Consistent community assembly but contingent species pool effects drive ß-diversity patterns of multiple microbial groups in desert biocrust systems.

One of the key goals of ecology is to understand how communities are assembled. The species co-existence theory suggests that community ß-diversity is influenced by species pool and community assembly processes, such as environmental filtering, dispersal events, ecological drift and biotic interactions. However, it remains unclear whether there are similar ß-diversity patterns among different soil microbial groups and whether all these mechanisms play significant roles in mediating ß-diversity patterns. By conducting a broad survey across Chinese deserts, we aimed to address these questions by investing biological soil crusts (biocrusts). Through amplicon-sequencing, we acquired ß-diversity data for multiple microbial groups, that is, soil total bacteria, diazotrophs, phoD-harbouring taxa, and fungi. Our results have shown varying distance decay rates of ß-diversity across microbial groups, with soil total bacteria showing a weaker distance-decay relationship than other groups. The impact of the species pool on community ß-diversity varied across microbial groups, with soil total bacteria and diazotrophs being significantly influenced. While the contributions of specific assembly processes to community ß-diversity patterns varied among different microbial groups, significant effects of local community assembly processes on ß-diversity patterns were consistently observed across all groups. Homogenous selection and dispersal limitation emerged as crucial processes for all groups. Precipitation and soil C:P were the key factors mediating ß-diversity for all groups. This study has substantially advanced our understanding of how the communities of multiple microbial groups are structured in desert biocrust systems.

Rituximab potentially improves clinical outcomes of CAR-T therapy for r/r B-ALL via sensitizing leukemia cells to CAR-T-mediated cytotoxicity and reducing CAR-T exhaustion.

PURPOSE: Despite chimeric antigen receptor (CAR) T-cell therapy has achieved great advances in recent year, approximately 50% of relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) patients treated with CAR-T experience relapse 6 months post CAR-T treatment. CD20 express on 30 to 50% of B-ALL, which makes CD20 Monoclonal Antibody as one of the potential therapy strategies to decrease the tumor burden and improve the efficacy of CAR-T therapy. Adding Rituximab to chemotherapy protocol had been demonstrated to improve the outcome for CD20-positive ALL. However, rare study explored the influence of Rituximab combined with CAR-T therapy. METHODS: We retrospectively analyzed 20 r/r B-ALL patients who received CAR-T therapy, all of whom had failed multiple lines of therapy. Before CAR-T infusion, we administered Rituximab to 10 patients with high CD20 expression at a dose of 375 mg/m2 for 1 day. Meanwhile, we selected 10 patients with the comparable features who underwent CAR-T treatment without Rituximab in the same period as the control group. In vitro, the surface molecule expression and killing of CAR-T post Rituximab-treated B-ALL cells co-incubated with CAR-T cells were detected by flow cytometry. RESULTS: The median follow-up of Rituximab and Control groups were 29.27 and 9.83 months. We found that adding Rituximab may confer a favorable prognosis compared with Control group. The 2-year overall survival (OS) and leukemia-free survival (LFS) rates both were longer in the Rituximab group (90% vs. 26.7%, p = 0.0342; 41.7% vs. 25%, p = 0.308). In vitro, we observed that Rituximab-treated tumour cells are more sensitive to CAR-T killing and a broad range of cytokines and chemokines were produced when Rituximab-treated Nalm-6 cells co-cultured with 19-22CAR-T cells, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). To investigate whether Rituximab has an effect on CAR-T persistence, we stimulated CAR-T cells repeatedly in vitro with Rituximab-treated Nalm-6 to evaluate the changes in CAR-T surface exhaustion molecules at different times. We found that the expression of exhaustion molecules (LAG-3, PD-1, TIM-3) on CAR-T cells were significantly lower in the Rituximab group than in the Control group. CONCLUSION: Rituximab combined with CAR-T therapy is effective for improving the long-term prognosis of B-ALL patients who have failed multiple lines of therapy. In vitro, we observed that rituximab potentially improves CAR-T efficacy by sensitizing ALL to CART-mediated cytotoxicity and reducing CAR-T exhaustion.

