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Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients have a low survival rate and a high recurrence rate, and AML is a highly heterogeneous disease without an effective and specific targeted therapy. Aims: Therefore, it is urgent to explore new AML markers to enable early diagnosis and find drug targets for individualized treatment. Results: Herein, we demonstrate that O‐linked‐N‐acetylglucosamine transferase (OGT) is significantly upregulated in AML tissues compared with normal tissues. The high level of OGT expression is significantly related to poor overall survival (OS) in AML. Inhibition of OGT can inhibit AML cell proliferation and promote AML cell apoptosis. Conclusion: These results suggest that OGT plays an important role in the pathogenesis of AML, and may become a potential biomarker and molecular drug target for precision therapy for AML. [ABSTRACT FROM AUTHOR]

Abstract: Recently, studies involving uterine cervical cancer and uterine corpus cancer have been reported from many institutes. The presence of regulatory T cells (Treg cells) in human uterine cancer is crucial for maintaining immunological homeostasis. To improve treatment strategies, I will be reviewing recent studies in the field. This work will discuss the central role that Treg cells play in the development of uterine cancer, which makes these cells a key missing component in current cancer immunotherapy. [Copyright &y& Elsevier]

B cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematologic malignancy with limited treatment strategies. Histone deacetylases inhibitors (HDACis) are promising novel tools for cancer therapy, whose anti-tumor effects and the underlying mechanisms on B-ALL remain to be elucidated. Recently, Notch1 signaling activation has been reported to be involved in the anti-tumor effects of HDACis. This study was conducted to determine: the influence of two HDACis, valproic acid (VPA) and suberic bishydroxamic acid (SBHA), on Notch1 signaling as well as the role of Notch1 signaling in the anti-tumor effects of HDACis in B-ALL cells. To address this issue, we treated Nalm-6 B-ALL cell line with VPA and SBHA (HDACis), then, cell proliferation, cell cycle, apoptosis, and expression of Notch1 related genes were analyzed. We found that VPA and SBHA dramatically inhibited cell growth, induced a G1/S cell cycle block in accompany with an elevated level of P21 protein in Nalm-6 cells. The levels of cleaved caspase-9, caspase-3, and PARP were elevated, indicating the activation of apoptosis. However, no change in the expression of Notch1 and its downstream genes were found by quantitative real-time PCR and Western blot. Our result suggested that Notch1 signaling is irresponsible for the anti-leukemic effect of HDACis in B-ALL cells. New hypotheses and future studies are needed to explore the underlying mechanisms of the anti-cancer effect in B-ALL. [ABSTRACT FROM AUTHOR]

Aims: Notch signaling molecules play crucial roles in cell proliferation and apoptosis, yet their function in breast cancer remains unclear. Methods: Samples and clinical data from 62 breast cancer patients were collected. After total RNA isolation, reverse transcription polymerase chain reaction was applied to analyze the expression of Notch receptors (Notch1, Notch3 and Notch4) and ligands (DLL4 and JAG1), and their clinical association. Immunohistochemical analysis was used to detect the intracellular domain of Notch1 (Notch1-IC) expression. Results: Notch1 was the dominant receptor while DLL4 was the dominant ligand. The Notch molecules expression pattern for infiltrating ductal carcinoma (IDC) was similar to that for infiltrating lobular carcinoma (ILC) except for JAG1, while Notch1 standard coefficients in ILC were statistically higher than that in IDC. Immunohistochemical results showed that Notch1-IC protein expression paralleled the mRNA level. Breast cancer patients' clinical parameters suggested that Notch1 expression was higher in stage II disease and lower in more advanced stages. The Notch3 positive rate was higher in patients with lower levels of Notch1, and the Notch3 positive rate was lower in patients with higher levels of Notch1. No apparent correlation of Notch molecules with estrogen receptor (ER), progesterone receptor (PR) was found. Though high Notch1 and Notch3 RNA levels tended to correlate with c-erbB2 expression, no statistical significance was found. Conclusion: Notch molecules are useful biomarkers in breast cancer especially for Notch1 and DLL4, and Notch1 is expressed differently in different stages of human breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: IL-21, the newest member of the common γ-chain family of cytokines, has pleiotropic biological effects through regulating a variety of immune cells. Recently, the role of IL-21 in the treatment of cancers has been widely investigated. Conducted phase I trials in metastatic malignant melanoma and renal cell carcinoma have shown that rIL-21 has a favorable antitumor activity. Expression of IL-21 and IL-21R has also been found in many types of hematological malignancies, such as chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and lymphoma. Through binding with IL-21R, IL-21 induces activation of different JAK/STAT signal transduction pathways and regulates proliferation or apoptosis of tumor cells. In this review, we will discuss the expression of IL-21/IL-21R and its effect in different types of hematological malignancies. [Copyright &y& Elsevier]

Abstract: Background: Th17/Treg was reported to play critical roles in immunoregulation, and its imbalance may lead to autoimmune diseases and allergic reactions. Information on Th17/Treg in cancer bearing hosts is still limited. Methods: We examined the expression of IL-17, Foxp3 and IL-10 in uterine cervical cancer (UCC) patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls by flow cytometry and enzyme-linked immunosorbent assay. Interleukin (IL)-17-producing CD4+ cells as Th17 and CD4+CD25+Foxp3+ cells as Treg were expressed as a percentage of the total CD4+ cells. Results: Compared with controls, patients with UCC or CIN had a higher proportion of Th17 cells. UCC patients also revealed a significant increase in Treg number and IL-17 and IL-10 concentrations in plasma, while CIN patients did not. Notably, in UCC patients, the increased Th17 prevalence was associated with clinical stage, lymph node metastases and vasoinvasion, while the increased Treg frequency was associated with tumor differentiation. Remarkably, an attractive imbalance of Th17/Treg was observed in UUC and CIN patients. Furthermore, in UCC patients with lymph node metastases or vasoinvasion, the ratio of Th17/Treg was significantly higher than that in negative patients respectively. Conclusions: Our results indicated a possible role of Th17 in UCC patients correlated to Treg cells, and the imbalance of Th17/Treg may be involved in the development and progression of UCC. [Copyright &y& Elsevier]

