Search Results (94)

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

MET exon 14 (METex14) skipping mutations differ from other non-small cell lung cancer (NSCLC) genomic biomarkers as they result in aberrantly spliced MET transcripts and increased MET-signaling. However, the most accurate method for their detection remains debated. We conducted a retrospective study of previously identified METex14 skipping NSCLC samples by using different, commercially available, diagnostic targeted DNA- /RNA-Next-Generation Sequencing (NGS) panels. We primarily used small DNA-NGS panels covering the 5′ splice site of METex14 and supplemented by targeted RNA sequencing for selected cases. Using this approach, we identified <0.2% patients with METex14 mutations. Due to this low frequency, we validated and introduced complementary NGS testing using combined DNA/RNA-panels. This resulted in an increased number of METex14-positive patients (3.5%) and allowed us to identify METex14 skipping transcripts. Collectively, data from our cohort (n = 34) demonstrated that optimal diagnostics of METex14 variants require a complementary DNA-NGS performed with targeted panels covering both METex14 splice sites, and RNA-NGS. Consequently, we propose a new workflow for interpretation of concordant and discordant findings in METex14 detection. Finally, the potential of DNA-identified METex14 variants to cause aberrant splicing was in silico assessed by the MaxEntScan tool, providing a quantitative approach to splicing disruption. Interestingly, we also identified two novel variants located inside METex14, which also produced the METex14 skipping transcript despite being located outside the canonical splice sites. The altered binding site resulting from these exonic mutations was in silico determined by SpliceTransformer. Full article

To meet the requirements of high resolution, compact size, and ultra-lightweight for micro–nano satellite optoelectronic payloads while ensuring high structural stability during launch and in-orbit operation, mirrors were designed with high surface accuracy. The opto-thermo-mechanical system of the space camera was designed and analyzed accordingly. First, an optical system was designed to achieve high resolution and a compact form factor. A coaxial triple-reflector configuration with multiple refractive paths was adopted, which significantly shortened the optical path and laid the foundation for a lightweight, compact structure. This design also defined the accuracy and tolerance requirements for the primary and secondary mirrors. Subsequently, mathematical models for topology optimization and dimensional optimization were established to optimize the design of the main support structure, primary mirror, and secondary mirror. Two design schemes for the main support structure and primary mirror were compared. Steady-state thermal analysis and thermal control design were carried out for both mirrors. Simulations were then performed on the main system (including the primary/secondary mirror assemblies and the main support structure). Under the combined effects of gravity, a 4 °C temperature increase, and an assembly flatness deviation of 0.01 mm, the surface accuracy of both mirrors, the displacement of the secondary mirror relative to the primary mirror reference, and the tilt angle all met the overall specification requirements. The system’s first-order natural frequency was 156.731 Hz. After precision machining, fabrication, and assembly, wavefront aberration testing was conducted on the main system with the optical axis horizontal. Under gravity, the root mean square (RMS) wavefront error at the center of the field of view was 0.073λ, satisfying the specification of ≤1/14λ. The fundamental frequency measured during vibration testing was 153.09 Hz, which aligned closely with the simulated value and well exceeded the requirement of 100 Hz. Additionally, in-orbit imaging verification was conducted. All results satisfied the technical specifications of the satellite’s overall requirements. Full article

