Search

Background: Myelodysplastic syndrome (MDS) is a complicated hematopoietic malignancy characterized by bone marrow (BM) dysplasia with symptoms like anemia, neutropenia, or thrombocytopenia. MDS exhibits considerable heterogeneity in prognosis, with approximately 30% of patients progressing to acute myeloid leukemia (AML). Single cell RNA-sequencing (scRNA-seq) is a new and powerful technique to profile disease landscapes. However, the current available scRNA-seq datasets for MDS are only focused on CD34+ hematopoietic progenitor cells. We argue that using entire BM cell for MDS studies probably will be more informative for understanding the pathophysiology of MDS. Methods: Five MDS patients and four healthy donors were enrolled in the study. Unsorted cells from BM aspiration were collected for scRNA-seq analysis to profile overall alteration in hematopoiesis. Results: Standard scRNA-seq analysis of unsorted BM cells successfully profiles deficient hematopoiesis in all five MDS patients, with three classified as high-risk and two as low-risk. While no significant increase in mutation burden was observed, high-risk MDS patients exhibited T-cell activation and abnormal myelogenesis at the stages between hematopoietic stem and progenitor cells (HSPC) and granulocyte–macrophage progenitors (GMP). Transcriptional factor analysis on the aberrant myelogenesis suggests that the epigenetic regulator chromatin structural protein-encoding gene HMGA1 is highly activated in the high-risk MDS group and moderately activated in the low-risk MDS group. Perturbation of HMGA1 by CellOracle simulated deficient hematopoiesis in mouse Lineage-negative (Lin-) BM cells. Projecting MDS and AML cells on a BM cell reference by our newly developed MarcoPolo pipeline intuitively visualizes a connection for myeloid leukemia development and abnormalities of hematopoietic hierarchy, indicating that it is technically feasible to integrate all diseased bone marrow cells on a common reference map even when the size of the cohort reaches to 1,000 patients or more. Conclusion: Through scRNA-seq analysis on unsorted cells from BM aspiration samples of MDS patients, this study systematically profiled the development abnormalities in hematopoiesis, heterogeneity of risk, and T-cell microenvironment at the single cell level. [ABSTRACT FROM AUTHOR]

This article presents the findings of a study on paroxysmal nocturnal haemoglobinuria (PNH), a rare blood disorder. The study used single-cell sequencing to analyze bone marrow cells from PNH patients and healthy controls. The researchers discovered alterations in the differentiation of bone marrow haematopoietic cells in PNH patients, which may contribute to the development of the disorder. The article includes clinical data on four PNH patients and discusses the mechanisms involved in PNH. The study highlights the differences in bone marrow cells between PNH patients and healthy individuals, providing insights into the impact of PNH on the distribution and function of hematopoietic cells in the bone marrow. [Extracted from the article]

Municipal solid waste incineration (MSWI) fly ash is classified as hazardous waste due to high leachable heavy metals, and incineration leachate belongs to organic wastewater with high biodegradability. Electrodialysis (ED) has shown potential for the removal of heavy metals from fly ash, and bioelectrochemical system (BES) employs biological and electrochemical reactions to generate electricity and remove contaminants from a wide range of substrates. In this study, the ED-BES coupled system was constructed for the co-treatment of fly ash and incineration leachate, where the ED was driven by BES. The treatment effect of fly ash by varying additional voltage, initial pH and liquid-to-solid (L/S) ratio was evaluated. Results showed that the highest removal rates of Pb, Mn, Cu and Cd were 25.43%, 20.13%, 32.14% and 18.87% after 14 days treatment of the coupled system, respectively. These values were obtained under 300 mV of additional voltage, L/S 20 and initial pH3. After the treatment of the coupled system, the fly ash leaching toxicity was lower than the threshold of GB5085.3-2007. The highest energy saving for removed Pb, Mn, Cu and Cd were 6.72, 15.61, 8.99 and 17.46 kWh/kg, respectively. The ED-BES can be considered a cleanliness approach to treating fly ash and incineration leachate simultaneously. [ABSTRACT FROM AUTHOR]

