Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal human cancer. Gemcitabine-based chemotherapy remains the cornerstone for advanced PDAC. However, resistance to chemotherapy greatly limits its clinical therapeutic efficacy. Accordingly, the identification of novel therapeutic targets to overcome chemoresistance and improve prognosis is urgently needed. Screening of deubiquitinase family members, tandem affinity purification, mass spectrometry, and RNA sequencing (RNA-Seq) analysis were performed to predict the interactions and function of the CDK5-USP32-Rap1 axis in PDAC. In vitro and in vivo experiments were performed to elucidate the regulatory mechanism and biological roles of this axis in glycolytic reprogramming and chemoresistance in PDAC. Finally, TCGA database analysis and immunohistochemistry were performed to determine the expression and clinical significance of CDK5, USP32, and Rap1 in PDAC tissues. USP32 was identified as a bona fide deubiquitinase of Rap1. USP32 deubiquitinates and stabilizes Rap1, thereby promoting glycolytic reprogramming and chemoresistance in PDAC cells. Moreover, we unexpectedly found that CDK5-mediated phosphorylation of USP32 is required for its deubiquitinase activity toward Rap1 and drives malignant phenotypes of PDAC. Additionally, these functions can be significantly inhibited by pharmacological inhibition (roscovitine) or genetic ablation of CDK5. Importantly, combining a CDK5 inhibitor with gemcitabine has a synergetic anticancer effect. Indeed, the effectiveness of targeting CDK5 to sensitize PDAC cells to gemcitabine was confirmed in a patient-derived xenograft (PDX) model. CDK5 and USP32 expression is markedly elevated in PDAC samples and positively associated with Rap1 expression. Increased expression of CDK5, USP32, and Rap1 is significantly associated with poorer prognosis in PDAC. We identified the previously unrecognized oncogenic function and clinical importance of the CDK5-USP32-Rap1 axis, providing preclinical evidence for potential new combination strategies for PDAC therapy.

Cases with coexistence of myeloproliferative neoplasms related gene mutations and BCR-ABL are rare. Herein, A 61-year-old female was identified as CML with BCR-ABL gene fusion and CALR exon 9 mutation, which is eventually diagnosed Chronic myeloid leukemia with CALR mutation.

Background:Immunosuppressive therapy (IST) with horse or rabbit anti-human thymocyte immunoglobulin (h-/r-ATG) and hematopoietic stem cell transplantation (HSCT) are two baseline treatments for severe aplastic anemia (SAA) and transfusion-dependent non-severe aplastic anemia (TD-NSAA) patients. Addition of thrombopoietin receptor agonists (TPO-RAs) to standard IST therapy (h-/r-ATG) has greatly improved the survival of SAA, whereas porcine anti-lymphocyte globulin (p-ALG) combined with TPO-RAs still had a matter of debate. Methods:We retrospectively compared the data of 48 AA patients in our center between 2020 and 2022, 23 AA patients received with p-ALG ± TPO-RAs, 25 AA patients underwent matched sibling donor (MSD-) or haploidentical (haplo-) HSCT. Results:For patients in the HSCT group, the ORR was 90.9% which was significantly higher than that in the IST±TPO-RAs group (45.5%, P = 0.001) at 3 months; moreover, patients who underwent HSCT achieved faster transfusion independence, better CR rate, shorter time of recovery normal blood routine, and the percentage of normal blood routine (all P < 0.05) compared with IST±TPO-RAs group. However, the ORR were similary at 6 months in the two groups (95.5% vs 81.8% P = 0.342), with a median follow up of 19.8 months (range, 0.3-38.2 months), the 2-year FFS and OS in the two cohorts has no different. Subgroup analysis further indicated that the 2-year FFS and OS were similar between IST+TPO-RAs and haplo-HSCT subgroups, as well as in IST+TPO-RAs and MSD-HSCT cohorts. Moreover, the first-time hospitalizations were much more expensive in the HSCT group than in the IST±TPO-RAs group (402 756 vs. 292 902 yuan, P = 0.002). Conclusion:P-ALG-based-IST±TPO-RAs is a good treatment option with similar FFS and OS compared to allo- HSCT for AA patients without the opportunity of HSCT.

