[Research Progress on the Roles of Rapamycin for the Prophylaxis and Treatment of Graft-Versus-Host Disease --Review].

Graft-versus-host disease (GVHD) reduces the clinical effect and life quality of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Especially for steroid-resistant GVHD, it becomes essential to explore new prevention and treatment strategies. Rapamycin has shown certain clinical advantages in the prevention and treatment of acute and chronic GVHD by inhibiting the mTOR signal pathway. Furthermore, rapamycin exhibits the ability to regulate cell subsets, including T cells, B cell, dendritic cells and myeloidderived suppressor cells, which elucidates the mechanism on effective preventing and treating GVHD. This article reviewed the roles of mTOR inhibitor-rapamycin on GVHD, and discussed how to optimize the usage of rapamycin.

Efficiency and Toxicity of Imatinib Mesylate combined with Atorvastatin Calcium in the Treatment of Steroid-Refractory Chronic Graft-Versus-Host Disease: A Single-center, Prospective, Single-arm, Open-label study.

INTRODUCTION: Steroid-refractory cGVHD (SR-cGVHD) presents new great challenges for treatment. We have reported imatinib monotherapy was effective to SR-cGVHD, but the CR rate was not satisfactory and the benefit was not showed specific to some target organs, previously. Imatinib and statin drugs have been recognized to regulate T-cell function, statins also have been demonstrated endothelia protection, but whether this combination therapy was able to improve the efficacy remains unknown. Therefore, we designed this prospective, single-arm, open-label trial to investigate the efficacy of imatinib-based combination therapy in the treatment of SR-cGVHD for the first time. METHODS: 60 SR-cGVHD patients were entered into this trial to investigated the combination of imatinib mesylate and atorvastatin calcium for the treatment of SR-cGVHD. The primary endpoint included the overall response rate (ORR) after 6 months of combined treatment. The secondary endpoints included an evaluation of survival, changes in T-cell subsets and adverse events. RESULTS: At baseline, 45% (27/60) of patients had moderate cGVHD, and 55.0% (33/60) of patients had severe cGVHD. At the 6-month follow-up, a clinical response was achieved in 70.0% of patients, and a complete response (CR) was achieved in 26.7%. A total of 11.7% (7/60) of patients stopped immunosuppressive therapy at this point. After 6 months of treatment, the ORR rates of the liver, skin, eyes and oral cavity were 80.6%, 78.1%, 61.5%, and 60.9%, respectively, with the liver also having the highest CR of 58.1%. The patients with moderate cGVHD had a better CR rate than those with severe cGVHD (55.6% vs. 3.0%, P<0.0001). The overall survival in patients who with ORR was improved (P = 0.0106). Lung involvement is an independent risk factor to affected ORR achievement (P = 0.021, HR = 0.335, 95%CI 0.133-0.847), and the dosage of steroids was reduced in ORR patients. In clinical response patients, the ratio of CD8+ T cells (P = 0.0117) and Th17 cells (P = 0.0171) decreased, while the number of Treg cells (P = 0.0147) increased after 3 months. The most common adverse events were edema, nausea, and neutropenia which were 13.3%, 11.7%, and 11.7%, respectively. CONCLUSION: Combination treatment with imatinib mesylate and atorvastatin calcium was effective in treating SR-cGVHD and significantly decreased target organ injury, especially liver damage, indicating that T-cell regulatory function may play an important role in this process.

Optimizing the therapeutic window of sirolimus by monitoring blood concentration for the treatment of immune thrombocytopenia.

Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP. Thus, in this study, we used a retrospective cohort of ITP patients treated with sirolimus to propose the therapeutic dosage window for sirolimus. A total of 275 laboratory results of SRL blood concentration from 63 ITP patients treated with SRL were analyzed retrospectively. The ITP patients were divided into five groups based on their SRL blood concentration: 0-4 ng/ml, 4-8 ng/ml, 8-12 ng/ml, 12-16 ng/ml and ≥16 ng/ml. In addition to the SRL blood concentration, platelet counts and adverse events that occurred during the first 6 weeks of SRL treatment were analyzed. These findings were then used to establish the decision matrix tables and ROC curves, which helped identify the therapeutic window of SRL. Based on the values and trends of true-positive rate (TPR) and false-positive rate (FPR) in the ROC curve, patients who achieved a SRL blood concentration of 4-12 ng/ml displayed a higher response rate compared to those with a SRL concentration of 0-4 ng/ml or ≥16ng/ml. Additionally, the response rate was better for patients with a SRL concentration of 8-12 ng/ml compared to 4-8 ng/ml. Adverse events were related to the concentration of SRL; however, there was no significant difference in the incidence of adverse events between the concentrations of 4-8 ng/ml and 8-12 ng/ml (P > .05). Regression analysis suggested that the concentration of SRL correlated with the patient's age, PLT count at the start of SRL administration, and the dose of SRL. It is suggested that the optimal blood concentration of SRL monotherapy for managing ITP is 8-12 ng/ml. This range may achieve a favorable balance between clinical efficacy and the severity of adverse events.

