The aryl hydrocarbon receptor (AHR) has been identified as a significant driver of tumorigenesis. However, its clinical significance in acute myeloid leukemia (AML) remains largely unclear. In this study, RNA-Seq data from AML patients (bone marrow samples from 173 newly diagnosed AML patients) obtained from the TCGA database, and normal human RNA-Seq data (bone marrow samples from 70 healthy individuals) obtained from the GTEX database are downloaded for external validation and complementarity. The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes. In vitro experiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance. These findings deepen our understanding of the AHR signaling pathway’s involvement in AML.

Abstract Background the mortality associated with severe malaria due to Plasmodiun falciparum remains high despite improvements in malaria management. Case prensentation: this case series aims to describe the efficacy and safety of the exchange transfusion combined with artesunate (ET-AS) regimen in severe P. falciparum malaria. Eight patients diagnosed with severe P. falciparum malaria were included. All patients underwent ET using the COBE Spectra system. The aimed for a post-exchange hematocrit of 30%. Half the estimated blood volume was removed and replaced using fresh frozen plasma. The regimen was well-tolerated without complications. The parasite clearance time ranged from 1 ~ 5 days. Five patients with cerebral malaria exhibited full improved consciousness within 3 days, while patient2 with hemolysis improved on day 2. Liver function improved within 1 ~ 6 days, and patient 1 and patient 6 showed improvements renal function on days 18 and 19, respectively. The length of intensive care unit stay range from 2 ~ 10 days, and all patients treated with ET-AS remained in the hospital for 3 ~ 19 days. Conclusions: these preliminary results suggest that ET-AS regimens are a safe and effective therapy for severe P. falciparum malaria and can benefit patients in clinical settings.

Acute myeloid leukemia (AML) is challenging to treat due to its heterogeneity, prompting a deep understanding of its pathogenesis mechanisms, diagnosis, and treatment. Here, we found reduced expression and acetylation levels of WISP2 in bone marrow mononuclear cells from AML patients and that AML patients with lower WISP2 expression tended to have reduced survival. At the functional level, overexpression of WISP2 in leukemia cells (HL-60 and Kasumi-1) suppressed cell proliferation, induced cell apoptosis, and exerted antileukemic effects in an in vivo model of AML. Our mechanistic investi-gation demonstrated that WISP2 deacetylation was regulated by the deacetylase histone deacetylase (HDAC)3. In addition, we determined that crosstalk between acetylation and ubiq-uitination was involved in the modulation of WISP2 expression in AML. Deacetylation of WISP2 decreased the stability of the WISP2 protein by boosting its ubiquitination mediated by NEDD4 and proteasomal degradation. Moreover, pan-HDAC inhibitors (valproic acid and trichostatin A) and an HDAC3-specific inhibitor (RGFP966) induced WISP2 acetylation at lysine K6 and prevented WISP2 degradation. This regulation led to inhibition of proliferation and induction of apoptosis in AML cells. In summary, our study revealed that WISP2 con-tributes to tumor suppression in AML, which provided an experimental framework for WISP2 as a candidate for gene therapy of AML.

Bone marrow hematopoietic stem cell transplantation (BMT) is one of the most effective treatments for hematological malignancies, and cord blood hematopoietic stem cell transplantation is one of them [1]. Human herpesvirus-6B (HHV-6B) is known as a series of broadly widespread herpes viruses. Primary infection occurs in infants and young children. After infection, the virus is in a state of quiescence, and often reactivates after bone marrow transplantation with a decline in immunity [2]. HHV-6B infection is fatal in bone marrow transplant patients due to the absence of clinical manifestations. In this study, a 15-year-old myeloproliferative neoplasm (MDS/MPN) with eosinophilia patient was infected with HHV-6B 24 days after cord blood hematopoietic stem cell transplantation with pruritus as the initial symptom. The bone marrow diagnosis was shown in Figure 1, and the patient showed an increased proportion of bone marrow blasts, as well as a significant rise in eosinophils. Moreover, abnormalities were observed in the development of the myeloid lineage. The morphology of the patient’s lymphocytes appeared