Immune thrombocytopenia (ITP) is a common hematological disorder. Our previous study has found that exosomal miR-146a-5p derived from bone marrow mesenchymal stromal cells (BMSCs) regulate Th17/Treg balance to alleviate ITP. This work further investigated the role of miR-146a-5p in ITP with pregnancy. Compared with healthy pregnant volunteers, the levels of Th1 cells and IFN-γ were increased, the levels of Th2 cells and IL-4 were decreased in peripheral blood of ITP patients with pregnancy. Then, human BMSCs-exosomes repressed the ratio of Th1/Th2 cells in CD4+ T cells, while BMSCs-exosomes with miR-146a-5p inhibitor increased Th1/Th2 cell ratio. Moreover, an ITP mouse model with pregnancy was constructed by administering anti-CD41 antibody in pregnant mice to verify the role of BMSCs-Exo in vivo. BMSCs-Exo elevated the number of platelet and megakaryocyte, improved the function of gastric, spleen and thymus tissues in ITP mice with pregnancy, which attributed to delivery miR-146a-5p. Furthermore, miR-146a-5p interacted with CARD10, and then repressed CARD10/NF-κB signaling pathway. BMSCs-exosomes promoted proliferation and inhibited apoptosis of Dami cells. In conclusion, BMSCs-exosomal miR-146a-5p reduced Th1/Th2 cell ratio to elevate proliferation and inhibit apoptosis of Dami cells, thereby alleviating ITP with pregnancy development. Therefore, miR-146a-5p may be a target for ITP with pregnancy treatment.

OBJECTIVE:To analyze the efficacy and safety of flumatinib in the treatment of patients with chronic myeloid leukemia (CML).METHODS:The clinical data of 56 CML patients treated with flumatinib from January 2020 to December 2021 in the First Affiliated Hospital of Nanchang University were retrospectively analyzed. Patients were divided into three groups: 35 new diagnosed CML patients treated with flumatinib (group A), 10 patients with imatinib/dasatinib intolerance (group B) and 11 patients with imatinib/dasatinib resistance (group C) switched to flumatinib treatment, respectively. The molecular response and adverse effects of flumatinib treatment were evaluated.RESULTS:In group A, the early molecular response (EMR) at 3 months was 40.0%, and the major molecular response (MMR) at 6 and 12 months was 43.7% and 46.2%, respectively. In group B, the EMR was 50.0% at 3 months, and the MMR was 70.0% and 66.2% at 6 and 12 months, respectively. Among evaluable patients, 6 cases in group B achieved molecular response of 4.5 (MR4.5) at 12 months after switching to flumatinib treatment. In group C, 3 cases who switched from imatinib resistance to flumatinib achieved MR4.5 at 12 months, but 2 cases who switched from dasatinib resistance to flumatinib failed. Subgroup analysis showed significant differences in EUTOS long-term survival (ELTS) scores for patients in the medium-risk/high-risk group compared with those in the low-risk group for 3-month EMR (18.8% vs 57.9%), 6-month MMR (15.4% vs 63.2%) and 12-month MR4.5 (15.4% vs 69.2%) (P =0.036, P =0.012,P =0.015). The most common adverse effect in group A was thrombocytopenia, accounting for 54.5%, and 22.8% (8/35) patients discontinued the drug due to haematological adverse effects. Compared with patients who did not discontinue the drug or whose recovery time from discontinuation due to haematological toxicity was <1 month, patients whose recovery time from discontinuation was ≥1 month had a significantly worse 3-month EMR, 6-month MMR and 12-month MR4.5 (P =0.028, P =0.021, P =0.002).CONCLUSIONS:Flumatinib has better molecular response and tolerance in patients with primary, imatinib/dasatinib-intolerant or resistant CML. Medium-risk/high-risk in ELTS score and time to recovery from discontinuation due to haematological toxicity ≥1 month are important factors influencing achievement of better molecular response in flumatinib treatment.

Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

ObjectiveTo determine the prognostic significance of PTPN11 mutation in patients with newly diagnosed acute myeloid leukemia (AML). MethodsA total of 526 patients newly diagnosed with AML (non-M3) were screened for gene mutations by whole-exome next generation sequencing. Then, the clinical characteristics, treatment efficacy, and patient survival rate were collected. Patients with PTPN11 mutation were categorized as the PTPN11mut group. The same number of non-PTPN11mut patients were selected as the control group (PTPN11wt), using 1:1 propensity score matching (PSM) for sex, age, and ELN 2017 risk stratification. The differences in efficacy, overall survival, and median relapse-free survival (mRFS) were compared between PTPN11mut and PTPN11wt groups. Results PTPN11 mutations were detected in 51 (9.7%) of 526 patients newly diagnosed with AML, including 72 mutation types, all of which were missense mutations. NRAS, DNMT3A, FLT3, NPM1, and KRAS were the most frequently co-mutated genes of PTPN11. No significant differences were observed in the complete remission (CR) (70.8% vs. 56.3%, P=0.138) and overall response rates (ORR) (77.1% vs. 66.7%, P=0.256) between PTPN11mut and PTPN11wt groups after propensity score matching analysis. The mRFS time of patients with PTPN11mut was 19 months, significantly lower than that of patients with PTPN11wt (not reached, P=0.02), while the median overall survival (mOS) time (21.3 months vs. 31.4 months, P=0.416) did not differ significantly between the two groups. Thirteen patients in the PTPN11mut group underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Moreover, the mOS (not reached vs. 11 months, P=0.001) and mRFS (not reached vs. 5.7 months, P=0.018) in this group were significantly longer than in those who did not receive allo-HSCT. Multivariate analysis showed that no allo-HSCT, failure to achieve CR at first induction, and relapse were independent and significant risk factors in the prognosis of AML patients with PTPN11 mutation (P<0.05). ConclusionsPatients with AML that exhibit PTPN11 mutation have a poor prognosis; allo-HSCT significantly improves the prognosis of these patients.

To explore the efficacy and survival of venetoclax based (VEN-based) regimen in the treatment of acute myeloid leukemia（AML）.A retrospective study was conducted in patients who received VEN-based regimen and completed at least 1 course of efficacy evaluation at the The First Affiliated Hospital of Nanchang University from July 2019 to July 2022. The incidence of complete remission （CR）/CR with incomplete hematologic recovery （CRi） rate, objective remission rate（ORR） and survival of patients with different risk strati- fication and gene subtypes were analyzed.A total of 79 patients were enrolled, including 43 patients with newly diagnosed unfit AML （unfit AML） and 36 relapsed/refractory AML (R/R AML). The median age of the patients was 62(14-83) years old. 36 out of 79 patients achieved CR/CRi and the ORR of the whole cohort was 64.6%. The CR/CRi rate of unfit AML patients was significantly higher than that of R/R AML patients (60.5% vs 27.8%, P=0.004). In unfit AML cohort, the patients with NPM1 and IDH1/2 mutations were benefited, 8 out of 9 patients ahcieved CR/CRi, 7/8 and 5/8 patients achieved minimal residual disease (MRD) negativity, respectively. Six out of 9 patients with TET2 mutation achieved CR/CRi, 3/6 patients achieved MRD negativity. In R/R AML cohort, 2 out of 3 patients with RUNX1 mutation achieved CR/CRi, without MRD negative, while the CR/CRi rate of patients with other gene mutations was lower than 40%. The median follow-up time was 10.1(95%CI: 8.6-11.6) months. In whole cohort, the median overall survival (mOS) time was 9.1 months and the relapse free survival (RFS) time was not reached. The mOS and RFS of unfit AML patients were significantly longer than those of R/R AML patients (14.1 vs 6.8 months, P=0.013; not reached vs 3.3 months, P=0.000). In unfit AML cohort, the mOS of patients with NPM1 or IDH1/2 mutations was not reached, while that of patients without NPM1 or IDH1/2 mutations was 8.0 months (P=0.009; P=0.022). Furthermore, the mOS of patients with TP53 mutaion was significantly shorter than that of patients without TP53 mutation (5.2 vs 14.1 months， P=0.049). In R/R AML cohort, there was no significant difference in mOS between patients with mutation in each gene subtype and those without gene mutation (P>0.05). All patients had hematology adverse reactions, 91.1% patients had AE grade≥3. The most common non-hematology adverse reactions was infection, with an incidence of 91.1%. VEN-based regimen was tolerable for AML patients.VEN-based regimen can achieve a high response rate, especially in unfit AML with acceptable safety, and some patients can achieve MRD negative. It is also effective in NPM1-, IDH1/2-positive patients with long survival time.维奈克拉为基础的方案治疗急性髓系白血病疗效及生存分析.探讨维奈克拉为基础（VEN-based）的方案治疗急性髓系白血病（AML）（非M3型）的疗效及生存情况.回顾性分析2019年7月至2022年7月在南昌大学第一附属医院接受VEN-based方案治疗且至少完成1个疗程疗效评估的AML患者，分析患者的完全缓解（CR）/完全缓解伴血细胞计数未完全恢复（CRi）率、客观缓解率（ORR）及生存情况.本研究共纳入79例患者，包括43例初治不适合强化疗（unfit）AML患者，36例复发难治（R/R）AML患者，中位年龄62（14-83）岁。总队列获得CR/CRi患者36例，ORR为64.6%。Unfit AML患者CR/CRi率明显高于R/R AML患者（60.5% vs 27.8%，P=0.004）。Unfit AML各基因亚型患者均可从中获益，其中NPM1及IDH1/2突变患者获益最大，均有8例患者获得CR/CRi（8/9），微小残留病（MRD）转阴患者分别为7例（7/8）和5例（5/8）；其次为TET2突变患者，6例获得CR/CRi（6/9），MRD转阴率为50%。R/R AML队列中，3例伴RUNX1突变患者中2例获得CR/CRi，MRD均未转阴，伴其他基因突变患者CR/CRi率均低于40%。中位随访时间为10.1（95%CI： 8.6-11.6）个月，中位总生存（mOS）时间为9.1个月，无复发生存时间（RFS）未达到。Unfit AML患者mOS及RFS均明显长于R/R AML患者（14.1 vs 6.8个月，P=0.013；未达到 vs 3.3个月, P=0.000）。Unfit AML患者中伴NPM1和IDH1/2突变者mOS均未达到，无NPM1和IDH1/2突变患者mOS均为8个月（P=0.009; P=0.022）；伴TP53突变者mOS明显短于无突变患者（5.2 vs 14.1个月，P=0.049）。R/R AML患者中各基因亚型突变与未突变患者间mOS均无显著差异（P>0.05）。所有患者均发生血液学不良反应，91.1%患者血液学AE分级≥3级；非血液学不良反应最常见为感染，发生率为91.1%，VEN-based方案总体耐受性好.VEN-based的方案尤其在初治unfit患者中，可以获得高应答率，且安全性可接受。该方案在伴NPM1、IDH1/2基因突变的unfit AML患者中疗效显著，这部分患者可快速获得MRD转阴，且生存期延长.

