Search Results (126)

Background: Genetic alterations in CSF3R, typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. Methods: This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid neoplasms with CSF3R alterations. Patients (median age, 77 years) were categorized into groups with a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) (n = 5), acute leukemia (n = 4), and other myeloid neoplasms (n = 4) based on the WHO 2022 and ICC criteria. Results: The CSF3R p.Thr618Ile mutation was most frequent (11/13), with additional pathogenic variants including p.Gln743Ter and frameshift mutations affecting the cytoplasmic tail. Variant allele frequencies (VAFs) ranged from 2% to 49%, with the highest median VAF in the MDS/MPN group. Co-mutations varied by subtype; MDS/MPN, NOS, and CMML cases frequently harbored mutations in epigenetic regulators (ASXL1, TET2) and splicing factors (SF3B1, SRSF2, ZRSR2), while acute leukemia cases showed alterations in JAK3, STAT3, and NRAS. Survival analysis revealed distinct patterns across the three diagnostic groups, with MDS/MPN having the poorest prognosis. Conclusion: This study expands the recognized spectrum of CSF3R-related myeloid neoplasms and highlights the clinical and molecular heterogeneity associated with these mutations, emphasizing the need for comprehensive molecular profiling and the potential for targeted therapies. Full article

Debris flows pose significant risks to mountainous regions, and quick, accurate volume estimation is crucial for hazard assessment and post-disaster response. Traditional volume estimation methods, such as ground surveys and aerial photogrammetry, are often limited by cost, accessibility, and timeliness. While remote sensing offers wide coverage, existing optical and Synthetic Aperture Radar (SAR)-based techniques face challenges in direct volume estimation due to resolution constraints and rapid terrain changes. This study proposes a Super-Resolution Shape from Shading (SRSFS) approach enhanced by a Non-local Piecewise-smooth albedo Constraint (NPC), hereafter referred to as NPC SRSFS, to estimate debris-flow erosion volume using single high-resolution optical satellite imagery. By integrating publicly available global Digital Elevation Model (DEM) data as prior terrain reference, the method enables accurate post-disaster topography reconstruction from a single optical image, thereby reducing reliance on stereo imagery. The NPC constraint improves the robustness of albedo estimation under heterogeneous surface conditions, enhancing depth recovery accuracy. The methodology is evaluated using Gaofen-6 satellite imagery, with quantitative comparisons to aerial Light Detection and Ranging (LiDAR) data. Results show that the proposed method achieves reliable terrain reconstruction and erosion volume estimates, with accuracy comparable to airborne LiDAR. This study demonstrates the potential of NPC SRSFS as a rapid, cost-effective alternative for post-disaster debris-flow assessment. Full article

Hepatocellular carcinoma (HCC) presents significant intertumoral heterogeneity, complicating prognosis and treatment. To address this, we performed an integrated single-cell RNA-sequencing analysis of HCC specimens using Seurat and identified malignant cells via Infercnv. Through a systematic evaluation of 101 machine learning algorithms used in combination, we developed tumor-cell-specific gene signatures (TCSGs) that demonstrated strong predictive performance, with area under the curve (AUC) values ranging from 0.72 to 0.74 in independent validation cohorts. Risk stratification based on these signatures revealed distinct therapeutic vulnerabilities: high-risk patients showed increased sensitivity to sorafenib, while low-risk patients exhibited enhanced responses to immunotherapy and transarterial chemoembolization (TACE). Pharmacogenomic analysis with Oncopredict identified four chemotherapeutic agents, including sapitinib and dinaciclib, with risk-dependent efficacy patterns. Furthermore, CRISPR/Cas9-dependency screening prioritized SRSF7 as essential for HCC cell survival, a finding confirmed by the identification of protein-level overexpression in tumors via immunohistochemistry. This multi-omics framework bridges single-cell characterization to clinical decision-making, offering a clinically actionable prognostic system that can be used to optimize therapeutic selection in HCC management. Full article

