Circulating Blood Prognostic Biomarker Signatures for Hemorrhagic Cerebral Cavernous Malformations (CCMs).

Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes.

BACKGROUND: Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5%-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation. PATIENTS AND METHODS: We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003 and 2021 and compared them based on presence or absence of the three classical phenotypic driver mutations. RESULTS: A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; P = .009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib. CONCLUSION: TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL, and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.

Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.

The patterns of low risk myelodysplastic syndrome (MDS) progression, and the clinical and molecular features of those patterns are not well described. We divided our low risk (LR) MDS patients (n=1914) into 4 cohorts: 1) Patients who remained LR-MDS (LR-LR; n=1300; 68%), 2) Patients who progressed from LR to HR MDS (LR-HR) without AML transformation (n=317; 16.5%), 3) Patients who progressed from LR to HR MDS and then AML (LR-HR-AML; n=124; 6.5%), 4) Patients who progressed from LR MDS to AML directly (LR-AML; n=173; 9%). Risk factors for progression included male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin.

Draft genomes of four Kluyveromyces marxianus isolates retrieved from the elaboration process of henequen (Agave fourcroydes) mezcal.

We report the draft genomes of four Kluyveromyces marxianus isolates obtained from the elaboration process of henequen (Agave fourcroydes) mezcal, a Mexican alcoholic beverage. The average nucleotide identity analysis revealed that isolates derived from agave plants are distinct from those from other environments, including agave fermentations.

Identification of a specific APOE transcript and functional elements associated with Alzheimer's disease.

INTRODUCTION: The APOE gene is the strongest genetic risk factor for late-onset Alzheimer's Disease (LOAD). However, the gene regulatory mechanisms at this locus have not been fully characterized. METHODS: To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with RNA-seq, DNA methylation, and ChIP-seq data from human postmortem brains. RESULTS: We identified an AD-linked APOE transcript (jxn1.2.2) observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features in DLPFC. We prioritized an independent functional SNP, rs157580, significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. rs157580 is located within active chromatin regions and predicted to affect brain-related transcriptional factors binding affinity. rs157580 shared the effects on the jxn1.2.2 transcript between European and African ethnic groups. DISCUSSION: The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease's etiology.

Drivers of deep molecular response and long-term outcomes in patients with core binding factor acute myeloid leukemia.

A swimmer plot on clinical course of patients undergoing allogeneic stem cell transplant for core binding factor acute myeloid leukemia.

Evaluation of nuclear and mitochondrial phylogenetics for the subtyping of Cyclospora cayetanensis.

Cyclospora cayetanensis is an enteric coccidian parasite responsible for gastrointestinal disease transmitted through contaminated food and water. It has been documented in several countries, mostly with low-socioeconomic levels, although major outbreaks have hit developed countries. Detection methods based on oocyst morphology, staining, and molecular testing have been developed. However, the current MLST panel offers an opportunity for enhancement, as amplification of all molecular markers remains unfeasible in the majority of samples. This study aims to address this challenge by evaluating two approaches for analyzing the genetic diversity of C. cayetanensis and identifying reliable markers for subtyping: core homologous genes and mitochondrial genome analysis. A pangenome was constructed using 36 complete genomes of C. cayetanensis, and a haplotype network and phylogenetic analysis were conducted using 33 mitochondrial genomes. Through the analysis of the pangenome, 47 potential markers were identified, emphasizing the need for more sequence data to achieve comprehensive characterization. Additionally, the analysis of mitochondrial genomes revealed 19 single-nucleotide variations that can serve as characteristic markers for subtyping this parasite. These findings not only contribute to the selection of molecular markers for C. cayetanensis subtyping, but they also drive the knowledge toward the potential development of a comprehensive genotyping method for this parasite.

Urbanisation generates multiple trait syndromes for terrestrial animal taxa worldwide.

Cities can host significant biological diversity. Yet, urbanisation leads to the loss of habitats, species, and functional groups. Understanding how multiple taxa respond to urbanisation globally is essential to promote and conserve biodiversity in cities. Using a dataset encompassing six terrestrial faunal taxa (amphibians, bats, bees, birds, carabid beetles and reptiles) across 379 cities on 6 continents, we show that urbanisation produces taxon-specific changes in trait composition, with traits related to reproductive strategy showing the strongest response. Our findings suggest that urbanisation results in four trait syndromes (mobile generalists, site specialists, central place foragers, and mobile specialists), with resources associated with reproduction and diet likely driving patterns in traits associated with mobility and body size. Functional diversity measures showed varied responses, leading to shifts in trait space likely driven by critical resource distribution and abundance, and taxon-specific trait syndromes. Maximising opportunities to support taxa with different urban trait syndromes should be pivotal in conservation and management programmes within and among cities. This will reduce the likelihood of biotic homogenisation and helps ensure that urban environments have the capacity to respond to future challenges. These actions are critical to reframe the role of cities in global biodiversity loss.