Hemophagocytic lymphohistiocytosis (HLH) represents a grave and potentially fatal systemic inflammatory condition. Lymphoma associated hemophagocytic lymphohistiocytosis (LAHS), as a common type in secondary HLH, suffers the worst outcome among sHLH. B cell Lymphoma associated hemophagocytic lymphohistiocytosis (B-LAHS) typically presents as high-risk lymphoma and is associated with a poorer prognosis compared to B cell lymphoma without HLH with standard first-line chemoimmunotherapy. As a result, there is an urgent need for more effective therapeutic strategies. Recent advancements in chimeric antigen receptor (CAR) T-cell therapy have demonstrated remarkable responses in relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL), as well as in some high-risk newly diagnosed B-cell lymphoma. However, There have been no clinical reports regarding the application of CAR-T cell treatment as part of first-line therapy in B-LAHS. We assessed the effectiveness and safety of autologous anti-CD19 CAR-T cell therapy following an immunochemotherapeutic regimen based on R-DEP (Rituximab-doxorubicin-etoposide-methylprednisolone) as a first-line treatment option for patients with B-LAHS. As of 1 July 2023, a cohort of 13 patients diagnosed with B-LAHS（with 3 cases enrolled before registration for clinical trials）was recruited for evaluation and met the criteria for assessing treatment efficacy at our institution. The overall response rate (ORR) for HLH was 100% (with 7 cases achieving complete response and 6 cases achieving partial response) prior to infuse CAR-T cells and the ORR for lymphoma also was 100% (with 10 cases achieving complete response and 3 cases achieving partial response) on the time of a month after CAR-T cell infusion. As of the follow-up date on 1 July 2023 (with a median follow-up time of 14 months), all 13 patients were still alive, 12 cases maintained sustained remission, while 1 case experienced relapse at 16 months after CAR-T cell infusion. The median overall survival (OS) has not been reached, and the median progression-free survival (PFS) was 31.5 months. To provide comparison, we included a group of 26 patients diagnosed with B-LAHS who did not receive CAR-T cell therapy during the same period. The non-CAR-T group demonstrated a significantly lower median OS of 5.93 months and a median PFS of 4.43 months, highlighting the superior prognosis of the CAR-T group (p < 0.001). Regarding adverse events, the CAR-T group exhibited a cytokine release syndrome (CRS) incidence of 53.8% (7/13) and an immune effector cell-associated neurotoxicity syndrome (ICANS) incidence of 30.7% (4 /13), all of which were classified as grade 1. None of the patients experienced non-hematologic toxicity of grade ≥3. While all 13 patients developed cytopenias, hematologic toxicity reactions ≥ grade 3 were observed in 76.9% (10 /13) of patients, but blood cell counts recovered within 3 weeks. Robust expansion of CAR T-cells occurred in all patients, with a median time to peak expansion of 8 days. Importantly, no exacerbation of hemophagocytic syndrome occurred following CAR-T cell infusion, and no patients succumbed to adverse events. In conclusion, our findings suggest that CD19 CAR-T cell treatment exhibits high efficacy as part of first-line therapy for B-LAHS, with a manageable safety profile.

