ORCID Profile
0000-0001-8051-1481
Current Organisations
Shandong University
,
Shandong Provincial Hospital
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Publisher: American Association for Cancer Research (AACR)
Date: 07-2022
DOI: 10.1158/0008-5472.CAN-22-0917
Abstract: Metabolic reprogramming is a hallmark of cancer progression. Metabolic activity supports tumorigenesis and tumor progression, allowing cells to uptake essential nutrients from the environment and use the nutrients to maintain viability and support proliferation. The metabolic pathways of malignant cells are altered to accommodate increased demand for energy, reducing equivalents, and biosynthetic precursors. Activated oncogenes coordinate with altered metabolism to control cell-autonomous pathways, which can lead to tumorigenesis when abnormalities accumulate. Clinical and preclinical studies have shown that targeting metabolic features of hematologic malignancies is an appealing therapeutic approach. This review provides a comprehensive overview of the mechanisms of metabolic reprogramming in hematologic malignancies and potential therapeutic strategies to target cancer metabolism.
Publisher: Frontiers Media SA
Date: 25-03-2021
Abstract: Although pegylated liposomal doxorubicin (PLD) has been approved in combination with bortezomib for relapsed/refractory multiple myeloma (MM), the antitumor efficacy and tolerability of PLD in different regimens for patients with newly diagnosed MM (NDMM) have not been fully defined. A total of 249 NDMM patients diagnosed between January 2008 and October 2019 were included in this retrospective study. Among them, 112 patients received vindesine-based chemotherapy (35 vDD and 77 vAD) and 137 received bortezomib-based chemotherapy (58 VDD and 79 VD). In bortezomib-containing regimens, the complete response rate (48.3 vs. 30.4%, p = 0.033) and very good partial response or better rate (74.1 vs . 57.0%, p = 0.038) of VDD were significantly higher than those of VD subgroup. While no superior survival was found between VDD and VD subgroup. In vindesine-containing regimens, no statistical significance was identified between vDD and vAD in terms of response rate and survival. The occurrence rates of all cardiac AEs were similar between VDD and VD. The vDD regimen was similar with vAD in the aspect of response rate, survival, and toxicity in NDMM patients. The addition of PLD to VD brought deeper response without increased toxicity, while no superior survival was found.
Publisher: Springer Science and Business Media LLC
Date: 07-09-2020
DOI: 10.1186/S40364-020-00222-3
Abstract: Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with high heterogeneity in the western world. Thus, investigators identified a number of prognostic biomarkers and scoring systems to guide treatment decisions and validated them in the context of immunochemotherapy. A better understanding of prognostic biomarkers, including serum markers, flow cytometry outcomes, IGHV mutation status, microRNAs, chromosome aberrations and gene mutations, have contributed to prognosis in CLL. Del17p/ TP53 mutation, NOTCH1 mutation, CD49d, IGHV mutation status, complex karyotypes and microRNAs were reported to be of predictive values to guide clinical decisions. Based on the biomarkers above, classic prognostic models, such as the Rai and Binet staging systems, MDACC nomogram, GCLLSG model and CLL-IPI, were developed to improve risk stratification and tailor treatment intensity. Considering the presence of novel agents, many investigators validated the conventional prognostic biomarkers in the setting of novel agents and only TP53 mutation status/del 17p and CD49d expression were reported to be of prognostic value. Whether other prognostic indicators and models can be used in the context of novel agents, further studies are required.
Publisher: Frontiers Media SA
Date: 12-05-2023
DOI: 10.3389/FNUT.2023.1080181
Abstract: Patients with aggressive lymphomas are at high risk of losing body resources, resulting in malnutrition, immunodeficiency and inferior outcomes. Nutritional status is closely associated with survival, but often neglected in the prognostic assessment. This study aimed to explore the significance of nutritional status in extranodal NK/T-cell lymphoma (ENKTL). Univariate and multivariate Cox regression analyses were conducted to examine the significance of nutritional index on overall survival (OS) and progression-free survival (PFS). A nutrition-incorporated score system was constructed based on the multivariate results, and its calibration, discrimination and clinical utility were tested in the training and validation cohort. Multivariate analysis revealed controlling nutritional status (CONUT) score could independently predict OS (HR 10.247, P =0.001) and PFS (HR 5.587, P =0.001) in addition to prognostic index of natural killer lymphoma plus EBV (PINK-E). Herein, a reformative model, CONUT-PINK-E, was developed and further verified in external validation cohort. CONUT-PINK-E classified patients into three risk grades with significant survival differences ( P & 0.001). Compared with the current models, CONUT-PINK-E presented superior discrimination, calibration and clinical benefit. In this study, we firstly verified that CONUT score was efficient to screen prognosis-related malnutrition in ENKTL. Moreover, we developed the first nutritional assessment-covered scoring system, CONUT-PINK-E, which might be a promising tool to provide references for clinical decision-making of ENKTL patients.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2019
DOI: 10.1007/S00432-019-02994-0
Abstract: Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase that regulates centriole duplication. PLK4 deregulation causes centrosome number abnormalities, mitotic defects, chromosomal instability and, consequently, tumorigenesis. Therefore, PLK4 has emerged as a therapeutic target for the treatment of multiple cancers. In this review, we summarize the critical role of centrosome lification and PLK4 in cancer. We also highlight recent advances in the development of PLK4 inhibitors and discuss potential combination therapies for cancer. The relevant literature from PubMed is reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. PLK4 is aberrantly expressed in multiple cancers and has prognostic value. Targeting PLK4 with inhibitors suppresses tumor growth in vitro and in vivo. PLK4 plays an important role in centrosome lification and tumor progression. PLK4 inhibitors used alone or in combination with other drugs have shown significant anticancer efficacy, suggesting a potential therapeutic strategy for cancer. The results of relevant clinical trials await evaluation.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2016
DOI: 10.1007/S11655-014-1813-7
Abstract: To analyze changes in gene lification in the mitochondrial genome and in the ID4 gene promoter methylation region in patients with chronic aplastic anemia (CAA) suffering from Kidney (Shen) yin deficiency or Kidney yang deficiency. Bone marrow and oral epithelium s les were collected from CAA patients with Kidney yin deficiency or Kidney yang deficiency (20 cases). Bone marrow s les were collected from 20 healthy volunteers. The mitochondrial genome was lified by polymerase chain reaction (PCR), and PCR products were used for sequencing and analysis. Higher mutational rates were observed in the ND1-2, ND4-6, and CYTB genes in CAA patients suffering from Kidney yin deficiency. Moreover, the ID4 gene was unmethylated in bone marrow s les from healthy in iduals, but was methylated in some CAA patients suffering from Kidney yin deficiency (positive rate, 60%) and Kidney yang deficiency (positive rate, 55%). These data supported that gene mutations can alter the expression of respiratory chain enzyme complexes in CAA patients, resulting in energy metabolism impairment and promoting the physiological and pathological processes of hematopoietic failure. Functional impairment of the mitochondrial respiration chain induced by gene mutation may be an important reason for hematopoietic failure in patients with CAA. This change is closely related to maternal inheritance and Kidney yin deficiency. Finally, these data supported the assertion that it is easy to treat disease in patients suffering from yang deficiency and difficult to treat disease in patients suffering from yin deficiency.
Publisher: Informa UK Limited
Date: 02-2019
Publisher: Spandidos Publications
Date: 23-08-2018
DOI: 10.3892/OL.2018.9356
Publisher: Informa UK Limited
Date: 26-11-2019
DOI: 10.1080/10428194.2019.1691194
Abstract: Although current immunochemotherapy has increased the therapeutic efficacy in diffuse large B-cell lymphoma (DLBCL), there are still some patients who present unfavorable outcomes. Novel effective treatment strategies are needed to improve the prognosis of DLBCL. In this review, we discussed the functional mechanisms and therapeutic applications of histone deacetylases inhibitors (HDIs) in DLBCL from preclinical and clinical studies. The mechanistic rationale of HDIs involved a wide range of effects including the regulation of transcription factors, tumor suppressors, and cell surface molecules. Histone deacetylases inhibitors as monotherapy performed limited activity in the treatment of DLBCL in present clinical trials, but its combination with other regimens has emerged as potential treatment candidates with generally acceptable and manageable adverse effects. Further investigation on the anti-tumor mechanisms of HDIs and ongoing clinical trials will hopefully facilitate the application of HDIs in patients with DLBCL.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 02-2023
DOI: 10.1038/S41420-023-01311-6
Abstract: Prostaglandin D2 (PGD2), an arachidonic acid metabolite, has been implicated in allergic responses, parasitic infection and tumor development. The biological functions and molecular mechanisms of PGD2 in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we firstly found the high concentration of serum PGD2 and low expression of PGD2 receptor CRTH2 in DLBCL, which were associated with clinical features and prognosis of DLBCL patients. Interestingly, different concentration of PGD2 displayed ergent effects on DLBCL progression. Low-concentration PGD2 promoted cell growth through binding to CRTH2 while high-concentration PGD2 inhibited it via regulating cell proliferation, apoptosis, cell cycle, and invasion. Besides, high-concentration PGD2 could induce ROS-mediated DNA damage and enhance the cytotoxicity of adriamycin, bendamustine and venetoclax. Furthermore, HDAC inhibitors, vorinostat (SAHA) and panobinostat (LBH589) regulated CRTH2 expression and PGD2 production, and CRTH2 inhibitor AZD1981 and high-concentration PGD2 enhanced their anti-tumor effects in DLBCL. Altogether, our findings demonstrated PGD2 and CRTH2 as novel prognostic biomarkers and therapeutic targets in DLBCL, and highlighted the potency of high-concentration PGD2 as a promising therapeutic strategy for DLBCL patients.
Publisher: Bentham Science Publishers Ltd.
Date: 24-01-2020
DOI: 10.2174/1871520619666190925143216
Abstract: Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma which is heterogeneous both clinically and morphologically. Over the past decades, significant advances have been made in the understanding of the molecular genesis, leading to the identification of multiple pathways and molecules that can be targeted for clinical benefit. The current review aims to present a brief overview of signal pathways of DLBCL, which mainly focus on B-cell antigen Receptor (BCR), Nuclear Factor-κB (NF-κB), Phosphatidylinositol-3-Kinase (PI3K) – protein kinase B (Akt) – mammalian Target of Rapamycin (mTOR), Janus Kinase (JAK) – Signal Transducer and Activator (STAT), Wnt/β-catenin, and P53 pathways. Activation of signal pathways may contribute to the generation, development, chemotherapy sensitivity of DLBCL, and expression of pathway molecules is associated with the prognosis of DLBCL. Some agents targeting these pathways have been proved effective and relevant clinical trials are in progress. These agents used single or combined with chemotherapy/each other might raise the possibility of improving clinical outcomes in DLBCL. This review presents several signal pathways of DLBCL and targeted agents had a tendency to improve the curative effect, especially in high-risk or relapsed/refractory DLBCL.