The mechanism underlying autophagy in paroxysmal nocturnal hemoglobinuria (PNH) remains largely unknown. We previously sequenced the entire genome exon of the CD59– cells from 13 patients with PNH and found genes such as CUX1 encoding Cut-like homeobox 1. Peripheral blood samples from 9 patients with PNH and 7 healthy control subjects were obtained to measure CUX1 expression. The correlation between CUX1 messenger RNA expression and PNH clinical indicators was analyzed. To simulate CUX1 expression in patients with PNH, we generated a panel of PNH cell lines by knocking out PIGA in K562 cell lines and transfected lentivirus with CUX1. CCK-8 and EDU assay assessed cell proliferation. Western blotting was used to detect Beclin-1, LC3A, LC3B, ULK1, PI3K, AKT, p-AKT, mTOR, and p-mTOR protein levels. Autophagosomes were observed with transmission electron microscopy. Chloroquine was used to observe CUX1 expression in PNH after autophagy inhibition. Leukocytes from patients with PNH had lower levels of CUX1 messenger RNA expression and protein content than healthy control subjects. The lactose dehydrogenase level and the percentage of PNH clones were negatively correlated with CUX1 relative expression. We reduced CUX1 expression in a PIGA knockout K562 cell line, leading to increased cell proliferation. Levels of autophagy markers Beclin-1, LC3B, LC3A, and ULK1 increased, and autophagosomes increased. Furthermore, PI3K/AKT/mTOR protein phosphorylation levels were lower. CUX1 expression did not change and cell proliferation decreased in CUX1 knocked down PNH cells after inhibition of autophagy by chloroquine. In brief, CUX1 loss-of-function mutation resulted in stronger autophagy in PNH. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of semaglutide combined with metformin in treating type 2 diabetes mellitus (T2DM) patients who are overweight or obese., Methods: We conducted a comprehensive search across multiple databases including Wanfang, CNKI, Chinese Biomedical Literature, VIP, Embase, PubMed, Cochrane Library, and Web of Science. Studies were screened to include randomized controlled trials (RCTs) comparing semaglutide combined with metformin versus metformin alone in T2DM patients with obesity or who are overweight. Primary outcomes included glycemic efficacy and body mass index (BMI). Secondary endpoints included pancreatic function, blood lipids, and incidence of adverse effects. Pooled and sensitivity analyses were performed, and risk of bias was assessed., Results: Ten studies met the inclusion criteria, all involving oral semaglutide. Compared with placebo, semaglutide with metformin significantly reduced fasting blood glucose (SMD: -0.94; 95% CI: -1.53 to -0.35) and 2-hour postprandial glucose (SMD: -0.97; 95% CI: -1.44 to -1.50; P<0.0001). It also lowered HbA1c levels (SMD: -1.13; 95% CI: -1.85 to -0.42; P<0.001) and BMI (SMD: -1.08; 95% CI: -1.47 to -0.69). Improvements were also noted in HOMA-IR and blood lipid levels. However, there were no significant differences in the incidence of adverse reactions, such as hypoglycemia, gastrointestinal reactions, and dizziness and headache between the two groups (all P>0.05)., Conclusion: Treatment with semaglutide combined with metformin significantly improved glycemic control, insulin resistance, weight, BMI, and lipid profiles in patients with T2DM who are overweight or obese., Competing Interests: None., (AJTR Copyright © 2024.)

Objectives: To suggest the presence of a hyperimmune state in patients, and indicate that immune system attack on glycosylphosphatidylinositol (+) (GPI + ) cells while escaping GPI - cell immunity., Methods: We retrospective the immune cell subtypes in peripheral blood from 25 patients visiting Tianjin Medical University General Hospital, Tianjin, China, with classical paroxysmal nocturnal hemoglobinuria (PNH) and 50 healthy controls., Results: The total CD3 + and CD3 + CD8 + cell levels were higher in patients with PNH. The CD3 + cells are positively, correlated with lactate dehydrogenase (LDH; r=0.5453, p =0.0040), indirect bilirubin (r=0.4260, p =0.0379) and Flear - cells in monocytes (r=0.4099, p =0.0303). However, a negative correlation was observed between CD3 + cells and hemoglobin (r= -0.4530, p =0.0105). The total CD19 + cells decreased in patients, and CD19 + cells were negatively correlated with LDH (r= -0.5640, p =0.0077) and Flear - cells in monocytes (r= -0.4432, p =0.0341). Patients showed an increased proportion of total dendritic cells (DCs), with a higher proportion of myeloid DCs (mDCs) within the DC population. Moreover, the proportion of mDC/DC was positively correlated with CD59 - cells (II + III types) in red cells (r=0.7941, p =0.0004), Flear - cells in granulocytes (r=0.5357, p =0.0396), and monocytes (r=0.6445, p =0.0095)., Conclusion: Our results demonstrated that immune abnormalities are associated with PNH development., (Copyright: © Saudi Medical Journal.)

