👤 C Henry

Children who experience cardiac arrest often suffer lasting neurological deficits, including impairments to learning and memory, due to global cerebral ischemia (GCI). Using a juvenile mouse model of cardiac arrest and resuscitation, we investigated the long-term effects of GCI and potential therapeutic interventions. Following juvenile GCI, long-term potentiation (LTP) and memory were impaired for several weeks followed by endogenous recovery coinciding with changes in brain-derived neurotrophic factor (BDNF) levels, an essential regulator of synaptic plasticity specifically in juveniles but not adults. Given that BDNF is unstable in plasma and cannot cross the blood-brain barrier, we explored the use of type II ampakines, positive allosteric modulators of AMPA receptors, to increase BDNF protein levels in the brain. In vivo administration of type II ampakines 14 days after GCI increased hippocampal BDNF levels, restored LTP, and improved hippocampal-dependent memory and learning behavior. These findings highlight the potential of type II ampakines as an innovative therapeutic intervention to restore synaptic and cognitive function at delayed time points after juvenile GCI. Show less

Global cerebral ischemia (GCI) during childhood is a leading cause of long-term cognitive impairment, yet no therapies currently exist to promote recovery in survivors. We previously demonstrated that juvenile mice exhibit transient hippocampal synaptic dysfunction after GCI, associated with reduced brain-derived neurotrophic factor (BDNF) expression and partial endogenous recovery over time. In this study, we tested whether delayed treatment with fluoxetine (FLX)-a selective serotonin reuptake inhibitor (SSRI) known to enhance BDNF-TrkB signaling-could accelerate synaptic recovery. Juvenile mice underwent cardiac arrest and cardiopulmonary resuscitation, followed by in vivo FLX or vehicle administration from postinjury days 10-13. Electrophysiological recordings on day 14 revealed that FLX restored hippocampal long-term potentiation (LTP) in males but not females. This effect was paralleled by an increase in hippocampal BDNF expression in FLX-treated males, whereas no change was observed in females. Paired ex vivo experiments further confirmed that acute FLX exposure rescued LTP in GCI-injured male slices. These findings suggest that FLX promotes synaptic recovery through BDNF-TrkB signaling in males, while recovery in females may proceed via alternate, hormone-dependent mechanisms. Together, these results identify a novel therapeutic window for enhancing neuroplasticity after juvenile GCI and underscore the importance of developmental stage and biological sex in shaping responses to treatment. Show less

Familial hypobetalipoproteinemia 1 (FHBL-SD2) is the most common monogenic form of primary hypocholesterolaemia, related to truncating variants in the APOB gene encoding apolipoprotein B. Due to its high level of complexity, variants of uncertain significance (VUS) require further investigations. This study aims to demonstrate the value of setting minigene assays in the FHBL-SD2's genetic diagnosis. Four APOB VUS occurring in patients with a FHBL-SD2 phenotype were considered. In silico analysis were performed with six software programs supposed to predict the potential splicing effect. Then, functional consequences were studied in vitro using a minigene splicing reporter assay. An effect on splicing was predicted in silico for the 4 variants, with the activation of a cryptic acceptor site for c.694-13A>G and c.1471-6A>G variants, and the use of a cryptic donor site for c.1123A>G and c.1470G>A variants. Minigene study showed a complete effect on splicing for 3 mutations, confirming the in silico predictions. All of these transcripts result in premature truncated variants. Therefore, these variants were reclassified as likely pathogenic and causative of FHBL-SD2. However, no effect was shown either in HeLA and HuH7 cells for the c.1470G>A variant. Minigene study appears to be a promising and valuable tool to enhance the diagnostic accuracy of FHBL-SD2. It emphasizes the challenge in interpreting VUS and underscores the importance of establishing a clear strategy to assess their significance. Therefore, promoting minigene studies would be beneficial to understand precisely the impact of splicing variants. Show less