Serine/arginine splicing factors (SRSFs) are critical regulators of gene expression that influence alternative splicing through RNA binding via the RNA recognition motif (RRM). Circular RNAs (circRNAs) are a subset of non-coding RNAs that exhibit differential expression in WSSV-infected Litopenaeus vannamei. This study investigates the role of LvSRSF2 in regulating circRNA expression in response to WSSV infection. LvSRSF2 was highly expressed in hemocytes and upregulated during WSSV infection. Silencing LvSRSF2 using dsRNA significantly upregulated the expression of circRNAs (circ-Alpha2, circ-Anillin, circ-Hemocytin, circ-Nephrin, and circ-Toll) in both WSSV-infected and uninfected shrimps at 72 h post-injection with dsRNAs. Knockdown of LvSRSF2 also significantly reduced WSSV copy numbers at 24 h post-infection and extended shrimp survival, with knockdown shrimp surviving up to 9 d compared to the control group. In addition, circ-Hemocytin, an SRSF2-related circRNA, was predicted to interact with six miRNAs targeting immune-related genes such as Toll, STAT, NF-κB, and Vago4. Following WSSV infection, circ-Hemocytin expression increased at 24 and 48 hpi, and the immune genes STAT and Vago4 were also upregulated, suggesting a potential circRNA–miRNA–mRNA regulatory axis in shrimp antiviral defense. Furthermore, targeted suppression of circ-Hemocytin expression using siRNAs significantly reduced its expression without affecting the corresponding linear transcript and resulted in a notable decrease in WSSV load in shrimp gills, highlighting its potential role in antiviral defense. Full article

Background: Wilms’ tumor gene 1 (WT1) is a critical player in acute myeloid leukemia (AML), often serving as a biomarker for measurable residual disease (MRD). The WT1 gene is overexpressed in the majority of AML cases at diagnosis, with apparently no correlation with prognosis, and in the meantime, its role in patients with low-level expression is still undefined. This study investigates the mutational landscape and clinical outcomes of AML patients with low WT1 expression at diagnosis. Methods: We analyzed 34 AML patients with low WT1 expression (WT1/ABL1 < 250) diagnosed and treated from 2013 to 2017 at three institutions. Next-generation sequencing (NGS) was employed to investigate the mutational status of 32 genes commonly mutated in AML. The presence of specific mutations, as well as clinical outcomes, was compared to the general AML population. Results: Patients with low WT1 expression showed a significantly higher mutational burden, with a median of 3.4 mutations per patient, compared to the general AML population. Notably, clonal hematopoiesis (CHIP) or myelodysplasia-related (MR) mutations, particularly in ASXL1, TET2, and SRSF2, were present in most patients with low WT1 expression. All but one case of NPM1- or FLT3-mutant AML in the low-WT1 cohort harbored more CHIP or MR mutations. Patients with low WT1 expression had an overall survival (OS) that was superimposable to the OS expected in MR AML. Conclusions: Low WT1 expression in AML is associated with a distinct and complex mutational profile, marked by frequent CHIP and MR mutations. Full article

Alternative splicing is one of the processes that contributes to producing a vast protein diversity from the limited number of protein-coding genes in higher eukaryotes. The Methyl CpG Binding Protein 2 (Mecp2) gene, whose mutations cause Rett syndrome, generates two protein isoforms, MeCP2E1 and MeCP2E2, by alternative splicing. These isoforms likely possess non-redundant functions. However, the molecular mechanism for Mecp2 pre-mRNA alternative splicing remains to be understood. Here, we analyzed the alternative splicing mechanism of MeCP2 pre-mRNA and found that exon 2 is efficiently recognized through adjacent strong splice sites. In addition, exonic splicing enhancer (ESE) in exon 2 plays an important role in exon 2 inclusion, which is highly likely to be mediated by SRSF9. Full article

