-
Pediatric Transplantation Jun 2024The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for...
The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.
BACKGROUND
The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA).
METHODS
This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment.
RESULTS
The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65).
CONCLUSIONS
Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.
Topics: Humans; Anemia, Aplastic; Hematopoietic Stem Cell Transplantation; Adolescent; Child; Retrospective Studies; Male; Female; Child, Preschool; Young Adult; Adult; Infant; Treatment Outcome; Immunosuppression Therapy; Tissue Donors; Immunosuppressive Agents
PubMed: 38766976
DOI: 10.1111/petr.14784 -
BioRxiv : the Preprint Server For... May 2024Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Upon entry, species modulate immune (e.g., macrophages; MΦ) and...
UNLABELLED
Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Upon entry, species modulate immune (e.g., macrophages; MΦ) and non-immune cell (e.g., endothelial cells) responses to create a habitable environment for host colonization. In particular, MΦ play a crucial role in either terminating an infection at an early stage or succumbing to bacterial replication and colonization. However, our understanding on how species modulate crucial cellular processes within MΦ, including phagocytosis, and host cell defenses, to establish an intracytosolic replication niche, remain poorly defined. In this study, we describe a previously unappreciated mechanism, in which pathogenic rickettsiae infection is mediated by the phosphatidylserine (PS)-binding receptor, CD300f. We found that CD300f mice but not wild-type (WT) C57BL/6J mice were protected against - or [ ]-induced fatal rickettsiosis. Adoptative transfer studies further revealed that CD300f-expressing bone marrow-derived macrophages (BMDMΦ) are important mediators to control rickettsiosis in WT mice. Mechanistical analysis, using WT or CD300f BMDMΦ, showed that CD300f facilitates the engulfment of both pathogenic and species, likely via a PS-mediated mechanism. Furthermore, CD300f was involved in the intracytosolic replication of both pathogenic rickettsiae by differentially modulating the anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1α and IL-1β cytokine responses. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment and the intracellular survival of pathogenic rickettsiae within the host.
SIGNIFICANCE STATEMENT
Vector-borne diseases, which are transmitted by hematophagous arthropods, like ticks and fleas, present a perilous threat to public health. In fact, tick- and flea-borne rickettsial diseases are on the rise globally and our current inadequate understanding on how interacts with their mammalian host has significantly impaired the development of effective interventions against pathogenic rickettsial infections. Here, we identified the phosphatidylserine (PS)-receptor, CD300f, as an important mediator of pathogenic rickettsiae infection and . Specifically, we showed that CD300f-expressing macrophages facilitate rickettsial infection by differentially modulating anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1α and IL-1β cytokine responses. In sum, our data described CD300f as an important regulator of rickettsial infection and may present a target for therapeutic intervention.
PubMed: 38766217
DOI: 10.1101/2024.05.10.593542 -
Npj Imaging 2024Macrophages are key inflammatory mediators in many pathological conditions, including cardiovascular disease (CVD) and cancer, the leading causes of morbidity and...