Decreased snow depth inhibits litter decomposition via changes in litter microbial biomass and enzyme activity.

Decreased snow depth resulting from global warming has the potential to significantly impact biogeochemical cycles in cold forests. However, the specific mechanisms of how snow reduction affects litter decomposition and the underlying microbial processes remain unclear, this knowledge gap limits our ability to precisely predict ecological processes within cold forest ecosystems under climate change. Hence, a field experiment was conducted in a subalpine forest in southwestern China, involving a gradient of snow reduction levels (control, 50 %, 100 %) to investigate the effects of decreased snow on litter decomposition, as well as microbial biomass and activity, specifically focused on two common species: red birch (Betula albosinensis) and masters larch (Larix mastersiana). After one year of incubation, the decomposition rate (k-value) of the two types of litter ranged from 0.12 to 0.24 across three snow treatments. A significant lower litter mass loss, microbial biomass and enzyme activity were observed under decreased snow depth in winter. Furthermore, a hysteresis inhibitory effect of snow reduction on hydrolase activity was observed in the following growing season. Additionally, the high initial quality (lower C/N ratio) of red birch litter facilitated the colonization by a greater quantity of microorganisms, making it more susceptible to snow reduction compared to the low-quality masters larch litter. Structural equation models indicated that decreased snow depth hindered litter decomposition by altering the biological characterization of litter (e.g., microbial biomass and enzyme activity) and environmental variables (e.g., mean temperature and moisture content). The findings suggest that the potential decline in snow depth could inhibit litter decomposition by reducing microbial biomass and activity, implying that the future climate change may alter the material cycling processes in subalpine forest ecosystems.

Lycium barbarum arabinogalactan alleviates intestinal mucosal damage in mice by restoring intestinal microbes and mucin O-glycans.

Structurally defined arabinogalactan (LBP-3) from Lycium barbarum have effect on improving intestinal barrier function. However, whether its intestinal barrier function depended on the changes of intestinal mucin O-glycans have not been investigated. A dextran sodium sulfate-induced acute colitis mouse model was employed to test prevention and treatment with LBP-3. The intestinal microbiota as well as colonic mucin O-glycan profiles were analyzed. Supplementation with LBP-3 inhibited harmful bacteria, including Desulfovibrionaceae, Enterobacteriaceae, and Helicobacteraceae while significantly increased the abundance of beneficial bacteria (e.g., Lachnospiraceae, Ruminococcaceae, and Lactobacillaceae). Notably, LBP-3 augmented the content of neutral O-glycans by stimulating the fucosylation glycoforms (F1H1N2 and F1H2N2), short-chain sulfated O-glycans (S1F1H1N2, S1H1N2, and S1H2N3), and sialylated medium- and long-chain O-glycans (F1H2N2A1, H2N3A1, and F1H3N2A1). In summary, we report that supplement LBP-3 significantly reduced pathological symptoms, restored the bacterial community, and promoted the expression of O-glycans to successfully prevent and alleviate colitis in a mouse model, especially in the LBP-3 prevention testing group. The underlying mechanism of action was investigated using glycomics to better clarify which the structurally defined LBP-3 were responsible for its beneficial effect against ulcerative colitis and assess its use as a functional food or pharmaceutical supplement.

Response of soil phosphorus fractions to litter removal in subalpine coniferous forest.

Litter plays a crucial role in phosphorus (P) cycling, and its role in forest ecosystems may vary with different treatments and forest types. In this study, we investigated soil P fraction responses to litter removal in different forest types and how forest conversion affects the acquisition pathway of bioavailable P through an in situ controlled litter experiment. The results showed that the soil P content increased with the conversion of primary to secondary forest, which may be mostly related to the differences in nutrients and species richness between the two forest types. In addition, the main source of bioavailable P in primary forests was active organic P, while mineral P was the main bioavailable P source in secondary forests. Moreover, the three-year litter removal treatment significantly decreased the primary forest soil P fraction content while significantly increasing the secondary forest bioavailable P content. The main driving factors of the soil P fraction are also different between the two forest types, with AP activity and SOC as the major factors in the primary forest and pH as the main factor in the secondary forest.

