Search Results (254)

Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive subtype of cervical adenocarcinoma. Despite its clinical significance, its molecular carcinogenesis and therapeutic targets remain poorly understood. This study aimed to compare the clinicopathological, immunohistochemical, and molecular profiles of GCA and usual-type cervical adenocarcinoma (UCA), exploring prognostic and therapeutic biomarkers in a Japanese population. A total of 110 cervical adenocarcinoma cases, including 16 GCA and 94 UCA cases, were retrospectively analyzed for clinicopathological features, and a panel of immunohistochemical markers was assessed. Sanger sequences were performed for the KRAS, PIK3CA, and BRAF genes, and survival and clinicopathological correlations were assessed using Kaplan–Meier and Cox regression analyses. GCA was significantly associated with more aggressive features than UCA, including lymph node involvement, advanced FIGO stages, increasing recurrence rate, and poor survival status. High ARID1B expression was observed in a subset of GCA cases and correlated with worse progression-free and overall survival. Additionally, PD-L1 expression was more frequent in GCA than UCA and was associated with unfavorable prognostic factors. Conversely, UCA cases showed strong p16 expression, supporting their HPV-driven pathogenesis. Molecular profiling revealed KRAS and PIK3CA mutations in both subtypes, while BRAF mutations were identified exclusively in GCA. These findings reveal distinct clinical and molecular profiles for both tumor types and underscore ARID1B and PD-L1 as predictive prognostic and therapeutic biomarkers in GCA, implicating the use of subtype-specific treatment strategies. 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

Treatment of Mycobacterium tuberculosis requires multi-drug regimens, and resistance to any individual antibiotic can compromise outcomes. For slow-growing organisms like M. tuberculosis, rapid detection of resistance-conferring mutations enables timely initiation of effective therapy. Conversely, confirming wild-type status in resistance-associated genes supports confidence in standard regimens. We developed an amplicon-based next generation sequencing (amplicon tNGS) assay on the Illumina platform targeting eight genes linked to resistance to isoniazid, rifampin, ethambutol, pyrazinamide, and fluoroquinolones. Sequencing results were analyzed using a custom bioinformatics pipeline. Forty-seven samples were used for assay development, and 37 additional samples underwent post-implementation clinical validation. Compared to whole genome sequencing (WGS), amplicon tNGS demonstrated 97.7% sensitivity, 98.9% specificity, and 98.7% overall accuracy for variant detection in targeted regions. Resistance prediction showed 79.3% concordance with WGS; discrepancies were primarily due to mutations outside of target regions. Among post-implementation samples, 27/37 passed quality metrics for all targets, with 95.7% concordance between amplicon tNGS results and final susceptibility results. This assay is now in use in our laboratory and offers significantly faster turnaround than both WGS and phenotypic methods on cultured isolates, enabling more rapid, informed treatment decisions for tuberculosis patients. Full article

Lavender species hold substantial economic importance due to their widespread cultivation for essential oils (EOs). Lavender EOs contain terpenes essential for industries such as cosmetics, personal care, and pharmaceuticals. In the biosynthetic pathway of EOs, Lavandula angustifolia bornyl diphosphate synthase (LaBPPS) catalyzes the conversion of geranyl diphosphate (GPP) to bornyl diphosphate (BPP). However, the functional mechanisms of LaBPPS remain poorly understood. Here, we conducted mutational experiments based on the molecular docking results, and found that mutations at positions D356A, D360A, R497A, D501A, or E508A led to a 50- to 100-fold reduction in the activity. Deletion of region 1–58 (∆1–58) did not affect activity compared to the wild-type (WT) protein, while deletions of regions 1–74 or 59–74 (∆1–74 or ∆59–74) significantly decreased the activity. Conversely, deletion of residues 578–602 (∆578–602) dramatically increased the activity. The LaBPPS gene showed dramatically higher expression levels in flowers compared to other tissues (stems, leaves and roots), peaking at 8:00. Our results provide valuable insights into EO biosynthesis in lavender and suggest potential strategies for genetic engineering aimed at improving EO quality. Full article