Publisher: Spandidos Publications
Date: 15-09-2016
DOI: 10.3892/OR.2016.5091
Abstract: Nasal-type natural killer/T-cell lymphoma (nasal NKTCL) is an aggressive hematological neoplasm with poor prognosis, and its incidence is higher in Asia than in Western countries. Increasing evidence suggests that aberrant activation of signal transducers and activators of transcription 3 (STAT3) is related to numerous malignancies. However, the involvement of STAT3 in the pathogenesis of nasal NKTCL is poorly understood. In this study, immunohistochemistry (IHC) showed that 21/28 (75.0%) nasal NKTCL tissues harbored constitutively expression of phospho‑STAT3 (p‑STAT3) which was positively correlated with the Ki‑67 levels (P﹤0.05). Immunofluorescence (IF) also detected p‑STAT3 expression in SNK6 cells (NKTCL cell line). Furthermore, WP1066 (a novel selective STAT3 inhibitor) was able to inhibit proliferation and induce apoptosis of SNK6 cells. Moreover, western blot analysis and RT‑PCR demonstrated that WP1066 downregulated the protein and mRNA expressions of the pro‑survival molecules (including c‑Myc, cyclin D1, and Bcl‑2) in SNK6 cells. These results suggested that STAT3 activation represents a potential target in nasal NKTCL. WP1066 may be a promising agent in antitumor therapy against nasal NKTCL.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2020
DOI: 10.1186/S12935-020-01195-X
Abstract: Extracellular adenosine triphosphate (eATP) and its main metabolite adenosine (ADO) constitute an intrinsic part of immunological network in tumor immunity. The concentrations of eATP and ADO in tumor microenvironment (TME) are controlled by ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed on immune cells, endothelial cells and cancer cells. Once accumulated in TME, eATP boosts antitumor immune responses, while ADO attenuates immunity against tumors. eATP and ADO, like yin and yang, represent two opposite aspects from immune-activating to immune-suppressive signals. Here we reviewed the functions of eATP and ADO in tumor immunity and attempt to block eATP hydrolysis, ADO formation and their contradictory effects in tumor models, allowing the induction of effective anti-tumor immune responses in TME. These attempts documented that therapeutic approaches targeting eATP/ADO metabolism and function may be effective methods in cancer therapy.
Publisher: Springer Science and Business Media LLC
Date: 06-11-2022
DOI: 10.1038/S41418-021-00880-2
Abstract: Glycoprotein prostaglandin D2 synthase (PTGDS) is a member of the lipocalin superfamily and plays dual roles in prostaglandins metabolism and lipid transport. PTGDS has been involved in various cellular processes including the tumorigenesis of solid tumors, yet its role in carcinogenesis is contradictory and the significance of PTGDS in hematological malignancies is ill-defined. Here, we aimed to explore the expression and function of PTGDS in diffuse large B-cell lymphoma (DLBCL), especially the potential role of PTGDS inhibitor, AT56, in lymphoma therapy. Remarkable high expression of PTGDS was found in DLBCL, which was significantly correlated with poor prognosis. PTGDS overexpression and rhPTGDS were found to promote cell proliferation. Besides, in vitro and in vivo studies indicated that PTGDS knockdown and AT56 treatment exerted an anti-tumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and invasion, and enhanced the drug sensitivity to adriamycin and bendamustine through promoting DNA damage. Moreover, the co-immunoprecipitation-based mass spectrum identified the interaction between PTGDS and MYH9, which was found to promote DLBCL progression. PTGDS inhibition led to reduced expression of MYH9, and then declined activation of the Wnt-β-catenin-STAT3 pathway through influencing the ubiquitination and degradation of GSK3-β in DLBCL. The rescue experiment demonstrated that PTGDS exerted an oncogenic role through regulating MYH9 and then the Wnt-β-catenin-STAT3 pathway. Based on point mutation of glycosylation sites, we confirmed the N-glycosylation of PTGDS in Asn51 and Asn78 and found that abnormal glycosylation of PTGDS resulted in its nuclear translocation, prolonged half-life, and enhanced cell proliferation. Collectively, our findings identified for the first time that glycoprotein PTGDS promoted tumorigenesis of DLBCL through MYH9-mediated regulation of Wnt-β-catenin-STAT3 signaling, and highlighted the potential role of AT56 as a novel therapeutic strategy for DLBCL treatment.
Publisher: Spandidos Publications
Date: 08-02-2019
Publisher: Informa UK Limited
Date: 04-02-2019
DOI: 10.1080/10428194.2018.1523400
Abstract: Chronic lymphocytic leukemia (CLL) constitutes the largest percentage of adult leukemia cases in Western countries. Classically, fludarabine (Flu) is an effective drug used as a first-line therapy for CLL however, Flu resistance limits its clinical effect. Minichromosome maintenance (MCM) complex components 2-7 exert important functions in maintaining genomic stability. Replication stress occurs upon dysregulation of MCM7, which potentiates malignant phenotypes. In this study, primary CLL cells and CLL-derived cell lines displayed elevated MCM7 expression. In CD40-stimulated primary CLL cells, MCM7 inhibition resulted in increased Flu-induced apoptosis and delayed repair of DNA damage. In the MEC-1 and EHEB cell lines, knockdown of MCM7 with lentivirus significantly inhibited cell proliferation and promoted cell cycle arrest at S phase. Moreover, MCM7 silencing sensitized both cell lines to Flu by increasing replication stress. The combination of Flu administration with MCM7 inhibition represents a novel approach to reverse Flu resistance in CLL.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2020
DOI: 10.1186/S13045-020-00976-1
Abstract: With covalently closed circular structures, circular RNAs (circRNAs) were once misinterpreted as by-products of mRNA splicing. Being abundant, stable, highly conserved, and tissue-specific, circRNAs are recently identified as a type of regulatory RNAs. CircRNAs bind to certain miRNAs or proteins to participate in gene transcription and translation. Emerging evidence has indicated that the dysregulation of circRNAs is closely linked to the tumorigenesis and treatment response of hematological malignancies. CircRNAs play critical roles in various biological processes, including tumorigenesis, drug resistance, tumor metabolism, autophagy, pyroptosis, and ferroptosis. The N6-methyladenosine modification of circRNAs and discovery of fusion-circRNAs provide novel insights into the functions of circRNAs. Targeting circRNAs in hematological malignancies will be an attractive treatment strategy. In this review, we systematically summarize recent advances toward the novel functions and molecular mechanisms of circRNAs in hematological malignancies, and highlight the potential clinical applications of circRNAs as novel biomarkers and therapeutic targets for future exploration.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2023
DOI: 10.1186/S11658-023-00445-W
Abstract: N 6 -methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined. The expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments. Dysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo–YAP signaling, reprogramming the expression of Hippo target genes. Our results revealed a new mechanism by which the Hippo–YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.AMJMS.2019.01.008
Abstract: A few studies have evaluated the expression of chemokine receptors CXCR4 and CCR7 in diffuse large B-cell lymphoma (DLBCL) however, the association between CXCR4 and CCR7 with bone marrow (BM) involvement and their synergistic effect on prognosis is still unclear. Our study investigated this aspect. Specimens were obtained from 61 primary nodal DLBCL patients and 100 reactive proliferative lymphadenitis patients. CXCR4 and CCR7 expression levels were examined by immunohistochemical staining the relationship between these levels and clinical parameters and the differences in overall survival were analyzed. CXCR4 and CCR7 overexpression was observed in the malignant lymph node tissues from most DLBCL patients. CCR7 expression was significantly higher in the non-GCB than the GCB subtype CXCR4 positivity rates showed no significant difference between the 2 subtypes. In DLBCL patients with BM involvement, CXCR4 was overexpressed in almost all BM s les, but CCR7 expression was low in BM. CXCR4 overexpression was associated with advanced Ann Arbor stages, MYC overexpression, and increased extranodal infiltration CCR7 was associated with advanced Ann Arbor stages and elevated LDH. Like the case for CCR7, the survival rate of CXCR4-positive DLBCL patients was significantly lower than that of the CXCR4-negative patients. CXCR4 There is a positive correlation between CXCR4 overexpression and BM involvement. CXCR4 and CCR7 overexpression is associated with poorer overall survival, especially in CXCR4 and CCR7 copositive patients. CXCR4, CCR7, Ki-67 index, and MYC were independent prognostic factors for DLBCL. Blocking CXCR4 and/or CCR7 can be a novel therapeutic strategy for DLBCL.
Publisher: Wiley
Date: 26-08-2019
DOI: 10.1002/JCB.29241
Abstract: Exosomes are highly specialized and functional bilayer membranous particles. They have been considered as vehicles for transporting and delivering a large number of proteins, lipids, and nucleic acids (gene, noncoding RNA, DNA) from parental to recipient cells. In hematological malignancies, exosomes are involved in the tumorigenesis, including producing growth factors, hindering antitumor immunoreaction, promote inflammation, angiogenesis, and hypercoagulation. With the deepening of understanding, exosomes have ignited great interests and ever‐increasing efforts into the therapeutic application among scientists, such as biomarkers, therapeutic target, drug delivery system, and vaccines. Here, we discuss the most recent studies on the functions and the emerging therapeutic applications of exosomes in lymphoma.
Publisher: Wiley
Date: 04-02-2022
DOI: 10.1002/AJH.26475
Abstract: Steroid‐refractory (SR) acute graft‐versus‐host disease (aGVHD) is one of the leading causes of early mortality after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We investigated the efficacy, safety, prognostic factors, and optimal therapeutic protocol for SR‐aGVHD patients treated with basiliximab in a real‐world setting. Nine hundred and forty SR‐aGVHD patients were recruited from 36 hospitals in China, and 3683 doses of basiliximab were administered. Basiliximab was used as monotherapy ( n = 642) or in combination with other second‐line treatments ( n = 298). The cumulative incidence of overall response rate (ORR) at day 28 after basiliximab treatment was 79.4% (95% confidence interval [CI] 76.5%–82.3%). The probabilities of nonrelapse mortality and overall survival at 3 years after basiliximab treatment were 26.8% (95% CI 24.0%–29.6%) and 64.3% (95% CI 61.2%–67.4%), respectively. A 1:1 propensity score matching was performed to compare the efficacy and safety between the monotherapy and combined therapy groups. Combined therapy did not increase the ORR conversely, it increased the infection rates compared with monotherapy. The multivariate analysis showed that combined therapy, grade III–IV aGVHD, and high‐risk refined Minnesota aGVHD risk score before basiliximab treatment were independently associated with the therapeutic response. Hence, we created a prognostic scoring system that could predict the risk of having a decreased likelihood of response after basiliximab treatment. Machine learning was used to develop a protocol that maximized the efficacy of basiliximab while maintaining acceptable levels of infection risk. Thus, real‐world data suggest that basiliximab is safe and effective for treating SR‐aGVHD.
Publisher: Frontiers Media SA
Date: 27-04-2021
DOI: 10.3389/FCELL.2021.667800
Abstract: Exosomes, nanometer-sized membranous vesicles in body fluids, have emerged as promising non-invasive biomarkers for cancer diagnosis. However, the function of exosomes in diffuse large B-cell lymphoma (DLBCL) remains elusive. This study aimed to investigate the role of exosomal miR-107 in lymphomagenesis and explore its clinical significance. In this study, decreased exosomal miR-107, miR-375-3p, and upregulated exosomal miR-485-3p were detected in the plasma of DLBCL patients and showed potential diagnostic value. Downregulated miR-107 expression was associated with advanced Ann Arbor stage, high IPI score, LDH, and β 2 -MG level in DLBCL patients. Overexpression of miR-107 by miR-107 Agomir significantly abrogated cell proliferation, induced apoptosis, and inhibited cell invasion in vitro , and repressed tumor growth in vivo . Moreover, the downregulation of miR-107 went in the opposite direction. The target genes of miR-107 were mainly enriched in the PI3K-Akt, Hippo, and AMPK signaling pathways. Notably, upregulated 14-3-3η (YWHAH) was suppressed by miR-107 in DLBCL, suggesting that miR-107 may restrain tumorigenesis by targeting 14-3-3η. In summary, this study unveils the function of miR-107 in lymphomagenesis, highlighting its potential as a diagnostic and prognostic indicator and as a new therapeutic target in the management of DLBCL.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2023
DOI: 10.1186/S40164-022-00364-0
Abstract: Cytidine triphosphate synthase 2 (CTPS2) is an essential metabolic enzyme that catalyzes the biosynthesis of CTP. CTP synthases contribute to lymphocytes proliferation and tumorigenesis, but the role of CTPS2 in chronic lymphocytic leukemia (CLL) remains undefined. In silico analysis was performed to quantified the expression and clinical analysis of CTPS2 and BRCA1. The expression was then validated on the internal sets. Loss-and gain-of-function assays were conducted to investigate the physiological phenotypes in CLL. RNA-seq was employed to probe the molecular mechanism of CTPS2. Herein, significant elevated expression of CTPS2 was observed in CLL patients compared to normal CD19 + B cells, which was verified in three independent cohorts. Furthermore, overexpression of CTPS2 was closely associated with undesired prognostic indicators, including unmutated IGHV status and chromosome 11q23 deletion. Additionally, elevated CTPS2 expression predicted adverse overall survival and treatment-free survival with independent prognostic significance. Downregulation of CTPS2 in CLL cells exhibited attenuated cell proliferation, arrested G2/M cell cycle and increased apoptosis. The addition of CTP or glutamine could reverse the above effects. Since RNA-seq showed the enrichment in DNA damage and response signaling, we subsequently found that silence of CTPS2 remarkably elevated DNA damage and decreased DNA repair. It was demonstrated that CTPS2 mediated DNA damage response via interacting with Breast Cancer 1 (BRCA1) protein in CLL through CoIP assays and rescued experiments. Collectively, our study generated the novel findings that CTPS2 promoted CLL progression via DNA damage response and repair pathway. Targeting nucleotide metabolism potentially became an attractive strategy for treatment against CLL.