Replacing growth factors with a synthetic alternative molecule is an attractive opportunity to increase consistency, scalability, and cost-effectiveness of cell-based products. Herein, we describe the discovery of a chemical class of FGFR1 agonists that mimic the action of basic fibroblast growth factor (bFGF), an essential component of cell culture media. The guanylhydrazone-based molecule, TCB-32, was identified via structure-based virtual screening of the orthosteric binding site of FGFR1. It was shown to significantly increase cell proliferation by activating the FGFR1 signaling pathway like bFGF and exhibited enhanced thermostability over bFGF by retaining activity over the course of several days. After extensive structure-activity relationship studies, it was possible to increase potency and efficacy leading to three highly potent agonists. This finding has the potential to remove current bottlenecks in large-scale cell production, as required for applications such as cultivated meat or cell therapy. Show less

Endometriosis is a common gynaecological condition, with a long diagnostic delay. Surgery is required to confirm a diagnosis, highlighting the need for a non-invasive biomarker. Extracellular vesicles (EVs) may have a role in endometriosis pathogenesis, yet there is limited EV biomarker literature available. This study aimed to investigate the feasibility of isolating cervico-vaginal fluid EVs sampled using cervical brushes and vaginal swabs and to compare these methods. After providing informed consent, patients undergoing surgery for suspected endometriosis had cervical brush and vaginal swab samples collected under general anaesthetic. Isolated EVs were characterised through negative stain transmission electron microscopy (TEM), Western blotting (TSG101, CD63, Calnexin, ApoB, Albumin), tunable resistive pulse sensing (TRPS), microBCA assays and RT-qPCR of miRNAs. PCR was performed on samples prior to EV isolation to assess bacteria present in samples. Cervical brush and vaginal swab EVs were intact vesicles with limited co-isolated contaminants. Cervical brushes had higher concentrations of particles compared to match vaginal swabs, although both samples had low concentrations. Protein and miRNA yield were similar between matched samples. PCR demonstrated only a small amount DNA within samples was bacterial (>0.5%). Cervico-vaginal fluids EVs were successfully isolated from cervical brushes and vaginal swabs, demonstrating a new method of sampling reproductive EVs. EV yield from both sample types was low. Similar protein and miRNA levels suggest either sampling method may be suitable for biomarker studies. Show less

Genome-wide association studies implicate common genetic variations in the Fine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells were genome-edited using CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9) to delete or modify candidate enhancer regions and generate Multitrait colocalization analyses pointed at rs11172113 as the most likely causal variant in Our findings support allele-specific Show less

Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development. This systematic review was registered with Open Science Framework (DOI 10.17605/OSF.IO/N8TSA). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria. A total of 13 studies met our inclusion criteria, resulting in the identification of 251 unique proteins, with 27 (11%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found a subset of 3 proteins (C3, KNG1 & CFAH), 6 proteins (C3, C4A, APOA4, C4B, A2AP & BTD) and 7 proteins (C3, CLUS, APOA4, C6, A2AP, C1R & CFAI) have consistent regulation between multiple studies in samples from individuals at pre-seroconversion, post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development. Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays. Show less