Background Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia.Methods This randomised, double-blind, placebo-controlled, phase 1b/2 study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 x 109 platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT03951623.Findings Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40.0 years (IQR 33.0-50.0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded. Interpretation Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3 trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia.Funding HUTCHMED.Copyright & COPY; 2023 Published by Elsevier Ltd. All rights reserved.

Immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disorder characterized by persistent thrombocytopenia. It may be induced by different pathogenesis due to its heterogeneity, and the therapeutic effects vary on different patients. Bone marrow derived mesenchymal stem cells (BMMSCs) can modulate innate and adaptive immunity, thus resulting in a tolerant microenvironment. Functional defects and immunomodulatory disorders of BMMSCs are significant causes of ITP. Functional effects associated with the activation of the P53 pathway include decreased activity of the phosphatidylinositol 3 kinase/AKT pathway and activation of the TNFAIP3/NF-κB/SMAD7 pathway. Immune dysfunction appears to be correlated with an impaired ability of BMMSCs to induce various types of immune cells in ITP. An in-depth investigation into the pathogenesis of ITP facilitates the treatment of ITP, but larger-scale clinical trials are needed to verify the efficacy of exogenous BMMSCs in the clinical treatment of ITP.

ObjectiveTo evaluate the efficacy and safety of flumatinib combined with multi-agent chemotherapy in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). MethodsThe retrospective analysis involved 25 patients with Ph+ALL treated with flumatinib combined with CALLG-2008 chemotherapy at The First Affiliated Hospital of Nanchang University from December 2019 to February 2022. The efficacy and safety of the treatment were statistically analyzed. ResultsAmong the 25 patients, 21 (84%) and 4 (16%) patients were treated with flumatinib during and after the first induction period, respectively. Complete response (CR) rates at 28 days, 3 months, and 6 months were 88%, 91.67%, and 90.48%, respectively. The respective major molecular response (MMR) rates were 68%, 79.17%, and 80.95% . The respective complete molecular response (CMR) rates were 60%, 75%, and 80.95%. The patients were followed-up with a median follow-up time of 180 days (range, 75.6-458.1 days). The overall survival (OS) and recurrence-free survival (RFS) rates were 82.61% and 73.91%, respectively. During flumatinib treatment, 22 (88%) patients displayed grade Ⅳ myelosuppression. The non-hematologic adverse events mainly included diarrhea, elevated transaminase, fatigue, and nausea. All adverse events improved after treatment. ConclusionsFlumatinib combined with multi-agent chemotherapy is safe and effective in the treatment of patients with Ph+ALL.

Background: Multiple myeloma (MM) is a malignant hematopoietic disease that is usually incurable. However, the ubiquitin-proteasome system (UPS) genes have not yet been established as a prognostic predictor for MM, despite their potential applications in other cancers. Methods: RNA sequencing data and corresponding clinical information were acquired from Multiple Myeloma Research Foundation (MMRF)-COMMPASS and served as a training set (n=787). Validation of the prediction signature were conducted by the Gene Expression Omnibus (GEO) databases (n=1040). To develop a prognostic signature for overall survival (OS), least absolute shrinkage and selection operator regressions, along with Cox regressions, were used. Results: A six-gene signature, including KCTD12, SIAH1, TRIM58, TRIM47, UBE2S, and UBE2T, was established. Kaplan-Meier survival analysis of the training and validation cohorts revealed that patients with high-risk conditions had a significantly worse prognosis than those with low-risk conditions. Furthermore, UPS-related signature is associated with a positive immune response. For predicting survival, a simple to use nomogram and the corresponding web-based calculator (https://jiangyanxiamm.shinyapps.io/MMprognosis/) were built based on the UPS signature and its clinical features. Analyses of calibration plots and decision curves showed clinical utility for both training and validation datasets. Conclusions: As a result of these results, we established a genetic signature for MM based on UPS. This genetic signature could contribute to improving individualized survival prediction, thereby facilitating clinical decisions in patients with MM.