Background: The global rise of multidrug-resistant Gram-negative bacteria, particularly non-fermenting species and carbapenemase-producing Enterobacteriaceae, poses a significant challenge to hospital infection control. Methods: In this study, a total of 89 Acinetobacter spp. isolates, 14 Pseudomonas aeruginosa, and 14 carbapenem-resistant Enterobacteriaceae isolates were collected from patients in a tertiary hospital. Whole-genome sequencing and antimicrobial susceptibility testing were conducted. Resistance mechanisms and evolutionary relationships were analyzed using phylogenetic analysis and genetic context mapping. Results: Among the non-fermenting isolates, A. baumannii exhibited high resistance to carbapenems, clustering into distinct clonal groups enriched with genes associated with biofilm formation and virulence genes. P. aeruginosa isolates harbored fewer resistance genes but carried notable mutations in the efflux pump systems and the oprD gene. In Enterobacteriaceae, four bla_NDM alleles were identified within a conservative structural sequence, while bla_KPC-2 was located in a non-Tn4401 structure flanked by IS481- and IS1182-like insertion sequences. Phylogenetic analysis revealed that bla_NDM-positive E. coli strains were closely related to susceptible lineages, indicating horizontal gene transfer. Conversely, K. pneumoniae isolates harboring bla_KPC-2 formed a tight clonal cluster, suggesting clonal expansion. Conclusions: The study reveals distinct transmission patterns between resistance genes: horizontal dissemination of bla_NDM and clonal expansion of bla_KPC-2 in K. pneumoniae. These findings emphasize the need for resistance-gene-specific genomic surveillance and infection control strategies to prevent further nosocomial dissemination. Full article

Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder affecting a large number of individuals in Europe. The disease arises from mutations in the CFTR gene encoding the cystic fibrosis transmembrane conductance regulator, a chloride ion channel crucial for maintaining epithelial ion and fluid homeostasis. Dysfunctional CFTR disrupts mucociliary clearance, particularly in the respiratory tract, resulting in persistent bacterial colonization, chronic inflammation, and progressive pulmonary damage—ultimately leading to respiratory failure, the principal cause of mortality in CF patients. Early diagnosis and advances in therapy have substantially improved both survival and quality of life. A hallmark of CF pathology is the establishment of polymicrobial infections within the thickened airway mucus. Pseudomonas aeruginosa is the dominant pathogen in chronic CF lung infections and demonstrates a remarkable capacity for adaptation via biofilm formation, metabolic reprogramming, and immune evasion. Biofilms confer increased tolerance to antimicrobial agents and facilitate long-term persistence in hypoxic, nutrient-limited microenvironments. P. aeruginosa exhibits a wide range of virulence factors, including exotoxins (e.g., ExoU, ExoS), pigments (pyoverdine, pyochelin), and motility structures (flagella and pili), which contribute to tissue invasion, immune modulation, and host damage. During chronic colonization, P. aeruginosa undergoes significant genotypic and phenotypic changes, such as mucoid conversion, downregulation of acute virulence pathways, and emergence of hypermutator phenotypes that facilitate rapid adaptation. Persistent cells, a specialized subpopulation characterized by metabolic dormancy and antibiotic tolerance, further complicate eradication efforts. The dynamic interplay between host environment and microbial evolution underlies the heterogeneity of CF lung infections and presents significant challenges for treatment. Elucidating the molecular mechanisms driving persistence, hypermutability, and biofilm resilience is critical for the development of effective therapeutic strategies targeting chronic P. aeruginosa infections in CF. Full article