An integrative analysis of the tumor suppressors and oncogenes from sexual dimorphism and gene expression alteration features in thyroid cancer.

BACKGROUND: The incidence of thyroid cancer has risen rapidly over the last decades. Although mortality rates are relatively low compared to other cancers, the rate of new cases started to increase in the early 2000s. While tumor suppressors and oncogenes were recently identified in thyroid cancer, the potential roles of these genes in thyroid cancer remain unclear. OBJECTIVE: Analyze the roles and functions of tumor suppressors and oncogenes in thyroid cancer. METHODS: Thyroid cancer data were collected from public databases, such as the UCSC Xena database of TCGA thyroid cancer, TISIDB, and UALCAN. The genes frequently associated with unfavorable thyroid cancer were examined and validated. The association of these target genes with thyroid tumorigenesis, stages, subtypes, and survival rates were analyzed. Additionally, the genes aberrantly expressed in thyroid cancer and significantly involved in thyroid tumorigenesis, stages, subtypes, and survival rates were identified. RESULTS: Female sex was identified as a risk factor for thyroid cancer. The expression of PAPSS2, PDLIM3, COPZ2, ALDH1B1, ANTXR1, GUF1, and SENP6 negatively correlated with thyroid cancer prognosis. CONCLUSION: Female sex was a risk factor for thyroid cancer. In addition, our analysis suggested that PAPSS2, PDLIM3, COPZ2, ALDH1B1, ANTXR1, GUF1, and SENP6 are negatively correlated with the prognosis of thyroid cancer. The expression of ANTXR1, GUF1, and PDLIM3 was weakly associated with thyroid cancer's immune and molecular subtypes.

Decitabine in combination with fludarabine and cyclophosphamide as a lymphodepletion regimen followed by CD19/CD22 bispecific targeted CAR T-cell therapy significantly improves survival in relapsed/refractory B-ALL patients.

Relapse is a major limitation of chimeric antigen receptor (CAR) T-cell therapy. Here, we speculated that decitabine (DAC) in combination with fludarabine and cyclophosphamide (FC) as a lymphodepletion regimen may improve the efficacy of CD19/CD22 CAR T-cell therapy. Fourteen of 26 patients with relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) without remission before lymphodepletion treatment were treated with DAC (total dose 100 mg/m2 in 3 days) followed by the FC regimen (DAC group), while twelve patients received the FC regimen (CON group). On Day 28 after CAR T-cells infusion, no significant differences in complete remission (CR) and minimal residual disease negative CR rates were found between both groups. However, there were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 92.3% (DAC) versus 41.7% (CON), P = 0.005 and 3-year LFS, 92.9% (DAC) versus 27.3% (CON), P < 0.001. There was no significant difference in the incidence of cytokine release syndrome between both groups. Median time to platelet and neutrophil counts recovery was similar in both groups. All adverse events were reversible and manageable. In conclusion, DAC in combination with the FC lymphodepletion regimen may be a new treatment option that can improve the efficacy of CAR T-cell therapy in r/r B-ALL.

Which one is better for refractory/relapsed acute B-cell lymphoblastic leukemia: Single-target (CD19) or dual-target (tandem or sequential CD19/CD22) CAR T-cell therapy?