Macrophages are key inflammatory mediators in many pathological conditions, including cardiovascular disease (CVD) and cancer, the leading causes of morbidity and mortality worldwide. This makes macrophage burden a valuable diagnostic marker and several strategies to monitor these cells have been reported. However, such strategies are often high-priced, non-specific, invasive, and/or not quantitative. Here, we developed a positron emission tomography (PET) radiotracer based on apolipoprotein A1 (ApoA1), the main protein component of high-density lipoprotein (HDL), which has an inherent affinity for macrophages. We radiolabeled an ApoA1-mimetic peptide (mA1) with zirconium-89 (Zr) to generate a lipoprotein-avid PET probe (Zr-mA1). We first characterized Zr-mA1's affinity for lipoproteins in vitro by size exclusion chromatography. To study Zr-mA1's in vivo behavior and interaction with endogenous lipoproteins, we performed extensive studies in wildtype C57BL/6 and hypercholesterolemic mice. Subsequently, we used in vivo PET imaging to study macrophages in melanoma and myocardial infarction using mouse models. The tracer's cell specificity was assessed by histology and mass cytometry (CyTOF). Our data show that Zr-mA1 associates with lipoproteins in vitro. This is in line with our in vivo experiments, in which we observed longer Zr-mA1 circulation times in hypercholesterolemic mice compared to C57BL/6 controls. Zr-mA1 displayed a tissue distribution profile similar to ApoA1 and HDL, with high kidney and liver uptake as well as substantial signal in the bone marrow and spleen. The tracer also accumulated in tumors of melanoma-bearing mice and in the ischemic myocardium of infarcted animals. In these sites, CyTOF analyses revealed that Zr-mA1 was predominantly taken up by macrophages. Our results demonstrate that Zr-mA1 associates with lipoproteins and hence accumulates in macrophages in vivo. Zr-mA1's high uptake in these cells makes it a promising radiotracer for non-invasively and quantitatively studying conditions characterized by marked changes in macrophage burden.
PubMed: 38765879
DOI: 10.1038/s44303-024-00009-3 -
Current Research in Toxicology 2024Nicotinamide mononucleotide (NMN) is an intermediate in biosynthesis pathway of Nicotinamide adenine dinucleotide (NAD+), an essential cofactor in all living cells...
Nicotinamide mononucleotide (NMN) is an intermediate in biosynthesis pathway of Nicotinamide adenine dinucleotide (NAD+), an essential cofactor in all living cells involved in fundamental biological processes. Evidence stemming from recent studies have unveiled numerous roles of NAD+ metabolism on aging, longevity, delaying the progression of age-related diseases. A three-study genetic toxicity (genetox) battery (bacterial mutagenesis, in vitro cytogenetics, and in vivo mammalian test) is usually required to confirm safety of a new dietary ingredient and this study showed the data from in vivo mutagenicity test for the first time. The acute oral LD50 of NMN was greater than 2000 mg/kg body weight with 5000 mg/kg body weight as LD50 cut-off value and was classified under "Category 5 or Unclassified" as per Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Based on 90 days repeated dose toxicity test the NOAEL was considered to be NLT 800 mg NMN/kg body weight in Wistar rats. The bacterial reverse mutation test, the in vitro and in vivo chromosomal aberration test, found NMN to be non-mutagenic. In the mammalian bone marrow chromosomal aberration test, it was concluded that NMN is non clastogenic at and up to 2,000 mg/kg body weight in all the animals tested to confirm safety of a new dietary ingredient and this study showed the data from in vivo mutagenicity test for the first time.
PubMed: 38765763
DOI: 10.1016/j.crtox.2024.100171 -
Case Reports in Infectious Diseases 2024classically causes pulmonary and central nervous system (CNS) infection in immunocompromised hosts and can lead to disseminated disease. Two cases of atypical...
classically causes pulmonary and central nervous system (CNS) infection in immunocompromised hosts and can lead to disseminated disease. Two cases of atypical cryptococcal infection are presented-an elderly Human Immunodeficiency Virus- (HIV-) negative male with a urinary source of infection and a young HIV-positive male with bone marrow infiltration complicated by haemophagocytic lymphohistiocytosis (HLH). A literature review of systemic cryptococcal infections involving the genitourinary tract and bone marrow was performed. These cases highlight the importance of clinicians considering uncommon manifestations of cryptococcal disease.
PubMed: 38765693
DOI: 10.1155/2024/2245391 -
Cureus Apr 2024Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders, of which type II CDA is the most common. Mutations in the gene located on chromosome 20...
Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders, of which type II CDA is the most common. Mutations in the gene located on chromosome 20 result in this autosomal recessive disorder. In this case report, we present a case of CDA II with unique biopsy findings being detected via genetic testing. A female aged 30 years presented with major complaints of pallor weakness and easy fatiguability since childhood. The patient gave a history of 25 units of blood transfusion, the majority of which were transfused during pregnancy, followed by regular transfusions thereafter. On examination, all her vitals were in the normal range. Pallor, frontal bossing, and malocclusion of teeth were noted. Her laboratory workup showed the following: hemoglobin (Hb): 3.7 g/dl; mean corpuscular volume: 83 fl; mean corpuscular Hb: 29 g/dl; mean corpuscular Hb concentration: 34.9 g/dl; red cell distribution width: 30.4%; reticulocyte count (RC): 6.2%; corrected RC: 1.3%; lactate dehydrogenase: 441 IU/L; direct Coombs test/indirect Coombs test: negative; serum iron: 242 microgram/dl; transferrin saturation: 96.08%; ferritin: 1,880 ng/ml; and normal high-performance liquid chromatography and eosin-5'-maleimide binding test. The peripheral blood film showed normocytic normochromic anemia with anisopoikilocytosis in the form of a few spherocytes. No immature cells were seen. After obtaining the patient's consent, we performed a hereditary hemolytic anemia gene analysis test, which showed homozygous missense variation in exon 12 of the gene. The bone marrow examination showed hyperplasia in the erythroid series with dyserythropoiesis, and surprisingly, myelofibrosis grade I-II (WHO 2017) was also observed on biopsy. Patients with CDA type II generally present with variable degrees of anemia along with pallor, icterus, splenomegaly, gallstones, and iron overload. In our case, the diagnosis of CDA type II was made at an adult age. Also, evidence of myelofibrosis was noted in our case, making it worth reporting. The use of a hereditary hemolytic anemia gene analysis panel test came as a rescue for its exact diagnosis. This case report emphasizes the role of molecular genetic testing for early and accurate diagnosis, which, in turn, could help in appropriate treatment planning and proper genetic counseling. The prevalence of CDA type II is still vaguely known; hence, extensive workup of persistent anemias and proper follow-up would be beneficial.
PubMed: 38765414
DOI: 10.7759/cureus.58515 -
Infectious Medicine Jun 2024Given the preventable nature of most healthcare-associated infections (HAIs), it is crucial to understand their characteristics and temporal patterns to reduce their...
BACKGROUND
Given the preventable nature of most healthcare-associated infections (HAIs), it is crucial to understand their characteristics and temporal patterns to reduce their occurrence.
METHODS
A retrospective analysis of medical record cover pages from a Chinese hospital information system was conducted for surgery inpatients from 2010 to 2019. Association rules mining (ARM) was employed to explore the association between disease, procedure, and HAIs. Joinpoint models were used to estimate the annual HAI trend. The time series of each type of HAI was decomposed to analyze the temporal patterns of HAIs.
RESULTS
The study included data from 623,290 surgery inpatients over 10 years, and a significant decline in the HAI rate was observed. Compared with patients without HAIs, those with HAIs had a longer length of stay (29 days vs. 9 days), higher medical costs (96226.57 CNY vs. 22351.98 CNY), and an increased risk of death (6.42% vs. 0.18%). The most common diseases for each type of HAI differed, although bone marrow and spleen operations were the most frequent procedures for most HAI types. ARM detected that some uncommon diagnoses could strongly associate with HAIs. The time series pattern varied for each type of HAI, with the peak occurring in January for respiratory system infections, and in August and July for surgical site and bloodstream infections, respectively.
CONCLUSIONS
Our findings demonstrate that HAIs impose a significant burden on surgery patients. The differing time series patterns for each type of HAI highlight the importance of tailored surveillance strategies for specific types of HAI.
PubMed: 38764728
DOI: 10.1016/j.imj.2024.100103 -
Journal of Inflammation Research 2024Repeated exposure to recombinant profilin from (rAc-PF) induces allergic airway responses in vitro and in vivo. Based on the role of toll-like receptors (TLRs) in...
BACKGROUND
Repeated exposure to recombinant profilin from (rAc-PF) induces allergic airway responses in vitro and in vivo. Based on the role of toll-like receptors (TLRs) in allergic airway diseases, TLRs play a central role in innate immune responses and the adaptive immune system and regulate responses against antigens through antigen-specific receptors. In this study, we attempted to determine the molecular mechanisms underlying rAc-PF-induced allergic inflammatory responses.