Although sirolimus (SRL) has been proven to be an effective alternative agent for refractory/relapsed immune thrombocytopenia (R/R ITP), there is currently no recommended optimal blood concentration during its administration. We collected data on SRL drug concentration, platelet response, and drug side effects in ITP patients, constructed ROC curves to evaluate the relationship between the SRL concentration and both efficacy and side effects, and finally suggested a most appropriate SRL blood concentration (8­12ng/ml). This concentration window ensured optimal efficacy of SRL in the treatment of ITP while maintaining tolerable side effects. Additionally, we conducted a multivariate analysis to explore factors that may influence SRL blood concentration. The present study made an important contribution to the precision therapy of ITP with sirolimus by clarifying the optimal blood concentration range.

Myeloid/Lymphoid Neoplasms with ETV6::PDGFRB Fusion Gene: A Rare Case of Poor Response to Imatinib and Possible Transformation Mechanisms from Myeloid Neoplasms of Bone Marrow to T-Cell Lymphoblastic Lymphoma Invasion in Lymph Nodes.

The ETV6::PDGFRB fusion gene is commonly reported in chronic myelomonocytic leukemia with eosinophilia, yet patients with ETV6::PDGFRB presenting myeloid and lymphoid neoplasms successively have not been reported. Here, we report the first case of a 35-year-old man with myeloid and lymphoid neoplasms harboring an ETV6::PDGFRB fusion gene who demonstrated poor response to imatinib. The patient was diagnosed with an ETV6::PDGFRB fusion gene myeloid neoplasm on initial diagnosis at our hospital. After 5 months of treatment with imatinib, he was diagnosed with T-cell lymphoblastic lymphoma. ETV6::PDGFRB turned negative after increasing the dose of imatinib, but enlarged superficial lymph nodes reappeared the following year. Notably, the patient exhibited a worse response to imatinib treatment. This study describes this rare case and speculates on a possible mechanism.

Thrombopoietin receptor agonists for refractory thrombocytopenia in patients after autologous hematopoietic stem cell transplantation.

OBJECTIVE: Autologous hematopoietic stem cell (ASC) transplantation (ASCT) is an effective treatment method for patients with hematological disorders and malignant diseases. The patient's ASCs are harvested prior to radiotherapy/chemotherapy, cryopreserved and then transfused back after the high-dose radiotherapy/chemotherapy conditioning treatment. Since some patients develop thrombocytopenia after receiving ASCT, it is difficult for them to bear simultaneously the management of their original disease and thrombocytopenia. The present study aimed to evaluate the efficacy and safety of thrombocytopenia therapy with thrombopoietin receptor agonists (TPORAs) after ASCT. METHODS: We retrospectively analyzed the clinical safety and efficacy of TPORA treatment for the enrolled 20 patients who developed thrombocytopenia after ASCT. The measured parameters were prolonged isolated thrombocytopenia (PIT), secondary failure of platelet recovery (SFPR) and other calculated response index. Patients with platelet count (PC) ≤ 50×109/L were treated with TPORA, namely with either eltrombopag (Elt), hetrombopag (Het), or avatrobopag (Ava). RESULTS: The group of 20 patients, who received TPORA administration for their thrombocytopenia after ASCT, had a median age of 50 years (ranging between 17 and 60 years). The median administration time of TPORA application was 48 days (ranging from 7 to 451 days); an overall response rate (ORR) was 85% with no response in 15% of patients, while with complete response (CR) in 70% of patients and partial response (PR) in 15% of patients. The median platelet count was 19 × 109/L before TPORA treatment and increased to 87×109)/L after the treatment. The TPORA treatment was safe as only 4 patients (20%) displayed a mild transaminase elevation. No other reported side effects occurred, such as thrombosis, joint pain, diarrhea, and myelofibrosis. It was demonstrated that the short response time to TPORA treatment correlated to the fast platelet recovery, when the number of megakaryocytes in the bone marrow smear exceeded 35/4.5 cm2 under a low magnification of 100 times (p = 0.015). CONCLUSION: TPORA therapy for thrombocytopenia occurring after the radiotherapy/ chemotherapy-conditioned ASCT was well tolerated and effective for platelets recovery.