目的 探讨自体造血干细胞移植治疗急性髓系白血病(AML)的临床疗效及安全性.方法 回顾性分析2017 年3 月至2022 年10 月于济宁医学院附属医院血液内科行自体造血干细胞移植治疗的 18 例AML患者的临床资料.根据法、英、美分型系统(FAB)分型,M2 型3 例,M4 型9 例,M5 型6 例.根据美国国立综合癌症网络(NCCN)指南,低危6 例,中危8 例,高危4 例.其中11 例患者为移植前第1 次完全缓解(CR1),7 例患者为移植前第2 次完全缓解(CR2).所有患者的造血干细胞来自于外周血,其中18 例采用化疗药物+粒细胞集落刺激因子(G-CSF)动员;2 例因第1 次采集CD34+数量不足,第 2 次采用普乐沙福动员.18 例患者输注CD34+计数中位数为4.05×106/kg(1.87×106～27.40×106/kg),单个核细胞计数中位数为 14.48×108/kg(4.07×108～24.74×108/kg).结果 18 例患者中性粒细胞植入的中位时间为 10(9～13)d,血小板植入的中位时间为15(10～19)d.3 年的总生存率及无白血病生存率分别为73.00%及72.00%.BuCy预处理患者复发率为33.33%,含BuMel预处理方案复发率为 12.50%.18 例患者均有不同的消化道反应.6 例以BuCy为预处理方案的患者,血液外的不良反应表现为Ⅰ～Ⅱ度腹泻,心慌、胸闷,转氨酶升高,低钾血症.1 例移植后出现植入综合征.8 例含BuMel预处理方案的患者,血液外的不良反应表现为Ⅰ～Ⅱ度口腔溃疡,低钾血症.18 例患者未发生移植相关死亡.结论 自体造血干细胞移植是AML患者缓解后安全、有效的巩固治疗选择.BuMel预处理方案有更轻的不良反应及更低的复发率,可作为AML患者自体造血干细胞移植预处理的首要选择.

Background: The emergence of resistance to Venetoclax-based combinations for whom intensive chemotherapy is not suitable has become an important clinical dilemma. Some studies have found that the overall remission rate (ORR) of acute monocytic leukemia (AML-M5) patients receiving Venetoclax plus Azacitidine (VA) was only 40%. Myeloid cell leukemia 1 (MCL1) plays a critical role in the regulation of cell apoptosis, and high expression of MCL1 has been observed in acute AML-M5. Chidamide, a new selective histone deacetylase inhibitor, has been shown to decrease the protein level of MCL1 and overcome drug resistance to a certain extent. Aims: This study was to investigate the therapeutic safety and efficacy of VAC for newly diagnosed (ND) AML-M5 patients who are ineligible for or decline to undergo intensive chemotherapy. Methods: ND AML-M5 patients who were ineligible for or chose not to undergo intensive chemotherapy were enrolled.For the first cycle of treatment, patients were administered 10 mg of Chidamide orally daily for 7 days, 75 mg/m2 of Azacitidine subcutaneously daily for 7 days, and Venetoclax orally daily (100 mg on d1, 200 mg on d2, 400 mg on d3–d28). Disease state was assessed on d21-d28 through bone marrow aspiration. The second cycle of treatment, which was either VAC or other chemotherapy, was started at that time regardless of disease state. For post-remission therapy, patients could continue to receive VAC or other regimens, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be performed on eligible patients. Results: Between March 10, 2022, and August 12, 2022, 13 ND AML-M5 patients (seven male and six female) were enrolled. The median age was 53 years (range, 16–63) (Table 1). During cycle 1, 12 (92.3%) of these 13 patients achieved CRc (CR+CRi+MLFS), and one patient (7.7%) with TP53 mutation reached NR. Ten (81.8%) of the 12 patients who achieved CRc had measurable residual disease (MRD) negativity as assessed by multiparameter flow cytometry with a sensitivity of 10-4. As of the cut-off date, January 31, 2023, five patients who achieved CRc underwent the second cycle of the VAC regimen. The CRc rates in patients with favorable, intermediate, and adverse risk as categorized by the 2022 ELN were 100% (5/5), 100% (3/3), and 80% (4/5), respectively. At a median follow-up of 7.0 months (range, 1.4–10.6), the median OS and EFS were not reached. The estimated 12-month OS was 67.7% (95% CI, 51–84) and EFS was 69.2% (95% CI, 57–81) (Figure 1). One patient died of disease progression, and one patient experienced relapse after one cycle of VAC and consolidation without allo-HSCT. Three (23.1%) of 13 patients received haploidentical HSCT at CR1. One patient died of severe infection after allo-HSCT, and the other two patients are still alive. Notable serious adverse events were pneumonia, observed in two (15.4%) patients, and sepsis, observed in one (7.7%) patient. The treatment-related mortality (TRM) rates were 7.7% (1/13) as of 8 weeks. In cycle 1, 12 patients received blood transfusions. Conclusion: The VAC regimen was an effective low-intensity regimen that was well tolerated by this cohort of ND AML-M5 patients who were either ineligible for or declined to undergo intensive chemotherapy. Even one cycle could produce high rates of CR and encouraging OS and EFS results.Keywords: Acute monoblastic leukemia, Acute myeloid leukemia