CD19 chimeric antigen receptor (CAR) T-cell therapy has shown great success against B-cell acute lymphoblastic leukemia (B-ALL). Tandem and sequential CD19/CD22 dual-target CAR T-cell therapies have been developed to reduce the possibility of CD19-negative relapse; however, the superior strategy is still uncertain. This study screened 219 patients with relapsed/refractory B-ALL who were enrolled in clinical trials of either CD19 (NCT03919240) or CD19/CD22 CAR T-cell therapy (NCT03614858). The complete remission (CR) rates in the single CD19, tandem CD19/CD22, and sequential CD19/CD22 groups were 83.0% (122/147), 98.0% (50/51), and 95.2% (20/21), respectively (single CD19 vs. tandem CD19/CD22, P = 0.006). Patients with high-risk factors achieved a higher rate of CR in the tandem CD19/CD22 group than in the single CD19 group (100.0% vs. 82.4%, P = 0.017). Tandem CD19/CD22 CAR T-cell therapy was one of the significant favorable factors in the multivariate analysis of the CR rate. The incidence of adverse events was similar among the three groups. Multivariable analysis in CR patients showed that a low frequency of relapse, a low tumor burden, minimal residual disease-negative CR and bridging to transplantation were independently associated with better leukemia-free survival. Our findings suggested that tandem CD19/CD22 CAR T-cell therapy obtains a better response than CD19 CAR T-cell therapy and a similar response to sequential CD19/CD22 CAR T-cell therapy.

The intervention effects of konjac glucomannan with different molecular weights on high-fat and high-fructose diet-fed obese mice based on the regulation of gut microbiota.

Konjac is a high-quality dietary fiber rich in ß-glucomannan, which has been reported to possess anti-obesity effects. To explore the effective components and the structure-activity relationships of konjac glucomannan (KGM), three different molecular weight components (KGM-1 (90 kDa), KGM-2 (5 kDa), KGM-3 (1 kDa)) were obtained, and systematical comparisons of their effects on high-fat and high-fructose diet (HFFD)-induced obese mice were investigated in the present study. Our results indicated that KGM-1, with its larger molecular weight, reduced mouse body weight and improved their insulin resistance status. KGM-1 markedly inhibited lipid accumulation in mouse livers induced by HFFD by downregulating Pparg expression and upregulating Hsl and Cpt1 expressions. Further investigation revealed that dietary supplementation with konjac glucomannan at different molecular weights caused ß-diversity changes in gut microbes. The potential weight loss effect of KGM-1 maybe attributed to the abundance of changes in Coprobacter, Streptococcus, Clostridium IV, and Parasutterella. The results provide a scientific basis for the in-depth development and utilization of konjac resources.

Variations and patterns of C and N stoichiometry in the first five root branch orders across 218 woody plant species.

Despite the vital role in carbon (C) sequestration and nutrient retention, variations and patterns in root C and nitrogen (N) stoichiometry of the first five root orders across woody plant species remains unclear. We compiled a dataset to explore variations and patterns of root C and N stoichiometry in the first five orders of 218 woody plant species. Across the five orders, root N concentrations were greater in deciduous, broadleaf, and arbuscular mycorrhizal species than in evergreen, coniferous species, and ectomycorrhizal association species, respectively. Contrasting trends were found for root C : N ratios. Most root branch orders showed clear latitudinal and altitudinal trends in root C and N stoichiometry. There were opposite patterns in N concentrations between latitude and altitude. Such variations were mainly driven by plant species, and climatic factors together. Our results indicate divergent C and N use strategies among plant types and convergence and divergence in the patterns of C and N stoichiometry between latitude and altitude across the first five root orders. These findings provide important data on the root economics spectrum and biogeochemical models to improve understanding and prediction of climate change effects on C and nutrient dynamics in terrestrial ecosystems.

Soil arthropods promote litter enzyme activity by regulating microbial carbon limitation and ecoenzymatic stoichiometry in a subalpine forest.