ß-Cyclocitric acid enhances drought tolerance in peach (Prunus persica) seedlings.

The ß-cyclocitric acid (ß-CCA) is a bioactive apocarotenoid previously shown to improve drought tolerance in annual plants. However, the underlying molecular mechanism of this process remains largely elusive. Moreover, the question about the activity of ß-CCA in perennial fruit crops is still open. Here, we found that treatment of ß-CCA enhances drought tolerance in peach seedlings. The application of ß-CCA significantly increased the relative water content and root activity and reduced the electrolyte leakage of peach seedlings under drought stress. Moreover, treatment with ß-CCA under drought stress increased chlorophyll fluorescence, indicating a positive effect on photosynthesis, while also enhancing superoxide dismutase and peroxidase activity and reducing reactive oxygen species (ROS) levels. Consistent with these alterations, transcriptome analysis revealed an up-regulation of photosynthesis and antioxidant-related genes upon the application of ß-CCA under drought stress. We also detected an induction in genes related to detoxification, environmental adaptation, primary metabolism, phytohormone, phenylpropanoid and the biosynthesis of cutin, suberine and wax, which might contribute to the induction of drought resistance. Altogether, our study reveals that ß-CCA positively modulates peach drought tolerance, which is mainly mediated by enhancing photosynthesis and reducing ROS, indicating the potential of utilizing ß-CCA for drought control in peach and perhaps other fruit crops.

Enzymatically prepared alginate oligosaccharides improve broiler chicken growth performance by modulating the gut microbiota and growth hormone signals.

BACKGROUND: Alginate oligosaccharide (AOS) holds great potential as a novel feed supplement in farm animals. However, the effects of AOS on chicken health and the underlying mechanisms are not fully understood. This study aimed to optimize the enzymatic preparation of AOS by using bacterial alginate lyases expressed in yeast, investigate the effects of the prepared AOS on the growth performance and gut health of broiler chickens, and reveal the underlying mechanisms. RESULTS: Five alginate lyases from bacteria were cloned into Pichia pastoris GS115 and the alginate lyase PDE9 was expressed at relatively high yield, activity and stability in P. pastoris. Animal trials were carried out using 320 1-day-old male Arbor Acres broilers (four groups; 8 replicates/group × 10 chicks/replicate) receiving either a basal diet or the same diet supplemented with 100, 200 and 400 mg/kg PDE9-prepared AOS for 42 d. The results showed that dietary supplementation of 200 mg/kg AOS displayed the highest activity in promoting the birds' ADG and ADFI (P < 0.05). AOS ameliorated the intestinal morphology, absorption function and barrier function, as indicated by the enhanced (P < 0.05) intestinal villus height, maltase activity, and the expression of PEPT, SGLT1, ZNT1, and occludin. AOS also increased serum insulin-like growth factor-1, ghrelin (P < 0.05), and growth hormone (P < 0.1). Moreover, the concentrations of acetate, isobutyrate, isovalerate, valerate, and total SCFAs in cecum of birds fed AOS were significantly higher than the control birds (P < 0.05). Metagenomic analysis indicated that AOS modulated the chicken gut microbiota structure, function, and microbial interactions and promoted the growth of SCFAs-producing bacteria, for example, Dorea sp. 002160985; SCFAs, especially acetate, were found positively correlated with the chicken growth performance and growth-related hormone signals (P < 0.05). We further verified that AOS can be utilized by Dorea sp. to grow and to produce acetate in vitro. CONCLUSIONS: We demonstrated that the enzymatically produced AOS effectively promoted broiler chicken growth performance by modulating the chicken gut microbiota structure and function. For the first time, we established the connections among AOS, chicken gut microbiota/SCFAs, growth hormone signals and chicken growth performance.

Azacitidine and lenalidomide combination: a novel relapse prophylaxis regimen after allogeneic hematopoietic stem-cell transplantation in patients with acute myeloid leukemia.