Background: While NPM1-mutated AML in the absence of FLT3-ITD generally carries a favorable prognosis, large registry studies suggest the positive prognostic benefit may not extend to patients > 65 years of age. We examined this preferential, age-dependent prognostic impact through a real-world analysis of 2811 adult AML patients. Results: The median overall survival (OS) was significantly better in NPM1^MT compared to NPM1^WT patients [20.86 vs. 17 mo., p = 0.003]. When stratified by age, NPM1^MT patients had higher OS than NPM1^WT patients in the 55–65-year age group (28.62 vs. 16.3 mo., p ≤ 0.0001). This OS benefit was heterogenous and prevailed most strikingly in the 55–60 (68.3 vs. 15.6 mo., p = 0.002), and up to the 60–65-year group (mOS not estimable vs. 20 mo., p = 0.007), but not beyond 65 y. Notably, the ≤65 cohort was more enriched with dominant NPM1 (21% vs. 15%, p ≤ 0.001), while the >65 cohort was enriched with abnormal karyotype (20% in >65 years vs. 16% in ≤65 years, p = 0.001), and co-occurring SRSF2 and ASXL1 mutations (18.7% vs. 7.5%, p ≤ 0.0001 and 13.5% vs. 4.1%, p ≤ 0.0001 resp.). Conclusions: We demonstrate that in a real-world setting, the prognostic benefit of NPM1 does not extend beyond age 65, underscoring the need for age-adapted risk stratification models. This granular approach could prevent the potential overestimation of prognosis in older patients with NPM1^MT AML and inform therapeutic decision making. Full article

Purpose: This study aimed to investigate the efficacy and the clinical and molecular predictors of response and survival following venetoclax plus hypomethylating agents (VEN + HMAs) in adult relapsed/refractory acute myeloid leukemia (R/R AML) patients. Methods: We retrospectively analyzed 197 adult R/R AML patients who received the VEN + HMAs regimen. Molecular profiling was performed using targeted next-generation sequencing (NGS) of 139 genes to explore potential response and survival genetic predictors. Results: The median treatment cycle was 1 (1–4) cycle. The composite complete remission (CRc) rate, encompassing complete remission (CR) and CR with incomplete hematologic recovery (CRi), was 44.7%, while the overall response rate (ORR) reached 59.9%. With a median follow-up period of 14.0 months (range: 0.7–54.0 months), the 1-year and 2-year overall survival (OS) rates were 55.4% and 40.2%, respectively. Multivariate analyses revealed that mutations in NPM1 and SRSF2 were significantly associated with improved response rates. Conversely, prior exposure to HMA therapy, early relapse, and the presence of GATA2 mutations were linked to lower response rates. Regarding survival outcomes, the CBFB-MYH11 fusion gene, as well as mutations in NPM1 and IDH1/2, were found to be favorable prognostic factors for OS, whereas mutations in FLT3-ITD, TP53, DNMT3A, and GATA2 were associated with worse OS. Conclusions: The VEN + HMAs regimen demonstrated considerable efficacy in the treatment of R/R AML patients, with both response rates and overall survival being influenced by distinct genetic features. These findings provide valuable insights into optimizing personalized treatment strategies for this challenging patient population. Full article

Background: Despite advances in uveal melanoma (UM) diagnosis and treatment, about 50% of patients develop distant metastases, thereby displaying poor overall survival. Molecular profiling has identified several genetic alterations that can stratify patients with UM into different risk categories. However, these genetic alterations are currently dispersed over multiple studies and several methodologies, emphasizing the need for a defined workflow that will allow standardized and reproducible molecular analyses. Methods: Following the findings published by “The Cancer Genome Atlas–UM” (TCGA-UM) study, we developed an NGS-based gene panel (called the UMpanel) that classifies mutation sets in four categories: initiating alterations (CYSLTR2, GNA11, GNAQ and PLCB4), prognostic alterations (BAP1, EIF1AX, SF3B1 and SRSF2), emergent biomarkers (CDKN2A, CENPE, FOXO1, HIF1A, RPL5 and TP53) and chromosomal abnormalities (imbalances in chromosomes 1, 3 and 8). Results: Employing commercial gene panels, reference mutated DNAs and Sanger sequencing, we performed a comparative analysis and found that our methodological approach successfully predicted survival with great specificity and sensitivity compared to the TCGA-UM cohort that was used as a validation group. Conclusions: Our results demonstrate that a reproducible NGS-based workflow translates into a reliable tool for the clinical stratification of patients with UM. Full article