Introduction: Relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (R/R T-ALL/LBL) is highly heterogeneous. The available salvage treatment options for relapsed patients showed remission rates of less than 50% and a 5-year overall survival (OS) rate of less than 25%. Venetoclax, a Bcl-2 inhibitor, in combination with azacitidine, has demonstrated a high remission rate in 5 patients with R/R T-ALL/LBL in our previous report. Here, we report the interim analysis of a phase 2 study (NCT05149378) for the treatment of venetoclax combined with azacitidine for R/R T-ALL/LBL. Methods: From November 2021 to May 2023, a total of 18 R/R T-ALL/LBL patients were enrolled in the study. Among them, 11 were male and 7 were female. These patients were from seven hospitals, including the central hospital of the First Affiliated Hospital of Soochow University. All patients received salvage treatment with venetoclax (orally, 100mg on day 1, 200mg on day 2, and 400mg on days 3-21) and azacitidine（75mg/m 2/d on days 1-7, subcutaneously). Bone marrow evaluation was performed after the blood cell count recovery or within 42 days since the initiation of the treatment. Results: Among the 18 patients enrolled, 8 were diagnosed with T-ALL, 7 with ETP-ALL, and 3 with T-LBL (Table). 5/18 patients were relapsed T-ALL/LBL, 13/18 patients were refractory to previous treatments. The median age of the patients was 39 years (range: 30-53). After 1-2 courses of venetoclax in combination with azacitidine regimen. 4 (22.2%) achieved CR, 1 patient (5.6%) achieved CRh, 9 (50.0%) patients achieved CRi and 2 (11.1%) achieved MLFS. The overall response rate was 88.9%. With a median follow-up time of 24.1 months (95% CI: 6.8-41.4), the estimated median OS was 24.1 months (95% CI: 6.8-41.4) (Figure a) and the median relapse-free survival was 14.0 (95% CI: 3.8-24.2) months (Figure b). After the treatment, 12/18 (66.7%) patients underwent allogeneic hematopoietic stem cell transplantation. Five patients experienced relapse between 6 to 19 months after the venetoclax and azacitidine treatment. Four patients died because of relapse after the regimen, two patients died because of COVID-19. Grade 3 or higher treatment-related hematologic AE included neutropenia (15/18, 83.3%), anemia (6/18, 33.3%), and thrombocytopenia (4/18, 22.2%). Treatment-related non-hematologic AE included infections (6/18, 33.3%. 4 patients developed pneumonia, 1 patient had perianal infection, 1 patient developed sepsis), elevation of ALT and AST (5/18, 27.8%), and renal function impairment (2/18, 11.1%). There was no other grade 3 or higher non-hematologic AE and no treatment-related death was observed. Conclusion: Our results showed that venetoclax in combination with azacitidine was an effective salvage regimen for R/R T-ALL/LBL patients. The benefit of this regimen for distinct cytogenetic groups in R/R T-ALL/LBL needs to be analyzed in more cases.

直肠癌Hartmann术后放射性肠炎(RE)导致肠梗阻并小肠-直肠残端内瘘是临床上罕见的并发症,对于这种情况的治疗策略仍然难以处理.该文报道了1例RE导致肠梗阻并小肠-直肠残端内瘘患者的临床表现、影像学发现和治疗过程,以期为RE导致肠梗阻引起的小肠-直肠残端内瘘成功治疗提供参考.

目的 探讨粪菌移植治疗慢传输型便秘及缓解患者抑郁症状的临床疗效.方法 选取2019年8月至2021年5月本院收治的70例慢传输型便秘患者作为研究对象,按随机数字表法分为对照组和观察组,每组35例.对照组行聚乙二醇电解质散剂治疗,观察组在对照组基础上行粪菌移植治疗.比较两组临床疗效、Bristol粪便性状评分(BSFS),汉密尔顿焦虑量表(HAMA)评分、便秘患者生活质量评估量表(PAC-QOL)评分.结果 观察组治疗总有效率为82.86％,高于对照组的54.29％,差异有统计学意义(P＜0.05);治疗后,两组BSFS评分高于治疗前,且观察组高于对照组,差异有统计学意义(P＜0.05);治疗后,两组HAMA、PAC-QOL评分均低于治疗前,且观察组低于对照组,差异有统计学意义(P＜0.05).结论 粪菌移植治疗慢传输型便秘效果显著,可帮助改善患者病情,改变粪便性状,缓解焦虑情绪,提高患者生活质量,值得临床推广.