Notch and epidermal growth factor receptor (EGFR) signaling play critical roles in cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of breast cancer. We constitutively overexpressed active Notch1 in human breast cancer cells to explore the consequences of Notch1 signaling on cell growth and to investigate the underlying molecular mechanisms. We found that EGFR expression was increased. Then, using EGFR inhibitor, we found it exhibited an inhibitory role on human breast cancer cells. Overexpression of Notch1 could reverse EGFR inhibitor-induced cell toxicity, suggesting that Notch and EGFR signaling may be positively cross-linked in human breast cancer. [ABSTRACT FROM AUTHOR]

Syntaxin-11 is a member of a family of membrane-trafficking proteins referred to as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Recent studies have shown that syntaxin-11 is expressed in natural killer cells and cytotoxic T cells and is likely to play a role in the granule exocytosis pathway. However, the biological role of syntaxin-11 in other immune cells has remained elusive. This study found that stimulation with interferon-γ upregulated syntaxin-11 expression in primary monocytes. Experiments using monocytes from patients with familial haemophagocytic lymphohistiocytosis harbouring mutations in the gene encoding syntaxin-11 ( STX11), or monocytes from healthy individuals in which syntaxin-11 was downregulated using specific short-interfering RNA, demonstrated that syntaxin-11 was not required for antibody-dependent cellular cytotoxicity. On the other hand, silencing of syntaxin-11 expression in primary macrophages enhanced the phagocytosis of apoptotic target cells with a concomitant increase in macrophage secretion of tumour necrosis factor-α. Moreover, Fcγ-receptor-mediated uptake of target cells was also enhanced following silencing of syntaxin-11 expression in macrophages. In addition, syntaxin-11 localized to the plasma membrane in macrophages ingesting apoptotic cell corpses. Syntaxin-11 thus appears to act as a negative regulator of human macrophage engulfment of apoptotic cells and IgG-opsonized red blood cells. [ABSTRACT FROM AUTHOR]

Short-chain fatty acids (SCFAs), particularly propionate and butyrate, have been reported in many cancers. However, the relationship between propionate and acute myeloid leukemia (AML) remains unclear. Additionally, Acyl-CoA synthetase long chain family member 4 (ACSL4) has been reported to regulate immunity in solid tumors, but there are still many gaps to be filled in AML. Here, we discovered the underlying mechanism of propionate and ACSL4-mediated ferroptosis for immunotherapy. Our results showed that the level of propionate in the AML patients' feces was decreased, which was correlated to gut microbiota dysbiosis. Moreover, we demonstrated that propionate suppressed AML progression both in vivo and in vitro. In mechanism, propionate induced AML cells apoptosis and ferroptosis. The imbalance of reactive oxygen species (ROS) and redox homeostasis induced by propionate caused mitochondrial fission and mitophagy, which enhanced ferroptosis and apoptosis. Furthermore, ACSL4-mediated ferroptosis caused by propionate increased the immunogenicity of AML cells, induced the release of damage-associated molecular patterns (DAMPs), and promoted the maturation of dendritic cells (DCs). The increased level of immunogenicity due to ferroptosis enable propionate-based whole-cell vaccines to activate immunity, thus further facilitating effective killing of AML cells. Collectively, our study uncovers a crucial role for propionate suppresses AML progression by inducing ferroptosis and the potential mechanisms of ACSL4-mediated ferroptosis in the regulation of AML immunity. [ABSTRACT FROM AUTHOR]

Purpose: Stem cells are known to play an important role in tumor treatment and many of them have shown tumor-suppressing ability in different cancers; however, whether hematopoietic stem cells (HSCs) have growth-inhibiting effects on leukemia cells has not been fully evaluated. Herein, we aimed to demonstrate the growth-restraining function of HSCs in acute leukemia treatment. Methods: Cell fusion experiment was conducted by PEG-1500. The viability, proliferation, apoptosis and differentiation of leukemia cells were evaluated by cell counting, CCK-8 and flow cytometry analysis. The morphological changes were imaged using a fluorescence microscope. The expression of genes was detected by quantitative reverse transcription PCR (qRT-PCR). Results: We observed that HSCs and their lytic extracts had the capability to suppress leukemia cells proliferation, promote apoptosis and especially induce acute myelogenous leukemia (AML) cells differentiation, which might have an effect on differentiation therapy to leukemia especially AML treatment. The expression levels of Bcl-2, Survivin decreased and Bax increased following HSCs extracts treatment. Furthermore, the expression of inflammatory cytokines also changed in AML cells which might have to do with the mechanism of HSCs/extracts suppressing effect. Conclusion: HSCs and their extracts can suppress the proliferation of leukemia cells and enhance the differentiation of AML cells and using the extracts of HSCs might be a probable therapeutic option for acute leukemia. [ABSTRACT FROM AUTHOR]

