Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion.

Adult-born granule cells (GCs), a minor population of cells in the hippocampal dentate gyrus, are highly active during the first few weeks after functional integration into the neuronal network, distinguishing them from less active, older adult-born GCs and the major population of dentate GCs generated developmentally. To ascertain whether young and old GCs perform distinct memory functions, we created a transgenic mouse in which output of old GCs was specifically inhibited while leaving a substantial portion of young GCs intact. These mice exhibited enhanced or normal pattern separation between similar contexts, which was reduced following ablation of young GCs. Furthermore, these mutant mice exhibited deficits in rapid pattern completion. Therefore, pattern separation requires adult-born young GCs but not old GCs, and older GCs contribute to the rapid recall by pattern completion. Our data suggest that as adult-born GCs age, their function switches from pattern separation to rapid pattern completion.

Defined Sensing Mechanisms and Signaling Pathways Contribute to the Global Inflammatory Gene Expression Output Elicited by Ionizing Radiation.

Environmental insults are often detected by multiple sensors that activate diverse signaling pathways and transcriptional regulators, leading to a tailored transcriptional output. To understand how a tailored response is coordinated, we examined the inflammatory response elicited in mouse macrophages by ionizing radiation (IR). RNA-sequencing studies revealed that most radiation-induced genes were strongly dependent on only one of a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, which regulated many IR-response genes, including interferon response genes, via an atypical IRF1-dependent, STING-independent mechanism. Moreover, small, defined sets of genes activated by p53 and NRF2 accounted for the selective response to radiation in comparison to a microbial inducer of inflammation. Our findings reveal that genes comprising an environmental response are activated by defined sensing mechanisms with a high degree of selectivity, and they identify distinct components of the radiation response that might be susceptible to therapeutic perturbation.

Low-dose mepolizumab is effective as an add-on therapy for treating long-lasting peripheral neuropathy in patients with eosinophilic granulomatosis with polyangiitis.

OBJECTIVE: To assess the effectiveness of low-dose mepolizumab as an add-on therapy for treating peripheral neurological symptoms in eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: We prospectively studied 13 EGPA patients with conventional treatment-resistant peripheral neuropathy. Their symptoms (pain, numbness, and muscle weakness) were assessed on a visual analogue scale (VAS) before and after 12 months of mepolizumab therapy (100 mg every 4 weeks). Peripheral eosinophil levels and several biomarkers including urinary levels of eosinophil-derived neurotoxin (EDN) were measured before and after therapy. RESULTS: VAS scores for pain and numbness significantly improved after 12 months of mepolizumab therapy (from 67.0 to 48.0, P = 0.012, and from 67.0 to 51.0, P = 0.017, respectively). However, the VAS score for muscle weakness did not improve (P = 0.36). There were significant correlations between treatment-related changes in urinary EDN levels from baseline to 6 months later and percent changes in the VAS scores of pain and numbness (r = 0.75, P = 0.020; r = 0.88, P = 0.002). CONCLUSIONS: Treatment-resistant peripheral neuropathy in EGPA was significantly improved by low-dose mepolizumab, and effectiveness was correlated with decreased urinary EDN. Because the possibility of a placebo effect cannot be formally excluded, placebo-controlled studies will be required in the future.

Exploring Automated Contouring Across Institutional Boundaries: A Deep Learning Approach with Mouse Micro-CT Datasets.

Image-guided mouse irradiation is essential to understand interventions involving radiation prior to human studies. Our objective is to employ Swin UNEt Transformers (Swin UNETR) to segment native micro-CT and contrast-enhanced micro-CT scans and benchmark the results against 3D no-new-Net (nnU-Net). Swin UNETR reformulates mouse organ segmentation as a sequence-to-sequence prediction task, using a hierarchical Swin Transformer encoder to extract features at 5 resolution levels, and connects to a Fully Convolutional Neural Network (FCNN)-based decoder via skip connections. The models were trained and evaluated on open datasets, with data separation based on individual mice. Further evaluation on an external mouse dataset acquired on a different micro-CT with lower kVp and higher imaging noise was also employed to assess model robustness and generalizability. Results indicate that Swin UNETR consistently outperforms nnU-Net and AIMOS in terms of average dice similarity coefficient (DSC) and Hausdorff distance (HD95p), except in two mice of intestine contouring. This superior performance is especially evident in the external dataset, confirming the model's robustness to variations in imaging conditions, including noise and quality, thereby positioning Swin UNETR as a highly generalizable and efficient tool for automated contouring in pre-clinical workflows.

Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity.

Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1-/- tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.

NRF2 Mediates Cellular Resistance to Transformation, Radiation, and Inflammation in Mice.

Nuclear factor erythroid 2-related factor 2 (NRF2) is recognized as a master transcription factor that regulates expression of numerous detoxifying and antioxidant cytoprotective genes. In fact, models of NRF2 deficiency indicate roles not only in redox regulation, but also in metabolism, inflammatory/autoimmune disease, cancer, and radioresistancy. Since ionizing radiation (IR) generates reactive oxygen species (ROS), it is not surprising it activates NRF2 pathways. However, unexpectedly, activation is often delayed for many days after the initial ROS burst. Here, we demonstrate that, as assayed by γ-H2AX staining, rapid DNA double strand break (DSB) formation by IR in primary mouse Nrf2-/- MEFs was not affected by loss of NRF2, and neither was DSB repair to any great extent. In spite of this, basal and IR-induced transformation was greatly enhanced, suggesting that NRF2 protects against late IR-induced genomic instability, at least in murine MEFs. Another possible IR- and NRF2-related event that could be altered is inflammation and NRF2 deficiency increased IR-induced NF-κB pro-inflammatory responses mostly late after exposure. The proclivity of NRF2 to restrain inflammation is also reflected in the reprogramming of tumor antigen-specific lymphocyte responses in mice where Nrf2 k.o. switches Th2 responses to Th1 polarity. Delayed NRF2 responses to IR may be critical for the immune transition from prooxidant inflammation to antioxidant healing as well as in driving cellular radioresistance and survival. Targeting NRF2 to reprogram immunity could be of considerable therapeutic benefit in radiation and immunotherapy.

[Steroid resistance of severe asthma - mechanisms and therapeutic targets].

Asthma therapy in general has improved a lot in recent years, but it is still a major problem that severe asthma, which accounts for 10 to 20%, still suffers from strong symptoms on a daily basis despite all therapeutic agents used in combination. American SARP and European ENFUMOSA started in 2000 to advance pathophysiological insights of severe asthma. Clinical usage of antibodies and inhibitors against IgE, TNF, IL-5, IL-4, IL-13, and TSLP are also accumulating. Some of these molecular-targeted drugs improve respiratory function and reduce acute exacerbations in patients with severe asthma. Until now, cytokines have been assumed to be involved in chronic inflammation, but it is also interesting to elucidate the pathways of how cytokines are involved in respiratory function and acute exacerbations. We registered approximately 100 steroid-dependent asthma patients in Japan. Although long-lasting poor control of the disease was considered the cause of severe asthma in the past, steroid dependence in one third of the cases occurred within 2-3 years after the onset. Steroid resistance seems a key process from the early stage of the disease. Steroid resistance of T cell level was induced by extracellular co-stimulation and cytokine signals. The inhibition may improve steroid sensitivity and treat steroid-resistant asthma. Therefore, we established a steroid-resistant asthma model for the first time by transferring steroid resistant T cell clones, and analyzed the steroid sensitivity recovery effect of CTLA4-Ig. In addition, a multicenter, double-blind, placebo-controlled exploratory trial was performed as a POC study investigating the efficacy of abatacept in treatment-resistant severe asthma. Elucidation of the pathophysiology and mechanism by which steroids do not work is expected to be a breakthrough for the prevention and treatment of severe asthma.

Weak Magnetic Fields Enhance the Efficacy of Radiation Therapy.

PURPOSE: The clinical efficacy of radiation therapy is mechanistically linked to ionization-induced free radicals that cause cell and tissue injury through direct and indirect mechanisms. Free radical reaction dynamics are influenced by many factors and can be manipulated by static weak magnetic fields (WMF) that perturb singlet-triplet state interconversion. Our study exploits this phenomenon to directly increase ionizing radiation (IR) dose absorption in tumors by combining WMF with radiation therapy as a new and effective method to improve treatment. METHODS AND MATERIALS: Coils were custom made to produce both homogeneous and gradient magnetic fields. The gradient coil enabled simultaneous in vitro assessment of free radical/reactive oxygen species reactivity across multiple field strengths from 6 to 66 G. First, increases in IR-induced free radical concentrations using oxidant-sensitive fluorescent dyes in a cell-free system were measured and verified. Next, human and murine cancer cell lines were evaluated in in vitro and in vivo models after exposure to clinically relevant doses of IR in combination with WMF. RESULTS: Cellular responses to IR and WMF were field strength and cell line dependent. WMF was able to enhance IR effects on reactive oxygen species formation, DNA double-strand break formation, cell death, and tumor growth. CONCLUSIONS: We demonstrate that the external presence of a magnetic field enhances radiation-induced cancer cell injury and death in vitro and in vivo. The effect extends beyond the timeframe when free radicals are induced in the presence of radiation into the window when endogenous free radicals are produced and therefore extends the applicability of this novel adjunct to cancer therapy in the context of radiation treatment.