Utilization of Serial Next-Generation Sequencing Among Patients Receiving CPX-351 for Newly Diagnosed Acute Myeloid Leukemia.

BACKGROUND: The phase III trial that led to the approval of CPX-351 for treating secondary acute myeloid leukemia (sAML) in 2017 did not study the effect of specific mutations on outcomes. METHODS: This retrospective study was done to evaluate the effect of next-generation sequencing (NGS) results at the time of best response and before allogeneic stem cell transplant (alloSCT) in patients treated with CPX-351 as frontline therapy for sAML between 2017 and 2021. RESULTS: The most common mutations seen were DNMT3A (n = 17, 29.8%), SRSF2 (n = 13, 22.8%), RUNX1 (n = 13, 22.8%), TET2 (n = 9, 15.8%), ASXL1 (n = 9, 15.8%), and BCOR (n = 9, 15.8%). Median OS (mOS) for the entire cohort was 47 months. Though 64.7% patients cleared the DNMT3A mutation, only 44.4% and 22.2% of patients cleared the TET2 and ASXL1 mutations, respectively. The mOS for patients who cleared their mutations vs. for those who did not was not significantly longer (46 vs. 30 months; P = .991). The relapse-free survival (RFS) for patients who cleared mutations was numerically longer compared to those who had persistent mutations; however, this did not reach statistical significance (44 months vs. 26 months; P = .786). CONCLUSION: This is the first study reporting NGS at best response and before alloSCT and its effect on OS and RFS. We found that OS and RFS were numerically longer among patients who cleared mutations; however, this did not reach statistical significance. In addition, alloSCT led to improved RFS irrespective of mutational clearance.

Assessment and validation of the molecular international prognostic scoring system for myelodysplastic syndromes.

The Molecular International Prognostic Scoring System (IPSS-M) is a novel risk stratification model for myelodysplastic syndromes (MDS) that builds on the IPSS and IPSS-R by incorporating mutational data. The model showed improved prognostic accuracy over the IPSS-R across three endpoints: overall survival (OS), leukemia-free survival (LFS) and leukemic transformation. This study aimed to validate the findings of the original in a large cohort of MDS patients, as well as assess its validity in therapy-related and hypoplastic MDS. We retrospectively reviewed clinical, cytogenetic and molecular data for 2355 MDS patients treated at the Moffitt Cancer Center. Correlative analysis between IPSS-R and mean IPSS-M scores and outcome predictions was performed on LFS, OS and leukemic transformation. Using the IPSS-M, patients were classified as Very Low (4%), Low (24%), Moderate-Low (14%), Moderate-High (11%), High (19%) and Very-High risk (28%). Median OS was 11.7, 7.1, 4.4, 3.1, 2.3, and 1.3 years from VL to VH risk subgroups. Median LFS was 12.3, 6.9, 3.6, 2.2, 1.4, and 0.5 years respectively. For patients with t-MDS and h-MDS the model retained its prognostic accuracy. Generalized use of this tool will likely result in more accurate prognostic assessment and optimize therapeutic decision-making in MDS.

Updates in Risk Stratification in Myelodysplastic Syndromes.

ABSTRACT: Risk stratification plays an essential role in treatment planning in myelodysplastic syndromes. For decades, the International Prognostic Scoring System and its revised version have provided unified consensus for clinical trial enrollment and design. These models relied on laboratory and cytogenetic data to estimate prognosis and dictate treatment paradigms. Critical developments in DNA sequencing techniques in recent years, as well as our growing understanding of the clonal dynamics of myelodysplastic syndromes and the role that specific mutations have in shaping disease-specific phenotypes and treatment susceptibilities, have made it possible to identify molecular markers that carry critical diagnostic and therapeutic relevance and remained unaccounted for in the older models. The Molecular International Prognostic Scoring System is a novel risk stratification model that integrates clinical, cytogenetic, and molecular data to devise a more refined prognostic tool that builds on the accuracy of the traditional models.