Background: Natural killer (NK) cells play important immunoregulatory roles in the immune pathogenesis of severe aplastic anemia (SAA). Our previous research showed that SAA caused a decrease in T cell immunoglobulin mucin-3 (TIM3) expression on NK cells. Here we investigated the expression of surface receptors, and the cytotoxicity of peripheral TIM3 + NK and TIM3 - NK cells in patients with SAA., Methods: The expressions of surface receptors and cytoplasmic protein of TIM3 + NK and TIM3 - NK cells from peripheral blood were detected by FCM. The functions of mDCs, and apoptosis rate of K562 cells after co-culture with TIM3 + NK and TIM3 - NK cells were maesured by FCM. Westren-blot was used to detect the changes of TIM3 + NK and TIM3 - NK signaling pathway proteins (AKT, P-AKT) and compare the functional activity of the two groups., Results: Activating receptors NKG2D and Granzyme B were higher, while inhibiting receptors NKG2A, CD158a and CD158b were lower on TIM3 - NK cells compared with TIM3 + NK cells in patients with SAA. In SAA, the expression of CD80 and CD86 on mDCs (Myeloid dendritic cells) was significantly decreased after incubation with TIM3 - NK cells. The apoptosis rate (AR) of K562 cells was significantly increased after being incubated with TIM3 - NK cells in SAA. The level of signal pathway protein AKT of TIM3 - NK cells in SAA was similar to that of TIM3 + NK cells, and the levels of P-AKT and P-AKT/AKT ratio of TIM3 - NK cells were significantly higher than those of TIM3 + NK cells., Conclusions: Therefore, TIM3 exerts its inhibitory effect on NK cells and participates in the immune pathogenesis of SAA. Low expression of TIM3 contributes to the enhancement of NK cell activity which in turn inhibits the immune activation state of SAA and improves the disease state. Our research may aid the development of new therapeutic strategies based on TIM3-NK cells infusion for the treatment of SAA., Competing Interests: Conflict of Interest The authors declare that there are no conflicts of interest., (© 2024 Shaoxue Ding, Tian Zhang, Yingying Lei, Chunyan Liu, Zhaoyun Liu, Rong Fu, published by De Gruyter on behalf of Scholar Media Publishing.)

Disitamab vedotin (RC48) is a novel cleavable antibody-drug conjugate (ADC) that has shown promising preclinical activity in HER2-positive breast cancer. However, real-world data regarding its efficacy and safety is lacking, especially in patients previously treated with trastuzumab and heavily treated patients. This retrospective study aimed to evaluate the effectiveness and safety of RC48 in HER2-positive metastatic breast cancer (MBC) in non-clinical trial settings. Eighty-one patients with metastatic HER2-positive BC who received RC48 in Shandong Cancer Hospital and Institute between September 2021 to November 2022 were included in this study. The primary endpoints were real-world progression-free survival (RWPFS) and objective response rate (ORR), and the secondary endpoints included safety and exploratory subgroup analyses. Results showed that the median RWPFS was 5.9 months, and the ORR was 29.6%, including one patient who achieved complete remission. Two-thirds of the patients had received more than one line of prior anti-HER2 treatment, and 76.6% were exposed to anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Patients who received RC48 in ≤3 lines of treatment had significantly longer RWPFS than those who received it in ≥4 lines of treatment. The median RWPFS of RC48 in patients with trastuzumab resistance and refractoriness was 6.5 months and 5.6 months, respectively. The sequence of pyrotinib and RC48 did not influence their total efficacy. To conclude, RC48 exhibited promising efficacy in HER2-positive MBC with manageable toxicity, particularly in patients previously treated with trastuzumab and those who had undergone extensive treatment. RC48 exhibited potent activity for patients regardless of trastuzumab resistance or refractory. The sequence of pyrotinib and RC48 did not influence their total efficacy, indicating no cross-resistance., Competing Interests: None., (AJCR Copyright © 2024.)