In order to prevent broken seams cause by higher grammaged plug wrapper on recess filter and to increase the controllability of circumference and roundness of filter rods and the hardness of the recess section, the characteristics of hotmelt adhesive and high grammaged plug wrapper and the forming technologies for the roundness design and recess section length design of the base filter rods were studied. The results showed that:1) Adopting the hotmelt adhesive with a high melting point at about 180℃, the seam's bonding strength of the recess filter was the highest, with cracked seams effectively being eliminated. 2) With the increase of plug wrapper grammage, the hardness of the recess section and the roundness of the recess filter increased gradually, and the appropriate grammage for the plug wrapper ranged from 100 to 110 g/m2. 3) For the filter rod with the target circumference of 24.25 mm, the circumference and pressure drop of the recess filter rod could meet the standard design requirements when the base rod circumference was controlled at 23.60-23.70 mm. 4) The hardness of the recess section was higher when its length was 5 mm comparing with 8 mm. The composite structure of the recess filter adopted R-FF1(5+12+8), namely the length of recess section was 5 mm.

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by persistent thrombocytopenia resulting from increased platelet destruction and a loss of autoimmune tolerance. The pathogenesis of ITP is highly complex. Although ITP may be effectively controlled with currently available medications in some patients, a subset of cases remain refractory. The application of mesenchymal stem cells (MSCs) for human hematopoietic stem cell transplantation has increasingly demonstrated that MSCs modulate innate or adaptive immunity, thus resulting in a tolerant microenvironment. Functional defects and immunomodulatory disorders have been observed after the use of bone marrow mesenchymal stem cells (BM-MSCs) from patients with ITP. Here, we summarize the underlying mechanisms and clinical applications of various derived MSCs for ITP treatment, focusing on the main mechanisms underlying the functional defects and immune dysfunction of BM-MSCs from patients with ITP. Functional effects associated with the activation of the p53 pathway include decreased activity of the phosphatidylinositol 3 kinase/Akt pathway and activation of the TNFAIP3/NF-κB/SMAD7 pathway. Immune dysfunction appears to be associated with an impaired ability of BM-MSCs to induce various types of immune cells in ITP. At present, research focusing on MSCs in ITP remains in preliminary stages. The application of autologous or exogenous MSCs in the clinical treatment of ITP has been attempted in only a small case study and must be validated in larger-scale clinical trials.

Background: Primary immune thrombocytopenia (ITP) is characterized by increased platelet destruction and impaired platelet production, resulting in decreased platelet counts and increased bleeding risk. Spleen Tyrosine Kinase (Syk) plays a pivotal role in the regulation of downstream signals in immune receptors, including B cell receptors (BCRs) and has been implicated in autoantibody production. On the other hand, all activating Fc receptors signal via Syk, which has roles in cellular proliferation, differentiation, survival, immune regulation, and cytoskeletal rearrangements during phagocytosis. This randomized, double-blind, placebo-controlled phase 1b study (NCT03951623) aimed to assess the safety, pharmacokinetics (PK), determine the recommended phase 2 dose (RP2D) and evaluate preliminary efficacy of HMPL-523, a novel, potent and highly selective Syk inhibitor, in patients with ITP.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) produces similar survival outcomes as HLA-matched sibling donor allogeneic HCST in younger patients with acquired severe aplastic anemia (SAA). This study reported a 29-years-old man with SAA and intracranial hemorrhage who underwent haplo-HSCT with a modified BU/CY + ATG conditioning regimen. Neutrophil and platelet engraftment were both achieved on day 14 after HSCT. The patient developed grade IV acute graft-versus-host disease (aGVHD) on day 20 and acquired cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections on day 47. After the failure of methylprednisolone, basiliximab, ruxolitinib, and antiviral treatment, the patient was diagnosed with steroid-resistant grade IV aGVHD and refractory CMV and EBV infections. We performed fecal microbiota transplantation and infused CMV- and EBV-specific cytotoxic T lymphocytes. After that the stool volume and frequency gradually decreased, and viral DNA was undetectable on day 80. This report provides helpful clinical experience for treating steroid-resistant aGVHD and refractory viral infections.