Background: Though immunological abnormalities have been proven involved in the pathogenesis of lymphoma, the underlying mechanism remains unclear. Methods: We investigated 25 single nucleotide polymorphisms (SNPs) of 21 immune‐related genes and explored their roles in lymphoma. The genotyping assay of the selected SNPs was used by the Massarray platform. Logistic regression and Cox proportional hazards models were used to analyze the associations of SNPs and the susceptibility of lymphoma or clinical characteristics of lymphoma patients. In addition, Least Absolute Shrinkage and Selection Operator regression was used to further analyze the relationships with the survival of lymphoma patients and candidate SNPs, and the significant difference between genotypes was verified by the expression of RNA. Results: By comparing 245 lymphoma patients with 213 healthy controls, we found eight important SNPs related to the susceptibility of lymphoma, which were involved in JAK–STAT, NF‐κB and other functional pathways. We further analyzed the relationships between SNPs and clinical characteristics. Our results showed that both IL6R (rs2228145) and STAT5B (rs6503691) significantly contributed to the Ann Arbor stages of lymphoma. And the STAT3 (rs744166), IL2 (rs2069762), IL10 (rs1800871), and PARP1 (rs907187) manifested a significant relationship with the peripheral blood counts in lymphoma patients. More importantly, the IFNG (rs2069718) and IL12A (rs6887695) were associated with the overall survival (OS) of lymphoma patients remarkably, and the adverse effects of GC genotypes could not be offset by Bonferroni correction for multiple comparison in rs6887695 especially. Moreover, we determined that the mRNA expression levels of IFNG and IL12A were significantly decreased in patients with shorter‐OS genotypes. Conclusions: We used multiple methods of analysis to predict the correlations between lymphoma susceptibility, clinical characteristics or OS with SNPs. Our findings reveal that immune‐related genetic polymorphisms contribute to the prognosis and treatment of lymphoma, which may serve as promising predictive targets. [ABSTRACT FROM AUTHOR]

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive malignant blood disorder with a high rate of relapse. Patients relapse as a result of minimal residual disease (MRD), which originates from residual T‐ALL cells in the bone marrow microenvironment (BMM). In the present study, it is observed that adipocytes increase dramatically in the BMM of T‐ALL patients after exposure to chemotherapeutic drugs. Then, it is proved that adipocytes attract T‐ALL cells by releasing CXCL13 and support leukemia cell survival by activating the Notch1 signaling pathway via DLL1 and Notch1 binding. Furthermore, it is verified that dexamethasone (DEX) induces adipogenic differentiation by enhancing the expression of SREBF1 in bone marrow mesenchymal stromal cells (BMSCs), and an SREBF1 inhibitor significantly decreases the adipogenic potential of BMSCs and the subsequent ability of adipocytes to support T‐ALL cells in vitro and in vivo. These findings confirm that the differentiation of BMSCs to adipocytes induced by DEX contributes to MRD in T‐ALL and provides an auxiliary clinical treatment to reduce the recurrence rate. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is malignant hyperplasia of B lymphocytes and standard care cannot satisfactorily meet clinical needs. Potential diagnostic and prognostic DLBCL biomarkers are needed. NCBP1 could bind to the 5ʹ-end cap of pre-mRNAs to participate in RNA processing, transcript nuclear export and translation. Aberrant NCBP1 expression is involved in the pathogenesis of cancers, but little is known about NCBP1 in DLBCL. We proved that NCBP1 is significantly elevated in DLBCL patients and is associated with their poor prognosis. Then, we found that NCBP1 is important for the proliferation of DLBCL cells. Moreover, we verified that NCBP1 enhances the proliferation of DLBCL cells in a METTL3-dependent manner and found that NCBP1 enhances the m6A catalytic function of METTL3 by maintaining METTL3 mRNA stabilization. Mechanistically, the expression of c-MYC is regulated by NCBP1-enhanced METTL3, and the NCBP1/METTL3/m6A/c-MYC axis is important for DLBCL progression. We identified a new pathway for DLBCL progression and suggest innovative ideas for molecular targeted therapy of DLBCL. [ABSTRACT FROM AUTHOR]