Autologous transplantation of multilayered fibroblast sheets prevents postoperative pancreatic fistula by regulating fibrosis and angiogenesis.

INTRODUCTION: Postoperative pancreatic fistula (POPF) is a serious complication after gastrointestinal or pancreatic surgery. Despite intensive investigations, the occurrence has not significantly decreased in the past decades. The aims of this study were to clarify the pathophysiology of POPF and establish the preventive measures using multilayered fibroblast sheets. METHODS: We developed a pancreatic fistula (PF) model of rat with transection of the splenic duct and surrounding pancreatic parenchyma. Multilayered fibroblast sheets prepared from tails were autologously transplanted to this model. The preventive effect was biochemically and histologically evaluated by measuring the ascitic levels of pancreatic enzymes and conducting immunohistochemistry and real-time polymerase chain reaction analyses of pancreatic tissue. Findings were compared to those obtained with acellular materials simply sealing the wound. RESULTS: In the PF model, the ascitic levels of pancreatic enzymes were transiently up-regulated. Inflammation and necrosis were histologically observed in a wide range. Islets were damaged even in remote areas. Transplantation of multilayered fibroblast sheets dramatically reduced the ascitic leakage of enzymes, suppressed inflammation, and broadly preserved the islets. Compared with acellular materials, these sheets offered superior prevention of cellular activity through the spaciotemporal regulation of fibrosis and angiogenesis. Notably, the leakage hole appeared to have been plugged with the fibrotic matrix, which might have been the most crucial mechanism minimizing pancreatic damage. CONCLUSIONS: The autologous transplantation of multilayered fibroblast sheets significantly prevented PF and protected the pancreas, underscoring the potential utility of this approach for POPF prevention.

Classes of Drugs that Mitigate Radiation Syndromes.

We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the full analysis of the HTS screen of libraries with 85,000 small molecule chemicals that identified 220 "hits." Most of these hits could be allocated by maximal common substructure analysis to one of 11 clusters each containing at least three active compounds. Further screening validated 23 compounds as being most active; 15 of these were cherry-picked based on drug availability and tested for their ability to mitigate acute hematopoietic radiation syndrome (H-ARS) in mice. Of these, five bore a 4-nitrophenylsulfonamide motif while 4 had a quinoline scaffold. All but two of the 15 significantly (p < 0.05) mitigated H-ARS in mice. We had previously reported that the lead 4-(nitrophenylsulfonyl)-4-phenylpiperazine compound (NPSP512), was active in mitigating multiple acute and late radiation syndromes in mice of more than one sex and strain. Unfortunately, the formulation of this drug had to be changed for regulatory reasons and we report here on the synthesis and testing of active analogs of NPSP512 (QS1 and 52A1) that have increased solubility in water and in vivo bioavailability while retaining mitigator activity against H-ARS (p < 0.0001) and other radiation syndromes. The lead quinoline 057 was also active in multiple murine models of radiation damage. Taken together, HTS of a total of 150,000 bioactive or chemical substances, combined with maximal common substructure analysis has resulted in the discovery of diverse groups of compounds that can mitigate H-ARS and at least some of which can mitigate multiple radiation syndromes when given starting 24 h after exposure. We discuss what is known about how these agents might work, and the importance of formulation and bioavailability.

University of California Replacement of Cesium Irradiators with Alternative Technologies.