Rosacea is a chronic inflammatory skin disorder of multifactorial pathogenesis, in which dysregulated innate immunity, neurovascular dysfunction, oxidative stress, and microbiome imbalance are central contributors. Recent molecular studies have revealed altered cytokine expression (e.g., IL-1β, IL-6, IL-36 family), aberrant activation of signaling pathways (STAT3, NF-κB, MAPKs), and enhanced expression of innate immune receptors such as TLR2,b TLR4, and TLR7, all of which promote chronic inflammation, angiogenesis, and barrier dysfunction. This systematic review was performed according to PRISMA guidelines. A total of 1425 records were retrieved from PubMed, Scopus, and Web of Science, and 14 studies met the inclusion criteria. The included studies comprised both clinical cohorts and translational experimental investigations using human samples. Reported findings consistently confirmed systemic and tissue-specific inflammatory activity, with elevated circulating monocytes, indoleamine 2,3-dioxygenase, and inflammatory indices, as well as tissue expression of STAT3, NF-κB, MAPKs, and cathelicidin fragments. Oxidative stress markers (TOS, OSI, AOPP, MMP-9) and hypoxia-related molecules (HIF-1α) were significantly increased in patients, correlating with disease severity and vascular manifestations. Taken together, these results highlight that rosacea involves both cutaneous and systemic molecular alterations. The evidence identifies multiple biomarkers with diagnostic potential and provides mechanistic insights into immune, vascular, and metabolic dysregulation. Future research should aim to validate these findings in larger cohorts, establish standardized biomarker panels, and explore novel therapeutic strategies targeting key molecular pathways. Full article

Background/Objectives: Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by uncontrolled accumulation of B lymphocytes. A key feature of CLL is the presence of genetic aberrations, particularly alterations of chromosome 17, such as deletion of 17q and/or mutations in the TP53 gene. Since these abnormalities are highly relevant for therapeutic decision-making, assessment of TP53 mutational status is strongly recommended in routine diagnostics. This study aimed to evaluate the reliability of TP53 sequencing results depending on the type of DNA sample analyzed. Methods: DNA was isolated from two different sample types of the same patient: mononuclear cells (CLL1) and purified CD19+ cells (CLL2). The entire coding region of TP53 (exons 2–11), including splice sites (+/− 10 bp), was analyzed using capture-based next-generation sequencing (NGS). Reads were aligned to the GRCh37/hg19 reference genome, and variants were interpreted using DRAGEN Enrichment (Illumina) and Franklin (QIAGEN). Results: In sample CLL1, the NM_000546.6:c.626_627del mutation (Tier I) was identified with a variant allele frequency (VAF) of 57.06%. The same mutation was confirmed in CLL2, but with a higher VAF of 94.78%. Importantly, an additional Tier I mutation (NM_000546.6:c.825_826del) was detected exclusively in CLL2 at a VAF of 1.59%. Both findings met the required sequencing depth as well as coverage per sample, confirming their validity. Conclusions: The study demonstrates that inadequate starting material for DNA isolation may mask low-frequency TP53 mutations, resulting in false-negative results. Accurate detection requires ensuring sufficient CD19+ cell content, which is critical for reliable diagnostics and supports personalized treatment approaches in CLL. Full article

Inflammatory bowel diseases (IBDs) encompass Crohn’s disease and ulcerative colitis. They represent idiopathic and chronic inflammatory conditions. Mucosal immune dysfunction and compromised gastrointestinal barrier integrity are implicated in the pathophysiological mechanisms of inflammatory bowel diseases. Recent studies have identified endothelial dysfunction as a pivotal mediator in IBD pathogenesis. Through multiple cellular and molecular interactions, endothelial dysfunction orchestrates inflammatory responses. Objectives: This systematic review examines contemporary evidence (2019–2025), emphasising the role of endothelial dysfunction in intestinal inflammation mechanisms, focusing on vascular-epithelial crosstalk, molecular signalling pathways, and therapeutic implications. Methods and results: A comprehensive literature search was conducted using PubMed, Google Scholar, Europe PMC and DOAJ databases, focusing on peer-reviewed articles published between 2019 and 2025. Following the database search and screening process, a total of 53 studies met the eligible criteria and were included in the final analysis. Keywords included “endothelial dysfunction,” “inflammatory bowel disease,” “gut-vascular barrier,” “nitric oxide,” and “intestinal inflammation.” Contemporary research demonstrates that endothelial dysfunction in IBD manifests through decreased nitric oxide bioavailability, enhanced oxidative stress, aberrant cytokine networks, pathological angiogenesis, and compromised gut-vascular barrier integrity. The emerging concept of dual barrier dysfunction highlights the interdependent relationship between epithelial and endothelial barriers in maintaining intestinal homeostasis. Conclusions: Offering novel therapeutic targets for precision medicine approaches, endothelial dysfunction represents a central driver in the pathophysiological mechanism in IBD. Understanding vascular-epithelial interactions provides fundamental insights for developing targeted interventions to restore intestinal barrier function and resolve chronic inflammation. Full article