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological malignancy with a poor prognosis, urging for novel therapeutic targets and treatment strategies. N6‐methyladenosine (m6A) is a crucial methylation modification that affects the pathogenesis of leukemia by regulating the mRNA of key genes. Interferon regulatory factor 8 (IRF8) is a crucial transcription factor for hematological lineage commitment, but its role in T‐ALL is unclear. Here, IRF8 is shown to suppress T‐ALL. The expression of IRF8 is abnormally silenced in patients with T‐ALL. Knockout of Irf8 significantly hastens the progression of Notch1‐induced T‐ALL in vivo. Overexpression of IRF8 suppresses the proliferation and invasion of T‐ALL cells by inhibiting the phosphatidylinositol 3‐kinase/AKT signaling pathway. The fat mass‐ and obesity‐associated protein (FTO), an m6A demethylase, is responsible for directly binding to m6A sites in 3′ untranslated region of IRF8 messenger RNA (mRNA) and inducing mRNA degradation via m6A modification. Targeting the FTO‐IRF8 axis is used as a proof of concept therapy; inhibition of FTO's demethylase activity drastically alleviates the proliferation of leukemic cells and prolongs the survival of T‐ALL mice by restoring IRF8 expression. This study elucidates the pathogenesis of T‐ALL from the perspective of epitranscriptomics and provides new insight into the genetic mechanisms and targeted therapy of T‐ALL. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy with a prognosis that varies with genetic heterogeneity of hematopoietic stem/progenitor cells (HSPCs). Induction chemotherapy with cytarabine and anthracycline has been the standard care for newly diagnosed AML, but about 30% of patients have no response to this regimen. The resistance mechanisms require deeper understanding. Methods: In our study, using single‐cell RNA sequencing, we analyzed the heterogeneity of bone marrow CD34+ cells from newly diagnosed patients with AML who were then divided into sensitive and resistant groups according to their responses to induction chemotherapy with cytarabine and anthracycline. We verified our findings by TCGA database, GEO datasets, and multiparameter flow cytometry. Results: We established a landscape for AML CD34+ cells and identified HSPC types based on the lineage signature genes. Interestingly, we found a cell population with CRIP1highLGALS1highS100Ashigh showing features of granulocyte‐monocyte progenitors was associated with poor prognosis of AML. And two cell populations marked by CD34+CD52+ or CD34+CD74+DAP12+ were related to good response to induction therapy, showing characteristics of hematopoietic stem cells. Conclusion: Our study indicates the subclones of CD34+ cells confers for outcomes of AML and provides biomarkers to predict the response of patients with AML to induction chemotherapy. This study indicates the subclones of CD34+ cells confer for outcomes of acute myeloid leukemia (AML) and provides biomarkers to predict the response of patients with AML to induction chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Cadherin-23 (CDH23) plays an important role in intercellular adhesion and is involved in the progression of several types of cancer. However, the biological functions and effect of CDH23 expression on the prognosis of patients with acute myeloid leukemia (AML) are unexplored. Herein, we aim to characterize the role and molecular functions of CDH23 in AML.Methods: We downloaded the transcriptomic profiles and clinical data from the Cancer Genome Atlas and Beat AML trial. The expression level of CDH23 was assessed using Gene Expression Profiling Interactive Analysis (GEPIA). Kaplan-Meier survival analysis was used to assess prognostic value of CDH23. Correlation and biological function analyses were performed using LinkedOmics and GeneMANIA. Relationship of CDH23 with immune infiltration level was determined using Tumor Immune Estimation Resource (TIMER).Results: We found that the CDH23 expression was aberrantly upregulated in patients with AML and could be used as an independent risk factor of overall survival using Cox multivariate analysis. Notably, we observed a negative correlation between CDH23 expression and immune cell infiltration abundance by calculating the immune and stromal scores. In addition, functional enrichment analysis established that CDH23 plays a crucial role in tumor immunity.Conclusions: Our findings indicate that upregulated CDH23 expression corresponds to decreased overall survival of patients with AML. CDH23 may be involved in mediating tumor immune environment, and this highlights the potential of CDH23 as a therapeutic target in AML. [ABSTRACT FROM AUTHOR]

• We performed integrative analysis of genetic variations DNA excision repair pathway and their association with chemosensitivity and survival outcome in AML. • ERCC8 rs158572 is deemed the most clinically impactful due to its association with MRD positivity and refractory group. • XPC rs2228001 is correlated with the high WBC count and overall survival (OS) of AML. Acute myeloid leukemia (AML) is a hematologic malignancy with a high recurrence rate and poor long-term prognosis. DNA excision repair systems, such as base excision repair (BER) and nucleotide excision repair (NER), play a major role in maintaining genomic stability and integrity. Further intensive investigations are necessary to uncover additional AML prognosis loci. In this study, we analyzed 16 candidate SNPs within NER and BER pathways in AML patients. Our results showed the GT/GG genotype of the XPC rs2228001 polymorphism was significantly associated with WBC count in dominant models (OR = 0.41, 95 % CI = 0.18–0.96, p = 0.039). Additionally, the rs25487 and rs3213245 SNPs in the XRCC1 gene, in both co-dominant and dominant models, were significantly associated with PLT count in AML (p < 0.05). The GG genotype of rs1130409 in APEX1 was more prone to adverse cytogenetics in both the codominant and recessive models (p < 0.05). Furthermore, the GA genotypes of ERCC8 rs158572 in codominant model was significantly correlated with refractory group (p < 0.05). ERCC8 rs158572 and XRCC1 rs3213245 in both codominant and dominant models were significantly correlated with the MRD positivity (p < 0.05). Kaplan-Meier analysis revealed an link between overall survival (OS) and the co-dominant, dominant, and recessive models of rs2228001 in XPC. Additionally, patients with the GG and GT/GG genotype in the co-dominant, dominant model and recessive model in XPC rs2228001 exhibited significantly longer survival (p < 0.05). Multivariate Cox analyses indicated that rs2228001 in both co-dominant and dominant models were independent favorable factors impacting patient OS (OR < 1). Our findings suggest that genetic polymorphisms in DNA excision repair pathway genetic polymorphisms contribute to the chemosensitivity and prognosis of acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Background: The B-cell prolymphocytic leukemia (B-PLL) diagnosis is challenging due to the superposition with mature B-cell leukemia and/or lymphoma. Objective: An insight case study of trisomy 5 with complex karyotype abnormalities in B-cell prolymphocytic leukemia. Subject and methods: A 72-year-old man was referred to the Hematology Department, Qilu Hospital, Shandong University, because of persistent fever (10 days) and lymphocytosis. A detailed diagnostic methods including complete blood count, bone marrow aspiration, flow cytometry, conventional karyotype analysis, fluorescence in situ hybridization (FISH), quantitative real-time polymerase chain reaction (qRT-PCR), next-generation sequencing technology (NGS) used to detect 41 kinds of mutant genes related to hematological malignancies were conducted and reasonable therapeutic regimens including emergent leukapheresis accompanied by basification of urine and hydrotherapy, followed by a regimen of cyclophosphamide and dexamethasone. Results: Subject white blood cell count was 143.43 × 109/L, and 56% prolymphocytes. He did not show lymphadenopathy but splenomegaly. Immunophenotyping of prolymphocytes was CD5(+low), CD10(−), CD11c(−), CD19(+), CD20(+), cCD22(+), CD23(−), cCD79a(+), CD79b(+), FMC7(±), CD43(−), CD3(−), CD56(−), CD103(−), HLA-DR(+), and Lambda(+). R-banding and FISH revealed that leukemia cells carried extra chromosome 5. Considering the rare occurrence of trisomy 5 found in prolymphocytic leukemia, especially in Asians, with rapid disease progression. We know that median survival of B-PLL is three years after diagnosis, while survival time of this patient was only 1 month. Conclusion: This study could provide the firsthand materials for precision, medicine and mechanism research in cytogenetics and molecular biology. It inferred that trisomy 5 might be a poor prognosis indicator, providing directions for clinical practice in the foreseeable future. [ABSTRACT FROM AUTHOR]

