Marrow Transplantation Research Articles

Macrophage MST4 exacerbates cardiac microvascular ischaemia/reperfusion injury by phosphorylating ACLY

Abstract Background Cardiac microvascular dysfunction is a contributing factor in the development of cardiac ischaemia/reperfusion (I/R) injury. The STE20-type kinases play important role in cardiovascular diseases. However, the impact of mammalian Ste20-like kinase 4 (MST4) on cardiac microvascular I/R injury remains unknown. Purpose To decipher the role of MST4 in cardiac microvascular I/R injury and the underlying mechanisms. Methods Single-cell RNA sequencing of I/R mouse heart was performed to explore the expression changes of MST4 in different cell types. MST4 flox (MST4 f/Y) mice was crossed with myeloid-specific LysM-Cre mice to generate myeloid-specific MST4 knockout mice (MST4 CKO). Bone marrow transplantation was used to testify the role of myeloid-derived MST4 in cardiac microvascular I/R injury. Bone-marrow-derived macrophage (BMDM) and cardiac microvascular endothelial cell (CMEC) were used to dissect molecular mechanisms. Adeno-associated virus and adenovirus were constructed to overexpress ATP Citrate Lyase (ACLY) with mutation of serine 455 (S455A) in vivo and in vitro, respectively. Phosphoproteomics, coimmunoprecipitation coupled with liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis and metabolomics were performed to decipher the downstream of MST4. Results MST4 is dominantly upregulated in CCR2+ monocyte-derived macrophages. Myeloid-specific deficiency of MST4 improves cardiac performance in I/R mouse model. Wild type (WT) mice transplanted with BMDM from MST4 CKO mice also exhibited improved cardiac function after I/R, however, MST4 CKO mice transplanted with BMDM from WT mice showed deteriorated cardiac performance. Metabolomics showed that primary bile acid biosynthesis pathway was upregulated in BMDM overexpressing MST4. The level of 7α-hydroxyl3-oxo-4-cholestenoic acid (7-HOCA), an intermediate of bile acid, was dramatically increased in I/R mice or BMDM overexpressing MST4, which can be reversed by knocking down MST4. Phosphoproteomics and LC-MS/MS analysis discovered that ACLY was one of the most important substrates of MST4 in the process of I/R injury. ACLY was directly phosphorylated by MST4 at serine 455, which increased ACLY enzyme activity. Mechanistically, ACLY promoted cholesterol catabolism through the bile acid synthesis pathway, leading to the accumulation of 7-HOCA in the macrophage-endothelial cell microenvironment. High level of 7-HOCA was able to promote endothelial cell mtDNA release, leading to endothelial cell pyroptosis through inflammasome pathway. However, mutation of serine 455 of ACLY blocked the role of MST4. Conclusions Our data defined a previously unrecognized role of MST4/ACLY pathway in cardiac microvascular I/R injury. MST4 led to the accumulation of 7-HOCA by phosphorylating ACLY, furthermore, 7-HOCA promoted endothelial cell injury. Targeting MST4/ACLY pathway ameliorated microvascular I/R injury, which may provide a novel therapeutic strategy for I/R injury.

Endothelial insulin-like growth factor-1 signaling regulates vascular barrier function and atherogenesis