Publisher: Spandidos Publications
Date: 22-09-2017
DOI: 10.3892/OL.2017.7030
Publisher: Frontiers Media SA
Date: 13-05-2022
Abstract: Waldenström macroglobulinemia/lymphoplasmacytoid lymphoma (WM/LPL) is a rare lymphoproliferative neoplasm characterized by clonally related lymphocytes, lymphoplasmacytic cells, and plasma cell proliferation. WM/LPL patients commonly present with elevated immunoglobulin, predominantly immunoglobulin M (IgM). Previous studies reported that thyroid dysfunction was associated with the development and progression of solid tumors. However, only limited information is available on the correlation between thyroid complications and lymphoid malignancies. The aim of our study was to explore the prognostic significance of thyroid complications in WM/LPL. Herein, 13.3% of WM/LPL patients were diagnosed with thyroid complications, which were significantly associated with unfavorable progression-free survival (PFS), overall survival (OS), and adverse treatment response. Co-existing thyroid disease was significantly related to alleviated serum IgM levels, providing an answer to practical problems. Furthermore, the presence of thyroid complications was identified as an independent prognostic indicator for PFS in WM/LPL. Incorporating the ISSWM score with thyroid complications was superior to ISSWM alone in risk stratification and prognostic prediction. Furthermore, subgroup analyses of WM/LPL patients revealed that subclinical hypothyroidism predicted undesirable outcomes at the early stage. These results were also supported by independent microarray dataset analyses. In conclusion, the primary strength of this study is that it provides robust real-world evidence on the prognostic role of thyroid complications, highlighting further clinical concerns in the management of WM/LPL patients.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.TRIM.2021.101486
Abstract: Anti-thymocyte globulin (ATG) is used prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for graft-versus-host disease (GVHD) prophylaxis. Two different ATG doses (7.5 or 10 mg/kg) were evaluated in comparison with a group without ATG therapy. We retrospectively analyzed 132 patients who were transplanted with HSCT without ATG (non-ATG), or who received 7.5 mg/kg ATG (ATG-7.5) or 10 mg/kg ATG (ATG-10) prior to transplantation. The immune cells (CD3 Compared with non-ATG group, combined ATG-7.5/ATG-10 groups had significantly lower CD3 The ATG therapy at higher and lower doses led to a delayed reconstitution of T cells and the inversion of CD4/CD8 ratio for at least one year after HSCT.
Publisher: Spandidos Publications
Date: 14-06-2021
Publisher: Springer Science and Business Media LLC
Date: 29-09-2020
DOI: 10.1186/S12935-020-01518-Y
Abstract: In recent years, the B cell receptor (BCR) signaling pathway has become a “hot point” because it plays a critical role in B-cell proliferation and function. Bruton’s tyrosine kinase (BTK) is overexpressed in many subtypes of B-cell lymphoma as a downstream kinase in the BCR signaling pathway. Ibrutinib, the first generation of BTK inhibitor, has shown excellent antitumor activity in both indolent and aggressive B-cell lymphoma. Ibrutinib monotherapy has been confirmed to be effective with a high response rate (RR) and well-tolerated in many B-cell lymphoma subgroups. To achieve much deeper and faster remission, combination strategies contained ibrutinib were conducted to evaluate their synergistic anti-tumor effect. For patients with indolent B-cell lymphoma, most of them respond well with ibrutinib monotherapy. Combination strategies contained ibrutinib might be a better choice to achieve deeper and faster remission in the treatment of aggressive subtypes of B-cell lymphoma. Further investigations on the long-term efficacy and safety of the ibrutinib will provide novel strategies for in idualized treatment of B-cell lymphoma.
Publisher: Spandidos Publications
Date: 07-09-2017
DOI: 10.3892/OR.2017.5945
Abstract: Mantle cell lymphoma (MCL) is an aggressive non‑Hodgkin lymphoma (NHL) with poor prognosis. The rapid progression and frequently relapse make it urgent to identify therapeutic agents with potent antitumor effect. Increasing evidence indicated that dysregulation of Wnt/β‑catenin pathway and abnormal methylation appeared to promote tumorigenesis. Arsenic trioxide (As2O3, ATO) has been reported effective in many hematologic malignancies in recent studies, however, the mechanism and effects of ATO in MCL still need further research. In this study, ATO was shown to promote apoptosis and to inhibit cell viability in MCL cell lines, whereas, the expression of DNA methyltransferase-1 (DNMT-1), β‑catenin and the downstream molecules of Wnt/β‑catenin pathway such as c‑myc, cyclin D1 and MMP7 were all decreased in a dose-dependent manner with ATO. ATO also attenuated upregulation of β‑catenin after LiCl stimulation and provided synergistic effect with 5-azacytidine (5-azaC) on the DNMT-1 inhibition. The results indicated that ATO may suppress MCL by targeting Wnt/β‑catenin pathway and DNMT-1. These findings may guide drug usage of ATO in clinical therapy for MCL.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2020
DOI: 10.1186/S13046-020-01623-W
Abstract: Sirtuin 6 (Sirt6) is a highly conserved ADP-ribosylase and NAD+ dependent deacylase, involved in broad cellular processes. This molecule possesses contradictory roles in carcinogenesis, as it has been documented to both suppressing and augmenting tumor growth. This project aimed to explore the expression and functions of Sirt6 in diffuse large B-cell lymphoma (DLBCL), especially with regards to the regulatory role of OSS_128167, a novel small molecular inhibitor targeting Sirt6. Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues. Microarray dataset GSE32918 and GSE83632 were obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. LY1 cell transfected with shSirt6 were performed RNA-sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID beige mice to establish xenograft models. Sirt6 is found to be overexpressed in DLBCL, and is related to poor prognosis. Sirt6-deprived DLBCL cells displayed augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation, and arrested cell cycle progression between the G2 and M phases. Selective OSS_128167-mediated Sirt6 blockage resulted in similar anti-lymphoma effects when compared to Sirt6 knocked-down DLBCL cells. PI3K signaling along with phosphorylation of its downstream targets was reduced upon Sirt6 downregulation. Xenograft models subjected to either OSS_128167 treatment or Sirt6-knockdown showed suppressed tumor growth and lower Ki-67 level. These findings provide mechanistic insights into the oncogenic activity of Sirt6 in DLBCL for the first time and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2022
DOI: 10.1186/S40364-022-00423-Y
Abstract: Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy that lacks specific biomarkers and drug targets. Competing endogenous RNAs (ceRNAs) play vital roles in oncogenesis and tumor progression by sponging microRNAs (miRNAs). Nevertheless, the regulatory mechanisms of survival-related ceRNA networks in CLL remain to be uncovered. We included 865 de novo CLL patients to investigate RNA expression profiles and Illumina sequencing was performed on four CLL patients, two CLL cell lines and six healthy donors in our center. According to univariate Cox regression, LASSO regression as well as multivariate Cox regression analyses, we established a novel risk score model in CLL patients. Immune signatures were compared between the low- and high-risk groups with CIBERSORT and ESTIMATE program. Afterwards, we analyzed the relationship between differentially expressed miRNAs (DEmiRNAs) and IGHV mutational status, p53 mutation status and del17p. Based on the survival analyses and differentially expressed RNAs with targeting relationships, the lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed. In addition, the circRNA circ_0002078/miR-185-3p/TCF7L1 axis was verified and their interrelations were delineated by dual-luciferase reporter gene assay. Totally, 57 differentially expressed mRNAs (DEmRNAs) and 335 DEmiRNAs were identified between CLL patient specimens and normal B cells. A novel risk score model consisting of HTN3, IL3RA and NCK1 was established and validated. The concordance indexes of the model were 0.825, 0.719 and 0.773 in the training, test and total sets, respectively. The high-risk group was related to del(13q14) as well as shorter overall survival (OS). Moreover, we identified DEmiRNAs that related to cytogenetic abnormality of CLL patients, which revealed that miR-324-3p was associated with IGHV mutation, p53 mutation and del17p. The survival-related lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed to further facilitate the development of potential predictive biomarkers. Besides, the expression of circ_0002078 and TCF7L1 were significantly elevated and miR-185-3p was obviously decreased in CLL patients. Circ_0002078 regulated TCF7L1 expression by competing with TCF7L1 for miR-185-3p. The comprehensive analyses of RNA expression profiles provide pioneering insights into the molecular mechanisms of CLL. The novel risk score model and survival-related ceRNA networks promote the development of prognostic biomarkers and potential therapeutic vulnerabilities for CLL.
Publisher: American Society of Hematology
Date: 10-08-2023
DOI: 10.1182/BLOODADVANCES.2022009168
Abstract: Relapsed or refractory (r/r) mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a poor prognosis. Bruton tyrosine kinase (BTK) is a mediator of B-cell receptor signaling and is associated with the development of B-cell lymphomas. Patients with r/r MCL were enrolled in this phase 1/2 study and treated with orelabrutinib, a novel, highly selective BTK inhibitor. The median number of prior regimens was 2 (range, 1-4). The median age was 62 years (range, 37-73 years). Eligible patients received oral orelabrutinib 150 mg once daily (n = 86) or 100 mg twice daily (n = 20) until disease progression or unacceptable toxicity. A dose of 150 mg once daily was chosen as the preferred recommended phase 2 dose. After a median follow-up duration of 23.8 months, the overall response rate was 81.1%, with 27.4% achieving a complete response and 53.8% achieving a partial response. The median duration of response and progression-free survival were 22.9 and 22.0 months, respectively. The median overall survival (OS) was not reached, and the rate of OS at 24 months was 74.3%. Adverse events (AEs) occurring in & % of patients were thrombocytopenia (34.0%), upper respiratory tract infection (27.4%), and neutropenia (24.5%). Grade ≥3 AEs were infrequent and most commonly included thrombocytopenia (13.2%), neutropenia (8.5%), and anemia (7.5%). Three patients discontinued treatment because of treatment-related adverse events (TRAEs), but no fatal TRAEs were reported. Orelabrutinib showed substantial efficacy and was well tolerated in patients with r/r MCL. This trial was registered at www.clinicaltrials.gov as #NCT03494179.