The University of California possesses a large number of Cs irradiators that are used in a wide variety of medical and research applications. The university president made a system-wide decision to reduce the potential threat of malevolent use of Cs by switching wherever feasible to x-ray irradiators over a 3-y period of time. A Radioactive Source Replacement Working Group of involved faculty was formed to study the topic and to make recommendations as to when alternative technologies could offer equivalency. The Working Group concluded that x-ray irradiators could replace Cs irradiators in most applications, with some likely exceptions. They found that the depth dose curve for the 320 kVp x-ray irradiator was found to be nearly identical to that of Cs down to a depth in tissue of 4 cm. It was concluded that x rays (energies ≤320 keV) are more biologically effective than Cs gamma rays, suggesting that lower doses of x rays will be required to achieve the same biological endpoint as Cs gamma rays. A simple conversion factor for equating x-ray effects to Cs effects was not recommended because relative biological effectiveness depends on multiple factors. They concluded that each experiment should be individually calibrated when converting from Cs irradiators to x-ray irradiators. The lessons learned from implementing the project to date have shown the importance of having senior management buy-in, involving the research community in the decision making process and allowing for exceptions where equivalency of Cs to x ray cannot be established.

Pulmonary nocardiosis caused by Nocardia blacklokiae in an immunocompetent patient.

A subset of Nocardia isolates, previously belonging to N. transvalensis, has recently been given the new species designation N. blacklokiae. Here we report a case of pulmonary nocardiosis caused by N. blacklokiae in a 52-year-old immunocompetent woman presenting with low-grade fever and fatigue. The isolated Nocardia strain was resistant to sulfamethoxazole-trimethoprim and amikacin, but susceptible to amoxicillin-clavunate, ceftriaxone, clarithromycin and linezolid. With amoxicillin-clavunate treatment, the patient recovered and her condition remained stable, although recurrence occurred after cessation of the initial treatment. While infection by Nocardia is rare, clinicians should be aware of its resistance to antimicrobials including amikacin and sulfamethoxazole-trimethoprim.

Identification of miRNA signatures associated with radiation-induced late lung injury in mice.

Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88-92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p, -100-5p, and -150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p, -96-5p, and -802-5p) was associated with TGF-ß/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.

Local irradiation of murine melanoma affects the development of tumour-specific immunity.

Radiation therapy affects the immune system. In addition to killing radiosensitive immune cells, it can induce functional changes in those cells that survive. Our recent studies showed that the exposure of dendritic cells (DCs) to radiation in vitro influences their ability to present tumour antigen in vivo. Here we show that local radiation therapy of B16 melanoma tumours inhibits the development of systemic immunity to the melanoma antigen MART-1. This inhibition could not be overcome by intratumoral injection of DCs expressing human MART-1 after radiation therapy, suggesting that a form of immune suppression might have developed. On the other hand, injection of MART-expressing DCs prior to tumour irradiation was able to prevent inhibition from developing. These results suggest that local radiation therapy may block the generation of immunity under some circumstances and that strategies may be required to prevent this and allow radiation-induced cell death to translate fully into the development of systemic immunity.

Epidermal growth factor receptor vIII expression in U87 glioblastoma cells alters their proteasome composition, function, and response to irradiation.

Little is known about the factors that influence the proteasome structures in cells and their activity, although this could be highly relevant to cancer therapy. We have previously shown that, within minutes, irradiation inhibits substrate degradation by the 26S proteasome in most cell types. Here, we report an exception in U87 glioblastoma cells transduced to express the epidermal growth factor receptor vIII (EGFRvIII) mutant (U87EGFRvIII), which does not respond to irradiation with 26S proteasome inhibition. This was assessed using either a fluorogenic substrate or a reporter gene, the ornithine decarboxylase degron fused to ZsGreen (cODCZsGreen), which targets the protein to the 26S proteasome. To elucidate whether this was due to alterations in proteasome composition, we used quantitative reverse transcription-PCR to quantify the constitutive (X, Y, Z) and inducible 20S subunits (Lmp7, Lmp2, Mecl1), and 11S (PA28alpha and beta) and 19S components (PSMC1 and PSMD4). U87 and U87EGFRvIII significantly differed in expression of proteasome subunits, and in particular immunosubunits. Interestingly, 2 Gy irradiation of U87 increased subunit expression levels by 16% to 324% at 6 hours, with a coincident 30% decrease in levels of the proteasome substrate c-myc, whereas they changed little in U87EGFRvIII. Responses similar to 2 Gy were seen in U87 treated with a proteasome inhibitor, NPI0052, suggesting that proteasome inhibition induced replacement of subunits independent of the means of inhibition. Our data clearly indicate that the composition and function of the 26S proteasome can be changed by expression of the EGFRvIII. How this relates to the increased radioresistance associated with this cell line remains to be established.