Abstract Background Progressive deposition of cholesterol in the arterial wall characterizes atherosclerosis, which underpins most cases of myocardial infarction and stroke. Insulin-like growth factor-1 (IGF-1) is a hormone that regulates systemic growth and metabolism and possesses anti-atherosclerotic properties. However, the role of IGF-1 in the endothelium remains unexplored. Purpose To study the effect of increased endothelial IGF-1 receptor (IGF-1R) expression on atherogenesis using in vivo and in vitro models. Methods We generated atherosclerosis prone ApoE-/- transgenic mice with endothelium restricted overexpression of human IGF-1R (hIGFREO-ApoE-/-) or signalling defective K1003R mutant IGF-1R (mIGFREO-ApoE-/-). ApoE-/- littermates were controls. Following 12 weeks of western diet, we assessed atherosclerosis, systemic metabolism, leukocyte homeostasis and vascular permeability using histology, flow cytometry, metabolic testing, bone marrow transplantation and in vivo perfusion with either VE-Cadherin, Evans blue or BODIPY-LDL. For in vitro studies, human umbilical vein endothelial cells were transduced with custom-made lentivirus particles allowing doxycyline-inducible wild-type or mutant K1003R IGF-1R overexpression; with transduced cells not exposed to doxycycline as controls. Confluent cells were exposed to 100mM hydrogen peroxide to model the permeability-inducing conditions observed in atherosclerosis. In vitro, we assessed junctional proteins, FITC-dextran permeability and transcellular BODIPY-LDL uptake. Results We show that mice with endothelial overexpression of IGF-1R have less atherosclerosis, arterial cholesterol uptake, and vascular leakage of multiple organs. Conversely, mice with endothelial overexpression of signalling defective IGF-1R did not exhibit these phenomena. We found no differences in systemic metabolism or growth. In complementary in vitro studies, overexpressing wildtype IGF-1R altered the localization of some tight junction proteins (VE-Cadherin and Claudin 5) and reduced leakage across human endothelial monolayers; this was not observed with signalling defective IGF-1R. Moreover, it reduced endothelial cell internalization of cholesterol-rich lipoproteins and increased the association of these particles with clathrin, but not caveolin-1, both of which participate in vesicular uptake of lipoproteins. Conclusion Overall, our findings indicate that endothelial IGF-1 signalling modulates both para- and trans-cellular vascular barrier function. This is particularly relevant to the phenomenon of atherosclerosis and suggests that increased vascular IGF-1 signalling reduces atherosclerosis. Beyond this, our data are potentially relevant to many disease processes associated with altered vascular barrier function. This discovery could lead to novel therapeutics to normalise vascular barrier function.

Bidirectional roles of extracellular and intracellular HMGB2 in the development of atherosclerosis

Abstract Rationale: HMGB family plays an important role in homeostasis of immunity and regulation of inflammation. However, the role of HMGB2 in atherosclerosis remains uncharacterized. Objective The current study aimed to ascertain the relation of HMGB2 levels in macrophages of atherosclerotic plaques and in circulatory monocytes/macrophages with coronary artery disease (CAD), and to investigate the influence of HMGB2 on atherogenesis in mice and inflammatory reaction in vitro. Methods/Results We evaluated HMGB2 levels in macrophages of atherosclerotic plaques in coronary endarterectomy tissue from patients with angiographically documented severe coronary artery disease (CAD)(n=23), and in coronary artery specimens from autopsy cases with no or mild atherosclerosis (n=11) by immunohistochemistry. HMGB2 levels were significantly decreased in macrophages of progressive atherosclerotic plaques, as compared with those from mild plaques. Moreover, we also analyzed HMGB2 levels in peripheral blood monocytes from patients with CAD (n=44) or age- and sex-matched non-CAD controls (n=44). The results showed that decreased intracellular HMGB2 protein levels in monocytes were associated with CAD. In experiments, HMGB2 deficiency significantly promoted atherosclerosis in ApoE-/- mice, whereas such increment of atherosclerosis was markedly attenuated after transplantation of bone marrow derived macrophages from ApoE-/-mice. Mechanistically, intracellular HMGB2 repressed IL-1 transcription and induced autophagic degradation of NLRP3, thus suppressing NLRP3 inflammasome priming and activation. Extracellular HMGB2 levels increased in progressive atherosclerotic plaques with macrophage apoptosis. Recombinant HMGB2 protein promoted inflammation in vitro via RAGE and intraperitoneal administration of this protein exacerbated atherosclerosis in mice. Conclusion This study indicates that decreased HMGB2 level in macrophage is associated with inflammation and atherosclerosis in patients with CAD. Intracellular HMGB2 inhibits NLRP3 inflammasome and atherosclerosis in mice, whereas released HMGB2 promotes inflammation and atherosclerosis in mice.