Publisher: Spandidos Publications
Date: 12-04-2018
DOI: 10.3892/OR.2018.6367
Abstract: Interleukin‑9 (IL‑9) can function as both a positive and negative regulator of immune response, however the role of IL‑9 in tumor immunity is poorly understood. Chronic lymphocytic leukemia (CLL) is the most common chronic lympho‑proliferative disorder. Twenty CLL patients from 2010 to 2011 were recruited in the study. Expression and phosphorylation of transcription factor STAT3 and differential microRNAs (miRs) in peripheral blood mononuclear cells (PBMCs) from CLL patient s les were analyzed. In a previous study, we found a high level of IL‑9 in CLL patients. Concomitantly, overexpression of pSTAT3, miR‑155, and miR‑21 were observed in PBMCs from CLL patients in the present study. To elucidate whether there was interaction among IL‑9, STAT3, miR‑155, and miR‑21, MEC‑1 cells were used for further study. Our results revealed that there was no detectable IL‑9 in the culture medium of MEC‑1 cells. However, the IL‑9 protein could be detected using western blotting in MEC‑1 cells. Notably, when recombinant human IL‑9 (rIL‑9) was added to the medium of culturing MEC‑1 cells, the expression levels of pSTAT3 and IL‑9 in MEC‑1 cells were increased in a time‑dependent manner, which could be blocked by STAT3 inhibitor. Both miR‑155 and miR‑21 could increase IL‑9 expression, which could also be suppressed by the inhibitor of STAT3. Our data indicated that the existence of the novel 'extracellular IL‑9 STAT3/miR‑155/miR‑21/intracellular IL‑9' positive feedback system in CLL cells, provides a novel insight in the pathogenesis and possible therapeutic strategy of CLL.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2017
Publisher: Wiley
Date: 09-2021
DOI: 10.1002/CTM2.539
Publisher: Springer Science and Business Media LLC
Date: 15-09-2010
Publisher: Springer Science and Business Media LLC
Date: 27-11-2019
DOI: 10.1186/S13062-019-0255-8
Abstract: Patients diagnosed as diffuse large B cell lymphoma (DLBCL) with CD5 positive normally have a worse outcome and poorly respond to the regulatory treatment strategy. We recently reported differently expressed tRFs and their potential target-genes of tRFs in patients with CD5+ R/R DLBCL. Differently expressed tRFs were detected by Illumina NextSeq instrument and the results were verified by quantitative real-time reverse transcription-PCR. tRF2Cancer database was searched to compared with the results. Further research was performed through bio-informatic analysis including gene ontology (GO) and pathway enrichment analyses, etc. A total of 308 tRFs were identified. Two sequences (AS-tDR-008946, AS-tDR-013492) were chosen for further investigated. The results of Bioinformatics analysis revealed that the target genes including NEDD4L and UBA52 and several associated pathways including PI3K/AKT and MAPK/ERK might be involved in the development of CD5+ R/R DLBCL. Our preliminary study on the associated tRFs might provide a valuable measure to explore the pathogenesis and progression of CD5+ R/R DLBCL. This article was reviewed by Zhen Qing Ye, Nagarajan Raju and Jin Zhuang Dou.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2012
Publisher: Elsevier BV
Date: 03-2020
Publisher: Frontiers Media SA
Date: 12-05-2022
Abstract: The biological and clinical features of chronic lymphocytic leukemia (CLL) exhibited profound heterogeneity across Chinese and patients of predominately European descent. However, the age-related peculiarities and risk assessment of Chinese CLL patients remained ill-defined. The present study demonstrated that CLL patients were characterized by the earlier age at onset in China (median age at diagnosis: 63 years old) than in the United States (median age at diagnosis: 69 years old). Young patients from Shandong Provincial Hospital CLL database displayed prolonged overall survival than the Surveillance, Epidemiology, and End Results cohort. Furthermore, among Chinese CLL patients, young patients showed an increased relapse rate compared with elderly patients. To optimize the risk assessment of CLL patients, novel risk score models named PR-Score and HBG-Score were developed for predicting the outcomes of young and elderly CLL patients respectively. The neonatal survival prediction systems were superior to international prognostic index for CLL (CLL-IPI) and Binet stage in assessing the overall survival and progression free survival of CLL patients. The analyses highlighted refinement of risk evaluation for CLL patients in different age groups, providing insights into in idualized diagnosis and treatment of CLL.
Publisher: Public Library of Science (PLoS)
Date: 22-05-2017
Publisher: Baskent University
Date: 12-2018
Abstract: We evaluated the safety and efficacy of 2 conditioning regimens (busulfan/fludarabine vs modified busulfan/cyclophosphamide) in patients with acute myeloid leukemia undergoing haploidentical hematopoietic stem cell transplant. Twenty patients with primary acute myeloid leukemia had been randomized into busulfan/fludarabine and modified busulfan/cyclophosphamide groups. We retrospectively compared hematopoietic engraftment, regimen-related toxicity, graft-versus-host disease, transplant-related mortality, leukemia-free survival, and overall survival between the groups. All patients achieved engraftment with 100% donor chimerism. The median times for the neutrophil and platelet engraftment in the busulfan/fludarabine and modified busulfan/cyclophosphamide groups were 14.1 versus 14.3 days and 12.7 versus 12.2 days, respectively. Significantly lower incidences of pretreatment toxicity, blood transfusion, and virus activation were observed in the busulfan/fludarabine group. Acute grade 1 graft-versus-host-disease developed in all patients, which was successfully controlled with methylprednisolone. There were no significant differences in engraftment, graft-versus-host disease, leukemia-free survival, and overall survival between groups. Both of these conditioning regimens achieved stable engraftment. Regimen-related toxicity in the busulfan/fludarabine group was well tolerated compared with that in the modified busulfan/cyclophosphamide group, without an increase in relapse rate. Our results demonstrated that myeloablative busulfan/fludarabine might be a highly effective and low-toxicity alternative for patients with acute myeloid leukemia.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 26-05-2022
DOI: 10.3324/HAEMATOL.2022.280758
Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for severe aplastic anemia (SAA), and transplantation from identical sibling donors (ISD) has been recommended as a first-line treatment. Haploidentical donor (HID) transplantation for SAA has made great advances thus, an increased role of HID-SCT in SAA should be considered. We performed a national registry-based analysis comparing long-term outcomes in the upfront HID or upfront ISD SCT setting. A total of 342 SAA patients were enrolled, with 183 patients receiving HID SCT and 159 receiving ISD SCT. The estimated 9-year overall survival and failure-free survival were 87.1±2.5% and 89.3±3.7% (P=0.173) and 86.5±2.6% versus 88.1±3.8% (P=0.257) for patients in the HID and ISD SCT groups, respectively. Transplantation from HID or ISD SCT has greatly improved quality of life (QoL) levels post-HSCT compared to pre-HSCT. The occurrence of chronic graft-versus-host disease was the only identified adverse factor affecting each subscale of QoL. Physical and mental component summaries in adults as well as physical, mental, social, and role well-being in children were all similar between HID and ISD SCT at 5-year time points. At the last follow-up, the proportion of returning to society was comparable between the HID and ISD groups, showing 78.0% versus 84.6% among children and 74.6% versus 81.2% among adults. These data suggest that haploidentical transplant can be considered a potential therapeutic option in the upfront setting for SAA patients in the absence of an HLA-identical related or unrelated donor.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2021
DOI: 10.1186/S40364-021-00278-9
Abstract: N6-methyladenosine (m 6 A) is a prevalent internal RNA modification in higher eukaryotic cells. As the pivotal m 6 A regulator, RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of m 6 A modification. This epigenetic regulation contributes to the structure and functional regulation of RNA and further promotes tumorigenesis and tumor progression. Accumulating evidence has illustrated the pivotal roles of METTL3 in a variety of human cancers. Here, we systemically summarize the interaction between METTL3 and RNAs, and illustrate the multiple functions of METTL3 in human cancer. METLL3 is aberrantly expressed in a variety of tumors. Elevation of METTL3 is usually associated with rapid progression and poor prognosis of tumors. On the other hand, METTL3 may also function as a tumor suppressor in several cancers. Based on the tumor-promoting effect of METTL3, the possibility of applying METTL3 inhibitors is further discussed, which is expected to provide novel insights into antitumor therapy.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2021
DOI: 10.1186/S12935-021-02042-3
Abstract: Mature T-cell lymphomas (MTCLs), a group of diseases with high aggressiveness and vulnerable prognosis, lack for the accurate prognostic stratification systems at present. Novel prognostic markers and models are urgently demanded. Aberrant lipid metabolism is closely related to the tumor progression but its prognostic significance in MTCLs remains unexplored. This study aims to investigate the relationship between dysregulated lipid metabolism and survival prognosis of MTCLs and establish a novel and well-performed prognostic scoring system for MTCL patients. A total of 173 treatment-naive patients were enrolled in this study. Univariate and multivariate Cox regression analysis were performed to assess the prognostic significance of serum lipid profiles and screen out independent prognostic factors, which constituted a novel prognostic model for MTCLs. The performance of the novel model was assessed in the training and validation cohort, respectively, by examining its calibration, discrimination and clinical utility. Among the 173 included patients, 115 patients (01/2006–12/2016) constituted the training cohort and 58 patients (01/2017–06/2020) formed the validation cohort. Univariate analysis revealed declined total cholesterol (TC, P = 0.000), high-density lipoprotein cholesterol (HDL-C, P = 0.000) and increased triglycerides (TG, P = 0.000) correlated to inferior survival outcomes. Multivariate analysis revealed extranodal involved sites ≥ 2 (hazard ratio [HR]: 2.439 P = 0.036), β2-MG ≥ 3 mg/L (HR: 4.165 P = 0.003) and TC 3.58 mmol/L (HR: 3.338 P = 0.000) were independent predictors. Subsequently, a novel prognostic model, EnBC score, was constructed with these three factors. Harrell’s C-index of the model in the training and validation cohort was 0.840 (95% CI 0.810–0.870) and 0.882 (95% CI 0.822–0.942), respectively, with well-fitted calibration curves. The model ided patients into four risk groups with distinct OS [median OS: not available (NA) vs. NA vs. 14.0 vs. 4.0 months, P 0.0001] and PFS (median PFS: 84.0 vs. 19.0 vs. 8.0 vs. 1.5 months, P 0.0001). Time-dependent receiver operating characteristic curve and decision curve analysis further revealed that EnBC score provided higher diagnostic capacity and clinical benefit, compared with International Prognostic Index (IPI). Firstly, abnormal serum lipid metabolism was demonstrated significantly related to the survival of MTCL patients. Furthermore, a lipid-covered prognostic scoring system was established and performed well in stratifying patients with MTCLs.
Publisher: Informa UK Limited
Date: 22-11-2017
DOI: 10.1080/10245332.2016.1258152
Abstract: Imatinib, a breakpoint cluster region-Abelson murine leukemia tyrosine kinase inhibitor, has revolutionized the treatment of chronic myelogenous leukemia (CML). However, the development of multidrug resistance (MDR) limits the clinical application of imatinib. In this study, we aimed to investigate the mechanisms of long noncoding RNA (lncRNA) HOTAIR in CML resistance to imatinib. Thirty-four CML patients were ided into multidrug resistance protein 1 (MRP1)-low and MRP1-high groups according to the median expression. Real-time PCR (qPCR) was used to detect the expression of lncRNA HOTAIR in CML patients, and MTT assay and flow cytometry assay were employed to detect the biological function of silencing lncRNA HOTAIR on the cell survival rate and apoptotic rate. An imatinib-resistant human CML cell line K562 (K562-R) was established, and western blot was used to detect the impact of lncRNA HOTAIR on the activation of PI3K/Akt signaling pathway. Our results showed that lncRNA HOTAIR was greatly upregulated in the MRP1-high patients as well as in the K562-imatinib-resistant cells compared with control. Knockdown of HOTAIR expression downregulated the MRP1 expression levels in the K562-imatinib cells and resulted in higher sensitivity to the imatinib treatment. In addition, the activation of PI3K/Akt was greatly attenuated when HOTAIR was knocked down in K562-imatinib cells. These data suggest that the knockdown of HOTAIR may play a crucial role in improving acquired resistance to imatinib in CML K562-R cells via PI3K/Akt pathway. LncRNA HOTAIR modulates CML cell MDR in a PI3K/Akt-dependent way.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2023
DOI: 10.1186/S12885-023-10830-5
Abstract: As an essential regulator of type I interferon (IFN) response, TMEM173 participates in immune regulation and cell death induction. In recent studies, activation of TMEM173 has been regarded as a promising strategy for cancer immunotherapy. However, transcriptomic features of TMEM173 in B-cell acute lymphoblastic leukemia (B-ALL) remain elusive. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were applied to determine the mRNA and protein levels of TMEM173 in peripheral blood mononuclear cells (PBMCs). TMEM173 mutation status was assessed by Sanger sequencing. Single-cell RNA sequencing (scRNA-seq) analysis was performed to explore the expression of TMEM173 in different types of bone marrow (BM) cells. The mRNA and protein levels of TMEM173 were increased in PBMCs from B-ALL patients. Besides, frameshift mutation was presented in TMEM173 sequences of 2 B-ALL patients. ScRNA-seq analysis identified the specific transcriptome profiles of TMEM173 in the BM of high-risk B-ALL patients. Specifically, expression levels of TMEM173 in granulocytes, progenitor cells, mast cells, and plasmacytoid dendritic cells (pDCs) were higher than that in B cells, T cells, natural killer (NK) cells, and dendritic cells (DCs). Subset analysis further revealed that TMEM173 and pyroptosis effector gasdermin D (GSDMD) restrained in precursor-B (pre-B) cells with proliferative features, which expressed nuclear factor kappa-B (NF-κB), CD19, and Bruton’s tyrosine kinase (BTK) during the progression of B-ALL. In addition, TMEM173 was associated with the functional activation of NK cells and DCs in B-ALL. Our findings provide insights into the transcriptomic features of TMEM173 in the BM of high-risk B-ALL patients. Targeted activation of TMEM173 in specific cells might provide new therapeutic strategies for B-ALL patients.
