Calibration curve for radiation dose estimation using FDXR gene expression biodosimetry - premises and pitfalls.

Purpose: Radiation-induced alterations in gene expression show great promise for dose reconstruction and for severity prediction of acute health effects. Among several genes explored as potential biomarkers, FDXR is widely used due to high upregulation in white blood cells following radiation exposure. Nonetheless, the absence of a standardized protocols for gene expression-based biodosimetry is a notable gap that warrants attention to enhance the accuracy, reproducibility and reliability.

Anxiety and depression among adults with haemophilia A: Patient and physician reported symptoms from the real-world European CHESS II study.

Introduction: The physical pain and disability affecting many people with haemophilia A (PwHA) are known detractors from psychological wellbeing. While psychosocial support is considered a core tenet of the haemophilia comprehensive care structure, the extent to which mental health challenges are detected and monitored by the individuals treating haematologist remains relatively unexplored.

Aim: To describe prevalence of anxiety and depression in a real-world cohort of adult PwHA and evaluate the congruence in reporting of anxiety or depression (A/D) between PwHA and their treating physicians.

Transcriptional Inflammatory Signature in Healthy Donors and Different Radiotherapy Cancer Patients.

Cancer and ionizing radiation exposure are associated with inflammation. To identify a set of radiation-specific signatures of inflammation-associated genes in the blood of partially exposed radiotherapy patients, differential expression of 249 inflammatory genes was analyzed in blood samples from cancer patients and healthy individuals. The gene expression analysis on a cohort of 63 cancer patients (endometrial, head and neck, and prostate cancer) before and during radiotherapy (24 h, 48 h, ~1 week, ~4-8 weeks, and 1 month after the last fraction) identified 31 genes and 15 up- and 16 down-regulated genes.

Epigenetic signature of ionizing radiation in therapy-related AML patients.

Therapy-related acute myeloid leukaemia (t-AML) is a late side effect of previous chemotherapy (ct-AML) and/or radiotherapy (rt-AML) or immunosuppressive treatment. t-AMLs, which account for ∼10-20 % of all AML cases, are extremely aggressive and have a poor prognosis compared to AML. Our hypothesis is that exposure to radiation causes genome-wide epigenetic changes in rt-AML.

R235C point mutation confers hypersensitivity to radiation-induced acute myeloid leukemia in mice.

Ionizing radiation (IR) is a risk factor for acute myeloid leukemia (rAML). Murine rAMLs feature both hemizygous chromosome 2 deletions (Del2) and point mutations (R235) within the hematopoietic regulatory gene . We generated a heterozygous CBA R235 mouse (CBA) which develops AML with 100% incidence by ∼12 months old and shows a dose-dependent reduction in latency following X-irradiation.

Deficient Radiation Transcription Response in COVID-19 Patients.

Purpose: The ongoing SARS-CoV-2 pandemic has resulted in over 6.3 million deaths and 560 million COVID-19 cases worldwide. Clinical management of hospitalized patients is complex due to the heterogeneous course of COVID-19.

Transcriptional Dynamics of DNA Damage Responsive Genes in Circulating Leukocytes during Radiotherapy.

External beam radiation therapy leads to cellular activation of the DNA damage response (DDR). DNA double-strand breaks (DSBs) activate the ATM/CHEK2/p53 pathway, inducing the transcription of stress genes. The dynamic nature of this transcriptional response has not been directly observed in vivo in humans.

A 4-Gene Signature of CDKN1, FDXR, SESN1 and PCNA Radiation Biomarkers for Prediction of Patient Radiosensitivity.

The quest for the discovery and validation of radiosensitivity biomarkers is ongoing and while conventional bioassays are well established as biomarkers, molecular advances have unveiled new emerging biomarkers. Herein, we present the validation of a new 4-gene signature panel of CDKN1, FDXR, SESN1 and PCNA previously reported to be radiation-responsive genes, using the conventional G2 chromosomal radiosensitivity assay. Radiation-induced G2 chromosomal radiosensitivity at 0.

An ionising radiation-induced specific transcriptional signature of inflammation-associated genes in whole blood from radiotherapy patients: a pilot study.

Background: This communication reports the identification of a new panel of transcriptional changes in inflammation-associated genes observed in response to ionising radiation received by radiotherapy patients.

Methods: Peripheral blood samples were taken with ethical approval and informed consent from a total of 20 patients undergoing external beam radiotherapy for breast, lung, gastrointestinal or genitourinary tumours. Nanostring nCounter analysis of transcriptional changes was carried out in samples prior and 24 h post-delivery of the 1st radiotherapy fraction, just prior to the 5th or 6th fraction, and just before the last fraction.

Role of blood derived cell fractions, temperature and sample transport on gene expression-based biological dosimetry.

Purpose: For triage purposes following a nuclear accident or a terrorist event, gene expression biomarkers in blood have been demonstrated to be good bioindicators of ionizing radiation (IR) exposure and can be used to assess the dose received by exposed individuals. Many IR-sensitive genes are regulated by the DNA damage response pathway, and modulators of this pathway could potentially affect their expression level and therefore alter accurate dose estimations. In the present study, we addressed the potential influence of temperature, sample transport conditions and the blood cell fraction analyzed on the transcriptional response of the following radiation-responsive genes: FDXR, CCNG1, MDM2, PHPT1, APOBEC3H, DDB2, SESN1, P21, PUMA, and GADD45.

Identification of two novel mutations in human acute myeloid leukemia cases.

