Summary
Chronic graft‐versus‐host disease (cGVHD) is a major complication affecting the long‐term survival of patients after allogeneic haematopoietic stem cell transplantation. The mechanism of ...cGVHD is unclear, and while previous studies have primarily focused on T cells, the role of B cells in the pathogenesis of cGVHD has been less reported. However, current studies on cGVHD are increasingly focused on the important role of B cells. In this review, we will introduce the newest studies and examine the role of B cells in cGVHD in detail with respect to the following aspects: altered B cell subpopulations, aberrant B cell signalling pathways, autoantibodies and T‐B cell interactions. Treatment strategies for the targeting of B cells during cGVHD will also be discussed.
Over the last decade, investigation of
(
) gene function and
mutation have become of increasing interest in the field of hematology. This heightened interest was sparked by the seminal discoveries ...that (1)
mutation is associated with development of hematological malignancies and that (2) the TET family of proteins is critical in promoting DNA demethylation and immune homeostasis. Since then, additional studies have begun to unravel the question "Does TET2 have additional biological functions in the regulation of hematopoiesis?" Here, we present a mini-review focused on the current understanding of TET2 in hematopoiesis, hematological malignancies, and immune regulation. Importantly, we highlight the critical function that TET2 facilitates in maintaining the stability of the genome. Based on our review of the literature, we provide a new hypothesis that loss of TET2 may lead to dysregulation of the DNA repair response, augment genome instability, and subsequently sensitize myeloid leukemia cells to PARP inhibitor treatment.
Live cell imaging of protein‐specific glycoforms is important for the elucidation of glycosylation mechanisms and identification of disease states. The currently used metabolic oligosaccharide ...engineering (MOE) technology permits routinely global chemical remodeling (GCM) for carbohydrate site of interest, but can exert unnecessary whole‐cell scale perturbation and generate unpredictable metabolic efficiency issue. A localized chemical remodeling (LCM) strategy for efficient and reliable access to protein‐specific glycoform information is reported. The proof‐of‐concept protocol developed for MUC1‐specific terminal galactose/N‐acetylgalactosamine (Gal/GalNAc) combines affinity binding, off‐on switchable catalytic activity, and proximity catalysis to create a reactive handle for bioorthogonal labeling and imaging. Noteworthy assay features associated with LCM as compared with MOE include minimum target cell perturbation, short reaction timeframe, effectiveness as a molecular ruler, and quantitative analysis capability.
A localized chemical remodeling strategy for live cell imaging of protein‐specific glycoform is reported. Compared with the currently used global chemical remodeling method, namely metabolic oligosaccharide engineering, desired assay features of this approach include minimum target cell perturbation, short reaction timeframe, effectiveness as a molecular ruler, and quantitative analysis capability.
Live cell imaging of protein‐specific glycoforms holds great promise for revolutionizing the study of glycochemistry. The imaging protocols developed thus far build upon the paired interplay of probe ...units, thus limiting the number of monosaccharide identification channels. A hierarchical coding (HieCo) imaging strategy, with DNA coding and decoding of protein and monosaccharides executed in fidelity to the hierarchical order of target glycoprotein, is reported herein and features expandable monosaccharide identification channels. A proof‐of‐concept protocol has been developed for MUC1‐specific imaging of terminal sialic acid (Sia) and fucose (Fuc) on MCF‐7, T47D, MDA‐MB‐231, and PANC‐1 cells, revealing distinct monosaccharide patterns for four types of cells. The protocol also permits dynamic monitoring of changes in MUC1‐specific monosaccharide patterns associated with both the alteration of cellular physiological states and the occurrence of a biologically important process.
Using code: A hierarchical coding strategy has been developed for live cell imaging of protein‐specific glycoform, in which DNA codes and decodes each structural motif in fidelity to the hierarchical order of the target glycoprotein. The strategy features expandable monosaccharide identification channels and should allow for a more comprehensive understanding of protein glycosylation mechanisms and functions.
