUB module of the SAGA complex) and mRNA transport (TREX-2). In Deuterostomes, the e(y)2 gene has undergone multiple independent retropositions, often giving rise to functional retrogenes. In contrast, among Protostomes, duplications of e(y)2 were identified only in Drosophilinae and a member of the Lepidoptera family (Manduca sexta). In Drosophila, the retrocopy e(y)2 acquired an almost ubiquitous expression pattern and compensates for the function of the parental gene in all tissues except the testes. The parental gene, e(y)2b, evolved a testis-specific expression pattern, lost the ability to incorporate into the DUB module, but retained nuclear envelope localization and the capacity to assemble into the TREX-2 complex. Knockout of the D. melanogaster e(y)2b gene resulted in reduced male fertility. Overall, our study highlights distinct evolutionary trajectories of the e(y)2 gene in Deuterostomes and Protostomes. Full article

Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease characterized by immune dysregulation, vasculopathy, and fibrosis. Objectives: To evaluate the genetic architecture and autoantibody profile in a Kazakh cohort of patients with SSc. Methods: A total of 26 Kazakh patients with diffuse SSc were examined for disease activity and organ impairment using EScSG and the modified Rodnan skin score (mRSS). Eighteen healthy volunteers were enrolled in the control group. Antinuclear factor (ANF) was estimated on HEp-2 cells, while antibodies to Scl-70, CENP-B, U1-snRNP, SS-A/Ro52, SS-A/Ro60, Sm/RNP, Sm, SS-B, Rib-P0, and nucleosomes were determined by immunoblotting. The level of IL-6 cytokine was detected using ELISA. To investigate the genetic basis of SSc in Kazakh patients, a custom AmpliSeq panel including targeting immune/fibrosis pathways and 120 genes was used on the Ion Proton sequencer. The statistical analysis of categorical variables was conducted using Fisher’s exact test and Chi-square (χ²) test. Results: The examination of SSc patients (mRSS 16 ± 7.2; EScSG 3.54 ± 2.18) revealed a broad range of antibodies to Scl-70, CENP-B, SS-A/Ro60, SS-A/Ro52, U1-snRNP, and RNP/Sm, which were undetectable in the control group. Genetic analysis identified multiple variants across immune regulatory genes, including likely pathogenic changes in SAMD9L, REL, IL6ST, TNFAIP3, ITGA2, ABCC2, AIRE, IL6R, AFF3, and TREX1. Variants of uncertain clinical significance were detected in LY96, IRAK1, RBPJ, IL6ST, ITGA2, AIRE, IL6R, JAZF1, IKZF3, IL18, IL12B, PRKCQ, PXK, and DNASE1L3. Novel variants at the following genomic coordinates were identified and have not been previously reported in association with SSc: LY96 (chr8:74922341 CT/C), PTPN22 (chr1:114381166 CT/C), IRAK1 (indels at chrX:153278833), and SAMD9L (chr7:92761606 GT/G; chr7:92764981 T/TT). Conclusions: The first immunogenetic investigation of SSc in Kazakhstan revealed a polygenic architecture involving immune signalling pathways that partially overlap with international cohorts while exhibiting region-specific variation. Although the limited sample size and lack of functional validation constrain the interpretability of the findings, the results provide a framework for larger research to confirm the pathogenic mechanisms and establish clinical relevance. Full article

The TREX-2 complex is conserved from yeast to humans and is responsible for mRNA export from the nucleus to the cytoplasm. In yeast and humans, the TPR and Nup153 nucleoporins of the nuclear pore complex are involved in TREX-2-dependent mRNA export, but data on their involvement in this process is rather controversial. In the present work, we have studied the role of TPR and Nup153 in the TREX-2-dependent export of hsp70 mRNA in Drosophila. We have shown that Nup153 and TPR are required for the TREX-2-dependent export of hsp70 mRNA, and their knockdown leads to mRNA accumulation in the cell nucleus. We have also demonstrated that Nup153 knockdown leads to TPR relocation to the nucleoplasm. Both nucleoporins are required for TREX-2 subunits’ association with the nuclear pore. Nup153 depletion leads to the TREX-2 subunits’ relocation from the nuclear pore to the nucleoplasm. The depletion of TPR leads to PCID2 relocation to the nucleoplasm and Xmas-2 retention at the nuclear pore and does not affect ENY2 redistribution. The TREX-2 subunits form several contacts with Nup153 and TPR. Hence, both nucleoporins are involved in the interaction with TREX-2 and TREX-2-dependent export in Drosophila. Full article

