Publications by authors named "Paul Milne"

Article Synopsis
  • Pathogenic mitochondrial DNA (mtDNA) variants are a frequent cause of mitochondrial diseases in adults, and their levels in blood decrease with age due to different metabolic needs among blood cell types.* -
  • A study involving cell-sorting and mtDNA sequencing found that T cells show a greater decline in these variants compared to other blood cells, driven by their ability to eliminate mutated mtDNA as they differentiate.* -
  • Compared to healthy controls, patients with these mtDNA variants have fewer T cells, highlighting the importance of mitochondrial function for maintaining T cell levels and differentiation status in the blood.*
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Article Synopsis
  • - The study investigates the genetic underpinnings of Erdheim-Chester disease (ECD), a rare condition characterized by abnormal immune cell activity, by conducting the first genome-wide association study to understand its inherited genetic factors.
  • - Researchers analyzed data from 255 ECD patients and 7,471 healthy individuals, identifying a significant genetic region (18q12.3) that could increase susceptibility to ECD, linked to the SETBP1 gene.
  • - The findings suggest that inherited genetic variants play a role in ECD development and point to new biological pathways that may contribute to the disease's progression.
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Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention.

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Most children with high-risk Langerhans cell histiocytosis (LCH) have BRAFV600E mutation. BRAFV600E alleles are detectable in myeloid mononuclear cells at diagnosis but it is not known if the cellular distribution of mutation evolves over time. Here, the profiles of 16 patients with high-risk disease were analyzed.

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  • The MLL/AF4 fusion gene is linked to a high-risk form of pro-B acute lymphoblastic leukemia, where relapses may switch the cancer type to acute myeloid leukemia, complicating treatment.
  • Research shows that during these relapses, the cancer cells retain specific genetic characteristics from the original leukemia and can develop from different stages of cell development.
  • Changes in chromatin accessibility and gene regulation, particularly involving the CHD4 gene, contribute to this lineage switching, suggesting that the cancer's development is driven by faulty epigenetic control.
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The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXLSIGLEC6 pre-DC, DC2 and DC3.

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Langerhans cells (LCs) in the skin are a first line of defense against pathogens but also play an essential role in skin homeostasis. Their exclusive expression of the C-type lectin receptor Langerin makes them prominent candidates for immunotherapy. For vaccine testing, an easily accessible cell platform would be desirable as an alternative to the time-consuming purification of LCs from human skin.

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Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder that is characterized by the inflammatory lesions with pathogenic CD1a+CD207+ dendritic cells (DCs). BRAFV600E and other somatic activating MAPK gene mutations have been identified in differentiating bone marrow and blood myeloid cells, but the origin of the LCH lesion CD1a+CD207+ DCs and mechanisms of lesion formation remain incompletely defined. To identify candidate LCH CD1a+CD207+ DC precursor populations, gene-expression profiles of LCH lesion CD1a+CD207+ DCs were first compared with established gene signatures from human myeloid cell subpopulations.

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Fms-like tyrosine kinase 3 (Flt3) is expressed on progenitor cells and acute myeloid leukemia (AML) blasts. Fms-like tyrosine kinase 3 ligand (Flt3L) is detectable during homeostasis and increases in hypoplasia due to genetic defects or treatment with cytoreductive agents. Conversely, Flt3+ AML is associated with depletion of Flt3L to undetectable levels.

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Purpose: Off-label use of vemurafenib (VMF) to treat mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.

Patients And Methods: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia.

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Article Synopsis
  • The ATR protein kinase helps cancer cells survive by responding to problems in DNA replication, which is often seen in cancers like acute myeloid leukemia (AML).
  • Researchers found that using ATR inhibitors together with drugs like hydroxyurea and gemcitabine greatly increased the effectiveness of treatment by disrupting ribonucleotide reductase (RNR) and slowing down replication fork progress.
  • In a mouse model of leukemia, combining the ATR inhibitor VX-970 with gemcitabine completely eliminated the disease and led to long-term survival, suggesting this combination could be a promising approach for treating AML and similar blood cancers.
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Background: The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function.

Objective: We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification.

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Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes. mutation is the most common mutation in both conditions and also occurs in the hematopoietic neoplasm hairy cell leukemia (HCL). It is not known if adult LCH or ECD arises from hematopoietic stem cells (HSCs), nor which potential blood borne precursors lead to the formation of histiocytic lesions.

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Objective: To identify a treatment-responsive mutation in brainstem neurohistiocytosis, where no lesional tissue was readily obtainable, using a cell-free DNA approach.

Methods: Cell-free DNA was extracted from urine and allele-specific PCR for the mutation was performed. Response to conventional treatment (corticosteroids and interferon) and targeted treatment with a BRAF inhibitor was assessed by clinical evaluation, gadolinium-enhanced MRI brain scan, and serial testing of urinary cell-free DNA for mutant alleles.

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Germinal centers (GCs) are microanatomical structures critical for the development of high-affinity Abs and B cell memory. They are organized into two zones, light and dark, with coordinated roles, controlled by local signaling. The innate lectin-like transcript 1 (LLT1) is known to be expressed on B cells, but its functional role in the GC reaction has not been explored.

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Purpose Of Review: This article summarizes recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions.

Recent Findings: Langerhans cells originate prenatally and may endure throughout life, independently of bone marrow-derived precursors. Fate-mapping experiments have recently resolved the relative contribution of primitive yolk sac and fetal liver hematopoiesis to the initial formation of Langerhans cells.

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The Applied Knowledge Test (AKT) of the Membership of the Royal College of General Practitioners (MRCGP) examination is a computer-based assessment delivered three times a year. A computerised questionnaire, administered immediately after the test, sought candidates' views as part of the test evaluation. Of 1681 candidates taking the test 1418 (84%) responded.

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Langerin is a C-type lectin expressed at high level by LCs of the epidermis. Langerin is also expressed by CD8(+)/CD103(+) XCR1(+) cross-presenting DCs of mice but is not found on the homologous human CD141(high) XCR1(+) myeloid DC. Here, we show that langerin is expressed at a low level on DCs isolated from dermis, lung, liver, and lymphoid tissue and that langerin(+) DCs are closely related to CD1c(+) myeloid DCs.

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Langerhans cells (LCs) are self-renewing in the steady state but repopulated by myeloid precursors after injury. Human monocytes give rise to langerin-positive cells in vitro, suggesting a potential precursor role. However, differentiation experiments with human lineage-negative cells and CD34(+) progenitors suggest that there is an alternative monocyte-independent pathway of LC differentiation.

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Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart.

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