Anti-infectives include molecules that target microbes in the context of infection but lack antimicrobial activity under conventional growth conditions. We previously described D66, a small molecule that kills the Gram-negative pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) within cultured macrophages and murine tissues, with low host toxicity. While D66 fails to inhibit bacterial growth in standard media, the compound is bacteriostatic and disrupts the cell membrane voltage gradient without lysis under growth conditions that permeabilize the outer membrane or reduce efflux pump activity. To gain insights into specific bacterial targets of D66, we pursued two genetic approaches. Selection for resistance to D66 revealed spontaneous point mutations that mapped within the gmhB gene, which encodes a protein involved in the biosynthesis of the lipopolysaccharide core molecule. E. coli and S. Typhimurium gmhB mutants exhibited increased resistance to antibiotics, indicating a more robust barrier to entry. Conversely, S. Typhimurium transposon insertions in genes involved in outer membrane permeability or efflux pump activity reduced fitness in the presence of D66. Together, these observations underscore the significance of the bacterial cell envelope in safeguarding Gram-negative bacteria from small molecules. Full article

DNA-deaminase AID plays a pivotal role in adaptive immunity, antibody diversification and epigenetic regulation. AID catalyzes cytidine deamination in immunoglobulin genes, facilitating somatic hypermutation (SHM), class-switch recombination (CSR) and gene conversion (GC). However, the dysregulation of AID activity can lead to oncogenic mutations and immune disorders such as hyper-IgM syndrome type 2 (HIGM2). At present the number of studies investigating the role of AID polymorphic variants in the promotion of pathology is low. The current review examines the structural and functional aspects of AID, focusing on the impact of amino acid substitutions—both natural polymorphisms and artificial mutations—on its catalytic activity, substrate binding and interactions with regulatory proteins. Additionally, a bioinformatic analysis of single-nucleotide polymorphisms of AID deposited in the dbSNP database was performed. SNPs leading to amino acid substitutions in the primary protein structure were analyzed. The bioinformatic analysis of SNPs in the AID gene predicts that among 208 SNPs causing amino acid substitutions in the primary protein structure, 62 substitutions may have significant negative impact on the functioning of AID. The integration of computational predictions with experimental data underscores the importance of AID regulation in maintaining immune homeostasis and highlights potential markers for immune-related pathologies. This comprehensive analysis provides insights into the molecular mechanisms of AID dysfunction and its implications for disease. Full article

Acute PM2.5 exposure has been implicated in lung cancer progression, yet its impact on genetically distinct NSCLC cells remains underexplored. This study investigates how mutation-specific transcriptional responses influence susceptibility to PM2.5-induced oncogenic alterations, focusing on A549 and NCI-H1975 cells. This provides preliminary insight into the transcriptomic effects of acute PM2.5 exposure in NSCLC cells with distinct oncogenic mutations (A549 and NCI-H1975), serving as a guide for understanding mutation-specific responses to environmental stress. Cells were exposed to PM2.5 (200 µg/mL, 24 h), followed by RNA sequencing and analysis. Gene ontology and pathway enrichment analyses were conducted to identify key molecular alterations associated with tumour progression. NCI-H1975 cells exhibited a stronger transcriptional response, with a higher fold change in differentially expressed genes (DEGs), indicating greater PM2.5 susceptibility. Upregulated genes were linked to oxidative stress, carcinogen activation, metabolic reprogramming, and therapy resistance, reinforcing tumour survival under PM2.5 stress. Conversely, the downregulation of tumour suppressor genes suggests immune suppression and potential immunotherapy resistance. This study reveals that acute PM2.5 exposure induces mutation-specific transcriptomic alterations in NSCLC, with EGFR-mutant cells exhibiting heightened oxidative stress, metabolic shifts, and immune evasion. The upregulation of key genes highlights the profound molecular impact of short-term exposure, paving the way for future studies on pollution-driven oncogenic mechanisms and resistance pathways. Full article