Conditional over-expression of heme-oxygenase 1 in myelomonocytic cells reduces AngII-induced hypertension and vascular inflammation in mice

Abstract Background Systemic arterial Hypertension is one of the most important risk factor responsible for morbidity and mortality world-wide. Angiotensin II (Ang II), a potent vasoconstrictor and key player in the renin-angiotensin-aldosterone system (RAAS) is responsible for vascular dysfunction, inflammation, and tissue damage. Heme oxygenase-1 (HO-1) overexpression may confer antioxidant and anti-inflammatory properties in Ang II-induced hypertension through its action on heme catabolism, generating carbon monoxide (CO), ferritin and biliverdin/bilirubin by the action of biliverdin reductase A (BLVRA). Methods and results Male 9–12-weeks-old HO-1indxLySMCre/wt and LySMCre/wt mice were infused with AngII (1mgAngII/Day/Kg) for 7 days to induce hypertension and compared to sham treatment. Blood pressure monitoring by tail-cuff method, and endothelium-dependent vasodilator studies via organ chamber system using acetylcholine (ACh) in isolated aortic segments (~4 mm), revealed that overexpression of HO-1 in myeloid cells resulted in decreased systolic blood pressure and improved endothelial function in AngII-infused HO-1indxLySMCre/wt mice compared to controls. Concurrently, increased BLVRA expression in liver tissue and elevated plasma bilirubin levels were detected by transcriptome analysis and high-performance liquid chromatography, respectively. These results were supported by a reduction in the expression of inducible cytokines and cell adhesion molecules (CAMs) in the aorta, assessed using qPCR. Bone marrow transplant experiments demonstrated that bone marrow from LysMcre mice in HO-1indxLySMCre/wt mice abrogated the protective effect of HO-1, resulting in endothelial damage and increased blood pressure, potentially due to decreased liver BLVRA expression and the accumulation of bone marrow-derived cells in the vessel wall in response to AngII. Additionally, adeno-associated viral vector (AAV) transfection targeting specifically BLVRA activity in liver lead to an increase in blood pressure values and worse endothelium relaxation, in parallel with higher oxidative stress and the blood neutrophils concentration, as assessed in whole blood by using oxidative burst method and blood count system respectively. Conclusion The overexpression of HO-1 in myeloid cells confers anti-inflammatory protection in AngII-induced arterial hypertension in mice. Myeloid cells bone marrow-derived overexpressing HO-1 regulate the differentiation and infiltration of pro-inflammatory immune cells in the vasculature. BLVRA expression and bilirubin levels downstream of HO-1 play a critical role in protecting against vascular damage by reducing leukocyte infiltration.

First reported case of thymoma-associated multiorgan autoimmunity induced by COVID-19.

Thymoma-associated multiorgan autoimmunity (TAMA) presents with skin symptoms similar to those of graft-versus-host disease (GVHD), liver dysfunction, and enteritis, in the absence of a history of hematopoietic stem cell or bone marrow transplantation. TAMA is a type of paraneoplastic syndrome associated with thymoma. Its etiology is unclear but is thought to be a result of breakdown of immune tolerance. Histopathologically, TAMA is characterized by epidermal acanthosis with parakeratosis, individual cell keratinization, liquefaction degeneration, and intraepidermal infiltration of CD8-positive lymphocytes. A 64-year-old female patient with a history of myasthenia gravis and thymoma treated with prednisolone (10 mg/day) and cyclosporine (150 mg/day) experienced erythema on her trunk after coronavirus disease 2019 (COVID-19) onset. A psoriatic drug eruption was suspected and the possible causative drug was discontinued, but the skin rash failed to improve. A skin biopsy demonstrated GVHD-like histopathological findings. Diarrhea, abdominal pain, and duodenal perforation occurred concurrently, leading to the diagnosis of TAMA. Thereafter, the patient continued prednisolone and cyclosporine in the same doses as the TAMA treatment and added topical steroids. During the disease course, candida fungemia and cytomegalovirus infection developed, resulting in the patient's death. The TAMA was considered to have been caused by the release of inflammatory cytokines, autoreactive T cell activation, and regulatory T cell dysfunction induced by COVID-19.

Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model

BackgroundMultiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD.MethodsTo test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive).ResultsAfter 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain.ConclusionsOur results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.

Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair.

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling.

IL-33/ST2 signaling in monocyte-derived macrophages maintains blood-brain barrier integrity and restricts infarctions early after ischemic stroke

BackgroundBrain microglia and infiltrating monocyte-derived macrophages are vital in preserving blood vessel integrity after stroke. Understanding mechanisms that induce immune cells to adopt vascular-protective phenotypes may hasten the development of stroke treatments. IL-33 is a potent chemokine released from damaged cells, such as CNS glia after stroke. The activation of IL-33/ST2 signaling has been shown to promote neuronal viability and white matter integrity after ischemic stroke. The impact of IL-33/ST2 on blood-brain barrier (BBB) integrity, however, remains unknown. The current study fills this gap and reveals a critical role of IL-33/ST2 signaling in macrophage-mediated BBB protection after stroke.MethodsTransient middle cerebral artery occlusion (tMCAO) was performed to induce ischemic stroke in wildtype (WT) versus ST2 knockout (KO) male mice. IL-33 was applied intranasally to tMCAO mice with or without dietary PLX5622 to deplete microglia/macrophages. ST2 KO versus WT bone marrow or macrophage cell transplantations were used to test the involvement of ST2+ macrophages in BBB integrity. Macrophages were cocultured in transwells with brain endothelial cells (ECs) after oxygen-glucose deprivation (OGD) to test potential direct effects of IL33-treated macrophages on the BBB in vitro.ResultsThe ST2 receptor was expressed in brain ECs, microglia, and infiltrating macrophages. Global KO of ST2 led to more IgG extravasation and loss of ZO-1 in cerebral microvessels 3 days post-tMCAO. Intranasal IL-33 administration reduced BBB leakage and infarct severity in microglia/macrophage competent mice, but not in microglia/macrophage depleted mice. Worse BBB injury was observed after tMCAO in chimeric WT mice reconstituted with ST2 KO bone marrow, and in WT mice whose monocytes were replaced by ST2 KO monocytes. Macrophages treated with IL-33 reduced in vitro barrier leakage and maintained tight junction integrity after OGD. In contrast, IL-33 exerted minimal direct effects on the endothelial barrier in the absence of macrophages. IL-33-treated macrophages demonstrated transcriptional upregulation of an array of protective factors, suggesting a shift towards favorable phenotypes.ConclusionOur results demonstrate that early-stage IL-33/ST2 signaling in infiltrating macrophages reduces the extent of acute BBB disruption after stroke. Intranasal IL-33 administration may represent a new strategy to reduce BBB leakage and infarct severity.

Real world comparison of filgrastim to filgrastim-sndz in patients with chemotherapy-induced neutropenia.