Soil arthropods are crucial decomposers of litter at both global and local scales, yet their functional roles in mediating microbial activity during litter decomposition remain poorly understood. Here, we conducted a two-year field experiment using litterbags to assess the effects of soil arthropods on the extracellular enzyme activities (EEAs) in two litter substrates (Abies faxoniana and Betula albosinensis) in a subalpine forest. A biocide (naphthalene) was used to permit (nonnaphthalene) or exclude (naphthalene application) the presence of soil arthropods in litterbags during decomposition. Our results showed that biocide application was effective in reducing the abundance of soil arthropods in litterbags, with the density and species richness of soil arthropods decreasing by 64.18-75.45 % and 39.19-63.30 %, respectively. Litter with soil arthropods had a greater activity of C-degrading (ß-glucosidase, cellobiohydrolase, polyphenol oxidase, peroxidase), N-degrading (N-acetyl-ß-D-glucosaminidase, leucine arylamidase) and P-degrading (phosphatase) enzymes than litter from which soil arthropods were excluded. The contributions of soil arthropods to C-, N- and P-degrading EEAs in the fir litter were 38.09 %, 15.62 % and 61.69 %, and those for the birch litter were 27.97 %, 29.18 % and 30.40 %, respectively. Furthermore, the stoichiometric analyses of enzyme activity indicated that there was potential C and P colimitation in both the soil arthropod inclusion and exclusion litterbags, and the presence of soil arthropods decreased C limitation in the two litter species. Our structural equation models suggested that soil arthropods indirectly promoted C-, N- and P-degrading EEAs by regulating the litter C content and litter stoichiometry (e.g., N/P, LN/N and C/P) during litter decomposition. These results demonstrate that soil arthropods play an important functional role in modulating EEAs during litter decomposition.

Case report: CD38-directed CAR-T cell therapy: A novel immunotherapy targeting CD38- positive blasts overcomes TKI and chemotherapy resistance of myeloid chronic myeloid leukemia in blastic phase.

Resistance to tyrosine kinase inhibitor (TKI) is a tough problem in the treatment of chronic myeloid leukemia in blastic phase (CML-BP), which was often associated with acquired mutations in the kinase domain and not eliminating the leukemic stem cells. The efficacy of TKI or combination with chemotherapy in CML-BP remains unsatisfactory. Chimeric antigen receptor T (CAR-T) cell immunotherapy may overcome TKI and chemotherapy resistance. However, lack of ideal targetable antigens is a major obstacle for treating patients with myeloid malignancies. CD38 is known to be expressed on most (acute myeloid leukemia) AML cells, and its lack of expression on hematopoietic stem cells renders it as a potential therapeutic target for myeloid CML-BP. We develop a CD38-directed CAR-T cell therapy for AML, and two patients with myeloid CML-BP were enrolled (NCT04351022). Two patients, harboring E255K and T315I mutation in the ABL kinase domain, respectively, were resistant to multiple TKIs (imatinib, dasatinib, nilotinib, and ponatinib) and intensive chemotherapy. The blasts in the bone marrow of two patients exhibited high expression of CD38. After tumor reduction chemotherapy and lymphodepletion chemotherapy, 1 × 107 CAR-T-38 cells per kilogram of body weight were administered. They achieved minimal residual disease-negative and BCR::ABL1-negative complete remission and experienced grade II cytokine release syndrome manifesting as fever. Our data highlighted that CAR-T-38 cell therapy may overcome TKI and chemotherapy resistance in patients with myeloid CML-BP.

Efficacy and safety of decitabine combined with HAAG (homoharringtonine, aclarubicin, low-dose cytarabine and G-CSF) for newly diagnosed acute myeloid leukemia.