Angiogenesis is suggested to be important for leukemogenesis and chemosensitivity in acute myeloid leukemia (AML). The vascular endothelial growth factor (VEGF) and Notch/Dll4 pathways have been identified as critical in the regulation of embryonic vascular development and tumor angiogenesis. However, the potential role of the Notch/Dll4 pathway in leukemia–endothelium cross-talk and its functional link with VEGF remains obscure. This study assessed the expression of VEGF and Notch/Dll4 pathway molecules in primary AML and investigated their biological function in the coculture of endothelial cells with AML cells. The results demonstrated that bone marrow vascularity in the newly diagnosed AML patients was increased and correlated with high VEGF and Dll4 expression. Patients with untreated AML expressed higher levels of VEGFR2, Notch1, Dll4 and Hes1 than healthy controls. Moreover, the activation of the Notch/Dll4 pathway is associated with poor prognosis in AML. In addition, AML cells were shown to increase endothelial cell proliferation in Transwell coculture. This was associated with concomitant activation of the Notch/Dll4 pathway and upregulation of its downstream genes, such as matrix metalloproteinases, resulting in the enhancement of endothelial cell migration and tube formation. Our study also showed that upregulation of Dll4 expression in AML cells by cDNA transfection suppressed VEGF-induced endothelial cell proliferation and angiogenesis in direct contact coculture. These results elucidate a novel mechanism by which the interplay between AML and endothelial cells promotes angiogenesis through the Notch/Dll4 pathway. Modulation of this pathway may, therefore, hold promise as a novel antiangiogenic strategy for the treatment of AML. [ABSTRACT FROM AUTHOR]

Abstract: Background: Recent studies suggest a potential impact of Th17 cells on tumor. In the present study, we investigated the distribution of Th17 cells in relation to Foxp3-expressing T cells in the tumor-infiltrating lymphocytes (TILs) from patients with uterine cervical cancer (UCC), cervical tissues from patients with cervical intraepithelial neoplasia (CIN) and healthy cervical tissues. Methods: Th17 cells and Foxp3-expressing T cells were evaluated by immunohistochemical staining. IL-6, TGF-β, IL-17 and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical staining for microvessel density (MVD) was performed in order to assess the association of IL-17 expression with angiogenesis. Results: Compared with controls, patients with UCC or CIN had a higher proportion of Th17 cells and Foxp3-expressing T cells, when the ratio of Th17/Foxp3-expressing T cells in TILs was decreased in individual cases, it was more markedly decreased in TILs than normal cervical tissues. Meanwhile, the cytokine(IL-6, TGF-β and IL-10) concentrations were significantly higher in UCC patients than those in healthy controls. Interestingly, the levels of intratumoral Th17 cells were positively correlated with MVD in tumors. Conclusions: The imbalance of Th17/Foxp3-expressing T cells may play critical roles in the development and progression of UCC and Th17 cells may promote tumor progression by fostering angiogenesis. [Copyright &y& Elsevier]

The Notch signaling pathway plays critical roles in human cancers, including osteosarcoma, suggesting that the discovery of specific agents targeting Notch would be extremely valuable for osteosarcoma. Curcumin, a naturally occurring phenolic compound found in curcuma longa, has been shown to inhibit proliferation and induce apoptosis of osteosarcoma cells in vitro and tumor growth in xenotransplant or orthotransplant models. However, the precise molecular mechanisms by which curcumin exerts its antitumor activity remain unclear. Here we used multiple molecular approaches, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the invasion assay, gene transfection, real-time RT-PCR, western blot and gelatin zymography, to investigate whether the downregulation of Notch-1 contributes to curcumin-induced inhibition of proliferation and invasion in osteosarcoma cells. The results showed that curcumin caused marked inhibition of osteosarcoma cell growth and G2/M phase cell cycle arrest. This was associated with concomitant attenuation of Notch-1 and downregulation of its downstream genes, such as matrix metalloproteinases, resulting in the inhibition of osteosarcoma cell invasion through Matrigel. We also found that specific downregulation of Notch-1 via small-interfering RNA prior to curcumin treatment resulted in enhanced inhibition of cell growth and invasion. These results suggest that antitumor activity of curcumin is mediated through a novel mechanism involving inactivation of the Notch-1 signaling pathway. Our data provide the first evidence that the downregulation of Notch-1 by curcumin may be an effective approach for the treatment of osteosarcoma. [ABSTRACT FROM AUTHOR]

The multidrug resistance (mdr) mediated by P-glycoprotein (P-gp), the mdr1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a suicide gene therapy approach targeting mdr1 for reversal of P-gp-mediated mdr in the mdr positive K562/A02 cells. To study targeted killing effects of cytosine deaminase (CD)-thymidine kinase (TK) fusion suicide gene on multi-drug resistant leukemia, the CD-TK fusion suicide gene expression vector driven by mdr1 promoter was constructed and transferred into K562 and K562/A02 cells using lipofectin™ 2000. RT-PCR was used to demonstrate that there were CD and TK genes expression in K562/A02 cells, but not in K562 cells. MTT analysis showed that, compared with that in K562/CDTK, the survival rate of K562/A02-CDTK cells decreased and at the same time the apoptotic rate increased after treatment with GCV and 5-FC (P < 0.05). In vivo studies showed that the tumor volume in the prodrug treated K562/A02-CDTK groups was significantly less than that in the NS-control and K562-CDTK groups (P < 0.05). These findings show that the CD and TK fusion suicide gene expression driven by mdr1 promoter is effective in killing multidrug resistant K562/A02 cells. [ABSTRACT FROM AUTHOR]