There exists some apprehension by prescribers, healthcare providers, and other stakeholders regarding the real-world safety and effectiveness of biosimilars. While some of the apprehension is likely due to clinician knowledge gaps in the biosimilarity exercise, additional data (including those generated from the real-world) regarding safety and efficacy could reduce a clinician's perception of biosimilar uncertainty and can potentially increase biosimilar acceptance and uptake. The published literature is lacking regarding the real-world impact on healthcare costs and clinical outcomes when a single healthcare institution converts from filgrastim to filgrastim-sndz as its short-acting Granulocyte Colony Stimulating Factor (GCSF), especially within diverse populations and indications not explicitly studied through the registration trials. Specifically, both filgrastim and filgrastim-sndz possess FDA-approved indications within patients with hematologic malignancies receiving high-dose chemotherapy and in those undergoing bone marrow transplantation. As a biosimilar to filgrastim, the FDA did not require prospective, randomized controlled trials to obtain these indications for filgrastim-sndz. The purpose of this study is to describe real-world healthcare resource costs, utilization patterns, and clinical outcomes in patients with hematologic malignancies who received filgrastim-sndz or filgrastim to support neutrophil recovery following chemotherapy (i.e., induction or consolidation) or a bone marrow transplant (BMT) at Yale New Haven Hospital (YNHH). A total of 148 patients were identified and met the following criteria: at least 18 years old, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, absence of fever or infection, newly diagnosed acute myeloid leukemia or newly post-bone marrow transplant and received filgrastim-sndz (Zarxio®) or reference filgrastim (Neupogen®). Healthcare resource utilization outcomes were compared between biosimilar and reference filgrastim using descriptive statistics. There were no major differences between either cohort, including duration of hospitalization, the number of overall emergency room visits and additional hospital admissions with a primary diagnosis of febrile neutropenia or neutropenia within 30 days post-discharge from initial hospital admission, time to neutrophil recovery following GCSF support, and the incidence and duration of both fever and febrile neutropenia. The total cost based on treatment of all patients in each arm differed significantly with filgrastim-sndz being the most cost-effective choice. filgrastim-sndz significantly reduced healthcare utilization costs compared to reference filgrastim with similar effect on absolute neutrophil count, incidence of fever, and febrile neutropenia.

A semiparametric accelerated failure time-based mixture cure tree

The mixture cure rate model (MCM) is the most widely used model for the analysis of survival data with a cured subgroup. In this context, the most common strategy to model the cure probability is to assume a generalized linear model with a known link function, such as the logit link function. However, the logit model can only capture simple effects of covariates on the cure probability. In this article, we propose a new MCM where the cure probability is modeled using a decision tree-based classifier and the survival distribution of the uncured is modeled using an accelerated failure time structure. To estimate the model parameters, we develop an expectation maximization algorithm. Our simulation study shows that the proposed model performs better in capturing nonlinear classification boundaries when compared to the logit-based MCM and the spline-based MCM. This results in more accurate and precise estimates of the cured probabilities, which in-turn results in improved predictive accuracy of cure. We further show that capturing nonlinear classification boundary also improves the estimation results corresponding to the survival distribution of the uncured subjects. Finally, we apply our proposed model and the EM algorithm to analyze an existing bone marrow transplant data.

Quantifying Spatial Distribution of Ventilation Defects in Multiple Pulmonary Diseases With Hyperpolarized 129Xenon MRI.

Hyperpolarized 129Xe MRI assesses lung ventilation, often using the ventilation defect percentage (VDP). Unlike VDP, defect distribution index (DDI) quantifies spatial clustering of defects. To quantify spatial distribution of 129Xe ventilation defects using DDI across pulmonary diseases. Retrospective. Four hundred twenty-one subjects (age = 23.1 ± 17.1, female = 230), comprising healthy controls (N = 60) and subjects with obstructive conditions (asthma [N = 25], bronchiolitis obliterans syndrome [BOS, N = 18], cystic fibrosis [CF, N = 90], lymphangioleiomyomatosis [LAM, N = 50]), restrictive conditions (bleomycin-treated cancer survivors [BLEO, N = 14]; fibrotic lung diseases [FLD, N = 92]), bone marrow transplantation (BMT, N = 53), and bronchopulmonary dysplasia (BPD, N = 19). 3 T, two-dimensional multi-slice gradient echo. Whole-lung mean DDI was extracted from DDI maps; correlated with VDP (percent of pixels <60% of whole-lung mean signal intensity) and pulmonary function tests (PFTs) including FEV1, FVC, and FEV1/FVC. DDI and DDI/VDP, a marker of defect clustering, were compared across diseases. Pearson correlation analysis and Kruskal-Wallis tests. P < 0.0056 for disease groups, P < 0.0125 for categories. DDI was significantly elevated in BMT (8.3 ± 11.5), BOS (30.1 ± 57.5), BPD (16.0 ± 46.8), CF (15.4 ± 27.2), and LAM (12.6 ± 34.2) compared to controls (1.8 ± 3.1). DDI correlated significantly with VDP in all groups (r ≥ 0.56) except BLEO, and with PFTs in CF, FLD, and LAM (r ≥ 0.56). Obstructive groups had significantly higher mean DDI (14.0 ± 32.0) than controls (1.8 ± 3.0) and restrictive groups (4.0 ± 12.0). DDI/VDP was significantly lower in the restrictive group (0.6 ± 0.6) than controls (0.8 ± 0.6) and obstructive group (1.0 ± 1.0). DDI may provide insights into the distribution of ventilation defects across diseases. 3 TECHNICAL EFFICACY: Stage 2.