Publisher: Informa UK Limited
Date: 28-02-2017
DOI: 10.1080/10428194.2017.1292354
Abstract: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Krüppel-like factor 4 (KLF4) has been reported as a bi-regulator in malignancies, but little is known about its role in MCL. Here, we showed that KLF4 was downregulated in three MCL cell lines and lymph nodes from MCL patients, which resulted in a negative prognosis. We also found that the regulation of KLF4 could inhibit the proliferation and induce apoptosis of Jeko-1 cells. The lentivirally over-expressed KLF4 protein was found bind to β-catenin and could inhibit downstream molecules such as cyclinD1 and c-Myc. Furthermore, 5-azacytidine could decrease the expression of methyltransferase-1 (DNMT-1) and restore the KLF4 expression in MCL cell lines, indicating that methylation might play an important role in the downregulation of KLF4. KLF4 may be a potential therapeutic target as a tumor suppressor in MCL.
Publisher: Informa UK Limited
Date: 02-07-2021
Publisher: Informa UK Limited
Date: 07-2020
DOI: 10.2147/CMAR.S258875
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2015
Publisher: Springer Science and Business Media LLC
Date: 07-2016
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.LFS.2019.117140
Abstract: Karyopherin α2 (KPNA2, also known as importinα-1), a member of the nuclear transporter family, is involved in the nucleocytoplasmic transport pathway of a variety of tumor-associated proteins. Recent studies have found that KPNA2 is overexpressed in various cancers, which is associated with poor prognosis. In addition, it has been shown to promote tumor formation and progression by participating in cell differentiation, proliferation, apoptosis, immune response, and viral infection. It is indicated that KPNA2 also plays an important role in the diagnosis, treatment and prognosis of tumors. Herein, we provide an overview of the function and mechanism of KPNA2 in cancer and the prospects in the diagnosis and treatment of cancer. In the future, KPNA2 provides new ideas for the early diagnosis of malignant tumors, the development of molecularly targeted drugs, and prognosis evaluation.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2021
DOI: 10.1007/S43032-021-00536-Z
Abstract: Sexual dysfunction (SD) is one of the late complications in survivors after hematopoietic stem cell transplantation (HSCT), and the gonadal hormones might be involved in the pathogenesis of this pathological process. This study aimed to investigate the incidence of SD by questionnaire, to explore the relationship between SD and the comprehensive gonadal hormones in patients post HSCT. We identified 72 survivors of hematological diseases who underwent HSCT. The sociodemographic characteristics and medical histories of participants were ascertained by a modified version of a questionnaire named "PPSAS-HSCT" in our study. Blood s les were regularly assayed for the global gonadal hormones. Forty-four percent of the females and 51% of the males reported a loss of interest in sexual activities. Ninety-two percent (23/25) of females exhibited decreased serum anti-Müllerian hormone (AMH) levels, and 74% (35/47) of males had elevated follicle-stimulating hormone (FSH) levels. The males with a higher level of oestradiol/testosterone (E2/T) had more symptoms of SD after HSCT. Patients with GVHD who received glucocorticoid (GC) therapy exhibited a lower level of testosterone and more serious SD, especially in the female population. SD and abnormal gonadal hormone homeostasis were present in more than half of the survivors after HSCT. Graft-versus-host disease (GVHD) and glucocorticoid treatment were confirmed to have a significant impact on the levels of testosterone among females. A multimodal intervention for the survivors after HSCT and a better consciousness of the medical staff are necessary for improving the quality of life of the recipients.
Publisher: Informa UK Limited
Date: 05-2019
DOI: 10.2147/CMAR.S193397
Publisher: Spandidos Publications
Date: 30-04-2019
Publisher: Springer Science and Business Media LLC
Date: 15-06-2017
Publisher: Springer Science and Business Media LLC
Date: 15-11-2021
DOI: 10.1038/S41419-021-04368-2
Abstract: Nucleolar and spindle-associated protein 1 (NUSAP1) is an essential regulator of mitotic progression, spindle assembly, and chromosome attachment. Although NUSAP1 acts as an oncogene involved in the progression of several cancers, the exact role of chronic lymphocytic leukemia (CLL) remains elusive. Herein, we first discovered obvious overexpression of NUSAP1 in CLL associated with poor prognosis. Next, the NUSAP1 level was modulated by transfecting CLL cells with lentivirus. Silencing NUSAP1 inhibited the cell proliferation, promoted cell apoptosis and G0/G1 phase arrest. Mechanistically, high expression of NUSAP1 strengthened DNA damage repairing with RAD51 engagement. Our results also indicated that NUSAP1 knockdown suppressed the growth CLL cells in vivo. We further confirmed that NUSAP1 reduction enhanced the sensitivity of CLL cells to fludarabine or ibrutinib. Overall, our research investigates the mechanism by which NUSAP1 enhances chemoresistance via DNA damage repair (DDR) signaling by stabilizing RAD51 in CLL cells. Hence, NUSAP1 may be expected to be a perspective target for the treatment of CLL with chemotherapy resistance.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2017
Publisher: Informa UK Limited
Date: 12-2020
DOI: 10.2147/CMAR.S278570
Publisher: Springer Science and Business Media LLC
Date: 16-06-2020
DOI: 10.1186/S13045-020-00906-1
Abstract: Hippo-Yes-associated protein (YAP) signaling is a key regulator of organ size and tumorigenesis, yet the underlying molecular mechanism is still poorly understood. At present, the significance of the Hippo-YAP pathway in diffuse large B-cell lymphoma (DLBCL) is ill-defined. The expression of YAP in DLBCL was determined in public database and clinical specimens. The effects of YAP knockdown, CRISPR/Cas9-mediated YAP deletion, and YAP inhibitor treatment on cell proliferation and the cell cycle were evaluated both in vitro and in vivo. RNA sequencing was conducted to detect dysregulated RNAs in YAP-knockout DLBCL cells. The regulatory effects of insulin-like growth factor-1 receptor (IGF-1R) on Hippo-YAP signaling were explored by targeted inhibition and rescue experiments. High expression of YAP was significantly correlated with disease progression and poor prognosis. Knockdown of YAP expression suppressed cell proliferation and induced cell cycle arrest in DLBCL cells. Verteporfin (VP), a benzoporphyrin derivative, exerted an anti-tumor effect by regulating the expression of YAP and the downstream target genes, CTGF and CYR61. In vitro and in vivo studies revealed that deletion of YAP expression with a CRISPR/Cas9 genome editing system significantly restrained tumor growth. Moreover, downregulation of IGF-1R expression led to a remarkable decrease in YAP expression. In contrast, exposure to IGF-1 promoted YAP expression and reversed the inhibition of YAP expression induced by IGF-1R inhibitors. Our study highlights the critical role of YAP in the pathogenesis of DLBCL and uncovers the regulatory effect of IGF-1R on Hippo-YAP signaling, suggesting a novel therapeutic strategy for DLBCL.
Publisher: Wiley
Date: 03-03-2023
DOI: 10.1002/CAM4.5733
Abstract: This study aimed to evaluate the predictive value of systemic inflammation response index (SIRI) in primary gastrointestinal diffuse large B‐cell lymphoma (PGI‐DLBCL) patients and establish a highly discriminating risk prediction model. This retrospective analysis included 153 PGI‐DCBCL patients diagnosed between 2011 and 2021. These patients were ided into a training set ( n = 102) and a validation set ( n = 51). Univariate and multivariate Cox regression analyses were conducted to examine the significance of variables on overall survival (OS) and progression‐free survival (PFS). An inflammation‐covered score system was established according to the multivariate results. The presence of high pretreatment SIRI (≥1.34, p 0.001) was significantly associated with poorer survival and identified as an independent prognostic factor. Compared with NCCN‐IPI, the prognostic and discriminatory capability of the novel model SIRI‐PI showed a more precise high‐risk assessment with a higher area under the curve (AUC) (0.916 vs 0.835) and C ‐index (0.912 vs 0.836) for OS in the training cohort, and similar results were obtained in the validation cohort. Moreover, SIRI‐PI also showed good discriminative power for efficacy assessment. This new model identified patients at risk of developing severe gastrointestinal complications following chemotherapy. The results of this analysis suggested that the pretreatment SIRI may be a potential candidate for identifying patients with a poor prognosis. And we established and validated a better‐performing clinical model, which facilitated the prognostic stratification of PGI‐DLBCL patients and can serve as a reference for clinical decision‐making.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.CRITREVONC.2019.05.007
Abstract: Long non-coding RNAs (lncRNAs), are over 200 nucleotides in length, and they rarely act as templates for protein synthesis. Mounting studies have shown that lncRNAs play a crucial regulatory role in various processes that sustain life, such as epigenetic regulation, cell cycle control, splicing, and post-transcriptional regulation. LncRNAs were aberrantly expressed in most hematological malignancies including lymphoma, participating in tumor suppression or promoting oncogenesis and modulating key genes in different pathways. The specific expression patterns of lncRNAs in lymphoma make them good candidates to be used as diagnostic biomarkers or as therapeutic targets. LncRNAs can be targeted by multiple approaches including nucleic acid therapeutics, CRISPR/Cas genome editing techniques, small molecule inhibitors, and gene therapy. Efforts are made to develop therapeutic strategies aimed at targeting lncRNAs, but there are still some avenues to be covered before they can be applied to the clinical treatment of lymphoma.
Publisher: Springer Science and Business Media LLC
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 05-04-2022
DOI: 10.1186/S40164-022-00269-Y
Abstract: YT521-B homology domain family member 2 (YTHDF2) is an N 6 -methyladenosine (m 6 A)-binding protein that was originally found to regulate the stability of mRNA. Growing evidence has shown that YTHDF2 can participate in multifarious bioprocesses, including embryonic development, immune response, and tumor progression. Furthermore, YTHDF2 is closely associated with the proliferation, apoptosis, invasion, and migration of tumor cells, suggesting its significant role in cancers. YTHDF2 primarily relies on m 6 A modification to modulate signaling pathways in cancer cells. However, the expression and function of YTHDF2 in human malignancies remain controversial. Meanwhile, the underlying molecular mechanisms of YTHDF2 have not been elucidated. In this review, we principally summarized the biological functions and molecular mechanisms of YTHDF2 in tumors and discussed its prognostic and therapeutic values.