Acute myeloid leukemia (AML) is an aggressive cancer that progresses rapidly with a poor prognosis. Cytogenetic analysis provides the most accurate determination of diagnosis and prognosis however, about 42-48% of AML patients have a cytogenetically normal karyotype. Genetic analysis can provide further information and the identification of new mutations could result in improved risk stratification, prognosis and better understanding of the mechanisms of AML leukaemogenesis.

In Vivo Validation of Alternative FDXR Transcripts in Human Blood in Response to Ionizing Radiation.

Following cell stress such as ionising radiation (IR) exposure, multiple cellular pathways are activated. We recently demonstrated that ferredoxin reductase (FDXR) has a remarkable IR-induced transcriptional responsiveness in blood. Here, we provided a first comprehensive FDXR variant profile following DNA damage.

Generation of a Transcriptional Radiation Exposure Signature in Human Blood Using Long-Read Nanopore Sequencing.

In the event of a large-scale event leading to acute ionizing radiation exposure, high-throughput methods would be required to assess individual dose estimates for triage purposes. Blood-based gene expression is a broad source of biomarkers of radiation exposure which have great potential for providing rapid dose estimates for a large population. Time is a crucial component in radiological emergencies and the shipment of blood samples to relevant laboratories presents a concern.

Kras mutations and PU.1 promoter methylation are new pathways in murine radiation-induced AML.

Therapy-related and more specifically radiotherapy-associated acute myeloid leukaemia (AML) is a well-recognized potential complication of cytotoxic therapy for the treatment of a primary cancer. The CBA mouse model is used to study radiation leukaemogenesis mechanisms with Sfpi1/PU.1 deletion and point mutation already identified as driving events during AML development.

Combining CDKN1A gene expression and genome-wide SNPs in a twin cohort to gain insight into the heritability of individual radiosensitivity.

Individual variability in response to radiation exposure is recognised and has often been reported as important in treatment planning. Despite many efforts to identify biomarkers allowing the identification of radiation sensitive patients, it is not yet possible to distinguish them with certainty before the beginning of the radiotherapy treatment. A comprehensive analysis of genome-wide single-nucleotide polymorphisms (SNPs) and a transcriptional response to ionising radiation exposure in twins have the potential to identify such an individual.

Dicentric Dose Estimates for Patients Undergoing Radiotherapy in the RTGene Study to Assess Blood Dosimetric Models and the New Bayesian Method for Gradient Exposure.

The RTGene study was focused on the development and validation of new transcriptional biomarkers for prediction of individual radiotherapy patient responses to ionizing radiation. In parallel, for validation purposes, this study incorporated conventional biomarkers of radiation exposure, including the dicentric assay. Peripheral blood samples were taken with ethical approval and informed consent from a total of 20 patients undergoing external beam radiotherapy for breast, lung, gastrointestinal or genitourinary tumors.

Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability .

: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). : We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR.

Influence of Confounding Factors on Radiation Dose Estimation Using In Vivo Validated Transcriptional Biomarkers.

For triage purposes following a nuclear accident, blood-based gene expression biomarkers can provide rapid dose estimates for a large number of individuals. Ionizing-radiation-responsive genes are regulated through the DNA damage-response pathway, which includes activation of multiple transcription factors. Modulators of this pathway could potentially affect the response of these biomarkers and consequently compromise accurate dose estimation calculations.

Tracking preleukemic cells in vivo to reveal the sequence of molecular events in radiation leukemogenesis.

Epidemiological studies have demonstrated an increased leukemia incidence following ionizing radiation exposure, but to date, the target cells and underlying mechanisms of radiation leukemogenesis remain largely unidentified. We engineered a mouse model carrying a different fluorescent marker on each chromosome 2, located inside the minimum deleted region occurring after radiation exposure and recognized as the first leukemogenic event. Using this tailored model, we report that following radiation exposure, more than half of asymptomatic CBA Sfpi1 mice presented with expanding clones of preleukemic hematopoietic cells harboring a hemizygous interstitial deletion of chromosome 2.

The first in vivo multiparametric comparison of different radiation exposure biomarkers in human blood.

The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.

Difficulties adjusting to post-discharge life following a spinal cord injury: an interpretative phenomenological analysis.

Individual semi-structured interviews were conducted with 17 individuals who had experienced a traumatic spinal cord injury (SCI), focusing on the participants' lived experience of SCI. The interviews were transcribed verbatim and were analysed for recurrent themes using interpretative phenomenological analysis (IPA). Here, we present three inter-related recurrent themes all concerning difficulties in adjusting to home life following hospital discharge: "loss of camaraderie", "lack of post-discharge care" and "other people's reactions to spinal cord injury".

Adjustment and coping in spousal caregivers following a traumatic spinal cord injury: an interpretative phenomenological analysis.

Semi-structured interviews were conducted with 11 spousal caregivers to people with a traumatic spinal cord injury and were subjected to interpretative phenomenological analysis (IPA). Here, we present two inter-related master themes: (1) coping with the spousal caregiver role; and (2) putting the pieces back together again. Within these, the analysis describes how regular venting of emotion, social support and focusing on the positive aspects of the situation all promoted coping.

The impact of assuming the primary caregiver role following traumatic spinal cord injury: An interpretative phenomenological analysis of the spouse's experience.

This study aimed to explore the lived experience of assuming the primary caregiver role in a group of spouses of individuals living with a traumatic spinal cord injury (SCI) (injuries ranged from paraplegia to quadriplegia). Individual in-depth interviews were conducted with 11 participants who were both the spouse and primary caregiver of an individual with a SCI; of these, 10 were female and 1 was male. All interviews were transcribed verbatim and were subjected to interpretative phenomenological analysis (IPA).