Autoimmune diseases (AIDs) are chronic, heterogeneous conditions developing from an aberrant immune response, impacting particular organs or multiple systems. This systematic review attempted to investigate and evaluate the correlation between autoimmune diseases and cardiovascular disease (CVD), emphasizing immunological and pathophysiological mechanisms. A comprehensive search for relevant research was conducted on the PubMed, SCOPUS, and ScienceDirect databases, resulting in the identification of 28 studies that met the inclusion criteria. Of the cohort studies, 26 (92.8%) demonstrated a significant association between autoimmune diseases and increased cardiovascular risk. The major mechanisms include chronic inflammation, endothelial dysfunction, oxidative stress, and immune cell dysregulation. Essential biological components, including T cells, B cells, and neutrophils, were identified as contributors to atherosclerotic processes through cytokine secretion, expression of adhesion molecules, and thrombogenic activity. In contrast, two studies (7.1%) found no statistically significant association. In conclusion, autoimmune diseases significantly increase cardiovascular risk through complicated immunological mechanisms. Comprehending these pathways could influence future therapeutic approaches to reduce cardiovascular complications in affected patients. Full article

Background: We reviewed outcomes of short and long-term chemotherapy with or without breaks in pancreatic ductal adenocarcinoma (PDAC) patients. Methods: PDAC patients receiving ≥3 chemotherapy cycles between 2019 and 2024 at three institutions were included. Progression-free survival after first-line chemotherapy (PFS1), overall survival (OS) and best overall response (BOR) to chemotherapy were assessed using the Wilcoxon test, Kaplan–Meier test, and univariate and multivariate Cox regression models. Results: We screened 237 patients, and 135 patients met the study criteria. Among these patients, 25 had resectable disease, and 110 had unresectable/metastatic disease (13% borderline resectable (BRPC), 20% locally advanced (LAPC), 10% localised developing metastases, 57% de novo metastatic). Ten patients (7%) underwent genetic profiling; KRAS aberrations (N = 4), actionable PLAB2/BRCA2/FGFR2 mutations (N = 3), ATM/BRIP1 alteration (N = 1). Two patients were managed with PARP inhibitors after receiving multiple lines of chemotherapy. Median PFS1 and OS were concordant with the published literature, but select patient groups achieved prolonged survival outcomes. Among the 36 BRPC/LAPC patients, we observed >1-year PFS1 in 9 (25%) patients and >2-year OS in 3 (8%) patients. Among the 63 de novo metastatic patients, we observed >1-year PFS1 and >2-year OS in 6 (10%) patients. Among patients with localised disease, smoking history was a poor prognostic factor with respect to OS (p = 0.03). Improved PFS1 and OS was associated with ≥6 cycles of first-line chemotherapy, its duration of ≥3.66 months, and local treatment after first chemotherapy (p < 0.05 for all). Stereotactic body radiotherapy following first-line chemotherapy was delivered in N = 6 (27%) and N = 1 (7%) of patients with LAPC and BRPC, respectively. Chemotherapy interruption duration, but not number, was associated with PFS1 and OS only in the localised cohort (p < 0.05). In patients with de novo metastatic disease, prevalence of type 2 diabetes was adversely associated with OS (p = 0.03). Improved PFS and OS was associated with ≥6 cycles of first-line chemotherapy, its duration of ≥4.37 months, and BOR to it (only in this cohort) (p < 0.05 for all). A favourable OS was associated with >1 line of chemotherapy (p = 0.003). Conclusion: Despite challenges, extended chemotherapy and multiple treatment lines may improve survival, with localised treatments benefiting select patients. Full article