MicroRNA 193a-3p (miR193a-3p) is a short non-coding RNA with tumor suppressor properties. Breast cancer (BC) progression is governed by active interaction between breast cancer cells, vascular (V)/lymphatic (L) endothelial cells (ECs), and BC secretome. We have recently shown that miR193a-3p, a tumor suppressor miRNA, inhibits MCF-7 BC cell-driven growth of VECs via direct antimitogenic actions and alters MCF-7 secretome. Since LEC-BC cross-talk plays a key role in BC progression, we investigated the effects of miR193a-3p on MCF-7 secretome and estradiol-mediated growth effects in LECs and LEC + MCF-7 spheroids, and delineated the underlying mechanisms. Transfection of LECs with miR193a-3p, as well as secretome from MCF-7 transfected cells, inhibited LEC growth, and these effects were mimicked in LEC + MCF-7 spheroids. Moreover, miR193a-3p inhibited ERK1/2 and Akt phosphorylation in LECs and LEC + MCF-7 spheroids, which are importantly involved in promoting cancer development and metastasis. Treatment of LECs and LEC + MCF-7 spheroids with estradiol (E2)-induced growth, as well as ERK1/2 and Akt phosphorylation, and was abrogated by miR193a-3p and secretome from MCF-7 transfected cells. Gene expression analysis (GEA) in LEC + MCF-7 spheroids transfected with miR193a-3p showed significant upregulation of 54 genes and downregulation of 73 genes. Pathway enrichment analysis of regulated genes showed significant modulation of several pathways, including interferon, interleukin/cytokine-mediated signaling, innate immune system, ERK1/2 cascade, apoptosis, and estrogen receptor signaling. Transcriptomic analysis showed downregulation in interferon and anti-apoptotic and pro-growth molecules, such as IFI6, IFIT1, OSA1/2, IFITM1, HLA-A/B, PSMB8/9, and PARP9, which are known to regulate BC progression. The cytokine proteome array of miR193a-3p transfected MCF secretome and confirmed the upregulation of several growth inhibitory cytokines, including IFNγ, Il-1a, IL-1ra, IL-32, IL-33, IL-24, IL-27, cystatin, C-reactive protein, Fas ligand, MIG, and sTIM3. Moreover, miR193a-3p alters factors in MCF-7 secretome, which represses ERK1/2 and Akt phosphorylation, induces pro-apoptotic protein and apoptosis in LECs, and downregulates interferon-associated proteins known to promote cancer growth and metastasis. In conclusion, miR193a-3p can potentially modify the tumor microenvironment by altering pro-growth BC secretome and inhibiting LEC growth, and may represent a therapeutic molecule to target breast tumors/cancer. Show less

The consumption of lycopene-rich foods may lower cardiovascular disease (CVD) risk. Lycopene circulates in the blood bound to lipoproteins, including high-density lipoproteins (HDLs). Preliminary data from our group showed that increased consumption of tomato-based food or lycopene supplement in middle-aged subjects led to functional changes to HDL's sub-fractions, HDL We carried out a comprehensive randomized controlled intervention trial with healthy middle-aged volunteers to assess whether the consumption of tomato-based foods or lycopene supplements affects HDL functionality and associated inflammatory markers, and lipoprotein subfractions size and distribution. Volunteers (225, aged 40-65 years) were randomly assigned to one of three dietary intervention groups and asked to consume a control diet (low in tomato-based foods, <10 mg lycopene/week), a lycopene-rich diet (224-350 mg lycopene/week), or the control diet with a lycopene supplement (70 mg lycopene/week). HDL Lycopene in serum and HDL significantly increased following consumption of both the high tomato diet and lycopene supplement ( Our results showed that dietary lycopene can significantly enhance HDL functionality, without associated changes in particle size and distribution, by modulating the activity of HDL-associated enzymes. Concomitantly, dietary lycopene significantly decreased serum- and HDL (https://www.isrctn.com), ISRCTN34203810. Show less

Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk. Show less

The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less

Ovarian deficiency, including premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR), represents one of the main causes of female infertility. POI is a genetically heterogeneous condition but current understanding of its genetic basis is far from complete, with the cause remaining unknown in the majority of patients. The genes that regulate DOR have been reported but the genetic basis of DOR has not been explored in depth. Both conditions are likely to lie along a continuum of degrees of decrease in ovarian reserve. We performed genomic analysis via whole exome sequencing (WES) followed by in silico analyses and functional experiments to investigate the genetic cause of ovarian deficiency in ten affected women. We achieved diagnoses for three of them, including the identification of novel variants in STAG3, GDF9, and FANCM. We identified potentially causative FSHR variants in another patient. This is the second report of biallelic GDF9 and FANCM variants, and, combined with functional support, validates these genes as bone fide autosomal recessive "POI genes". We also identified new candidate genes, NRIP1, XPO1, and MACF1. These genes have been linked to ovarian function in mouse, pig, and zebrafish respectively, but never in humans. In the case of NRIP1, we provide functional support for the deleterious nature of the variant via SUMOylation and luciferase/β-galactosidase reporter assays. Our study provides multiple insights into the genetic basis of POI/DOR. We have further elucidated the involvement of GDF9, FANCM, STAG3 and FSHR in POI pathogenesis, and propose new candidate genes, NRIP1, XPO1, and MACF1, which should be the focus of future studies. Show less