Introduction: While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a curative regimen for acute myeloid leukemia (AML), relapse of AML remains a serious risk post-transplantation. Once relapsed, salvage options are limited and management of AML is difficult. Here we designed a prospective study to examine the efficacy and tolerability of maintenance therapy with azacytidine (AZA) plus low-dose lenalidomide (LEN) to prevent relapse after allo-HSCT for AML patients (ChiCTR2200061803). Methods: AML patients post-allo-HSCT were treated with AZA (75 mg/m2 for 7 days), followed by LEN (5 mg/m2, day 10-28), and a 4-week resting interval, which was defined as one treatment cycle. A total of 8 cycles was recommended. Results: 37 patients were enrolled, 25 patients received at least 5 cycles, and 16 patients finished all 8 cycles. With a median follow-up time of 608 (43-1440) days, the estimated 1-year disease free survival (DFS) was 82%, cumulative incidence of relapse (CIR) was 18%, and overall survival (OS) was 100%. Three patients (8%) had grade 1-2 neutropenia without fever; one patient developed grade 3-4 thrombocytopenia and minor subdural hematoma; 4/37 patients (11%) developed chronic GVHD with a score of 1-2, without requiring systemic treatment; No patient developed acute GVHD. After AZA/LEN prophylaxis, increasing numbers of CD56+NK and CD8+ T, and decreasing of CD19+ B cells were observed. Discussion: Azacitidine combined with low-dose lenalidomide was observed to be an effective relapse prophylaxis option after allo-HSCT in AML patients, and can be administered safely without significantly increasing the risk of GVHD, infection and other AEs. Clinical Trial Registration: www.chictr.org, identifier ChiCTR2200061803.

Impact of a novel prognostic model on allogeneic hematopoietic stem cell transplantation outcomes in patients with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.

Outcomes of patients with hematological malignancies who undergo unrelated donor hematopoietic stem cell transplantation with ATG-Fresenius versus ATG-Genzyme.

To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.

Progress on the efficacy and potential mechanisms of rapamycin in the treatment of immune thrombocytopenia.

OBJECTIVE: 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. METHODS: 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. RESULTS 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-ß, BAFF, etc.) and promote platelet autophagy. CONCLUSIONS: 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.

Clinical characteristics in immune thrombocytopenia patients after COVID-19 vaccination.

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 × 109/L and recovered to an average of 80.6 × 109/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 × 109/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.

Analysis of the Efficacy and Safety of Avatrombopag Combined With MSCs for the Treatment of Thrombocytopenia After Allogeneic Hematopoietic Stem Cell Transplantation.

Platelet graft failure (PGF) is a frequent and serious complication after Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and lacks effective treatment strategies, which could affect the prognosis of patients and even cause death. The exact underlying mechanism of PGF remains unclear, and lacks standard treatment. Here, we conduct a retrospective study to evaluate the efficacy and safety of avatrombopag combined with mesenchymal stem cells (MSCs) in 16 patients with thrombocytopenia after allo-HSCT. Patients were administered the following treatment regimen: 20 mg/d avatrombopag; if the PLT count was less than 50×10^9/L for at least 2 weeks, the dose was increased to 40 mg/d; if the PLT count was 200-400×10^9/L, the dose was reduced; and if the PLT count was greater than 400×10^9/L, avatrombopag was terminated. Umbilical cord MSCs (1×10^6 cells/kg) infusion was performed every week for 4-6 weeks. Among the 16 patients, 13 patients (81.3%) achieved a complete response (CR), 2 patients (12.5%) got a partial response (PR), and 1 patient (6.3%) had no response (NR). The median time to obtain CR was 32 (7-426) days after treatment with avatrombopag combined with umbilical cord MSCs. The time to reach 20×10^9/L≤ PLT <50×10^9/L in the 2 patients with PR was 52 and 230 days after treatment, respectively. One patient had a severe pulmonary infection and died of cytomegalovirus pneumonia. Overall, our results indicated that combination of avatrombopag with MSCs can promote platelet recovery after transplantation, thereby improving the survival rate of patients and improving the quality of life of patients after transplantation, and providing a new method and strategy for the treatment of thrombocytopenia after allo-HSCT.

Pretransplantation minimal residual disease monitoring by multiparameter flow cytometry predicts outcomes of AML patients receiving allogeneic hematopoietic stem cell transplantation.