Sex Disparities in Myelodysplastic Syndromes: Genotype, Phenotype, and Outcomes.

Introduction/Background The impact of biological sex on the clinical phenotype, genotype, and outcomes among patients with MDS is not well characterized. Materials and Methods We retrospectively reviewed the clinical and genomic data from male and female patients included in our institutional MDS database at Moffitt Cancer Center. Results Among 4580 patients with MDS, 2922 (66%) were men and 1658 (34%) were women. Women were younger (mean age 66.5 vs. 69 years for men, P < .001) at diagnosis. There were more Hispanic/black women than men (9% vs. 5%, P =<.001). Women had lower hemoglobin and higher platelet counts than men. More women had del 5q/monosomy 5 abnormalities compared to men (P =<.001). Therapy related MDS were more common in women than men (25% vs.17%, P=<.001). On assessment of molecular profile, SRSF2, U2AF1, ASXL1, and RUNX1 mutations were more frequent in men. The median overall survival (mOS) was 37.5 months (mo) for females compared to 35 monthsfor males, (P = .002). The mOS was significantly prolonged for women in lower-risk MDS, but not in higher-risk MDS. Women were more likely to respond to immunosuppression with ATG/CSA than men (38% vs. 19%, P= 0.04).Conclusion Ongoing research is needed for understanding the impact of sex on phenotype, genotype, and outcomes in patients diagnosed with MDS.

Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome: A large single institution analysis of 1774 patients.

EZH2 mutations in myeloid neoplasms are loss of function type, and have been linked to poor overall survival (OS) in patients with myelodysplastic syndrome (MDS). However, the specific determinants of outcomes in EZH2-mutant (mut) MDS are not well characterized. In this single-center retrospective study, clinical and genomic data were collected on 1774 patients with MDS treated at Moffitt Cancer Center. In our cohort, 83 (4.7%) patients had a pathogenic EZH2 mutation. Patients with EZH2mut MDS were older than EZH2-wild type (wt) group (median age- 72 vs. 69 years, p = 0.010). The most common co-occurring mutation in EZH2mut MDS was ASXL1, with a significantly higher frequency than EZH2wt (54% vs. 19%, p < 0.001). Patients with EZH2mut MDS had lower response rates to hypomethylating agents compared to EZH2wt MDS (26% vs. 39%; p = 0.050). Median OS of patients with EZH2mut MDS was 30.8 months, with a significantly worse OS than EZH2wt group (35.5 vs. 61.2 months, p = 0.003) in the lower-risk IPSS-R categories. Among patients with EZH2mut MDS, co-presence of ASXL1 or RUNX1 mutations was associated with inferior median OS compared to their wt counterparts (26.8 vs. 48.7 months, p = 0.031). Concurrent chromosome 7 abnormalities (12%) were also associated with significantly worse OS (median OS- 20.8 vs. 35.5 months, p = 0.002) in EZH2mut MDS. Future clinical trials should explore the potential role of novel targeted therapies in improving outcomes in patients with EZH2mut MDS.

U2AF1 and EZH2 mutations are associated with nonimmune hemolytic anemia in myelodysplastic syndromes.

Hemolysis is a well-recognized but poorly characterized phenomenon in a subset of patients with myelodysplastic syndromes (MDS). Its pathobiological basis seems to underpin a nonimmune etiology whose clinical significance has not been adequately characterized. Hemolysis in MDS is often attributed to either ineffective intramedullary erythropoiesis or acquired hemoglobinopathies and red blood cell (RBC) membrane defects. These heterogeneous processes have not been associated with specific genetic subsets of the disease. We aimed to describe the prevalence of hemolysis among patients with MDS, their baseline characteristics, molecular features, and resulting impact on outcomes. We considered baseline serum haptoglobin <10 mg/dL a surrogate marker for intravascular hemolysis. Among 519 patients, 10% had hemolysis. The baseline characteristics were similar among both groups. Only 13% of patients with hemolysis were Coombs-positive, suggesting that hemolysis in MDS is largely not immune-mediated. Inferior survival trends were observed among lower-risk patients with MDS undergoing hemolysis. Decreased response rates to erythropoiesis-stimulating agents (ESA) and higher responses to hypomethylating agents (HMA) were also observed in the hemolysis group. U2AF1 and EZH2 hotspot mutations were more prevalent among those undergoing hemolysis (P < .05). U2AF1 mutations were observed in 30% of patients with hemolysis and occurred almost exclusively at the S34 hotspot. Somatic mutations encoding splicing factors may affect erythrocyte membrane components, biochemical properties, and RBC metabolic function, which underpin the development of atypical clones from erythroid precursors in MDS presenting with hemolysis. Future studies will explore the contribution of altered splicing to the development of acquired hemoglobinopathies.