Regulator of G Protein Signaling (RGS) 17 is an overexpressed promoter of cancer survival in lung and prostate tumors, the knockdown of which results in decreased tumor cell proliferation in vitro. Identification of drug-like molecules inhibiting this protein could ameliorate the RGS17's pro-tumorigenic effect. Using high-throughput screening, a chemical library containing natural products was interrogated for inhibition of the RGS17-Gα Show less

Bicuspid aortic valve (BAV) is the most frequent congenital heart defect and has a male predominance of 3 to 1. A large proportion of patients develop valvular and aortic complications. Despite the high prevalence of BAV, its cause and genetic origins remain elusive. The goal of this study was to identify genetic variants associated with BAV. Nine genes previously associated with BAV (NOTCH1, AXIN1, EGFR, ENG, GATA5, NKX2-5, NOS3, PDIA2, and TGFBR2) were sequenced in 48 patients with BAV using the Ion Torrent Personal Genome Machine. Pathogenicity of genetic variants was evaluated with the Combined Annotation Dependent Depletion framework. A selection of 89 variants identified by sequencing or in previous BAV genetic studies was genotyped, and allele frequencies were compared in 323 patients with BAV confirmed at surgery and 584 controls. Analyses were also performed by gender. Nine novel and 19 potentially pathogenic variants were identified by next-generation sequencing and confirmed by Sanger sequencing, but they were not associated with BAV in the case-control population. A significant association was observed between an in silico-predicted benign EGFR intronic variant (rs17290301) and BAV. Analyses performed by gender revealed different variants associated with BAV in men (EGFR rs533525993 and TEX26 rs12857479) and women (NOTCH1 rs61751489, TGFBR2 rs1155705, and NKX2-5 rs2277923). In conclusion, these results constitute the first association between EGFR genetic variants and BAV in humans and support a possible role of gender-specific polymorphisms in the development of BAV. Show less

Embryonic developmental studies under microgravity conditions in space are very limited. To study the effects of altered gravity on the embryonic development processes we established an in vitro methodology allowing differentiation of mouse embryonic stem cells (mESCs) under simulated microgravity within a fast-rotating clinostat (clinorotation) and capture of microarray-based gene signatures. The differentiating mESCs were cultured in a 2D pipette clinostat. The microarray and bioinformatics tools were used to capture genes that are deregulated by simulated microgravity and their impact on developmental biological processes. The data analysis demonstrated that differentiation of mESCs in pipettes for 3 days resultet to early germ layer differentiation and then to the different somatic cell types after further 7 days of differentiation in the Petri dishes. Clinorotation influences differentiation as well as non-differentiation related biological processes like cytoskeleton related 19 genes were modulated. Notably, simulated microgravity deregulated genes Cyr61, Thbs1, Parva, Dhrs3, Jun, Tpm1, Fzd2 and Dll1 are involved in heart morphogenesis as an acute response on day 3. If the stem cells were further cultivated under normal gravity conditions (1 g) after clinorotation, the expression of cardiomyocytes specific genes such as Tnnt2, Rbp4, Tnni1, Csrp3, Nppb and Mybpc3 on day 10 was inhibited. This correlated well with a decreasing beating activity of the 10-days old embryoid bodies (EBs). Finally, we captured Gadd45g, Jun, Thbs1, Cyr61and Dll1 genes whose expressions were modulated by simulated microgravity and by real microgravity in various reported studies. Simulated microgravity also deregulated genes belonging to the MAP kinase and focal dhesion signal transduction pathways. One of the most prominent biological processes affected by simulated microgravity was the process of cardiomyogenesis. The most significant simulated microgravity-affected genes, signal transduction pathways, and biological processes which are relevant for mESCs differentiation have been identified and discussed below. Show less