BACKGROUND AND PURPOSE: Is minimal residual disease (MRD) monitoring by multiparameter flow cytometry (MFC) prognostic for acute myeloid leukemia (AML) patients before allogeneic hemopoietic stem cell transplantation (allo-HSCT)? And if so, what level of MRD eradication can be used to help guide the timing of HSCT? Can haplo-HSCT improve the prognosis of AML patients with MRD positive? To figure out these questions, we initiated this retrospective study. METHODS: 96 AML patients were included retrospectively and divided into 5 groups, according to pre-transplantation MRD levels (from 5 × 10-2 to <1 × 10-4), to analyze the overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR). Secondly, we compared the prognosis of MRD-negative (MRDneg) and MRD-positive (MRDpos) AML patients (cutoff value = 1 × 10-3) who underwent allo-HSCT, and further analyzed the prognosis of MRDpos patients after received different transplantation modalities. RESULTS: It is found that the 2-year OS and DFS of MRD negative group were better than the MRD positive group, and that the deeper the eradication of MRD before transplantation, the better the prognosis of patients. The CIR in patients received HLA-identical transplantation, was higher in the MRDpos than in the MRDneg. Haploid transplantation reduced the CIR disparity between MRDpos and MRDneg group. Subsequently, in AML patients who remain MRD positive before HSCT, we show that haplo-HSCT offered a better prognosis than HLA-identical transplantation (MSDT and MUDT). CONCLUSION: It is suggested that achieving MFC-MRD <10-3 (10-4 or even better) before allo-HSCT could reduce the relapse of AML and improve OS and DFS significantly, while haplo-HSCT may be preferred for patients not achieving MRD negativity.

Single-cell transcriptome atlas of human mesenchymal stem cells exploring cellular heterogeneity.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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 Addition of Sirolimus to GVHD Prophylaxis After Allogeneic Hematopoietic Stem Cell Transplantation: A Meta-Analysis of Efficacy and Safety.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of sirolimus (SRL) in the prevention of graft-versus-host disease (GVHD) in recipients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Randomized controlled trials (RCTs) evaluating the safety and efficacy of SRL-based prophylaxis regimens in patients receiving allo-HSCT were obtained from PubMed, Embase, and the Cochrane database. Following specific inclusion and exclusion criteria, studies were selected and screened by two independent reviewers who subsequently extracted the study data. The Cochrane risk bias evaluation tool was used for quality evaluation, and RevMan 5.3 software was used for statistical analysis comparing the effects of SRL-based and non-SRL-based regimens on acute GVHD, chronic GVHD, overall survival (OS), relapse rate, non-relapse mortality (NRM), thrombotic microangiopathy (TMA), and veno-occlusive disease (VOD). RESULTS: Seven studies were included in this meta-analysis, with a total sample size of 1,673 cases, including 778 cases of patients receiving SRL-based regimens and 895 cases in which patients received non-SRL-based regimens. Our data revealed that SRL containing prophylaxis can effectively reduce the incidence of grade II-IV acute GVHD (RR = 0.75, 95% CI: 0.68∼0.82, p < 0.0001). SRL-based prophylaxis was not associated with an improvement of grade III-IV acute GVHD (RR = 0.78, 95% CI: 0.59∼1.03, p = 0.08), chronic GVHD (p = 0.89), OS (p = 0.98), and relapse rate (p = 0.16). Despite its immunosuppressant effects, SRL-based regimens did not increase bacterial (p = 0.68), fungal (p = 0.70), or CMV (p = 0.10) infections. However, patients receiving SRL-based regimens had increased TMA (p < 0.00001) and VOD (p < 0.00001). CONCLUSIONS: This meta-analysis indicates that addition of sirolimus is an effective alternative prophylaxis strategy for II-IV aGVHD but may cause endothelial cell injury and result in secondary TMA or VOD events.

Clinical characteristics and a decision tree model to predict death outcome in severe COVID-19 patients.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) spreads rapidly among people and causes a pandemic. It is of great clinical significance to identify COVID-19 patients with high risk of death. METHODS: A total of 2169 adult COVID-19 patients were enrolled from Wuhan, China, from February 10th to April 15th, 2020. Difference analyses of medical records were performed between severe and non-severe groups, as well as between survivors and non-survivors. In addition, we developed a decision tree model to predict death outcome in severe patients. RESULTS: Of the 2169 COVID-19 patients, the median age was 61 years and male patients accounted for 48%. A total of 646 patients were diagnosed as severe illness, and 75 patients died. An older median age and a higher proportion of male patients were found in severe group or non-survivors compared to their counterparts. Significant differences in clinical characteristics and laboratory examinations were found between severe and non-severe groups, as well as between survivors and non-survivors. A decision tree, including three biomarkers, neutrophil-to-lymphocyte ratio, C-reactive protein and lactic dehydrogenase, was developed to predict death outcome in severe patients. This model performed well both in training and test datasets. The accuracy of this model were 0.98 in both datasets. CONCLUSION: We performed a comprehensive analysis of COVID-19 patients from the outbreak in Wuhan, China, and proposed a simple and clinically operable decision tree to help clinicians rapidly identify COVID-19 patients at high risk of death, to whom priority treatment and intensive care should be given.