R2 retrotransposons reside exclusively within the 28S regions of 10–20% of all rDNA genes comprising the nucleolar organizer loci on the X and Y chromosomes of Drosophila melanogaster. These R2-inserted genes are normally silent and heterochromatic. When expressed, however, the R2 transcript is co-transcribed with the 28S rRNA. Self-cleavage releases a 3.6 kb mature R2 transcript that encodes a single protein with endonuclease and reverse transcriptase activities that facilitate R2 element transposition by target-primed reverse transcription. While we know the molecular details of R2 transposition, we know little about the genetic mechanisms that initiate R2 transcription. Here, we examine R2 expression in wild type versus mutant backgrounds. R2 expression in stage 1–4 wild type egg chambers was variable depending on the stock. R2 expression was silent in wild type stages 5–10 but was consistently active during nurse cell nuclear breakdown in stages 12–13 regardless of the genetic background. Massive R2 expression occurred in stages 5–10 upon loss of Udd, an RNA Pol I transcription factor. Similarly, loss of Nopp140, an early ribosome assembly factor, induced R2 expression more so in somatic tissues. Interestingly, over-expression of the Nopp140-RGG isoform but not the Nopp140-True isoform induced R2 expression in larval somatic tissues, suggesting Nopp140-RGG could potentially affect rDNA chromatin structure. Conversely, Minute mutations in genes encoding ribosomal proteins had minor positive effects on R2 expression. We conclude that R2 expression is largely controlled by factors regulating RNA Pol I transcription and early ribosome assembly. Full article

Bacterial tolerance, especially in Staphylococcus aureus (S. aureus), may arise under intermittent antibiotic regimens and act as a stepping stone toward resistance development. However, the transition from tolerance to resistance and its contributing factors remain poorly understood. This study explores the role of the efflux pump gene abcA in this process. abcA mutants (overexpression, knockout, and complementation) were constructed via homologous recombination. These strains were subjected to 21 cycles of intermittent exposure to oxacillin at 20× MIC, and the resistance evolution was monitored. Spontaneous mutation frequencies and survival abilities in these mutants were also measured to determine their involvement in resistance development. The abcA overexpression mutant exhibited a faster development of resistance compared to the wildtype strain. Conversely, the abcA knockout mutant maintained susceptibility to oxacillin, with no significant changes in the relative MIC. Increased mutation frequency and enhanced survival were observed in the overexpression strain, whereas both were reduced in the knockout. abcA overexpression significantly accelerated the development of oxacillin resistance in S. aureus by promoting spontaneous mutations and bacterial survival. Disrupting abcA may offer a novel strategy to prevent the evolution of antibiotic resistance. Full article

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe, multisystemic, autosomal dominant disease with variable penetrance caused by mutations in the TTR gene generating protein misfolding and accumulation of amyloid fibrils. The diagnosis is usually challenging because ATTRv may initially manifest with nonspecific multisystemic symptoms. Conversely, an early diagnosis is needed to start timely appropriate therapy. Hence, screening models have been proposed to improve ATTRv diagnosis. In this study, we propose a genetic screening model based on predefined “red flags” followed by “cascading screening” on first-degree relatives of patients who tested positive. Materials and methods: After obtaining written informed consent, genetic testing on salivary swabs was performed in individuals who met at least two major red flags for ATTRv (age > 65 years old, progressive sensory or sensorimotor neuropathy not responsive to steroids or immunomodulant therapies, recent and unexplained weight loss associated with gastrointestinal signs and symptoms, diagnosis of cardiac amyloidosis, bilateral or relapsing carpal tunnel syndrome, unexplained autonomic dysfunction) or one major flag and two minor flags (family history of neuropathy, ambulation disorders or cardiopathy, sudden cardiac death, a bedridden, wheelchaired patient without specific diagnosis excluding upper motor neuron diseases, infections, juvenile cardiac disease, ocular disorders, lumbar spine stenosis, biceps tendon rupture). Results: In the first screening phase, 29 suspected cases (individuals meeting at least two major red flags or one major red flag and two minor red flags) underwent genetic testing. One patient (3.5%) was diagnosed with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), carrying the Phe64Leu mutation. Then, cascade screening allowed for early recognition of two additional individuals (two pre-symptomatic carriers) among two first-degree relatives (100%). The identified patient was a 72-year-old man who had a family history of both cardiopathy, neuropathy, and a diagnosis of juvenile cardiac disease and progressive sensorimotor neuropathy unresponsive to steroids or immunomodulant therapies. Conclusions: ATTRv is a progressive and often fatal disease that should be promptly diagnosed and treated to stop progression and reduce mortality. Systematic screening for ATTRv yielded increased recognition of the disease in our neurological clinic. A focused approach for the screening of ATTRv-PN could lead to an earlier diagnosis and identification of asymptomatic carriers, enabling timely intervention through close clinical monitoring and early treatment initiation at symptom onset. Full article

