The significantly higher prevalence of CD in children with type 1 diabetes, in accordance with the large volume of data published in the literature, underlines the need for yearly screening of CD in patients with diabetes in order to promptly start a gluten-free diet when appropriate.
CLL remains incurable despite BCR-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate, which is activated by unmethylated CpG-DNA. Here, we show that plasma from CLL patients contains significantly more unmethylated DNA than plasma from healthy controls (p<0.0001) and that cell-free DNA levels correlate with the prognostic markers CD38, b2-microglobulin and lymphocyte doubling time. Furthermore, elevated cell-free DNA was associated with shorter time to first treatment (TTFT: p=0.003, HR=4.0). We went on to show that TLR9 expression was associated with in-vitro CLL cell migration (p<0.001) and intracellular endosomal TLR9 strongly correlated with aberrant surface expression ((sTLR9); r=0.9). In addition, lymph node-derived CLL cells showed increased sTLR9 (p=0.016) and RNA sequencing of paired sTLR9hi and sTLR9lo CLL cells revealed differential transcription of genes involved in TLR signaling, adhesion, motility and inflammation in sTLR9hi cells. Mechanistically, the TLR9 agonist, ODN2006, promoted CLL cell migration (p<0.001) that was mediated, by p65 NF-kB and STAT3 transcription factor activation. Importantly, autologous plasma induced the same effects, which were reversed by a TLR9 antagonist. Furthermore, high TLR9 expression promoted engraftment and rapid disease progression in a NSG mouse xenograft model. Finally, we showed that dual targeting of TLR9 and BTK was strongly synergistic (median CI=0.2 at ED50), which highlights the distinct role for TLR9 signaling in CLL and the potential for combined targeting of TLR9 and BTK as a more effective treatment strategy in this incurable disease.
The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom’s 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia.
Two distinct systems of different origin are involved in the pathogenesis of both infectious and immunological vasculitis syndrome: nitric oxide (NO) from endothelial cells and granulocyte NADPH oxidase. In this study, in 31 children with immune system dysfunction, NO, NO synthase (NOS) and antioxidant enzyme activities [catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx)], as well as immunological parameters, were investigated. On the basis of the clinical findings, all children were divided into three groups: group I, 8 children clinically showing macular skin manifestations; group II, 11 children with maculo-papulous changes; and group III, 12 children with clinical findings of papulous changes. Plasma NO values in groups II and III were significantly elevated (79.14+/-30.13 and 65.32+/-6.70 micromol/l), compared to the control group (41.24+/-3.65 micromol/l), while group I showed statistically lower values (32.38+/-3.37 micromol/l). In children with the highest level of NO (group II) NOS activity was two-fold higher (1.77+/-0.59 nmol/ml/min; p<0.01) than in controls (0.98+/-0.23 nmol/ml/min). Catalase activity showed a significant increase and SOD activity a significant decrease in all experimental groups, while GPx was not significantly changed. The results show that immune system dysfunction manifested as vasculitis is associated with significant disturbances in the NO system and free radicals scavengers.
We report here a case of acquired hypopituitarism in a female neonate with Salmonella enteritidis sepsis and cystic encephalomalacia, after prolonged dopamine administration. Severe hyponatremia was suggestive of hypopituitarism development and the later was documented by hormonal status. This is the first report of infectious hypophysitis in neonatal age. The careful monitoring of pituitary function should be recommended for septic patients exposed to prolonged use of dopamine.
Current prognostic indicators such as age, sex, and white blood cell count (WBC) fail to identify all children with more aggressive forms of B-precursor acute lymphoblastic leukemia (ALL), and a proportion of patients without poor prognostic indicators still relapse. Results obtained from an analysis of 65 pediatic B-precursor ALL patients indicated that subclone formation leading to clonal diversity, as detected by Ig and T-cell receptor (TCR) gene rearrangements, may represent a very useful prognostic indicator, independent of age, sex, and WBC. Disease-free survival was significantly shorter in those patients showing clonal diversity at presentation. Furthermore, clonal diversity was detected not only in the majority of high-risk patients who relapsed but was also associated with a high probability of relapse in standard-risk patients. Sixty-five percent (13/20) of standard-risk patients who also showed clonal diversity subsequently relapsed, whereas the percentage of relapses among standard-risk patients without clonal diversity was much lower at 19% (7/36). Continued clonal evolution during disease progression is an important feature of aggressive B-precursor ALL. All 5 patients with clonal diversity who were followed up in our study showed a change in the pattern of clonality between presentation and relapse. This implies an important role for clonal diversity as a mechanism of disease progression through the process of clonal variation and clonal selection. © 1998 by The American Society of Hematology.
711 Mutations or deletions of the tumor suppressor p53 or its upstream kinase ATM are well-known determinants of poor prognosis in Chronic Lymphocytic Leukemia (CLL). In recent years, genome wide sequencing has uncovered novel gene mutations that correspond with poor prognosis. Specifically, recurrent mutations in the splicing factor SF3B1 and the Notch and NRAS/KRAS oncogenes have been found. These mutations were (in part) mutually exclusive with p53 and/or ATM mutations, which suggested overlap in biological function. Here, we report results of a comparative analysis of p53 target genes and in vitro drug responses in CLL samples with either p53 (n=9), ATM (n=10), SF3B1 (n=11), Notch (n=6), or NRAS/KRAS (n=4) gene deletions/mutations. We found that upon irradiation, mRNA induction of all tested p53 targets genes (p21, Puma, CD95, Bax, PCNA, FXDR) was clearly decreased in all SF3B1 mutated CLL samples (overall p<0.001). SF3B1 samples resembled ATM mutated/11q− CLL in displaying a defective but not absent p53 response. In contrast, Notch and KRAS/NRAS mutations did not affect RNA induction of apoptosis inducers Puma and Bax. At the protein level, Puma and p21 induction were defective or absent in SF3B1 mutated CLL. This corresponded with decreased apoptosis after in vitro treatment with fludarabine. Treatment with nutlin, either alone or in combination with fludarabine, restored cell death induction, again indicating an overlap with ATM dysfunction. To establish possible causality between SF3B1 mutation and ATM dysfunction, more genetic and functional studies are ongoing and will be reported. In conclusion, the recently described mutations in a splicing factor in CLL can be linked at the functional level to defective ATM and/or p53 target gene responses, providing an explanation for the poor clinical prognosis of CLL patients with SF3B1 mutations. Disclosures: No relevant conflicts of interest to declare.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.