The trematode Fascioloides magna is originally a parasite of North American deer species. Upon its arrival to Europe, F. magna met new intermediate and final hosts. Depending on the type of host, the clinical picture, pathological findings, epidemiology and outcome can vary significantly. As an aberrant host, it was long believed that the roe deer (Capreolus capreolus) fails to develop pseudocysts, and therefore the infected animal dies before the parasite can mature and start to produce eggs. In this study, 676 roe deer livers were collected in Croatia during the hunting years of four consecutive years (2019–2023) in Bjelovar-Bilogora County (BB), and 184 livers were collected from Zagreb County (ZG) in the hunting year 2022/2023. Livers were analysed macroscopically and on a cut surface for lesions and any developmental stage of F. magna according to a standard protocol. The mean prevalence of infected livers during the whole study period was 12.86% in BB and 3.8% in ZG. No pseudocysts were detected in samples from ZG, while there was an increasing trend of pseudocyst presence over time in BB. The occurrence of pseudocysts in infected livers showed a rapid increase after the hunting season 2019/2020, before becoming constant (at approx. 40%). The odds of finding pseudocysts ranged between 2.7 (OR = 2.7317, CI 95% 0.3108 to 24.0095, p = 0.365) and 2.9 (OR = 2.9167, CI 95% 0.3163 to 26.8924, p = 0.345) times higher in later years compared to 2019/2020. Similarly, an increasing trend (though less pronounced) was observed in the numbers of livers simultaneously containing pseudocysts and fluke migratory stages. The results indicate a potential change in the roe deer–F. magna association, where an increasing number of roe deer are forming pseudocysts and can survive even multiple infections. Full article

Background: Recent research has increasingly highlighted alterations in the proto-oncogene MET, whose abnormal activation has been implicated in multiple cancers. MET encodes c-MET, a receptor tyrosine kinase critical for cellular growth, survival, and migration. Aberrant c-MET signaling, driven by mutations or gene amplification, promotes proliferation and invasion, contributing to tumorigenesis. Scope of the Review: While MET mutations are most often observed in non-small cell lung cancer (NSCLC), they also occur in other malignancies, including breast and gastric cancers. This review highlights key MET alterations, such as gene amplification, gene fusions, and exon 14 skipping deletions, and examines their prevalence across various tumor types. Major Conclusions: We discuss the clinical significance of c-MET as a therapeutic target and identify gaps in knowledge that could inform the development of alternative treatment strategies. Full article

The hepatocyte growth factor receptor (MET) is a receptor tyrosine kinase (RTK) that mediates the activity of a variety of downstream pathways upon its activation. These pathways regulate various physiological processes within the cell, including growth, survival, proliferation, and motility. Under normal physiological conditions, this allows MET to regulate various development and regenerative processes; however, mutations resulting in aberrant MET activity and the consequent dysregulation of downstream signaling can contribute to cellular pathophysiology. Mutations within MET have been identified in a variety of cancers and have been shown to mediate tumorigenesis by increasing RTK activity and downstream signaling. In lung cancer specifically, a number of patients have been identified as possessing MET alterations, commonly receptor amplification (METamp) or splice site mutations resulting in loss of exon 14 (METex14). Due to MET’s role in mediating oncogenesis, it has become an attractive clinical target and has led to the development of various targeted therapies, including MET tyrosine kinase inhibitors (TKIs). Unfortunately, these TKIs have demonstrated limited clinical efficacy, as patients often present with either primary or acquired resistance to these therapies. Mechanisms of resistance vary but often occur through off-target or bypass mechanisms that render downstream signaling pathways insensitive to MET inhibition. This review provides an overview of the therapeutic landscape for MET-positive cancers and explores the various mechanisms that contribute to therapeutic resistance in these cases. Full article