Background/Objectives: Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before the age of 50, has been increasing in incidence, particularly among Hispanic/Latino (H/L) populations. Despite this trend, the underlying molecular mechanisms driving EOCRC disparities remain poorly understood. The MAPK and JAK/STAT pathways play critical roles in tumor progression, proliferation, and treatment response; however, their involvement in ethnicity-specific differences in EOCRC remains unclear. This study aims to characterize molecular alterations in MAPK and JAK/STAT pathway genes among EOCRC patients, focusing on differences between H/L and Non-Hispanic White (NHW) patients. Additionally, we assess whether these pathway-specific alterations contribute to survival outcomes in H/L EOCRC patients. Methods: We conducted a bioinformatics analysis using publicly available CRC datasets to assess mutation frequencies in MAPK and JAK/STAT pathway genes. A total of 3412 patients were included in the study, comprising 302 H/L patients and 3110 NHW patients. Patients were stratified by age (EOCRC: <50 years, late-onset colorectal cancer—LOCRC: ≥50 years) and ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan–Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW EOCRC patients. Results: Significant differences were observed in MAPK pathway-related genes when comparing EOCRC and LOCRC in H/L patients. NF1 (11.6% vs. 3.7%, p = 0.01), ACVR1 (2.9% vs. 0%, p = 0.04), and MAP2K1 (3.6% vs. 0%, p = 0.01) were more prevalent in EOCRC, while BRAF mutations (18.3% vs. 5.1%, p = 9.1 × 10⁻⁴) were significantly more frequent in LOCRC among H/L patients. Additionally, when comparing EOCRC in H/L patients to EOCRC in NHW patients, key MAPK pathway genes such as AKT1 (5.1% vs. 1.8%, p = 0.03), MAPK3 (3.6% vs. 0.7%, p = 6.83 × 10⁻³), NF1 (11.6% vs. 6.1%, p = 0.02), and PDGFRB (5.8% vs. 2.1%, p = 0.02) were significantly enriched in H/L EOCRC patients. However, no significant differences were observed in JAK/STAT pathway-related genes when comparing EOCRC and LOCRC in H/L patients, nor when comparing EOCRC in H/L vs. NHW patients. Survival analysis revealed borderline significant differences in H/L EOCRC patients, whereas NHW EOCRC patients with no alterations in the JAK/STAT pathway exhibited significant survival differences. In contrast, MAPK pathway alterations were not associated with significant survival differences. These findings suggest that MAPK and JAK/STAT pathway alterations may have distinct prognostic implications in H/L EOCRC patients, justifying further investigation into their potential role in cancer progression and treatment response. Conclusions: These findings suggest that MAPK pathway dysregulation plays a distinct role in EOCRC among H/L patients, potentially contributing to disparities in CRC development and treatment response. The higher prevalence of MAPK alterations in H/L EOCRC patients compared to NHW patients underscores the need to explore ethnicity-specific tumor biology and therapeutic targets. Conversely, the lack of significant differences in JAK/STAT pathway alterations suggests that this pathway may not play a major differential role in EOCRC vs. LOCRC within this population. Survival analysis highlighted the prognostic relevance of pathway-specific alterations. These insights emphasize the importance of precision medicine approaches that consider genetic heterogeneity and pathway-specific alterations to improve outcomes for H/L CRC patients. Full article