Precision medicine results from equitable representation.

In this special issue of Bone Marrow Transplantation, investigators report the impact of IDH1 [1], IDH2 [2], and FLT3-TKD [3] measurable residual disease (MRD) pre-hematopoietic cell transplantation (HCT) in predicting relapse of acute myeloid leukemia (AML) in adults receiving allogeneic HCT. The patient population for these retrospective cohorts, reflecting clinical transplant practice patterns and research biobank participation, was 84-86% non-Hispanic White (NHW) in each study. In this commentary, we explore the implications of racial and ethnic disparities in access to both HCT and HCT-related research and propose strategies to promote representation in precision medicine, given the emerging impact of the field on HCT outcomes.

Latexin deficiency limits foam cell formation and ameliorates atherosclerosis by promoting macrophage phenotype differentiation

Latexin (LXN) is abundant in macrophages and plays critical roles in inflammation. Much is known about macrophages in atherosclerosis, the role of macrophage LXN in atherosclerosis has remained elusive. Here, the expression of LXN in human and mouse atherosclerotic lesions was examined by immunofluorescence and immunohistochemistry. LXN knockout and LXN/ApoE double-knockout mice were generated to evaluate the functions of LXN in atherosclerosis. Bone marrow transplantation (BMT) experimentation was carried out to determine whether macrophage LXN regulates atherosclerosis. We found that LXN is enriched in human and murine atherosclerotic lesions, mainly localized to macrophages. LXN deletion ameliorated atherosclerosis in ApoE-/- mice. BMT demonstrate that deletion of LXN in bone marrow protects ApoE-/- mice against atherosclerosis. Mechanistically, we found that LXN targets and inhibits JAK1 in macrophages. LXN deficiency stimulates the JAK1/STAT3/ABC transporter pathway, thereby enhancing the anti-inflammatory and anti-oxidant phenotype, cholesterol efflux, subsequently minimizing foam cell formation and atherosclerosis. Gene therapy by treatment of atherosclerotic mice with adeno-associated virus harbouring LXN-depleting shRNA attenuated the disease phenotype. In summary, our study provides new clues for the role of LXN in the pathological regulation of atherosclerosis, and determines that LXN is a target for preventing atherosclerosis, which may be a potential new anti-atherosclerosis therapeutic target.

Opportunistic Identification of Coronary Artery Calcium and Valve/Vascular Calcifications on Chest X-Ray: Improvements With Single-Exposure Dual-Energy Imaging.