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements. Show less

CBX5, CBX1, and CBX3 (HP1α, β, and γ, respectively) play an evolutionarily conserved role in the formation and maintenance of heterochromatin. In addition, CBX5, CBX1, and CBX3 may also participate in transcriptional regulation of genes. Recently, CBX3 binding to the bodies of a subset of genes has been observed in human and murine cells. However, the generality of this phenomenon and the role CBX3 may play in this context are unknown. Genome-wide localization analysis reveals CBX3 binding at genic regions, which strongly correlates with gene activity across multiple cell types. Depletion of CBX3 resulted in down-regulation of a subset of target genes. Loss of CBX3 binding leads to a more dramatic accumulation of unspliced nascent transcripts. In addition, we observed defective recruitment of splicing factors, including SNRNP70, to CBX3 target genes. Collectively, our data suggest a role for CBX3 in aiding in efficient cotranscriptional RNA processing. Show less

Most lung cancers are diagnosed too late for curative treatment to be possible, therefore early detection is crucial. Serum proteins are a rich source of biomarkers and have the potential to be used as diagnostic and prognostic indicators for lung cancer. In order to examine differences in serum levels of specific proteins associated with human lung squamous carcinoma, immunodepletion of albumin and five other high-abundant serum proteins followed by 2-D difference gel electrophoresis (DIGE) analysis and subsequent MS was used to generate a panel of proteins found to be differentially expressed between the cancer and normal samples. Proteins found to have increased abundance levels in squamous cell carcinoma sera compared to normal sera included apolipoprotein A-IV precursor, chain F; human complement component C3c, haptoglobin, serum amyloid A protein precursor and Ras-related protein Rab-7b. Proteins found to have lower abundance levels in squamous cell carcinoma sera compared to normal sera included alpha-2-HS glycoprotein, hemopexin precursor, proapolipoprotein, antithrombin III and SP40; 40. The data presented here demonstrate that high-abundant protein removal combined with 2-D DIGE is a powerful strategy for the discovery of potential biomarkers. The identification of lung cancer-specific biomarkers is crucial to early detection, which in turn could lead to a dramatic increase in survival rates. Show less

The t(12;21)(p13;q22) translocation is found in 20 to 25% of cases of childhood B-lineage acute lymphoblastic leukemia (B-ALL). This rearrangement results in the fusion of ETV6 (TEL) and RUNX1 (AML1) genes and defines a relatively uniform category, although only some patients suffer very late relapse. TEL/AML1-positive patients are thus an interesting subgroup to study, and such studies should elucidate the biological processes underlying TEL/AML1 pathogenesis. We report an analysis of gene expression in 60 children with B-lineage ALL using Agilent whole genome oligo-chips (44K-G4112A) and/or real time RT-PCR. We compared the leukemia cell gene expression profiles of 16 TEL/AML1-positive ALL patients to those of 44 TEL/AML1-negative patients, whose blast cells did not contain any additional recurrent translocation. Microarray analyses of 26 samples allowed the identification of genes differentially expressed between the TEL/AML1-positive and negative ALL groups. Gene enrichment analysis defined five enriched GO categories: cell differentiation, cell proliferation, apoptosis, cell motility and response to wounding, associated with 14 genes -RUNX1, TCFL5, TNFRSF7, CBFA2T3, CD9, SCARB1, TP53INP1, ACVR1C, PIK3C3, EGFL7, SEMA6A, CTGF, LSP1, TFPI - highlighting the biology of the TEL/AML1 sub-group. These results were first confirmed by the analysis of an additional microarray data-set (7 patient samples) and second by real-time RT-PCR quantification and clustering using an independent set (27 patient samples). Over-expression of RUNX1 (AML1) was further investigated and in one third of the patients correlated with cytogenetic findings. Gene expression analyses of leukemia cells from 60 children with TEL/AML1-positive and -negative B-lineage ALL led to the identification of five biological processes, associated with 14 validated genes characterizing and highlighting the biology of the TEL/AML1-positive ALL sub-group. Show less