Nematicidal, Acaricidal and Plant Growth-Promoting Activity of Enterobacter Endophytic Strains and Identification of Genes Associated with These Biological Activities in the Genomes.

In the present study, the nematicidal and acaricidal activity of three Enterobacter endophytic strains isolated from Mimosa pudica nodules was evaluated. The percentages of mortality of Enterobacter NOD4 against Panagrellus redivivus was 81.2%, and against Nacobbus aberrans 70.1%, Enterobacter NOD8 72.4% and 62.5%, and Enterobacter NOD10 64.8% and 58.7%, respectively. While against the Tyrophagus putrescentiae mite, the mortality percentages were 68.2% due to Enterobacter NOD4, 64.3% due to Enterobacter NOD8 and 77.8% due to Enterobacter NOD10. On the other hand, the ability of the three Enterobacter strains to produce indole acetic acid and phosphate solubilization, characteristics related to plant growth-promoting bacteria, was detected. Bioinformatic analysis of the genomes showed the presence of genes related to IAA production, phosphate solubilization, and nitrogen fixation. Phylogenetic analyzes of the recA gene, phylogenomics, and average nucleotide identity (ANI) allowed us to identify the strain Enterobacter NOD8 related to E. mori and Enterobacter NOD10 as E. asburiae, while Enterobacter NOD4 was identified as a possible new species of this species. The plant growth-promoting, acaricidal and nematicidal activity of the three Enterobacter strains makes them a potential agent to include in biocontrol alternatives and as growth-promoting bacteria in crops of agricultural interest.

Expert range maps of global mammal distributions harmonised to three taxonomic authorities.

Aim: Comprehensive, global information on species' occurrences is an essential biodiversity variable and central to a range of applications in ecology, evolution, biogeography and conservation. Expert range maps often represent a species' only available distributional information and play an increasing role in conservation assessments and macroecology. We provide global range maps for the native ranges of all extant mammal species harmonised to the taxonomy of the Mammal Diversity Database (MDD) mobilised from two sources, the Handbook of the Mammals of the World (HMW) and the Illustrated Checklist of the Mammals of the World (CMW). Location: Global. Taxon: All extant mammal species. Methods: Range maps were digitally interpreted, georeferenced, error-checked and subsequently taxonomically aligned between the HMW (6253 species), the CMW (6431 species) and the MDD taxonomies (6362 species). Results: Range maps can be evaluated and visualised in an online map browser at Map of Life (mol.org) and accessed for individual or batch download for non-commercial use. Main conclusion: Expert maps of species' global distributions are limited in their spatial detail and temporal specificity, but form a useful basis for broad-scale characterizations and model-based integration with other data. We provide georeferenced range maps for the native ranges of all extant mammal species as shapefiles, with species-level metadata and source information packaged together in geodatabase format. Across the three taxonomic sources our maps entail, there are 1784 taxonomic name differences compared to the maps currently available on the IUCN Red List website. The expert maps provided here are harmonised to the MDD taxonomic authority and linked to a community of online tools that will enable transparent future updates and version control.

DarkCideS 1.0, a global database for bats in karsts and caves.

Understanding biodiversity patterns as well as drivers of population declines, and range losses provides crucial baselines for monitoring and conservation. However, the information needed to evaluate such trends remains unstandardised and sparsely available for many taxonomic groups and habitats, including the cave-dwelling bats and cave ecosystems. We developed the DarkCideS 1.0 ( https://darkcides.org/ ), a global database of bat caves and species synthesised from publicly available information and datasets. The DarkCideS 1.0 is by far the largest database for cave-dwelling bats, which contains information for geographical location, ecological status, species traits, and parasites and hyperparasites for 679 bat species are known to occur in caves or use caves in part of their life histories. The database currently contains 6746 georeferenced occurrences for 402 cave-dwelling bat species from 2002 cave sites in 46 countries and 12 terrestrial biomes. The database has been developed to be collaborative and open-access, allowing continuous data-sharing among the community of bat researchers and conservation biologists to advance bat research and comparative monitoring and prioritisation for conservation.