The mTOR pathway plays a central role in many cellular processes, such as cellular growth, protein synthesis, glucose, and lipid metabolism. Aberrant regulation of mTOR is a hallmark of many cancers, ...including hematological malignancies. mTOR inhibitors, such as Rapamycin and Rapamycin analogs (Rapalogs), have become a promising class of agents to treat malignant blood diseases-either alone or in combination with other treatment regimens. This review highlights experimental evidence underlying the molecular mechanisms of mTOR inhibitors and summarizes their evolving role in the treatment of hematologic disease, including leukemia, lymphoma, myeloma, immune hemocytopenia, and graft-versus-host disease (GVHD). Based on data presented in this review, we believe that mTOR inhibitors are becoming a trusted therapeutic in the clinical hematologist's toolbelt and should be considered more routinely in combination therapy for the management of hematologic disease.
The heterogeneity of mesenchymal stem cells (MSCs) is poorly understood, thus limiting clinical application and basic research reproducibility. Advanced single-cell RNA sequencing (scRNA-seq) is a ...robust tool used to analyse for dissecting cellular heterogeneity. However, the comprehensive single-cell atlas for human MSCs has not been achieved.
This study used massive parallel multiplexing scRNA-seq to construct an atlas of > 130 000 single-MSC transcriptomes across multiple tissues and donors to assess their heterogeneity. The most widely clinically utilised tissue resources for MSCs were collected, including normal bone marrow (n = 3), adipose (n = 3), umbilical cord (n = 2), and dermis (n = 3).
Seven tissue-specific and five conserved MSC subpopulations with distinct gene-expression signatures were identified from multiple tissue origins based on the high-quality data, which has not been achieved previously. This study showed that extracellular matrix (ECM) highly contributes to MSC heterogeneity. Notably, tissue-specific MSC subpopulations were substantially heterogeneous on ECM-associated immune regulation, antigen processing/presentation, and senescence, thus promoting inter-donor and intra-tissue heterogeneity. The variable dynamics of ECM-associated genes had discrete trajectory patterns across multiple tissues. Additionally, the conserved and tissue-specific transcriptomic-regulons and protein-protein interactions were identified, potentially representing common or tissue-specific MSC functional roles. Furthermore, the umbilical-cord-specific subpopulation possessed advantages in immunosuppressive properties.
In summary, this work provides timely and great insights into MSC heterogeneity at multiple levels. This MSC atlas taxonomy also provides a comprehensive understanding of cellular heterogeneity, thus revealing the potential improvements in MSC-based therapeutic efficacy.
The complex pathogenesis of relapsed and refractory (R/R) immune thrombocytopenia (ITP) contributes to the varied efficacy and tolerability of current treatment regimens. Rapamycin, an ...immunomodulatory agent, was originally used in the prevention of organ rejection after organ transplantation. Additional evidence now shows that rapamycin can successfully treat R/R ITP. Here, we summarize recent clinical progress on the role and potential mechanism of rapamycin in the treatment of ITP.
PubMed, Web of Science and CNKI database were searched to identify eligible studies, and the clinical data and preclinical studies on the use of mTOR inhibitors in ITP treatment were reviewed. The key results (efficacy and safety) of the most recent clinical reports were summarized.
Case series provide evidence of the effectiveness and tolerable safety profile of rapamycin in ITP, including primary and some secondary ITP. Mechanistic explorations indicate that rapamycin can regulate immune cell subsets (Th1, Th2, Th17, Treg, Breg, MDSC, etc.), modulate cytokine secretion (IL-6, IL-10, TGF-β, BAFF, etc.) and promote platelet autophagy.