Background/Objectives: Massively parallel sequencing technologies have advanced chronic lymphocytic leukemia (CLL) diagnostics and precision oncology. Illumina platforms, while offering robust performance, require substantial infrastructure investment and a large number of samples for cost-efficiency. Conversely, third-generation long-read nanopore sequencing from Oxford Nanopore Technologies (ONT) can significantly reduce sequencing costs, making it a valuable tool in resource-limited settings. However, nanopore sequencing faces challenges with lower accuracy and throughput than Illumina platforms, necessitating additional computational strategies. In this paper, we demonstrate that integrating publicly available short-read data with in-house generated ONT data, along with the application of machine learning approaches, enables the characterization of the CLL transcriptome landscape, the identification of clinically relevant molecular subtypes, and the assignment of these subtypes to nanopore-sequenced samples. Methods: Public Illumina RNA sequencing data for 608 CLL samples were obtained from the CLL-Map Portal. CLL transcriptome analysis, gene module identification, and transcriptomic subtype classification were performed using the oposSOM R package for high-dimensional data visualization with self-organizing maps. Eight CLL patients were recruited from the Hematology Center After Prof. R. Yeolyan (Yerevan, Armenia). Sequencing libraries were prepared from blood total RNA using the PCR-cDNA sequencing-barcoding kit (SQK-PCB109) following the manufacturer’s protocol and sequenced on an R9.4.1 flow cell for 24–48 h. Raw reads were converted to TPM values. These data were projected into the SOMs space using the supervised SOMs portrayal (supSOM) approach to predict the SOMs portrait of new samples using support vector machine regression. Results: The CLL transcriptomic landscape reveals disruptions in gene modules (spots) associated with T cell cytotoxicity, B and T cell activation, inflammation, cell cycle, DNA repair, proliferation, and splicing. A specific gene module contained genes associated with poor prognosis in CLL. Accordingly, CLL samples were classified into T-cell cytotoxic, immune, proliferative, splicing, and three mixed types: proliferative–immune, proliferative–splicing, and proliferative–immune–splicing. These transcriptomic subtypes were associated with survival orthogonal to gender and mutation status. Using supervised machine learning approaches, transcriptomic subtypes were assigned to patient samples sequenced with nanopore sequencing. Conclusions: This study demonstrates that the CLL transcriptome landscape can be parsed into functional modules, revealing distinct molecular subtypes based on proliferative and immune activity, with important implications for prognosis and treatment that are orthogonal to other molecular classifications. Additionally, the integration of nanopore sequencing with public datasets and machine learning offers a cost-effective approach to molecular subtyping and prognostic prediction, facilitating more accessible and personalized CLL care. Full article

With ever-increasing incidence and high metastatic potential, cutaneous melanoma is the deadliest skin cancer. Risk prediction based on the Tumor-Node-Metastasis (TNM) staging system has medium accuracy with intermediate IIB-IIIB stages, as roughly 25% of patients with low-medium-grade TNM, and hence a favorable prognostic, undergo an aggressive disease with short survival and around 15% of deaths arise from metastases of thin, low-risk lesions. Therefore, reliable prognostic biomarkers are required. We used genomic and clinical information of melanoma patients from the TCGA-SKCM cohort and two GEO studies for discovery and validation of potential biomarkers, respectively. Neither mutation nor overexpression of major melanoma driver genes provided significant prognostic information. Conversely, expression of MGRN1 and the melanocyte-specific genes MLANA, PMEL, and TYRP1 provided a simple 4-gene signature identifying with high-sensitivity (>80%), low-medium TNM patients with adverse outcomes. Transcriptomic analysis of tumors with this signature, or from low-medium-grade TNM patients with poor outcomes, revealed comparable dysregulation of an inflammatory response, cell cycle progression, and DNA damage/repair programs. A functional analysis of MGRN1-knockout cells confirmed these molecular features. Therefore, the simple MGRN1-MLANA-PMEL-TYRP1 combination of biomarkers complemented TNM staging prognostic accuracy and pointed to the dysregulation of immunological responses and genomic stability as determinants of a melanoma outcome. Full article