Acute myeloid leukemia (AML) is a hematological malignancy with a low cure rate, especially in the elderly. Previous studies have shown that long non-coding RNA (lncRNA) may be an important factor in the pathogenesis of hematological malignancies, including acute myeloid leukemia (AML). However, the biological roles and clinical significances of most lncRNAs in AML are not fully understood. LncRNA CD27 Antisense RNA 1 (CD27-AS1), as a member of lncRNA family, has rare reports on its function. In present study, we found that the expression of CD27-AS1 examined by quantitative real-time PCR was markedly increased in the AML patients ( N = 40) compared with healthy volunteers ( N = 40). The overall survival time was significantly shorter in patients with higher CD27-AS1 expression than that in patients with lower CD27-AS1 ( P < 0.01). Furthermore, downregulation of CD27-AS1 in AML cells suppressed proliferative ability, arrested cell cycle in G0/G1 phase, and induced apoptosis. However, CD27-AS1 overexpression further enhanced the malignant phenotype of AML cells. Additionally, CD27-AS1 was proved to increase PBX3 expression through sponging miR-224-5p. CD27-AS1 knockdown blocked the MAPK signaling through PBX3 silencing and further inhibited the cell growth of AML cells. Taken together, we demonstrate that CD27-AS1 may be a potential prognostic biomarker of AML, and our finding also provides a new insight for non-coding RNA-based therapeutic intervention of AML.

Hepatic veno-occlusive disease (HVOD) characterized by endothelial cell dysfunction is one of the serious complications after hematopoietic stem-cell transplantation or chemotherapeutic drug application. The mortality of HVOD patients with multiorgan dysfunction is as high as 80%. The primary aim of this study was to evaluate whether the infusion of human umbilical cord-derived endothelial colony forming cells (hUC-ECFCs) could mitigate HVOD injury and investigate the underlying mechanism. We found that the expression of chemokine C-X-C chemokine ligand 12 (CXCL12) was markedly increased in the livers of HVOD mice. Meanwhile, hUC-ECFCs infusion could significantly ameliorate liver injury in HVOD mice, which was accompanied by hUC-ECFCs recruitment in the liver, reduced liver pathological alterations, and decreased serum alanine aminotransferase and aspartate aminotransferase activity. Besides, CXCL12-induced migration in hUC-ECFCs was partly impeded by chemokine receptor type 7 (CXCR7) silence or CXCR4 blockage. In conclusion, our results demonstrated that hUC-ECFCs could mitigate HVOD through homing to the injured liver via the CXCL12-CXCR4/CXCR7 signaling pathway.

High mobility group box 1 (HMGB1) is a non-histone nuclear protein which has been intensively studied in various physiological and pathological processes including leukemia. Here in this study, we further demonstrated that HMGB1 presents higher expression in the bone marrow mononuclear cells of acute myeloid leukemia (AML) patients compared with the normal controls and contributes to the AML pathogenesis and progression by inhibiting apoptosis, facilitating proliferation, and inducing myeloid differentiation blockade of AML cells. Mechanistic investigation revealed that transforming growth factor beta-induced (TGFBI) acts as a potential downstream target of HMGB1 and lentivirus-mediated knockdown of TGFBI expression impaired phorbol-12-myristate-13-acetate (PMA) and all-trans retinoic acid (ATRA)–induced myeloid differentiation of AML cell lines. On the other hand, chidamide, an orally histone deacetylase inhibitor, decreases HMGB1 expression significantly in AML cells with concomitant upregulation of TGFBI expression, and confers therapeutic effect on AML by inducing cell differentiation, apoptosis and inhibiting cell proliferation. In conclusion, our findings provide additional insights that HMGB1 is a promising therapeutic target of AML, and also present experimental evidence for the clinical application of chidamide as a novel agent in AML therapy by downregulating HMGB1 expression. Key messages HMGB1 induces cell proliferation and myeloid differentiation blockade and inhibits apoptosis of AML cells. TGFBI acts as a potential target of HMGB1. Chidamide, a selective HDAC inhibitor, confers promising therapeutic effect for AML via downregulating HMGB1 expression.

Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation has been implicated in the fatty bone marrow and defective hematopoiesis of aplastic anemia (AA). However, the underlying molecular mechanism remains to be investigated. In this study, we found that microRNA 199a-5p (miR-199a-5p) exhibits significantly higher expression in AA BM-MSCs compared with the normal control and is demonstrated to facilitate adipogenic differentiation of BM-MSCs through lentivirus-mediated miR-199a overexpression. Mechanistic investigation reveals that miR-199a-5p could be regulated by PPAR gamma (PPARγ) in a transcription-independent manner and regulates adipogenic differentiation by targeting the expression of transforming growth factor beta induced (TGFBI), which is subsequently validated as a negative regulator of adipogenesis. Besides, the positive correlation between PPARγ and miR-199a-5p expression as well as the inverse relationship between miR-199a-5p and TGFBI expression in normal and AA BM-MSCs was observed. Altogether, our work demonstrates that PPARγ-regulated miR-199a-5p promotes adipogenesis of BM-MSCs by inhibiting TGFBI expression, which might be a novel mechanism underlying the bone marrow adiposity in AA, and provides promising therapeutic targets for AA treatment.