Emerging clinical data and basic studies suggest that rapamycin, as a multifaceted regulator, could provide a new promising option for the therapy of ITP. Additional research is needed to identify those patients which may benefit the most, as well as therapeutic regimens with which rapamycin may be combined.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Myelodysplastic syndrome (MDS), a largely incurable hematological malignancy, is derived from aberrant clonal hematopoietic stem/progenitor cells (HSPCs) that persist after conventional therapies. ...Defining the mechanisms underlying MDS HSPC maintenance is critical for developing MDS therapy. The deacetylase SIRT1 regulates stem cell proliferation, survival, and self-renewal by deacetylating downstream proteins. Here we show that SIRT1 protein levels were downregulated in MDS HSPCs. Genetic or pharmacological activation of SIRT1 inhibited MDS HSPC functions, whereas SIRT1 deficiency enhanced MDS HSPC self-renewal. Mechanistically, the inhibitory effects of SIRT1 were dependent on TET2, a safeguard against HSPC transformation. SIRT1 deacetylated TET2 at conserved lysine residues in its catalytic domain, enhancing TET2 activity. Our genome-wide analysis identified cancer-related genes regulated by the SIRT1/TET2 axis. SIRT1 activation also inhibited functions of MDS HSPCs from patients with TET2 heterozygous mutations. Altogether, our results indicate that restoring TET2 function through SIRT1 activation represents a promising means to target MDS HSPCs.
Display omitted
•SIRT1 depletion enhances MDS HSPC self-renewal and growth•SIRT1 insufficiency in MDS promotes TET2 hyperacetylation•SIRT1 agonist treatment blocks MDS HSPC maintenance•SIRT1 activation deacetylates TET2 and enhances its catalytic activity
An improved understanding of the mechanisms regulating myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cell (HSPC) growth and self-renewal is critical for developing MDS therapy. Sun et al. report that SIRT1 deficiency-induced TET2 hyperacetylation promotes MDS HSPC function and provides an approach to target MDS HSPCs by activating SIRT1 deacetylase.
A heavy workload is required for sample collection for urban land use classification, and researchers are in urgent need of sampling strategies as a guide to achieve more effective work. In this ...paper, we make use of an urban land use survey to obtain a complete sample set of a city, test the impact of different training and validation sample sizes on the accuracy, and summarize the sampling strategy. The following conclusions are drawn based on our systematic analysis in Shenzhen. (1) For the best classification accuracy, the number of training samples should be no less than 40% of the total number of parcels or no less than 5500 parcels. For the best labor cost performance, the number should be no less than 7% or no less than 900. (2) The accuracy evaluation is stable and reliable and requires validation sample numbers of no less than 10% of the total or no less than 1200. (3) Samples with a purity of 60–90% are preferred, and the classification effectiveness is better in samples with a purity greater than 90% under the same number. (4) If spatial equilibrium sampling cannot be carried out, sampling areas with complex land use patterns should be preferred.
It is well documented that COVID-19 vaccines greatly reduce the severity and complications of SARS-CoV-2 infection. However, it has been reported that COVID-19 related vaccines may induce or ...exacerbate autoimmune hematological disorders, for example, a decrease in platelet numbers characteristic of immune thrombocytopenia (ITP). To investigate this, we retrospectively reported, for the first time, the clinical characteristics of 42 ITP patients after COVID-19 vaccination in southwest China. Of the 42 patients, 28 patients were historically diagnosed ITP, and their platelet counts (PC) decrease mainly occurred after the first-dose vaccinations. The average PC after vaccination was 39.5 × 10
9
/L and recovered to an average of 80.6 × 10
9
/L after treatment. Efficacy of treatment was 90%, and only 10% maintained low PC at the third month of treatment. More interestingly, of the 42 patients, 14 were newly diagnosed ITP following vaccination. Of these 14 patients, 6 patients (43%) were found PC deterioration after the first vaccine dose, and 7 patients (50%) after the second dose. Fortunately, the peripheral PC of all 14 patients recovered significantly after treatment, and the average PC was 139.4 × 10
9
/L, including 8 CRs (complete response) and 6 PRs (partial response). Notably, 9 of the 14 cases were found to have abnormal immune indices when thrombocytopenia diagnosed. No severe organ hemorrhage was found in either subgroup. These results are reassuring the vaccine safety for ITP patients, in that the risks of aggravating thrombocytopenia by COVID-19 vaccination do exist, but it was transient and can be effectively controlled through intensive clinical monitoring and management.
PDF