METHODS
We determined the correlation between rAc-PF and TLRs and analyzed changes in allergic immune responses after blocking multiple TLR signaling under rAc-PF treatment conditions in vitro. We also compared allergic inflammatory responses in TLR2 knockout (KO) and wild-type (WT) mice. To investigate the effect of TLR2 on antigen prototyping and T cell activation in the inflammatory response induced by rAc-PF, we assessed maturation of BMDCs and polarization of naïve T cells by rAc-PF stimulation. Additionally, we compared changes in inflammation-related gene expression by rAc-PF treatment in primary lung epithelial cells isolated from TLR2 KO and WT mice.
RESULTS
The rAc-PF treatment was increased the expression level of TLR2 and 9 in vitro. But, there were not significantly differ the others TLRs expression by rAc-PF treated group. And then, the mRNA expression levels of inflammation-related genes were reduced in the TLR2 or TLR9 antagonist-treated groups compared to those in the rAc-PF alone, were no difference the treated with the other TLRs (TLR4, 6, and 7/8) antagonist. The difference was higher in the TLR2 antagonist group. Additionally, the levels of airway inflammatory disease indicators were lower in the TLR2 KO group than in the WT group after rAc-PF treatment. Furthermore, the expression of bone marrow-derived dendritic cell (BMDC) surface molecular markers following rAc-PF stimulation was lower in TLR2 KO mice than in WT mice, and TLR2 KO in BMDCs resulted in a remarkable decline in Th2/17-related cytokine production and Th2/17 subset differentiation. In addition, the expression levels of rAc-PF-induced inflammatory genes were reduced inTLR2 KO primary lung cells compared to those in normal primary lung cells.
CONCLUSION
These results suggest that the rAc-PF-induced airway inflammatory response is regulated by TLR2 signaling.
PubMed: 38764493
DOI: 10.2147/JIR.S450866 -
Treatment of relapsed/refractory severe aplastic anemia in children: Evidence-based recommendations.Pediatric Blood & Cancer May 2024Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management... (Review)
Review
Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with relapsed or refractory SAA.
PubMed: 38764170
DOI: 10.1002/pbc.31075 -
Advances in Immunology 2024Hematopoiesis, a process which generates blood and immune cells, changes significantly during mammalian development. Definitive hematopoiesis is marked by the emergence... (Review)
Review
Hematopoiesis, a process which generates blood and immune cells, changes significantly during mammalian development. Definitive hematopoiesis is marked by the emergence of long-term hematopoietic stem cells (HSCs). Here, we will focus on the post-transcriptional differences between fetal liver (FL) and adult bone marrow (ABM) HSCs. It remains unclear how or why exactly FL HSCs transition to ABM HSCs, but we aim to leverage their differences to revive an old idea: in utero HSC transplantation. Unexpectedly, the expression of certain RNA-binding proteins (RBPs) play an important role in HSC specification, and can be employed to convert or reprogram adult HSCs back to a fetal-like state. Among other features, FL HSCs have a broad differentiation capacity that includes the ability to regenerate both conventional B and T cells, as well as innate-like or unconventional lymphocytes such as B-1a and marginal zone B (MzB) cells. This chapter will focus on RNA binding proteins, namely LIN28B and IGF2BP3, that are expressed during fetal life and how they promote B-1a cell development. Furthermore, this chapter considers a potential clinical application of synthetic co-expression of LIN28B and IGF2BP3 in HSCs.
Topics: Humans; Animals; RNA-Binding Proteins; Hematopoietic Stem Cells; B-Lymphocytes; Cell Differentiation; Hematopoiesis; RNA Processing, Post-Transcriptional; Lymphopoiesis; Hematopoietic Stem Cell Transplantation
PubMed: 38763703
DOI: 10.1016/bs.ai.2024.03.003