Publisher: Future Medicine Ltd
Date: 08-2019
Abstract: Innate lymphoid cells (ILCs) are an emerging family of innate immune cells and have been found to have an important role in infection, inflammation and tissue repair. In particular, recent work has identified significant alterations of ILC responses in tumor patients, suggesting potential roles of ILCs in tumor development. In this paper, we have focused on the basic features of ILCs and their interaction with other immune cells. Importantly, as the role of cytotoxic natural killer cells, assigned to ILC1 family, in cancer has been well established, we have summarized the new findings that showcase the potential role and mechanism of helper ILCs in different tumors. Helper ILCs might promote or inhibit tumor growth and metastasis, which depends on tumor type and ILC subset.
Publisher: Wiley
Date: 22-01-2023
DOI: 10.1002/AJH.26826
Abstract: Orelabrutinib is a novel, small molecule, selective irreversible Bruton's tyrosine kinase inhibitor. The aim of this study was to evaluate the efficacy and safety in patients with refractory or relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is single‐arm, multi‐center, open‐label, phase 2 study in 80 eligible Chinese patients, who were treated with monotherapy of orelabrutinib at 150 mg once daily. Overall response rate evaluated by an independent review committee was the primary endpoint, and secondary endpoints include progression‐free survival, overall survival, and safety. Independent review committee assessed overall response rate was 92.5% (74/80) complete response 21.3% (17/80), partial response 60.0% (48/80), partial response with lymphocytosis 11.3% (9/80). At a 32.3‐month median follow‐up, the median progression‐free survival had not been achieved, while the 30‐month progression‐free survival rate and overall survival rates were 70.9% (95% confidence interval [CI], 59.5–79.6) and 81.3% (95% CI, 70.8–88.2), respectively. Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy‐chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3‐year follow‐up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.
Publisher: Informa UK Limited
Date: 05-01-2021
Publisher: Springer Science and Business Media LLC
Date: 03-05-2021
DOI: 10.1186/S13045-021-01084-4
Abstract: Harnessing the power of immune cells, especially T cells, to enhance anti-tumor activities has become a promising strategy in clinical management of hematologic malignancies. The emerging bispecific antibodies (BsAbs), which recruit T cells to tumor cells, exemplified by bispecific T cell engagers (BiTEs), have facilitated the development of tumor immunotherapy. Here we discussed the advances and challenges in BiTE therapy developed for the treatment of hematologic malignancies. Blinatumomab, the first BiTE approved for the treatment of acute lymphocytic leukemia (ALL), is appreciated for its high efficacy and safety. Recent studies have focused on improving the efficacy of BiTEs by optimizing treatment regimens and refining the molecular structures of BiTEs. A considerable number of bispecific T cell-recruiting antibodies which are potentially effective in hematologic malignancies have been derived from BiTEs. The elucidation of mechanisms of BiTE action and neonatal techniques used for the construction of BsAbs can improve the treatment of hematological malignancies. This review summarized the features of bispecific T cell-recruiting antibodies for the treatment of hematologic malignancies with special focus on preclinical experiments and clinical studies.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2021
DOI: 10.1038/S41419-021-03919-X
Abstract: Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, has recently been shown to play key roles in tumorigenesis. Blocking PLK4 expression by interference or targeted drugs exhibits attractive potential in improving the efficacy of chemotherapy. Nevertheless, the role of PLK4 in diffuse large B-cell lymphoma (DLBCL) is still undefined. In this study, we discover that PLK4 is a potential target for the treatment of DLBCL, and demonstrate the efficacy of a PLK4 inhibitor when used in combination with doxorubicin. Pharmaceutical inhibition of PLK4 with CFI-400945 inhibited DLBCL cell proliferation and induced apoptotic cell death. The anti-tumor effects were accompanied by mitotic defects, including polyploidy and cytokinesis failure. Activation of p53 and Hippo/YAP tumor suppressor signaling pathway was identified as the potential mechanisms driving CFI-400945 activity. Moreover, CFI-400945 treatment resulted in activation of DNA damage response. Combining CFI-400945 with doxorubicin markedly delayed tumor progression in DLBCL xenografts. Finally, PLK4 was increased in primary DLBCL tissues and cell lines. High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2023
Publisher: Proceedings of the National Academy of Sciences
Date: 25-01-2021
Abstract: The APL2012 trial is currently the largest randomized, multicenter clinical study of APL based on ATRA-ATO treatment with risk stratification. We enrolled 855 newly diagnosed APL patients during December 2012 to December 2017 for careful follow-up. All patients received ATRA-ATO–based protocols for remission induction. At the consolidation phase, the key part of the trial, ATO was used to replace or reduce chemotherapy in a risk-stratified way. Patients were then treated with ATRA-ATO as maintenance. The results indicated not only the noninferiority of ATO compared to intensive chemotherapy in survival but also an advantage in adverse effects. The trial provides support for the ATO regimen as a standard for making further refinements in the treatment of this highly curable disease.
Publisher: Springer Science and Business Media LLC
Date: 09-2020
DOI: 10.1186/S13148-020-00923-4
Abstract: Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML. Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P 0.0001). Of the patients with mutations in epigenetic and transcription factor-related genes, but without internal tandem duplications in FMS-like tyrosine kinase3 ( FLT3 -ITDs), 55.6% achieved CR/CRi, whereas the ORR was 28.2% for patients with mutations in other genes. The CDCAG regimen was well tolerated and effective in r/r AML. Patients with epigenetic and transcription factor-related gene mutations, but without FLT3 -ITD mutations, may benefit from this regimen. Clinical Trials, NCT02886559 . Registered 01 September 2016
Publisher: Springer Science and Business Media LLC
Date: 24-09-2012
DOI: 10.1038/CMI.2012.34
Publisher: Elsevier BV
Date: 06-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-06-2020
Publisher: Springer Science and Business Media LLC
Date: 08-03-2018
DOI: 10.1007/S11427-017-9250-1
Abstract: The aim of the present study was to investigate the relationship between hypothyroidism and thrombocytopenia in hepatitis B-related compensatory liver cirrhosis and to determine whether treatment with levothyroxine and prednisone is superior in a multicenter, open-label, observational study in China. In total, 125 consecutive hepatitis B-related compensated liver cirrhosis patients with severe thrombocytopenia accompanied by hypothyroidism were included. The patients were ided into four groups according to treatment strategy: a control group (n=29), a prednisone group (n=25), a levothyroxine group (n=32) and a prednisone plus levothyroxine group (n=39). Severe thrombocytopenia was more prevalent in hepatitis B-associated compensatory liver cirrhosis patients with hypothyroidism than in euthyroid patients (29.6% vs. 14.7%, P<0.05). Combination treatment with prednisone and levothyroxine decreased the risk of bleeding and improved platelet recovery compared to control treatment and treatment with either prednisone or levothyroxine alone. The platelet count before therapy, serum thyroid stimulating hormone and combination treatment with prednisone and levothyroxine were associated with bleeding events. Therefore, the present study suggests that hypothyroidism is associated with severe thrombocytopenia in hepatitis B-associated compensatory liver cirrhosis. Treatment with prednisone plus levothyroxine may present a novel approach in these patients.
Publisher: Springer Science and Business Media LLC
Date: 30-04-2020
DOI: 10.1186/S13073-020-00739-0
Abstract: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy is widely used in peripheral T cell lymphoma (PTCL). Here we conducted a phase 2, multicenter, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in newly diagnosed PTCL. PTCL patients, except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, were 1:1 randomly assigned to receive CEOP/IVE/GDP (CEOP, cyclophosphamide 750 mg/m 2 , epirubicin 70 mg/m 2 , vincristine 1.4 mg/m 2 [maximum 2 mg] on day 1, and prednisone 60 mg/m 2 [maximum 100 mg] on days 1–5 every 21 days, at the first and fourth cycle IVE, ifosfamide 2000 mg/m 2 on days 1–3, epirubicin 70 mg/m 2 on day 1, and etoposide 100 mg/m 2 on days 1–3 every 21 days, at the second and fifth cycle and GDP, gemcitabine 1000 mg/m 2 on days 1 and 8, cisplatin 25 mg/m 2 on days 1–3, and dexamethasone 40 mg on days 1–4 every 21 days, at the third and sixth cycle) and CEOP (every 21 days for 6 cycles). Analysis of efficacy and safety was of the intent-to-treatment population. The primary endpoint was a complete response rate at the end of treatment. Meanwhile, whole exome sequencing and targeted sequencing were performed in 62 patients with available tumor s les to explore prognostic biomarkers in this cohort as an exploratory post hoc analysis. Among 106 patients, 53 each were enrolled to CEOP/IVE/GDP and CEOP. With 51 evaluable patients each in two groups, a complete response rate of the CEOP/IVE/GDP group was similar to that of the CEOP group (37.3% vs. 31.4%, p = 0.532). There was no difference in median progression-free survival (PFS 15.4 months vs. 9.2 months, p = 0.122) or overall survival (OS 24.3 months vs. 21.9 months, p = 0.178). Grade 3–4 hematological and non-hematological adverse events were comparable. Histone modification genes were most frequently mutated (25/62, 40.3%), namely KMT2D , KMT2A , SETD2 , EP300 , and CREBBP . Multivariate analysis indicated that CREBBP and IDH2 mutations were independent factors predicting poor PFS and OS (all p 0.001), while KMT2D predicting poor PFS ( p = 0.002). CEOP/IVE/GDP alternating regimen showed no remission or survival advantage to standard chemotherapy. Future clinical trials should aim to develop alternative regimen targeting disease biology as demonstrated by recurrent mutations in epigenetic factors. The study was registered on ClinicalTrial.gov (NCT02533700) on August 27, 2015.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2021
DOI: 10.1186/S40364-021-00309-5
Abstract: B-cell non-Hodgkin lymphoma (B-NHL) is a group of heterogeneous disease which remains incurable despite developments of standard chemotherapy regimens and new therapeutic agents in decades. Some in iduals could have promising response to standard therapy while others are unresponsive to standard chemotherapy or relapse after autologous hematopoietic stem-cell transplantation (ASCT), which indicates the necessity to develop novel therapies for refractory or relapsed B-NHLs. In recent years, a novel cell therapy, chimeric antigen receptor T-cell therapy (CAR-T), was invented to overcome the limitation of traditional treatments. Patients with aggressive B-NHL are considered for CAR-T cell therapy when they have progressive lymphoma after second-line chemotherapy, relapse after ASCT, or require a third-line therapy. Clinical trials of anti-CD19 CAR-T cell therapy have manifested encouraging efficacy in refractory or relapsed B-NHL. However, adverse effects of this cellular therapy including cytokine release syndrome, neurotoxicity, tumor lysis syndrome and on-target, off-tumor toxicities should attract our enough attention despite the great anti-tumor effects of CAR-T cell therapy. Although CAR-T cell therapy has shown remarkable results in patients with B-NHL, the outcomes of patients with B-NHL were inferior to patients with acute lymphoblastic leukemia. The inferior response rate may be associated with physical barrier of lymphoma, tumor microenvironment and low quality of CAR-T cells manufactured from B-NHL patients. Besides, some patients relapsed after anti-CD19 CAR-T cell therapy, which possibly were due to limited CAR-T cells persistence, CD19 antigen escape or antigen down-regulation. Quite a few new antigen-targeted CAR-T products and new-generation CAR-T, for ex le, CD20-targeted CAR-T, CD79b-targeted CAR-T, CD37-targeted CAR-T, multi-antigen-targeted CAR-T, armored CAR-T and four-generation CAR-T are developing rapidly to figure out these deficiencies.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CRITREVONC.2018.03.022
Abstract: Chronic lymphocytic leukemia (CLL) is a hematological malignancy which is characterized by progressive accumulation of functionally deficient B cells in blood, bone marrow, and lymphatic tissue. The tumor microenvironment (TME) appears to play a critical role in genesis and progression of CLL. High levels of extracellular adenosine (ADO) are detected in CLL as a consequence of expression of ecto-enzymes, such as CD39 and CD73. Extracellular ADO exhibits a broad range of effects on cell cycle control, immunoregulation, angiogenesis and cytokine regulation through both direct and indirect mechanisms. In this review, we focused on the multiple functions and related mechanisms of ADO signaling in CLL generation and progression.