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages. These clonal marrow disorders are extremely rare in pediatric patients. MPN is reported to occur 100 times more frequently in adults, and thus research is primarily focused on this patient group. At present, modern diagnostic techniques, primarily genetic, facilitate the identification of the biology of these diseases. The key genes are JAK2, MPL, and CALR, namely, driver mutations, which are present in approximately 90% of patients with suspected MPN. Moreover, there are more than 20 other mutations that affect the development of these hematological malignancies, as evidenced by a review of the literature. The pathogenic mechanism of MPNs is characterized by the dysregulation of the JAK/STAT signaling pathway (JAK2, MPL, CALR), DNA methylation (TET2, DNMT3A, IDH1/2), chromatin structure (ASXL1, EZH2), and splicing (SF3B1, U2AF2, SRSF2). Although rare, myeloproliferative neoplasms can involve young patients and pose unique challenges for clinicians in diagnosis and therapy. The paper aims to review the biological markers of MPNs in pediatric populations—a particular group of patients that has been poorly studied due to the low frequency of MPN diagnosis. Full article

The African clawed frog, Xenopus laevis, exhibits remarkable adaptations to survive in its arid habitat, including behavioral and metabolic changes during periods of drought. During extreme dehydration, X. laevis undergoes estivation, a state characterized by increased urea and ammonia levels, depression of the metabolic rate, and tissue hypoxia. To understand the molecular mechanisms underlying these adaptations, we investigated the potential role of N6-methyladenosine (m⁶A), a widespread mRNA modification, in X. laevis during extreme dehydration. We analyzed the protein levels of key components in the m⁶A pathway, including writers (METTL3, METTL14, and WTAP), erasers (ALKBH5 and FTO), and readers (SRSF3, YTHDF1, YTHDF2, YTHDF3, and eIF3a), in the liver and kidneys of control frogs and frogs that had lost 35 ± 0.93% of their total body water. The relative protein levels generally decreased or remained unchanged, with the exception of YTHDF3, which depicted a protein level increase in the liver. Notable changes included eIF3a, which was downregulated by 26 ± 8% and 80 ± 8% in the dehydrated liver and kidney tissues, respectively. Additionally, the total m⁶A increased by 353 ± 30% and 177 ± 17% in dehydrated liver and kidney RNA samples, respectively. This study highlights the importance of epigenetic mechanisms in stress tolerance and provides a foundation for further exploration of the role of epigenetics in dehydration tolerance. Full article

Application of the FOLFOX scheme to colorectal cancer (CRC) patients often results in the development of chemo-resistance, leading to therapy failure. This study aimed to develop a functional and easy-to-use algorithm to predict patients’ response to FOLFOX treatment. Transcriptomic data of CRC patient’s samples treated with FOLFOX were downloaded from the Gene Expression Omnibus database (GSE83129, GSE28702, GSE69657, GSE19860 and GSE41568). Comparing the expression of top up- and downregulated genes in FOLFOX responder and non-responder patients’ groups, we selected 30 potential markers that were used to create a step-by-step eliminative procedure based on modified radial data visualization, which depicts the interplay between the expression level of chosen attributes (genes) to locate data points in low-dimensional space. Our analysis proved that FOLFOX-resistant CRC samples are predominantly characterized by upregulated expression levels of TMEM182 and MCM9 and downregulated LRRFIP1. Additionally, the procedure developed based on expression levels of TMEM182, MCM9, LRRFIP1, LAMP1, FAM161A, KLHL36, ETV5, RNF168, SRSF11, NCKAP5, CRTAP, VAMP2, ZBTB49 and RIMBP2 proved to be capable in predicting FOLFOX therapy response. In conclusion, our approach can give a unique insight into clinical decision-making regarding therapy scheme administration, potentially increasing patients’ survival and, consequently, medical futility due to incorrect therapy application. Full article