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by vascular abnormalities, immune dysfunction, and progressive fibrosis. One of the most common manifestations of SSc is interstitial lung disease (ILD), known by a progressive course leading to significant morbidity and mortality. Aim: to investigate autoantibodies, cytokines, and genetic markers in SSc-ILD through a systematic review and analysis of a Kazakh cohort of SSc-ILD patients. Methods: A PubMed search over the past 10 years was performed with “SSc-ILD”, “autoantibodies”, “cytokines”, and “genes”. Thirty patients with SSc were assessed for lung involvement, EScSG score, and modified Rodnan skin score. IL-6 was measured by ELISA, antinuclear factor on HEp-2 cells by indirect immunofluorescence, and specific autoantibodies by immunoblotting. Genetic analysis was performed using a 120-gene AmpliSeq panel on the Ion Proton platform. Results: The literature review identified 361 articles, 26 addressed autoantibodies, 20 genetic variants, and 12 cytokine profiles. Elevated levels of IL-6, TGF-β, IL-33, and TNF-α were linked to SSc. Based on the results of the systemic review, we created a preliminary immunogenic panel for SSc-ILD with following analysis in Kazakh patients with SSc (n = 30). Fourteen of them (46.7%) demonstrated signs of ILD and/or lung hypertension, with frequent detection of antibodies such as Scl-70, U1-snRNP, SS-A, and genetic variants in SAMD9L, REL, IRAK1, LY96, IL6R, ITGA2B, AIRE, TREX1, and CD40 genes. Conclusions: Current research confirmed the presence of the broad range of autoantibodies and variations in IRAK1, TNFAIP3, SAMD9L, REL, IRAK1, LY96, IL6R, ITGA2B, AIRE, TREX1, CD40 genes in of Kazakhstani cohort of SSc-ILD patients. Full article

RNA-binding proteins (RBPs) are critical regulators of post-transcriptional processes, playing essential roles in nutrient metabolism and metabolic homeostasis. This literature review explores how RBPs influence the metabolism of glucose, lipid, and amino acid metabolism by controlling processes like mRNA stability and translation regulation. The dysregulation of RBPs, including HuR, PTB, and YTHDF1, is linked to metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease. Advances in techniques like TREX technology and transcriptome analysis have deepened our understanding of RBP functions. Additionally, RBPs show promise as potential biomarkers and targets for new therapies. Future research directions in RBPs could focus on tissue-specific regulation and nutrient–RBP interactions. This could pave the way for more personalized treatments and improved metabolic health. Full article

Direct stochastic optical reconstruction microscopy (dSTORM) circumvents the diffraction limit of light, emerging as a powerful superresolution technique for visualizing subcellular structures with a nanoscale resolution of 10–20 nm. Yet achieving ultrastructural resolution using dSTORM alone remains challenging, despite its advantage of requiring only minimal modifications to the imaging setup and sample preparation compared to conventional fluorescence microscopy. A recent advancement that integrates expansion microscopy (ExM), which embeds specimens in a swellable polymer gel, with dSTORM holds promise for attaining imaging resolutions below 10 nm. The combined resolution, however, is governed by the expansion factor of samples, and prior studies have primarily focused on integrations involving approximately 4-fold gel expansion, as dSTORM imaging of high-fold-expanded specimens is still technically demanding. Here, we propose a pragmatic expansion strategy—post-labeling ten-fold robust expansion microscopy (plTREx)—and outline a workflow to facilitate its compatibility with dSTORM, collectively termed plTREx-dSTORM. Specifically, this workflow enhances the mechanical stability of the expansion hydrogel and improves fluorescence signal density across both widefield and dSTORM imaging platforms. Furthermore, we optimize the re-embedding protocol to integrate hydrogel expansion with dSTORM while preventing gel shrinkage. Together, plTREx-dSTORM enables highly refined imaging capable of ultrastructural interpretation of cellular proteins, effectively bridging the resolution gap between electron microscopy and optical microscopy. Full article