Mental stress has been shown to activate sympathetic adrenergic system to produce dopamine and finally promote the progression of cancer. Dopamine can also regulate the immune system through secreting kinds of cytokines. However, what role does dopamine play in acute myeloid leukemia (AML) remains unclear. Here, we investigated the effects and mechanisms of dopamine in NLRP3 inflammasome activation and cellular viability of acute myeloid leukemia U937 cells. Our results showed that dopamine enhanced the viability of U937 cells and activated the NLRP3 inflammasome in U937 cells. To further explore the mechanism of dopamine on U937 cells, we examined the expression level of dopamine receptors (DRs). We found that the mRNA expression level of DR5 in U937 cells was significantly higher than other dopamine receptors. Furthermore, we treated U937 cells with DR1/2/3/5 antagonist before dopamine, and it manifestly reversed the NLRP3 inflammasome activation and the viability-enhancing effect in U937 cells induced by dopamine. Anti-IL-1β antibody also could partly reversed the viability-enhancing effect by dopamine. We concluded that dopamine could enhance the viability of U937 cells through DR1/5 receptor pathway and activate NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

The bone marrow microenvironment of acute myeloid leukemia (AML) characterized by immunosuppressive features fosters leukemia immune escape. Elucidating the immunosuppressive mechanism and developing effective immunotherapeutic strategies are necessary. Here, we found that the Th1% and IFN-γ level were downregulated in bone marrow of AML and NLRP3-activated BMDCs promoted CD4+ T cell differentiation into Th1 cells via IL-1β secretion. However, IFN-γ-producing Th1 cells were not induced by NLRP3-activated BMDCs in the presence of the NLRP3 inflammasome inhibitor MCC950 or anti-IL-1β antibody in vitro unless exogenous IL-1β was replenished. This inhibitory effect on Th1 differentiation was also observed in Nlrp3-/- mice or anti-IL-1β antibody-treated mice. Notably, elevated Th1 cell levels promoted apoptosis and inhibited proliferation in leukemia cells via IFN-γ secretion in vitro and in vivo. Thus, NLRP3-activated BMDCs promote the proliferation of IFN-γ-producing Th1 cells with antileukemic effects and may provide insight into the basis for leukemia immunotherapy in patients with AML. [ABSTRACT FROM AUTHOR]

• We performed integrative analysis of genetic mutations and their association with laboratory indexes, survival outcome and transformation outcome in MDS. • The study developed a risk score based on gene mutation data that demonstrated robust predictive capability and stability for the overall survival of MDS patients. Gene mutations are a pivotal component of the pathogenesis of MDS, and they hold profound prognostic significance for predicting treatment responses and survival outcomes. However, reports about mutation patterns in Chinese MDS patients are limited. In this study, we analyzed the genetic mutation of 23 genes in 231 patients with MDS using next-generation sequencing (NGS) technology, and explored the characteristics of gene mutations in MDS patients and their associations with clinical outcomes, survival, and transformation outcomes. Our results showed that 68.83% patients had at least one gene mutation, and the most common mutations were ASXL1 (21.65%), SF3B1 (17.32%), U2AF1 (16.02%), TET2 (14.72%) and TP53 (8.66%). We also showed that the genetic mutations of TP53, U2AF1 and DNMT3A are independent risk factors for death in patients with MDS, and the ETV6 gene mutation was an independent risk factor for the transformation of MDS patients to AML through the univariate and multivariate Cox regression analysis model. Additionally, the study developed a risk score based on gene mutation data that demonstrated robust predictive capability and stability for the overall survival of MDS patients. Our research provided a strong theoretical basis for the establishment of personalized treatment and prognostic risk assessment models for Chinese MDS patients. [ABSTRACT FROM AUTHOR]

The NLRP3 inflammasome plays a pro-tumorigenic role in various malignancies. However, its potential role in lymphomagenesis remains unclear. In this study, we identified an immunosuppressive state in patients with diffuse large B cell lymphoma (DLBCL), which was characterized by markedly elevated interleukin (IL)-18 levels in lymphoma tissues and positive correlation with programmed death ligand 1 (PD-L1) expression. Furthermore, NLRP3 inflammasome activation in DLBCL cell lines upregulated PD-L1 and reduced the proportion of cytotoxic T cells. NLRP3 inflammasome blockade in vivo suppressed lymphoma growth and ameliorated anti-tumor immunity by downregulating PD-L1 in the tumor microenvironment and decreasing the proportion of PD-1/TIM-3-expressing T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Further in vivo studies revealed IL-18 as the main effector cytokine involved in the negative regulation of anti-lymphoma immunity. Interestingly, NLRP3 blockers combined with anti-PD-L1 treatment exerted antagonistic effects during lymphoma therapy. Altogether, our findings indicate that NLRP3 inflammasome promotes immunosuppression by modulating PD-L1 and immune cells. Accordingly, this study highlights the prognostic and therapeutic values of the NLRP3 inflammasome in lymphoma. [ABSTRACT FROM AUTHOR]