Publisher: Springer Science and Business Media LLC
Date: 12-06-2018
DOI: 10.1038/S41388-018-0333-X
Abstract: TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL). Previous studies confirmed MELK inhibition abrogated cancer cell survival via p53 signaling pathway. Thus, we aimed to determine the biological function of MELK and therapeutic potential of OTSSP167 in CLL. Herein, MELK over-expression was observed in CLL cells, and correlated with higher WBC count, advanced stage, elevated LDH, increased β2-MG level, unmutated IGHV, positive ZAP-70, deletion of 17p13 and inferior prognosis of CLL patients. In accordance with functional enrichment analyses in gene expression profiling, CLL cells with depletion or inhibition of MELK exhibited impaired cell proliferation, enhanced fast-onset apoptosis, induced G2/M arrest, attenuated cell chemotaxis and promoted sensitivity to fludarabine and ibrutinib. However, gain-of-function assay showed increased cell proliferation and cell chemotaxis. In addition, OTSSP167 treatment reduced phosphorylation of AKT and ERK1/2. It decreased FoxM1 phosphorylation, expression of FoxM1, cyclin B1 and CDK1, while up-regulating p53 and p21 expression. Taken together, MELK served as a candidate of therapeutic target in CLL. OTSSP167 exhibits potent anti-tumor activities in CLL cells, highlighting a novel molecule-based strategy for leukemic interventions.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-08-2019
Publisher: China Anti-cancer Association
Date: 12-01-2023
Publisher: Wiley
Date: 19-10-2020
DOI: 10.1002/AJH.25989
Publisher: Spandidos Publications
Date: 22-03-2019
Publisher: Medknow
Date: 2018
Publisher: SAGE Publications
Date: 2022
DOI: 10.1177/17588359221093745
Abstract: Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive extranodal type of non-Hodgkin lymphoma. After the introduction and widespread use of high-dose-methotrexate (HD-MTX)-based polychemotherapy, treatment responses of PCNSL have been improved. However, long-term prognosis for patients who have failed first-line therapy and relapsed remains poor. Less invasive diagnostic markers, including the circulating tumor DNAs (ctDNAs), microRNAs, metabolomic markers, and other novel biomarkers, such as a proliferation inducing ligand (APRIL) and B-cell activating factor of the TNF family (BAFF), have shown potential to distinguish PCNSL at an early stage, and some of them are related with prognosis to a certain extent. Recent insights into novel therapies, including Bruton tyrosine kinase (BTK) inhibitors, immunomodulatory drugs, immune checkpoint inhibitors, PI3K/mTOR inhibitors, and chimeric antigen receptor (CAR) T cells, have revealed encouraging efficacy in treatment response, whereas the duration of response and long-term survival of patients with relapsed or refractory PCNSL (r/r PCNSL) need further improvement. In addition, the diagnostic efficiency of novel markers and the antitumor efficacy of novel therapies are needed to be assessed further in larger clinical trials. This review provides an overview of recent research on novel diagnostic markers and therapeutic strategies for PCNSL.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-03-2022
Publisher: Spandidos Publications
Date: 02-2017
DOI: 10.3892/OR.2017.5744
Abstract: Klotho is a transmembrane protein and acts as an upstream modulator of insulin-like growth factor-1 receptor (IGF-1R) signaling, which was indicated to be involved in the pathogenesis of solid cancer and hematological malignancies, including T‑cell lymphoma. Although Klotho was recently identified as a tumor suppressor in several types of human malignancies, the potential role of Klotho in T‑cell lymphoma has not been reported. In the present study, we investigated the expression level and the molecular events of Klotho in T‑cell lymphoma. Significantly lower expression of Klotho was observed in T‑cell lymphoma patient s les compared to normal lymph nodes. Functional analysis after Klotho overexpression revealed significantly inhibited tumor cell viability in T‑cell lymphoma. Moreover, apoptosis of T‑cell lymphoma cells were induced after transfected with Klotho-overexpressing vectors. Forced expression of Klotho resulted in decline of activation of IGF-1R signaling, accompanied by decreased phosphorylation of its downstream targets, including AKT and ERK1/2. These data indicated that Klotho acts as a tumor suppressor via inhibiting IGF-1R signaling, thus suppressing the viability and promoting apoptosis in T‑cell lymphoma. Taken together, Klotho may serve as a potential target for the therapeutic intervention of T‑cell lymphoma.
Publisher: American Society of Hematology
Date: 25-07-2022
DOI: 10.1182/BLOODADVANCES.2022007226
Abstract: Intracranial hemorrhage (ICH) is a rare and life-threatening hemorrhagic event in patients with immune thrombocytopenia (ITP). However, its mortality and related risk factors remain unclear. Herein, we conducted a nationwide multicenter real-world study of ICH in adult ITP patients. According to data from 27 centers in China from 2005 to 2020, the mortality rate from ICH was 33.80% (48/142) in ITP adults. We identified risk factors by logistic univariate and multivariate logistic regression for 30-day mortality in a training cohort of 107 patients as follows: intraparenchymal hemorrhage (IPH), platelet count ≤10 × 109/L at ICH, a combination of serious infections, grade of preceding bleeding events, and Glasgow coma scale (GCS) level on admission. Accordingly, a prognostic model of 30-day mortality was developed based on the regression equation. Then, we evaluated the performance of the prognostic model through a bootstrap procedure for internal validation. Furthermore, an external validation with data from a test cohort with 35 patients from 11 other centers was conducted. The areas under the receiver operating characteristic (ROC) curves for the internal and external validation were 0.954 (95% confidence interval [CI], 0.910-0.998) and 0.942 (95% CI, 0.871-1.014), respectively. Both calibration plots illustrated a high degree of consistency in the estimated and observed risk. In addition, the decision curve analysis showed a considerable net benefit for patients. Thus, an application (47.94.162.105:8080/ich/) was established for users to predict 30-day mortality when ICH occurred in adult patients with ITP.
Publisher: Frontiers Media SA
Date: 07-2021
Abstract: Lipid metabolism is related to lymphomagenesis, and is a novel therapeutic target in some hematologic tumors. Apolipoprotein A (ApoA), the major protein of high-density lipoprotein (HDL), plays a crucial role in lipid transportation and protecting against cardiovascular disease, and takes effect on anti-inflammation and anti-oxidation. It is correlated with the prognosis of some solid tumors. Yet, there is no investigation involving the role of ApoA plays in chronic lymphocytic leukemia (CLL). Our retrospective study focuses on the prognostic value of ApoA in CLL and its therapeutic potential for CLL patients. Herein, ApoA is a favorable independent prognostic factor for both overall survival (OS) and progression-free survival (PFS) of CLL patients. ApoA is negatively associated with β2-microglobulin (β2-MG) and advanced stage, which are poor prognostic factors in CLL. Age, Rai stage, ApoA, and adenosine deaminase (ADA) are included in a new risk scoring system named ARAA-score . It is capable of assessing OS and PFS of CLL patients. Furthermore, cell proliferation assays show that the ApoA-I mimetic L-4F can inhibit the proliferation of CLL cell lines and primary cells. In conclusion, ApoA is of prognostic value in CLL, and is a potential therapy for CLL patients. The ARAA-score may optimize the risk stratification of CLL patients.
Publisher: Springer Science and Business Media LLC
Date: 12-09-2017
DOI: 10.1038/S41598-017-11310-0
Abstract: T-cell clonality of peripheral T-cell lymphoma (PTCL) is routinely evaluated with a PCR-based method using genomic DNA. However, there are limitations with this approach. The purpose of this study was to determine the utility of RNA-seq for assessing T-cell clonality and T-cell antigen receptor (TCR) repertoire of the neoplastic T-cells in 108 PTCL s les. TCR transcripts, including complementarity-determining region 3 (CDR3) sequences, were assessed. In normal T cells, the CDR3 sequences were extremely erse, without any clonotype representing more than 2% of the overall TCR population. Dominant clones could be identified in 65 out of 76 PTCL cases (86%) with adequate TCR transcript expression. In monoclonal cases, the dominant clone varied between 11% and 99% of TCRβ transcripts. No unique Vα or Vβ usage was observed. Small T-cell clones were often observed in T- and NK-cell tumors in a percentage higher than observed in reactive conditions. γ chain expression was very low in tumors expressing TCRαβ, but its expression level was high and clonality was detected in a TCRγδ expressing tumor. NK cell lymphoma (NKCL) did not express significant levels of TCR Vβ or Vγ genes. RNA-seq is a useful tool for detecting and characterizing clonal TCR rearrangements in PTCL.