Precise and modular reconstruction of 3D tooth structures is crucial for creating interpretable, adaptable models for digital dental applications. To address the limitations of conventional segmentation approaches under conditions such as missing teeth, misalignment, or incomplete anatomical structures, we propose a process-oriented reconstruction pipeline composed of discrete yet integrated modules. The pipeline begins by decomposing 3D dental meshes into a series of 2D projections, allowing multi-view capture of morphological features. A fine-tuned Segment Anything Model (SAM), enhanced with task-specific bounding box prompts, performs segmentation on each view. T-Rex2, a general object detection module, enables automated prompt generation for high-throughput processing. Segmented 2D components are subsequently reassembled and mapped back onto the original 3D mesh to produce complete and anatomically faithful tooth models. This modular approach enables clear separation of tasks—view projection, segmentation, and reconstruction—enhancing flexibility and robustness. Evaluations on the MICCAI 3DTeethSeg’22 dataset show comparable or superior performance to existing methods, particularly in challenging clinical scenarios. Our method establishes a scalable, interpretable framework for 3D dental modeling, supporting downstream applications in simulation, treatment planning, and morphological analysis. Full article

This study assesses the environmental status and water quality of the Saraswati River, an ancient and endangered waterway in Bengal, using an integrated approach. By combining traditional knowledge, advanced geospatial tools, and field analysis, it examines natural and human-induced factors driving the river’s degradation and proposes sustainable restoration strategies. Tools such as the Garmin Global Positioning System (GPS) eTrex10, Google Earth Pro, Landsat imagery, ArcGIS 10.8, and Google Earth Engine (GEE) were used to map the river’s trajectory and estimate its water quality. Remote sensing-derived indices, including the Normalized Difference Water Index (NDWI), Modified Normalized Difference Water Index (MNDWI), Normalized Difference Salinity Index (NDSI), Normalized Difference Turbidity Index (NDTI), Floating Algae Index (FAI), and Normalized Difference Chlorophyll Index (NDCI), Total Dissolved Solids (TDS), were computed to evaluate parameters such as the salinity, turbidity, chlorophyll content, and water extent. Additionally, field data from 27 sampling locations were analyzed for 11 critical water quality parameters, such as the pH, Total Dissolved Solids (TDS), Electrical Conductivity (EC), Dissolved Oxygen (DO), Biochemical Oxygen Demand (BOD), and microbial content, using an arithmetic weighted water quality index (WQI). The results highlight significant spatial variation in water quality, with WQI values ranging from 86.427 at Jatrasudhi (indicating relatively better conditions) to 358.918 at Gobra Station Road (signaling severe contamination). The pollution is primarily driven by urban solid waste, industrial effluents, agricultural runoff, and untreated sewage. A microbial analysis revealed the presence of harmful species, including Escherichia coli (E. coli), Bacillus, and Entamoeba, with elevated concentrations in regions like Bajra, Chinsurah, and Chandannagar. The study detected heavy metals, fertilizers, and pesticides, highlighting significant anthropogenic impacts. The recommended mitigation measures include debris removal, silt extraction, riverbank stabilization, modern hydraulic structures, improved waste management, systematic removal of water hyacinth and decomposed materials, and spoil bank design in spilling zones to restore the river’s natural flow. Full article

High-grade B-cell lymphoma (HGBL), not otherwise specified (NOS), is a rare entity within the spectrum of B-cell lymphomas. HGBL, NOS remains a diagnosis of exclusion with limited data available on the optimal clinical approach. We report a case of a 67-year-old man with HGBL, NOS with a germinal center B-cell (GCB) immunophenotype. The disease was characterized by an aggressive clinical course, refractory to multiple lines of cytotoxic chemotherapy, immunotargeted treatment, therapy with a PD-1 inhibitor, and haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Ultimately, the disease progression led to the patient’s death nine months post-diagnosis. A FISH assay identified a sole genetic rearrangement: BCL2/IGH. Whole-exome sequencing revealed a number of significant somatic mutations, such as TP53 p.C238G, B2M p.L12R, STAT6 p.D419G, STAT3 p.S614R, TREX1 p.T49fs, and CREBBP p.C367Ter, as well as a high focal amplification of the MUC3A gene and the deletion of the short arm of chromosome 17 (del(17p)). An inactivating somatic mutation in the TREX1 gene (p.T49fs) has not been previously described in patients with non-Hodgkin lymphomas. Additionally, our analysis uncovered a key cancer hallmark: tumor genomic instability, manifested as a high tumor mutational burden, which likely contributed to the aggressive disease course. Full article