Background: Chronic lymphocytic leukemia (CLL) and myelodysplastic syndrome (MDS) existing simultaneously in untreated patients is extremely rare. There have only been nine cases of untreated CLL concurrent with or followed by the development of MDS. Of all nine cases, four patients exhibited results of cytogenetic phonotypes all showing more than one abnormal chromosome karyotype. It is unknown whether or not these abnormal chromosome karyotypes change during the development of the disease. Meanwhile, the optimal treatment for the concurrence of CLL with MDS has yet to be identified. Case Presentation: A 69-year-old Chinese man diagnosed with co-existing CLL with MDS was observed from diagnosis, treatment, relapse to death during an admission period of a total of 158 days. Since being diagnosed with CLL and MDS, he was treated by decitabine and his condition went into remission for three months. Four laboratory tests showed an abnormal chromosome cytogenetic karyotype successively changed during the progression of the disease. Conclusion: It is the first time the abnormal chromosome karyotype variation significantly associated with the change of the illness was discovered. In the relapse and deterioration stages of the disease, there was t(9;22)(q24; q11.2); add(11)(p15) and other chromosome translocation. Repeated occurrence of TET2 mutation is special at this stage of the disease. Furthermore, decitabine could be beneficial for the treatment of the disease. [ABSTRACT FROM AUTHOR]

Background: Chemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms. Therefore, unraveling molecular networks that drive this process constitutes an urgent unmet need. Herein, we aim to characterize the role and molecular mechanism of the tumor necrosis factor ɑ-induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, in AML chemoresistance. Methods: The expression levels of TNFAIP8 were assessed in AML patients and cell lines by RT-qPCR and western blots. The transcriptional regulation of TNFAIP8 was analyzed with luciferase reporter assay and ChIP followed by RT-qPCR. Functional experiments were conducted to evaluate the effects of TNFAIP8 on apoptosis, drug sensitivity and proliferation of AML cells. Potential effects of TNFAIP8 on the activation of extracellular signal-regulated kinase (ERK) pathway were detected by western blots. CoIP and P21-activated kinase (PAK) pull-down assay were performed to ascertain the upstream target. The overall effects of TNFAIP8 on AML were examined in murine models. Results: Upregulated TNFAIP8 expression was first confirmed in human AML patients and cell lines. E74 like ETS transcription factor 1 (ELF1) was then identified to contribute to its aberrant expression. Through manipulating TNFAIP8 expression, we described its role in protecting AML cells from apoptosis induced by chemotherapeutic agents and in promoting drug resistance. Notably, the leukemia-promoting action of TNFAIP8 was mediated by sustaining activity of the ERK signaling pathway, through an interaction with Rac family small GTPase 1 (Rac1). In addition, in vivo experiments confirmed that TNFAIP8 suppression lowered leukemia infiltration and improved survival. Conclusion: Our data provide a molecular basis for the role of TNFAIP8 in chemoresistance and progression of AML and highlight the unique function of TNFAIP8 as an attractive therapeutic target. [ABSTRACT FROM AUTHOR]

Inflammation plays a crucial role in the initiation, progression and prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which could be clinically subdivided into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasomes affect inflammatory diseases and carcinomas by excessive production of cytokines. To investigate a possible association of NLRP3 inflammasome signaling with MPN, we investigated the expression of selected inflammasome-related genes from bone marrow cells of 67 MPN patients as well as gene polymorphisms in NLRP3 (rs35829419), NF-κB1 (rs28362491), CARD8 (rs2043211), IL-1β (rs16944), and IL-18 (rs1946518). It showed that inflammasome-related genes (NLRP3, NF-κB1, CARD8, IL-1β, and IL-18) were highly expressed in BM cells from MPN patients and the increased expression was associated with JAK2V617F mutation, white blood cell counts and splenomegaly. Analysis of genetic polymorphisms in 269 MPN patients and 291 healthy controls demonstrated that NF-κB1 (rs28362491) was associated with MPN and increased expression of NF-κB1, NLRP3 and IL-1β. This research provided novel biomarkers and potential targets for MPN. [ABSTRACT FROM AUTHOR]

TET2 and EZH2 play important roles in the epigenetic regulation in many cancers. However, their specific roles in acute myeloid leukemia (AML) pathogenesis remain unknown. Here, the expression, methylation or mutation of EZH2 and TET2 was determined and further correlated with the levels of the chromosome instability (CIN) genes MAD2 and CDC20. We down-regulated EZH2 and TET2 in AML cell lines and assessed the effect on CIN using fluorescence in situ hybridization (FISH). Our results showed that TET2, EZH2, MAD2 and CDC20 were aberrantly expressed in AML patients. The expression level of MAD2 or CDC20 was positively correlated with that of TET2 or EZH2. Hypermethylation of the TET2 gene down-regulated its transcription. Down-regulation of EZH2 or TET2 expression inhibited apoptosis, affected MAD2 and CDC20 expression, and promoted CIN in AML cells. Decitabine treatment restored TET2 methylation and EZH2 transcription and ameliorated CIN in AML. Therefore, TET2 and EZH2 play a tumor-inhibiting role in AML that affects CIN via MAD2 and CDC20. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) participate in gene regulation and malignant tumor progression, including uterine cervical cancer (CC). In this study, the expression profile of circRNAs in CC was detected using circRNA microarrays. Then, we selected hsa_circ_0000745 for further examination from the significantly dysregulated circRNAs. Proliferation assays, Transwell assays, quantitative reverse transcription polymerase chain reaction, western blot analysis and tumorigenesis tests in vivo were used to validate the role of hsa_circ_0000745 in CC. hsa_circ_0000745 was upregulated in CC, and its level positively correlated with the level of its linear messenger RNA isoform. Patients with poorly differentiated tumors or vascular/lymphatic invasion presented higher expression of hsa_circ_0000745. The role of hsa_circ_0000745 was illuminated by knocking down hsa_circ_0000745 in CC cells, and the results revealed that reducing hsa_circ_0000745 inhibited cell proliferation, migration, and invasion in CC by upregulating E‐cadherin (E‐cad) expression. In summary, as a tumor promoter in CC, hsa_circ_0000745 enhances the cell's ability to proliferate, migrate, and invade by reducing the expression of E‐cad. hsa_circ_0000745 is a candidate target for the treatment of CC in the clinic. [ABSTRACT FROM AUTHOR]