The 7 + 3 regimen is the front-line induction chemotherapy in patients with newly diagnosed acute myeloid leukemia, with a response rate of 60-80%. But it's not suitable for all patients especially old/unfit patients because of a higher treatment related toxicity. Therefore, safer and more effective induction therapies are required. In this retrospective study, 50 patients with newly diagnosed acute myeloid leukemia received decitabine combined with HAAG (homoharringtonine, aclarubicin, low-dose cytarabine and G-CSF) as induction chemotherapy. Complete remission (CR) rate was 96% (48/50) and overall response rate was 100%. Of note, All 7 patients harboring FLT3-ITD mutation achieved CR. The median overall survival (OS) was 40.0 months (range 2.0, 58.0). The OS at 1, 3, and 5 years were 75.3%, 54.2%, and 49.3%. The median relapse free survival (RFS) was 38.0 months (range 2.0, 58.0). The RFS at 1, 3, and 5 years were 67.3%, 48.9%, and 45.1%. The OS and RFS of patients who received hematopoietic stem cell transplantation (HSCT) were significantly higher than those who did not undergo HSCT (p=0.017; 0.016). The incidence of grade 3-4 neutropenia and thrombocytopenia was 84% and 88%. Meanwhile, the incidence of grade 3-4 infection and bleeding was only 16% and 6%. There was no early death. In conclusion, DAC+HAAG regimen is effective and well-tolerated as induction therapy in patients with newly diagnosed AML.

Dietary Supplementation of Auricularia auricula-judae Polysaccharides Alleviate Nutritional Obesity in Mice via Regulating Inflammatory Response and Lipid Metabolism.

The incidence of lipid metabolism disorder and obesity that is caused by high-calorie diets is increasing year by year, which has become an urgent global health problem. This study was performed to explore the intervention effects of polysaccharides that were extracted from Auricularia auricula-judae resources in the Qinba Mountain area on nutritional obesity in C57BL/6J mice that was induced by high fat and high fructose diets (HFFD) and to investigate their underlying molecular mechanisms. The results showed that dietary supplementation of Auricularia auricula-judae polysaccharides (AAP) significantly improved mice's insulin resistance state, altered serum lipid metabolites, and slowed down body weight gain that was induced by HFFD. In addition, AAP supplementation decreased inflammatory factor levels and alleviated liver histomorphology changes. Furthermore, AAP down-regulated liver adipogenic-related gene expressions, suppressed cholesterol synthesis-related gene levels, up-regulated fatty acid ß-oxidation-related gene expressions, and promoted cholesterol efflux-related gene expressions, thus improving mice hepatic lipid metabolism homeostasis. Moreover, the intervention effects were closely related to mitochondrial function. These results provide a scientific basis for the further development and utilization of Auricularia auricula-judae resources in the Qinba Mountain area.

Identification of the Predictive Models for the Treatment Response of Refractory/Relapsed B-Cell ALL Patients Receiving CAR-T Therapy.

Background/Aims: Chimeric antigen receptor (CAR) T cells for refractory or relapsed (r/r) B-cell acute lymphoblastic leukemia (ALL) patients have shown promising clinical effectiveness. However, the factors impacting the clinical response of CAR-T therapy have not been fully elucidated. We here aimed to identify the independent factors of CAR-T treatment response and construct the models for predicting the complete remission (CR) and minimal residual disease (MRD)-negative CR in r/r B-ALL patients after CAR-T cell infusion. Methods: Univariate and multivariate logistic regression analyses were conducted to identify the independent factors of CR and MRD-negative CR. The predictive models for the probability of remission were constructed based on the identified independent factors. Discrimination and calibration of the established models were assessed by receiver operating characteristic (ROC) curves and calibration plots, respectively. The predictive models were further integrated and validated in the internal series. Moreover, the prognostic value of the integration risk model was also confirmed. Results: The predictive model for CR was formulated by the number of white blood cells (WBC), central neural system (CNS) leukemia, TP53 mutation, bone marrow blasts, and CAR-T cell generation while the model for MRD-negative CR was formulated by disease status, bone marrow blasts, and infusion strategy. The ROC curves and calibration plots of the two models displayed great discrimination and calibration ability. Patients and infusions were divided into different risk groups according to the integration model. High-risk groups showed significant lower CR and MRD-negative CR rates in both the training and validation sets (p < 0.01). Furthermore, low-risk patients exhibited improved overall survival (OS) (log-rank p < 0.01), higher 6-month event-free survival (EFS) rate (p < 0.01), and lower relapse rate after the allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T cell infusion (p = 0.06). Conclusions: We have established predictive models for treatment response estimation of CAR-T therapy. Our models also provided new clinical insights for the accurate diagnosis and targeted treatment of r/r B-ALL.