Clinical features and death risk factors in COVID-19 patients with cancer: a retrospective study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread around the world. This retrospective study aims to analyze the clinical features of COVID-19 patients with cancer and identify death outcome related risk factors. METHODS: From February 10th to April 15th, 2020, 103 COVID-19 patients with cancer were enrolled. Difference analyses were performed between severe and non-severe patients. A propensity score matching (PSM) analysis was performed, including 103 COVID-19 patients with cancer and 206 matched non-cancer COVID-19 patients. Next, we identified death related risk factors and developed a nomogram for predicting the probability. RESULTS: In 103 COVID-19 patients with cancer, the main cancer categories were breast cancer, lung cancer and bladder cancer. Compared to non-severe patients, severe patients had a higher median age, and a higher proportion of smokers, diabetes, heart disease and dyspnea. In addition, most of the laboratory results between two groups were significantly different. PSM analysis found that the proportion of dyspnea was much higher in COVID-19 patients with cancer. The severity incidence in two groups were similar, while a much higher mortality was found in COVID-19 patients with cancer compared to that in COVID-19 patients without cancer (11.7% vs. 4.4%, P = 0.028). Furthermore, we found that neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) were related to death outcome. And a nomogram based on the factors was developed. CONCLUSION: In COVID-19 patients with cancer, the clinical features and laboratory results between severe group and non-severe group were significantly different. NLR and CRP were the risk factors that could predict death outcome.

Case Report: PD-1 Blockade Combined Autologous Hematopoietic Stem Cell Transplantation With Modified BEAM Regimen Containing High-Dose Cytarabine to Treat R/R Hodgkin's Lymphoma.

The emergence of new drugs has provided additional options in the treatment of relapsed and refractory (R/R) Hodgkin's lymphoma (HL). However, the use of autologous stem cell transplantation (ASCT) has not been completely replaced in this setting. The use of anti-programmed death-1 (PD-1) antibody bridging to ASCT and as maintenance after transplantation is a novel approach in HL treatment. In this case, we report that PD-1 monoclonal antibody (mAb) plus ASCT with modified BEAM regimen (carmustine + etoposide + cytarabine + melphalan) containing high-dose cytarabine to treat R/R HL may represent a promising regimen in this difficult-to-treat setting.

Indications for and contraindications of immune checkpoint inhibitors in cancer patients with COVID-19 vaccination.

The COVID-19 pandemic has lasted over 1 year and will not disappear in a short time. There is no specific remedy against the virus as yet. Vaccination is thus far one of the most important strategies for preventing COVID-19. Cancer patients with COVID-19 have a higher mortality because of immunosuppression. Immune checkpoint inhibitors (ICIs) are a novel anticancer strategy for blocking inhibitory pathways, which are related to the immune response. There is a question regarding whether COVID-19 vaccination and ICI treatment impact each other in cancer patients. This review explores both sides of the relationship between ICI treatment and COVID-19 vaccination and suggests good efficacy and safety of ICI treatment after COVID-19 vaccination as well as little impact on the virus protection and toxicity associated with COVID-19 vaccination during ICI treatment.

Lay abstract The COVID-19 pandemic has lasted over 1 year. Vaccination is a promising strategy for preventing COVID-19. Cancer patients are prone to infection with COVID-19, and these patients have high mortality. Immune checkpoint inhibitors (ICIs) are a novel anticancer strategy. Whether COVID-19 vaccination and ICI treatment impact each other in cancer patients remains unknown. This review explores both sides of the relationship between ICI treatment and COVID-19 vaccination and suggests good efficacy and safety of ICI treatment after COVID-19 vaccination as well as little impact on the virus protection and toxicity associated with COVID-19 vaccination during ICI treatment.