Purpose: To evaluate whether single-exposure, dual-energy chest X-ray (DEX) improves visualization of coronary artery calcium (CAC) and valve/vascular calcifications compared to conventional X-ray. Materials and Methods: Sixty-one bone-marrow transplant patients (22- 79 years; median 61; IQR 15; w/m, 24/37), underwent single-exposure dual-energy X-ray (Reveal 35C, KA imaging) in pa and lateral projection, followed by a standard-of-care chest CT. Two DEX pairs (pa/lateral) were calculated: a composite image (COMP) and a bone image with soft-tissue subtraction (BI). The COMP pair was reviewed by 2 chest radiologists, assessing the presence/absence of CAC and valve/vascular calcifications on a confidence scale from -2 (confidently not present) to 2 (confidently present). Subsequently, the BI pair was revealed, and readers reevaluated both pairs (COMP and BI) jointly using the identical scale. CTCAC scores were categorized according to the CAC-DRS (0-3) and served as standard of reference, valve/vascular calcifications were categorized on CT as present or absent. Results: For detecting CAC on DEX in any CAC-DRS category (1-3), in category 2-3, in category 3, and for valve/vascular calcifications, the ROC-AUC (combined for both readers) for COMP images was 0.74 (CI: 0.64-0.84), 0.81 (CI: 0.68-0.94), 0.84 (CI: 0.69-0.98), and 0.90 (CI: 0.83-0.99), and for the BI images 0.91 (CI: 0.83-0.98), 0.94 (CI: 0.86- 1.00), 0.89 (CI: 0.77-1.00), and 0.98 (CI: 0.96-1.00), with P = .0003, P = .044, P = .42, and P = .55, respectively. The Intraclass-Correlation-Coefficient (ICC) for CAC on COMP/BI was 0.973/0.954, and for valve/vascular calcifications 0.971/0.965. Conclusion: Single-exposure, dual-energy acquisition improves diagnostic confidence for coronary artery calcium and valve/vascular calcification identification on chest X-rays.

Vitamin A to Keep GVHD Away: Single Oral High-Dose Vitamin A Before Bone Marrow Transplant Reduces Graft-Versus-Host Disease in Pediatric and Young Adult Patients

Vitamin A to Keep GVHD Away: Single Oral High-Dose Vitamin A Before Bone Marrow Transplant Reduces Graft-Versus-Host Disease in Pediatric and Young Adult Patients

Nutrition support pharmacy practices in hospitalized cancer patients admitted to bone marrow transplant units: A 3-year retrospective analysis of clinical nutrition support pharmacists’ interventions

Nutrition support pharmacy practices in hospitalized cancer patients admitted to bone marrow transplant units: A 3-year retrospective analysis of clinical nutrition support pharmacists’ interventions

Hoyeraal-Hreidarsson syndrome: a case report of dyskeratosis congenita with a novel PARN gene mutation

Introduction and importance: Dyskeratosis congenita (DC) is a rare multisystem disorder primarily characterized by bone marrow failure due to telomere shortening. Typical clinical features include oral leukoplakia, skin hyperpigmentation, and nail dystrophy, along with an increased risk of malignancies. Hoyeraal-Hreidarsson Syndrome (HH), a severe variant of DC, is associated with profound neurological and immunological complications, emphasizing the importance of early diagnosis and genetic evaluation to guide appropriate management. Case Presentation: We present a case of a 2-year-old girl diagnosed with Hoyeraal-Hreidarsson Syndrome, linked to a newly discovered mutation in the poly (A)-specific ribonuclease (PARN) gene. The patient exhibited intrauterine growth retardation (IUGR), congenital cytomegalovirus (CMV) infection, immunodeficiency, microcephaly, and cerebellar hypoplasia. Whole exome sequencing (WES) identified a novel mutation in the PARN gene. Clinical Discussion: Hoyeraal-Hreidarsson Syndrome, a severe form of DC, manifests with multisystem involvement and is genetically heterogeneous. Early genetic testing through techniques such as WES can aid in diagnosing rare syndromes like HH and guide treatment strategies, including bone marrow transplantation. Conclusion: This case underscores the importance of genetic evaluation in complex, rare syndromes like HH. Whole exome sequencing plays a crucial role in identifying pathogenic mutations and tailoring management. The patient’s prognosis is being closely monitored following bone marrow transplantation.