Efficacy and safety of mesenchymal stem cells treatment for multidrug-resistant graft-versus-host disease after haploidentical allogeneic hematopoietic stem cell transplantation.

PURPOSE: Graft-versus-host disease (GVHD) is an important complication after human leukocyte antigen (HLA) haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT), which may lead to poor prognosis. Our study intends to identify the efficacy and safety of mesenchymal stem cells (MSCs) for multidrug-resistant (MDR)-GVHD after HID HSCT. METHODS: MDR-GVHD was referring to GVHD remaining no response to at least two types of therapy, and hUCB-MSCs were given at the dose of (1.0-2.0) × 106/kg once a week. RESULTS: A total of 21 patients were enrolled in this retrospective study (acute GVHD (aGVHD): n = 14, chronic GVHD (cGVHD): n = 7). The median dose of MSCs was 1.2 × 106 cells/kg (range, 0.8-1.8 × 106) cells/kg, and the median numbers of infusion were 2 (range, 1-7) and 3 (range, 2-12) for MDR-aGVHD and MDR-cGVHD patients, respectively. In MDR-aGVHD patients, the overall response rate (ORR) was 57.1%, including 50.0% complete response (CR) and 7.1% partial response (PR), and the median time to response was 49.5 days (range, 16-118) days. The 2-year probability of overall survival after MSCs was 64.3%. Five patients (35.7%) developed infections after MSCs, and no obvious hematologic toxicities were observed. Five MDR-aGVHD patients died after MSCs treatments because of GVHD progression (n = 1), severe infection (bacterial central nervous system infection: n = 1; fungal pneumonia: n = 2), and poor graft function (n = 1). In MDR-cGVHD patients, three patients (42.9%) achieved PR after MSCs and the median time to response was 56 days (22-84) days. The ORRs for moderate and severe cGVHD were 50.0% and 33.3%, respectively. Four MDR-cGVHD patients died after MSCs treatments because of GVHD progression (n = 2), severe fungal pneumonia (n = 1), and relapse (n = 1). CONCLUSION: MSCs treatment may be safe and effective for MDR-GVHD after HID HSCT.

MRD-Negative Remission Induced in EP300-ZNF384 Positive B-ALL Patients by Tandem CD19/CD22 CAR T-Cell Therapy Bridging to Allogeneic Stem Cell Transplantation.

EP300-ZNF384-positive B cell acute lymphoblastic leukemia (B-ALL) patients are reported to have a unique immunophenotype with high expression of CD19 and CD22, weak expression of CD20 and aberrant expression of CD13 and/or CD33, sensitivity to chemotherapy and a favorable outcome. To date, the cases of only 53 patients have been reported, albeit few reports on salvage therapy when conventional chemotherapies failed. Here, we describe two relapsed and refractory adult B-ALL patients with EP300-ZNF384 who achieved second remission through tandem CD19/CD22 CAR T-cell therapy. Grade 3 and 2 cytokine release syndrome were observed in cases 1 and 2, respectively. No immune effector cell-associated neurotoxicity syndrome was detected. Both patients underwent consolidate haploidentical hematopoietic stem cell transplantation (HSCT), and each maintained measurable residual disease-negative remission for 14 and 13 months, respectively. Our study suggests that CD19/CD22 CAR T-cell therapy bridging to allogeneic HSCT may be a viable option for EP300-ZNF384-positive B-ALL.

C:N:P stoichiometry responses to 10 years of nitrogen addition differ across soil components and plant organs in a subtropical Pleioblastus amarus forest.