Although rare, Merkel cell carcinoma (MCC) is a highly aggressive and increasingly prevalent neuroendocrine cancer of the skin. While current interventions, including surgical resection, radiation, and immunotherapy have been employed in treating many patients, those who remain unresponsive to treatment are met with sparse alternatives and a grim prognosis. For this reason, it is of interest to expand the repertoire of available therapies for MCC patients who remain resistant to current primary interventions. Recently, our improved mechanistic understanding of aberrant cell signaling observed in both MCPyV-positive and -negative MCC has facilitated exploration into several small molecules and inhibitors, among them receptor tyrosine kinase inhibitors (TKIs) and somatostatin analogs (SSAs), both of which have positively improved response rates and reduced tumor volumes upon application to treatment of MCC. The introduction of such targeted therapies into treatment protocols holds promise for more personalized care tailored towards patients of diverse subtypes, thereby improving outcomes and mitigating tumor burden, especially for treatment-resistant individuals. In this review, we characterize recent findings surrounding targeted treatments that have been applied to MCC and provide an overview of emerging perspectives on translatable options that can be further developed to offer additional therapeutic avenues for patients with the disease. Full article

Patients affected by familial hypercholesterolemia possess elevated low-density lipoprotein cholesterol and therefore have greater risk for cardiovascular disease. About 90% of familial hypercholesterolemia cases are associated with aberrant LDLR. Over 3500 LDLR variants have been identified, 15% of which are considered “pathogenic.” Given the genetic diversity of LDLR variants, specific variants rarely receive attention. However, investigators have proposed the critical evaluation of individual variants as a method to clarify knowledge and to resolve discrepancies in the literature. This article reviews p.(Val429Met) (rs28942078) in the areas of pathology, epidemiology, lipid-lowering therapy, and genetic testing. The p.(Val429Met) variant is associated with a missense point substitution in exon 9 of chromosome 19. Biochemical studies have found severely reduced low-density lipoprotein receptor protein in autologous and heterologous expression systems. Additionally, there are inconsistencies regarding the functional classification of p.(Val429Met). Considered to be of European origin, p.(Val429Met) is found in extant populations due to founder effects. Evidence from clinical trials have also demonstrated variable responses to newer lipid-lowering therapies in patients with a p.(Val429Met) variant. Proper clinical detection and adequate genetic testing have been shown to greatly improve outcomes. Future research may be aimed at resolving discrepancies to better comprehend the implications of familial hypercholesterolemia. Full article

Targeting the dynamic image-motion problem of aerial cameras in the process of swing imaging, the image-motion compensation technology of aerial cameras based on the multi-dimensional motion of the secondary mirror was adopted. The secondary mirror was used as the image-motion compensation element, and the comprehensive image-motion compensation of the aerial camera was realized through the multi-dimensional motion of the secondary mirror. However, in the process of compensating for the image motion, the secondary mirror would be eccentric and inclined, which would cause the secondary mirror to be off-axis and affect the image quality. Therefore, a misalignment optical system model was established to study the relationship between the deviation vector and the misalignment of the secondary mirror, and the influence of the secondary mirror’s motion on the distribution of the aberration was analyzed. In order to verify the image-motion compensation ability of the multi-dimensional motion of the secondary mirror, an experimental platform was built to conduct a laboratory imaging experiment and flight experiment on the aerial camera. The experimental results showed that the dynamic resolution of the aerial camera using the image-motion compensation technology could reach 74 lp/mm, and the image-motion compensation accuracy was better than 0.5 pixels, which met the design expectation. In conclusion, the image-motion compensation technology is expected to be applied to various high-precision optical imaging as well as optical detection systems. Full article

Coronary arteries have a wide range of anatomical variability, and their spectrum ranges from asymptomatic cases to those predisposed to hemodynamic compromise or even sudden cardiac death. This paper aims to review the classification of coronary artery anomalies (CAAs) and illustrate their imaging characteristics by highlighting the important role of CT coronary angiography. Some of the coronary anomalies usually met in current practice are the high origin coronary artery, multiple ostia, aberrant origin from the opposite/non-coronary Valsalva sinus, single coronary artery, ALCAPA syndrome, duplications of the left anterior descending artery, coronary fistulas, and extracardiac terminations. CT coronary angiography is a non-invasive diagnostic modality for CAAs. The complex anatomy of these anomalies can be accurately described by employing 3D reconstructions and post-processing techniques. Knowledge of the imaging characteristics and potential functional impact of these anomalies is essential for accurate diagnosis and therapeutic planning of patients. Full article