Publisher: Springer Science and Business Media LLC
Date: 12-06-2023
DOI: 10.1038/S41420-023-01475-1
Abstract: Metabolic reprogramming is a hallmark of human malignancies. Dysregulation of glutamine metabolism is essential for tumorigenesis, microenvironment remodeling, and therapeutic resistance. Based on the untargeted metabolomics sequencing, we identified that the glutamine metabolic pathway was up-regulated in the serum of patients with primary DLBCL. High levels of glutamine were associated with inferior clinical outcomes, indicative of the prognostic value of glutamine in DLBCL. In contrast, the derivate of glutamine alpha-ketoglutarate (α-KG) was negatively correlated with the invasiveness features of DLBCL patients. Further, we found that treatment with the cell-permeable derivative of α-KG, known as DM-αKG, significantly suppressed tumor growth by inducing apoptosis and non-apoptotic cell death. Accumulation of a-KG promoted oxidative stress in double-hit lymphoma (DHL), which depended on malate dehydrogenase 1 (MDH1)-mediated 2-hydroxyglutarate (2-HG) conversion. High levels of reactive oxygen species (ROS) contributed to ferroptosis induction by promoting lipid peroxidation and TP53 activation. In particular, TP53 overexpression derived from oxidative DNA damage, further leading to the activation of ferroptosis-related pathways. Our study demonstrated the importance of glutamine metabolism in DLBCL progression and highlighted the potential application of α-KG as a novel therapeutic strategy for DHL patients.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2012
Publisher: Elsevier BV
Date: 05-2022
Publisher: Spandidos Publications
Date: 23-12-2015
Abstract: Long noncoding RNAs (lncRNAs) are endogenous transcribed RNA molecules without protein-coding potential, ranging between 200 and 100,000 nt in length. LncRNAs regulate the expression of specific genes in several ways, including guiding chromatin-remodeling, and affecting splicing, transcription or translation. The mutations and dysregulation of lncRNAs have been found to be important in various human diseases, but particularly in human cancer. Previous studies have demonstrated that changes to lncRNAs are closely associated with tumorigenesis, metastasis, prognosis and diagnosis. The current review aims to present a brief overview of the associated reports of lncRNAs in malignant neoplasms, including breast cancer, prostate cancer and hematological malignancies. LncRNAs may be evaluated as novel markers in disease diagnosis, and as prospective therapeutic targets for the prevention and treatment of human diseases.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2021
Publisher: Springer Science and Business Media LLC
Date: 17-08-2021
DOI: 10.1186/S13045-021-01134-X
Abstract: B-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex interaction between tumor cells and the tumor microenvironment (TME), which is composed of stromal cells and extracellular matrix. Although the roles of the TME have not been fully elucidated, accumulating evidence implies that TME is closely relevant to the origination, invasion and metastasis of B-cell lymphoma. Explorations of the TME provide distinctive insights for cancer therapy. Here, we epitomize the recent advances of TME in B-cell lymphoma and discuss its function in tumor progression and immune escape. In addition, the potential clinical value of targeting TME in B-cell lymphoma is highlighted, which is expected to pave the way for novel therapeutic strategies.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Baskent University
Date: 2022
Abstract: Antithymocyte globulin is extensively used for prophylaxis of graft-versus-host disease in patients undergoing haploidentical hematopoietic stem cell transplantation. However, different doses of antithymocyte globulin are administered in clinical practice. This study aimed to identify the optimal dose of antithymocyte globulin (thymoglobulin) in haploidentical hematopoietic stem cell transplantation. We retrospectively analyzed the effects of 10 mg/kg (2.5 mg/kg on days -5 to -2) versus 7.5 mg/kg thymoglobulin (2.5 mg/kg on days -4 to -2) on patients receiving haploidentical hematopoietic stem cell transplantation with myeloablative conditioning. We observed significant differences between the 2 treatment groups with regard to cumulative incidence of grade II to IV acute graft-versus-host disease (15.3% vs 14.6% P = .93) and 3-year chronic graft-versus-host disease (12.1% vs 14.3% P = .77). The probabilities of 3-year overall survival (68.9% vs 73.5% P = .98) and graft-versus-host disease-free/relapse-free survival (66.7% vs 53.1% P = .14) were comparable between the 2 groups. However, there was a trend for lower cumulative incidence of hemorrhagic cystitis in the 7.5 mg/kg treatment group compared with the 10 mg/kg treatment group (40.7% vs 24.4% P = .07). For patients who received a reduced dose of antithymocyte globulin (7.5 vs 10 mg/kg), there was no impaired effect on prophylaxis of graft-versus-host disease, with a trend of reduced incidence of hemorrhagic cystitis. Further studies of the 7.5 mg/kg dose of antithymocyte globulin are warranted for patients receiving haploidentical hematopoietic stem cell transplantation.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.CANLET.2015.01.021
Abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine produced by a variety of cell types, including fibroblasts, endothelial cells, lymphocytes, and bone marrow stromal cells (BMSCs). Levels of IL-6 are increased in serum of CLL patients and correlated with adverse clinical features and short survival. In our study, we observed that IL-6 induced the resistance of CLL cells to pan-histone deacetylase (HDAC) inhibitors vorinostat (SAHA) and panobinostat (LBH589). Furthermore, low concentrations of SAHA and LBH589 enhanced the activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway induced by IL-6 in CLL cells. All of these effects were blocked by the STAT3-selective inhibitor, WP1066. Meanwhile, WP1066 decreased the expressions of Mcl-1 and Bcl-xL protein induced by IL-6 with or without low concentrations of HDAC inhibitors. Co-culture of CLL cells with BMSCs could also facilitate the activation of STAT3 and protected CLL cells from apoptosis when treated with HDAC inhibitors, and this cytoprotection was reversed by WP1066. The present study indicated that IL-6 or co-culture with BMSCs prevented HDAC inhibitor-induced apoptosis of CLL cells. This prevention was mediated by activation of the STAT3 signaling pathway. Moreover, WP1066 reversed the resistance of CLL cells to SAHA and LBH589 induced by either IL-6 or co-culture with BMSCs. Our findings suggest that targeting the STAT3 pathway may be a novel way to improve the efficacy of the HDAC inhibitor in CLL patients by overcoming antiapoptotic signaling of the microenvironment.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2021
DOI: 10.1186/S13045-021-01097-Z
Abstract: Antibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. As the efficacy and safety of ADCs have moved in synchrony with advances in their design, a plethora of novel ADCs have garnered growing interest as treatments. In this review, we provide an overview of the essential elements of ADC strategies in lymphoma and elucidate the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field.
Publisher: Frontiers Media SA
Date: 04-11-2021
Abstract: Chidamide has demonstrated significant clinical benefits for patients with relapsed/refractory (R/R) PTCL in previous studies. This multi-center observational study was aimed to evaluate the objective response rate (ORR), overall survival (OS), and safety of chidamide. From February 2015 to December 2017, 548 patients with R/R PTCL from 186 research centers in China were included in the study. Among the 261 patients treated with chidamide monotherapy, ORR was 58.6% and 55 patients (21.1%) achieved complete response (CR). Among the 287 patients receiving chidamide-containing combination therapies, ORR was 73.2% and 73 patients (25.4%) achieved CR. The median OS of all patients was 15.1 months. The median OS of patients receiving chidamide monotherapy and combination therapies was 433 and 463 days, respectively. These results demonstrate a significant survival advantage of chidamide treatments as compared with international historical records. Common adverse effects (AEs) were hematological toxicities. Most AEs in both monotherapy and combined treatments were grade 1–2. No unanticipated AEs occurred. In conclusion, chidamide-based therapy led to a favorable efficacy and survival benefit for R/R PTCL. Future studies should explore the potential advantage of chidamide treatment combined with chemotherapy.
Publisher: Springer Science and Business Media LLC
Date: 12-2020
DOI: 10.1186/S13045-020-00990-3
Abstract: The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.
Publisher: Spandidos Publications
Date: 12-04-2016
Abstract: The B-cell receptor (BCR) signaling pathway serves an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and has been identified as a novel and effective therapeutic target of CLL, with particular focus its kinase factor, BTK. Previous studies have focused on combining the BTK inhibitor with additional chemotherapeutic agents to improve the prognosis of patients with CLL. Further investigation into the mechanism of the BTK inhibitor would promote an understanding of the pathogenesis of CLL. The current study investigated the association between ibrutinib and the Wnt signaling pathway, additionally focussing upon one of its regulators, metadherin (MTDH), which has been identified to be overexpressed in CLL and is considered a promoter of the Wnt pathway. The experiments in the current study were performed in the MEC-1 CLL cell line. Results indicated that MTDH, β-catenin and lymphoid-enhancing factor-1 were inhibited subsequent to ibrutinib treatment. The results indicate that in CLL, ibrutinib is likely to possess an inhibitory role in Wnt signaling.
Publisher: Wiley
Date: 06-11-2020
DOI: 10.1002/JCA.21756
Abstract: Smoking could reduce the CD34+ cells in peripheral blood of healthy in idual. This study aimed to investigate the correlation between smoking load and the effect of peripheral blood hematopoietic progenitor cells (PBPCs) mobilization by granulocyte colony-stimulating factor (G-CSF) alone in healthy donors. Retrospective analysis was performed on 145 healthy adult PBPCs donors who underwent PBPCs mobilization and collection. Smoking factors were evaluated and correlated with mobilization responses, as indicated by the collected CD34+ cells concentration. The collected CD34+ cells concentration was closely related to pre-CD34 (P < .001) and CD34+ cells collected per volume blood processed (P < .001) which suggested that collected CD34+ cells concentration was a reliable indicator of PBPCs mobilization efficiency. The heavy smoking donors revealed significantly lower collected CD34+ cells concentration, compared to that of the nonsmoking (P < .001) and light smoking donors (P < .05). The levels of collected CD34+ cells in light smoking were also obviously lower than that in nonsmoking donors (P < .05).There were no obvious differences in the collected CD34+ cells concentration, overall processed blood volume and total collected CD34+ cells between nonsmoking and smoking cessation groups (P = .490 P = .464 P = .819). Cigarette smoking is an important factor that affects the yield of PBPCs in male donors, especially when the smoking load is more than five pack-years. Mobilization of PBMCs could be restored by smoking cessation in chronic smokers.
Publisher: Springer Science and Business Media LLC
Date: 02-02-2017
Publisher: Springer Science and Business Media LLC
Date: 27-06-2022
DOI: 10.1186/S40164-022-00292-Z
Abstract: Metabolic reprogramming, fundamentally pivotal in carcinogenesis and progression of cancer, is considered as a promising therapeutic target against tumors. In chronic lymphocytic leukemia (CLL) cells, metabolic abnormalities mediate alternations in proliferation and survival compared with normal B cells. However, the role of metabolic reprogramming is still under investigation in CLL. In this review, the critical metabolic processes of CLL were summarized, particularly glycolysis, lipid metabolism and oxidative phosphorylation. The effects of T cells and stromal cells in the microenvironment on metabolism of CLL were also elucidated. Besides, the metabolic alternation is regulated by some oncogenes and tumor suppressor regulators, especially TP53, MYC and ATM. Thus, the agents targeting metabolic enzymes or signal pathways may impede the progression of CLL. Both the inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) statins and the lipoprotein lipase inhibitor orlistat induce the apoptosis of CLL cells. In addition, a series of oxidative phosphorylation inhibitors play important roles in decreasing the proliferation of CLL cells. We epitomized recent advancements in metabolic reprogramming in CLL and discussed their clinical potentiality for innovative therapy options. Metabolic reprogramming plays a vital role in the initiation and progression of CLL. Therapeutic approaches targeting metabolism have their advantages in improving the survival of CLL patients. This review may shed novel light on the metabolism of CLL, leading to the development of targeted agents based on the reshaping metabolism of CLL cells.
Publisher: Mary Ann Liebert Inc
Date: 08-2018
Abstract: To determine if Metadherin (MTDH) expression levels are positively correlated with the clinical stage of diffuse large B-cell lymphoma (DLBCL) based on MTDH being highly expressed in other type of tumors including melanoma, malignant glioma, breast cancer, and hepatocellular carcinoma. In this study, we investigated the pathologic significance of MTDH and its potential in predicting DLBCL outcomes. Tissue s les from 50 patients with DLBCL and 22 patients with lymph node reactive hyperplasia were collected and evaluated using immunohistochemical staining, microscopy, and western blotting. The Kaplan-Meier method and Cox regression model were used for survival analysis of patients. Our results show that the overexpression of the MTDH protein in tissues was observed in 66% of patients with DLBCL, whereas it was not overexpressed in the patients with reactive hyperplastic lymph nodes. While there was no correlation between MTDH overexpression with age, sex, presence of B symptoms, and lactate dehydrogenase (LDH) levels in patients with DLBCL, this parameter was positively correlated with clinical stages. Moreover, MTDH-negative patients had significantly better prognoses compared with the MTDH-positive patients. Our preliminary study indicates that MTDH may play an important role in the development of DLBCL, and that MTDH overexpression is potentially associated with the clinical progression of DLBCL. In addition, high expression levels of MTDH in tissues was correlated with a poorer prognosis for patients with DLBCL. As such, MTDH may be a potential therapeutic target for specific therapy. However, research on a larger group of patients is needed to verify these preliminary results.
Publisher: Wiley
Date: 28-06-2016
DOI: 10.1111/BJH.14225
Abstract: We conducted a prospective, multicentre study to confirm the feasibility of haplo-identical transplantation in treatment of severe aplastic anaemia (SAA) as salvage therapy, by analysing the outcomes of 101 patients who received haplo-identical transplantation between June 2012 and October 2015. All cases surviving for more than 28 d achieved donor myeloid engraftment. The median time for myeloid engraftment was 12 (range, 9-25) days and 15 (range, 7-101) days for platelets, with a cumulative platelet engraftment incidence of 94·1 ± 0·1%. With a median follow-up of 18·3 (3·0-43·6) months, recipients from haplo-identical transplantation had more cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD, 33·7% vs. 4·2%, P < 0·001), more chronic GVHD (22·4% vs. 6·6%, P = 0·014) at 1 year, but similar grade III-IV aGVHD (7·9% vs. 2·1%, P = 0·157), 3-year estimated overall survival (OS, 89·0% vs. 91·0%, P = 0·555) and failure-free survival (FFS, 86·8% vs. 80·3%, P = 0·659) when compared with 48 patients who received contemporaneous transplantation from matched related donors. Multivariate analysis showed no significant difference in engraftment and survival between the two cohorts. Both OS and FFS for the entire population correlated significantly with grades III-IV aGVHD. In conclusion, haplo-identical transplantation is a feasible choice for SAA with favourable outcomes.
No related grants have been discovered for Xin Wang.