How stoichiometry in different ecosystem components responds to long-term nitrogen (N) addition is crucial for understanding within-ecosystem biogeochemistry cycling processes in the context of global change. To explore the effects of long-term N addition on nutrient stoichiometry in soil and plant components in forest ecosystem, a 10-year N addition experiment using ammonium nitrate (NH4NO3) was conducted in a bamboo forest in the Rainy Zone of West China, where the background N deposition is the highest in the world. Four N treatment levels (+0, +50, +150, +300 kg N ha-1 yr-1) (CK, LN, MN, HN) were applied monthly since November 2007, and then, the C:N:P stoichiometry of soil, microbial biomass, and enzymes in rhizosphere soil and bulk soil, and plant organs were measured. N addition decreased the stoichiometry of C:N:P of soil, microbial biomass, and enzymes. Soil C:N:P change under N addition treatments was stronger in bulk soil, while C:N:P changes for microbial biomass and enzyme activity were significant in rhizosphere soil. N addition significantly decreased TOC in bulk soil. Changes in MBC:MBN:MBP in rhizosphere and bulk soil were mainly caused by MBN and MBP, and MBP performance was consistent with that of AP. The main variable leading to the change of enzyme C:N:P in rhizosphere soil was BG and AP, and in bulk soil was LAP + NAG activity. Plant root C:P and N:P increased with N addition, while those for leaves and twigs did not. N addition significantly reduced the pH of both rhizosphere and bulk soils. These results suggest that the stoichiometry responses of rhizosphere and bulk soils were different due to the influence of plant roots. Soil acidification, enhanced aluminum toxicity potential, decreased root biomass and enhanced microbial P limitation caused by N addition were the important mechanisms that promoted stoichiometry changes in this ecosystem. Under the chronic input of N deposition, the stoichiometry between plant and soil evolved in different directions, which may lead to the decoupling of plants from soils.

Early T-Cell Precursor Acute Lymphoblastic Leukemia and T/Myeloid Mixed Phenotype Acute Leukemia Possess Overlapping Characteristics and Both Benefit From CAG-Like Regimens and Allogeneic Hematopoietic Stem Cell Transplantation.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) and T-lymphoid/myeloid mixed phenotype acute leukemia (T/M-MPAL) are closely related entities and remain a therapeutic challenge. In this study, we characterized the clinical features of 43 ETP-ALL and 41 T/M-MPAL patients and compared clinical outcomes and safety between cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG)-like regimens in 34 patients and conventional ALL regimens in 50 patients. In our series, ETP-ALL and T/M-MPAL showed similar biological characteristics, immunophenotypes, genomic alterations, and outcomes. The complete remission (CR) rate and minimal residual disease (MRD)-negative CR rate of CAG-like regimens were significantly higher compared with conventional ALL regimens (CAG-like: 80.0% and 59.7%, respectively; P = .039; ALL: 51.4% and 31.3%, respectively; P = .048). Overall, 90.0% of cases (18/20) achieved CR using combined decitabine and CAG-like regimens. Additionally, CAG-like regimens had lower rates of grade 3 or 4 infection (18.8% vs. 38.2%; P = .059) and grade 1 or 2 hepatotoxicity (37.5% vs. 60.0%; P = .043) than conventional ALL regimens. The 38 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the first CR (CR1) had better overall survival (OS) and leukemia-free survival (LFS) than the 11 patients who underwent allo-HSCT in the second CR (CR2) or in no remission (median OS not reached vs. 7.6 months, P = .0004; median LFS not reached vs. 11.6 months, P = .0008). There was a significant difference in 3-year OS (95.7% vs. 52.5%; P = .0039) and LFS (95.8% vs. 43.5%; P = .0003) after allo-HSCT between pre-transplant MRD-negative and MRD-positive patients. The median OS for patients without allo-HSCT was 32.1 months in the CAG-like group compared with 12.1 months in the non-CAG-like group (P = .019). These findings suggest that ETP-ALL and T/M-MPAL possess overlapping characteristics and CAG-like regimens improve their clinical outcomes.