Imaging of radiation effects on cellular 26S proteasome function in situ.

PURPOSE: The classical radiobiological paradigm is that DNA is the target for cell damage caused by ionising radiation. However, evidence is accumulating that other constituents, such as the membrane, organelles, and proteins, are also important targets. We have shown that the isolated 26S proteasome is one such target and here we wish to substantiate it within the cell, in situ. MATERIALS AND METHODS: We used confocal microscopy to quantitatively detect and subcellularly localise radiation-induced 26S proteasome inhibition in cells expressing an ornithine decarboxylase degron that targets a fused Zoanthus species green (ZsGreen) fluorescent protein reporter specifically to the 26S proteasome. RESULTS: Exposure of cells to a range of radiation doses, even as low as 0.05 Gy inhibited 26S activity within minutes. Initially, punctate nuclear ZsGreen fluorescence was observed that became cytoplasmic after seven hours -- a pattern distinct from the diffuse homogeneous fluorescence of cells incubated in the conventional proteasome inhibitor MG-132. CONCLUSIONS: Our study clearly indicates that the 26S proteasome is a radiation target with physiological consequences and introduces a new perspective in mechanistic investigations of cellular responses to stresses.

Interstitial pneumonitis associated with dasatinib: two case reports and literature review.

Dasatinib has increasingly been used to treat chronic myeloid leukemia (CML), although interstitial pneumonitis has been found as a complication in large clinical trials. In the present study, 23 patients received dasatinib for CML between 2012 and 2017 at our institution, of whom 2 developed symptomatic interstitial pneumonitis. Notably, the first patient developed interstitial pneumonitis five years after initiating dasatinib. Interstitial pneumonitis should be considered as a complication in patients receiving dasatinib for CML, which may even occur after a long period of uncomplicated administration.

Association between Long-Term Second Malignancy Risk and Radiation: A Comprehensive Analysis of the Entire Surveillance, Epidemiology, and End Results Database (1973-2014).

PURPOSE: Second malignancies (SMs) after radiation therapy are rare but serious sequelae of treatment. This study investigates whether radiation therapy use is associated with changes in baseline SM risk. METHODS AND MATERIALS: We extracted all patients with cancer, with or without SM, in the Surveillance, Epidemiology, and End Results database from 1973 to 2014. Cumulative incidence of SM for patients stratified by radiation therapy status was calculated using a competing risk model, both for the entire cohort and for subgroups based on the primary tumor's anatomic location. RESULTS: We identified 2,872,063 patients with cancer, including 761,289 patients who received radiation therapy and 2,110,774 who did not. The SM rate at 20 years for patients receiving radiation therapy versus no radiation therapy was 21.4% versus 18.8%. The relative risk for SM associated with radiation therapy for the overall group was 1.138 at 20 years. The relative risks for SM associated with radiation therapy to malignancies arising from central nervous system and orbits, head and neck, thorax, abdomen, and pelvis at 20 years were 0.704, 1.011, 0.559, 0.646, and 1.106 for men and 0.792, 1.298, 1.265, 0.780, and 0.988 for women, respectively. CONCLUSIONS: The association between SM and radiation therapy varies with both sex and disease anatomic location, with the largest increase in SM seen in females irradiated to the head and neck region. Overall, the absolute change in SM rates associated with radiation therapy remains small, with differences in various clinical contexts.

Chronic Nodular Pulmonary Aspergillosis in a Patient with Rheumatoid Arthritis.

Chronic pulmonary aspergillosis, which features nodular lesions known as Aspergillus nodules, is a relatively uncommon disorder. We herein report a case of slowly progressing chronic multiple nodular pulmonary aspergillosis in a 59-year-old man with rheumatoid arthritis, dyspnea, and fatigue. One nodule was surgically resected. The surgical specimen featured central necrosis and was located adjacent to a respiratory bronchiole and pulmonary artery, without parenchymal invasion. Branching septate hyphae, compatible with Aspergillus, were seen inside this necrotic nodule. Chronic pulmonary aspergillosis should therefore be considered in the differential diagnosis of patients who present with slowly progressing pulmonary multiple nodules.

The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation.

Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD70/30 doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD70/30 doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.