Xeroderma Pigmentosum group D (XPD) gene has been shown to suppress hepatocellular carcinoma (HCC) progression, but its mechanism remains not fully understood. ETS-related gene (ERG) is generally known as an oncogenic gene. This study aimed to explore whether XPD regulated HCC cell proliferation, apoptosis and cell cycle by inhibiting ERG expression via the PPARγ pathway. The human hepatoma cells (HepG2) were transfected with the XPD overexpression vector (pEGFP-N2/XPD) or empty vector (pEGFP-N2). The PPARγ inhibitor GW9662 was used to determine whether XPD effects were mediated by activation of PPARγ pathway. Cell cycle and apoptosis were ascertained by flow cytometry, and cell viability was measured by MTT assay. Reverse transcription-polymerase chain reaction and Western blot were performed to determine the mRNA and protein levels. Overexpression of XPD significantly enhanced the expression of PPARγ and p-PPARγ, whereas it downregulated that of ERG and cdk7. Furthermore, XPD overexpression notably inhibited proliferation, promoted apoptosis and decreased the percentage of cells in the S + G2 phase of HepG2 cells. However, these effects of XPD overexpression were abrogated by GW9662. Collectively, XPD suppresses proliferation and promotes apoptosis of HepG2 cells by downregulating ERG expression via activation of the PPARγ pathway.

Bone marrow mesenchymal stem cells (BMSCs) in acute myeloid leukemia (AML) microenvironment undergo modification that includes expression of contents in the small-sized extracellular vesicles (EVs) they secrete. This study aims to investigate whether small-sized EVs from BMSCs of AML patients regulate AML progression by modifying the expression of miR-26a-5p. Small-sized EVs from BMSCs of AML patients (AML-BMSC-EVs) or healthy controls (HC-BMSC-EVs) were isolated by ultra-centrifugation and administered to AML cells (OCI/AML-2 and THP-1). Cell proliferation, migration, and invasion were evaluated by CCK-8 assay, Transwell migration and invasion assays, respectively. Compared with HC-BMSC-EVs, AML-BMSC-EVs contained higher expression of miR-26a-5p and promoted AML cell proliferation, migration, and invasion. Inhibition of miR-26a-5p expression in AML-BMSC-EVs could abrogate the promoting effects of AML-BMSC-EVs on AML cell proliferation, migration, and invasion. Furthermore, GSK3β was a direct target of miR-26a-5p. Moreover, AML-BMSC-EVs inhibited GSK3β expression and activated Wnt/β-catenin signaling in AML cells. Additionally, GSK3β overexpression in THP-1 cells counteracted the promoting effects of AML-BMSCs-EVs on THP-1 cell proliferation, migration, and invasion. AML-BMSC-EVs promoted AML progression by transferring miR-26a-5p to AML cells and subsequently activating the Wnt/β-catenin pathway.

Bone marrow mesenchymal stem cells (BMSCs) are associated with immune thrombocytopenia (ITP), the underlying mechanism has not been fully elucidated. Here, we attempted to investigate whether BMSCs can regulate Th17/Treg imbalance in ITP through the exosome pathway. We first assessed the proportions of Th17 cells and Tregs in ITP patients, showing that ITP patients exhibited an evident imbalance of Th17/Treg. BMSCs-exosomes' treatment significantly reduced Th17/Treg ratio in the CD4+ T cells of ITP patients. Moreover, miR-146a-5p was highly expressed in BMSCs-exosomes. The expression of miR-146a-5p was obviously increased in CD4+ T cells following the treatment of BMSCs-exosomes. BMSCs-exosomal miR-146a-5p silencing promoted the proportions of Th17 cells and repressed the proportions of Tregs in CD4+ T cells. In addition, miR-146a-5p directly interacted with IL-1R-associated kinase-1 (IRAK), and repressed IRAK1 expression. IRAK1 overexpression promoted Th17/Treg ratio in CD4+ T cells, which was abolished by BMSCs-exosomal miR-146a-5p. In conclusion, these findings demonstrate that BMSC-derived exosomal miR-146a-5p regulates Th17/Treg imbalance in ITP by repressing IRAK1 expression. Thus, this work suggests that BMSCs-exosomal miR-146a-5p may be a potential therapeutic target for ITP.