A 16-Year-Old Moroccan Child's Diffuse Bronchiectasis Exacerbation Revealed Deficient Expression of HLA Class II Molecules

Deficiency in HLA class II expression is an uncommon autosomal recessive immune deficiency associated with mutations in genes that regulate major histocompatibility complex class II (MHC II) expression. Despite being diagnosed during adolescence, our case is distinguished by a delayed diagnosis and a weak clinical presentation. We describe the medical history of a 16-year-old child who has been treated intermittently for constipation and meningitis since early childhood. The child also experienced alternating episodes of diarrhea and constipation. As a result of a bacterial exacerbation of diffuse bronchiectasis, the patient was hospitalized. Deficient expression of HLA class II molecules was confirmed by immune assessments. Favorable clinical development was achieved by starting antibiotic medication in conjunction with nutritional control. Bone marrow transplantation is the sole curative treatment available for this real-life Maghrebian illness.

DEVELOPMENT OF SYSTEMIC MASTOCYTOSIS AFTER BONE MARROW TRANSPLANTATION FOR AN ACUTE MYELOID LEUKEMIA: DONOR DERIVEN DISEASE OR SYSTEMIC MASTOCYTOSIS WITH AN ASSOCIATED MYELOID NEOPLASM

Abstract Introduction/Objective Systemic mastocytosis may have variable presentation ranging from an indolent disease to an aggressive form. Systemic mastocytosis with an associated myeloid neoplasm can occur simultaneously, or within an interval of a myeloid neoplasm and should meet the diagnostic criteria of both entities. Methods/Case Report Herein, we present a patient with history of acute myeloid leukemia with KMT2A(11q23) amplification who initially underwent an allogeneic hematopoietic stem cell transplantation from a matched sibling donor. One year later, the patient developed isolated central nervous system relapse, as well as evidence of molecular relapse in the bone marrow and underwent a second allogeneic transplantation, but this time, from a matched unrelated donor. The 100 days post second transplant bone marrow biopsy was negative for involvement by acute myeloid leukemia and the chimerism study revealed evidence of total engraftment with 100% donor cells. Additionally, Fluorescence in situ hybridization analysis detected no evidence of KMT2A amplification. However, morphologic examination of the bone marrow biopsy demonstrated involvement by systemic mastocytosis with multiple dense aggregates of CD117 and tryptase positive mast cells showing spindled cell morphology. Mast cells were positive for CD25 and demonstrated negative expression of CD2 and CD30. PCR analysis of the peripheral blood did not detect evidence of KIT mutation, but serum tryptase was elevated. Results (if a Case Study enter NA) NA Conclusion This case highlights a rare instance of systemic mastocytosis in the setting of remission from an acute myeloid leukemia in a post transplantation bone marrow and represents a diagnostic challenge. While development of systemic mastocytosis in a patient with prior history of an acute myeloid leukemia suggests the possibility of systemic mastocytosis with an associated myeloid neoplasm, some other features including the complete remission and total engraftment of the post transplantation bone marrow with 100% donor cells, raise the possibility of a donor driven disease.

Knowledge, attitude and acceptance regarding bone marrow transplantation in caregivers of beta-thalassemia major patients.

Knowledge, Attitude, and Acceptance regarding Bone marrow transplantation in caregivers of beta-thalassemia major patients. A cross-sectional study was conducted among the caregivers of pediatric patients with betathalassemia major in blood transfusion centres in Bangalore, India. Their knowledge, attitude, and acceptance regarding bone marrow transplantation were assessed using a validated questionnaire. The study aimed to identify factors that influence caregivers' decision about bone marrow transplantation. The knowledge, attitude, and acceptance of the caregivers towards bone marrow transplantation are shown to depend on gender, education and socio-economic status. The results of this study reveal that male caregivers generally exhibited higher levels of knowledge and had a better attitude towards it as compared to their female counterparts. Higher education and socio-economic status were associated with better knowledge, more favourable attitudes and a higher acceptance towards the procedure.