Leukemia represents the most prevalent malignancy in children, constituting 30% of childhood cancer cases, with acute lymphoblastic leukemia (ALL) being particularly heterogeneous. This paper explores the role of alternative splicing in leukemia, highlighting its significance in cancer development and progression. Aberrant splicing is often driven by mutations in splicing-factor genes, which can lead to the production of variant proteins that contribute to oncogenesis. The spliceosome, a complex of small nuclear RNAs and proteins, facilitates RNA splicing, a process critical for generating diverse mRNA and protein products from single genes. Mutations in splicing factors, such as U2AF1, SF3B1, SRSF2, ZRSR2, and HNRNPH1, are frequently observed across various hematological malignancies and are associated with poor prognosis and treatment resistance. This research underscores the necessity of understanding the mechanisms of RNA splicing dysregulation in order to develop targeted therapies to correct these aberrant processes, thereby improving outcomes for patients with leukemia and related disorders. Full article

Background: This retrospective cohort study investigates the prognostic significance of genetic mutations in Chronic Myelomonocytic Leukemia (CMML) and their association with treatment responses among patients treated at a single institution, juxtaposed with a statewide dataset from Kentucky. Methods: The study includes 51 patients diagnosed with CMML under the World Health Organization criteria from January 2005 to December 2023. It examines their genomic profiles and subsequent survival outcomes. The analysis also categorizes patients into CMML-1 and CMML-2 subtypes and assesses survival differences between transformed and non-transformed cases. Results: Mutations in TET2, ASXL1, and SRSF2 were found to significantly influence survival, establishing their roles as critical prognostic markers. Additionally, the cohort from the University of Kentucky exhibited distinct survival patterns compared to the broader Kentucky state population, suggesting that demographic and treatment-related factors could underlie these variances. Conclusions: This research underscores the pivotal role of targeted genetic profiling in deciphering the progression of CMML and refining therapeutic strategies. The findings emphasize the necessity for advanced genetic screening in managing CMML to better understand individual prognoses and optimize treatment efficacy, thereby offering insights that could lead to personalized treatment approaches. Full article

Background/Objectives: The non-canonical GC-5′ splice sites (5′ss) are the most common exception (~1%) to the classical GT/AG splicing rule. They constitute weak 5′ss and can be regulated by splicing factors, so they are especially sensitive to genetic variations inducing the misrecognition of their respective exons. We aimed to investigate the GC-5′ss of the breast/ovarian cancer susceptibility genes, ATM (exon 50), BRIP1 (exon 1), and PALB2 (exon 12), and their dysregulation induced by DNA variants. Methods: Splicing assays of the minigenes, mgATM_49-52, mgBRIP1_1-2, and mgPALB2_5-12, were conducted to study the regulation of the indicated GC-5′ss. Results: A functional map of the splicing regulatory elements (SRE) formed by overlapping exonic microdeletions revealed three essential intervals, ATM c.7335_7344del, PALB2 c.3229_3258del, and c.3293_3322del, which are likely targets for spliceogenic SRE-variants. We then selected 14 ATM and 9 PALB2 variants (Hexplorer score < −40) located at these intervals that were assayed in MCF-7 cells. Nine ATM and three PALB2 variants affected splicing, impairing the recognition of exons 50 and 12, respectively. Therefore, these variants likely disrupt the active SREs involved in the inclusion of both exons in the mature mRNA. DeepCLIP predictions suggested the participation of several splicing factors in exon recognition, including SRSF1, SRSF2, and SRSF7, involved in the recognition of other GC sites. The ATM spliceogenic variants c.7336G>T (p.(Glu2446Ter)) and c.7340T>A (p.(Leu2447Ter)) produced significant amounts of full-length transcripts (55–59%), which include premature termination stop codons, so they would inactivate ATM through both splicing disruption and protein truncation mechanisms. Conclusions: ATM exon 50 and PALB2 exon 12 require specific sequences for efficient recognition by the splicing machinery. The mapping of SRE-rich intervals in minigenes is a valuable approach for the identification of spliceogenic variants that outperforms any prediction software. Indeed, 12 spliceogenic SRE-variants were identified in the critical intervals. Full article