Introduction: Progression and chemoresistance of acute myeloid leukemia (AML) contribute to most of the treatment failure. Notch pathway has been proven to be involved in many biological processes and diseases, especially AML. In this study, we aimed to explore genes correlated with Notch1 pathway in AML and determine their roles in the regulation of AML progression and chemoresistance. Methods: TCGA database was used to explore Notch1 associated genes. Kaplan–Meier survival analysis was performed to evaluate the prognostic significance of genes. Quantitative RT-PCR (qRT-PCR) and Western blot were performed to examine the expression of genes. The expression of PRKD2 was up-regulated or knocked down in AML cell lines by lentivirus or siRNAs. CCK-8 and flow cytometry were used to analyze the effect of PRKD2 on cell proliferation and chemoresistance. Results: Based on TCGA database, PRKD2 was found to be positively correlated with Notch1 expression, cytogenetic risk status and poorer prognosis in AML. Moreover, the expression level of PRKD2 was higher in AML chemo-resistant cells than in chemo-sensitive cells. Functionally, knockdown of PRKD2-induced apoptosis and increased chemosensitivity of AML cells. PRKD2 overexpression promoted proliferation and chemoresistance of AML cells. Furthermore, we found PRKD2 could regulate Notch1 pathway. Besides, high PRKD2 expression was correlated with higher risk group of AML patients which indicated that PRKD2 was an independent prognostic marker for AML. Conclusion: Taken together, our results showed that PRKD2 could promote the proliferation and chemoresistance of AML cells by regulating Notch1 pathway. The study broadened our insights into the underlying mechanisms in chemoresistance and proliferation of AML, and provided a new prognostic marker and treatment target for AML. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy affecting pediatric and adult populations. Although the outcomes of ALL in children have improved markedly in previous years, limited treatment strategies are available at present for adult patients with ALL. Wee1 is a crucial cell cycle checkpoint kinase of G2/M that regulates cell cycle progression and maintains chromatin integrity. MK‑1775, a selective inhibitor of Wee1 has recently been identified to be able to induce apoptosis of tumor cells by abrogating G2/M checkpoint. The present study investigated the anti‑leukemic activity of MK‑1775 alone and in combination with doxorubicin (Adriamycin®; ADM) in various human ALL cell lines. MK‑1775 treatment induced apoptosis of ALL cells, accompanied by unscheduled mitotic entry and downregulation of Notch pathway. The anti‑leukemic activity of MK‑1775 was in a concentration‑ and time‑dependent manner. The data also indicated that it decreased the half‑maximal inhibitory concentration (IC50) of ADM compared with the control group. The combination of MK‑1775 and ADM induced an increased apoptotic rate compared with each agent alone. In addition, the human bone marrow stromal cell HS‑5 cell line was detected to exhibit an increased IC50 value of MK‑1775 treatment in contrast to ALL cell lines. It indicates that the hematopoietic supportive capability may remain intact during the treatment of MK‑1775. Taken together, the Wee1 inhibitor MK‑1775 may be an attractive agent in the treatment of patients with ALL. [ABSTRACT FROM AUTHOR]

The pathogenesis of multiple myeloma (MM) remains unclear and the NLRP3 inflammasome has been more and more recognized in the progression of many diseases. To investigate the role of the NLRP3 inflammasome in MM, we determined the genetic polymorphisms and expression of NLRP3 inflammasome-related genes (IL-1β, IL-18, CARD8, and NF-κB) in MM patients, and explored their clinical relevance. Furthermore, we investigated the relationship of the NLRP3 inflammasome with Th cells in MM. Our study showed that the CARD8-C10X (rs2043211) AT genotype contributed to the susceptibility of MM. CARD8-C10X TT patients had earlier clinical stage. The WBC count in the three CARD8 genotypes showed an increasing trend (AA

Background: The NLRP3 inflammasome plays important roles in the pathogenesis of autoimmune diseases. However, the role of the NLRP3 inflammasome in the pathophysiology of immune thrombocytopenia (ITP) remains unclear.Methods: RT-PCR was used to examine the polymorphism and expression of genes involved in the NLRP3 inflammasome in ITP patients. T helper cells and apoptosis of PBMC from ITP patients were analyzed by flow cytometry. The antiplatelet autoantibodies in plasma were determined by modified monoclonal antibody-specific immobilization of platelet antigens (MAIPA).Results: We found that the NF-κB-94ins/del ATTG genotype contributed to the susceptibility of ITP. Furthermore, the platelet counts of ITP patients with the WW genotype or WD genotype were lower than those with the DD genotype of NF-κB-94ins/del ATTG. Compared with controls, NF-κB gene expression was significantly decreased and WW or WD genotype ITP patients displayed higher mRNA expression than DD individuals. Similarly, the mRNA expression of NLRP3 was also increased in the WW genotype. There was a significant gene dose effect of the percentage of Th17 cells for the WW, WD, and DD genotypes (WW < WD < DD) in the unstimulated group and no significant difference was found after being stimulated. The activation of the NLRP3 inflammasome could upregulate Th17 in ITP patients.Conclusion: The NF-κB-94ins/del ATTG genotype might serve as a novel biomarker and potential target for ITP. [ABSTRACT FROM AUTHOR]

NLRP3 inflammasome has been recently reported as an important risk factor in the development of cancer. But the relationship between polymorphisms of NLRP3 inflammasome related genes and chronic myeloid leukemia (CML) is rarely reported. Therefore, the aim of the present study was to investigate the association of five genetic polymorphisms (NLRP3, IL-1β, IL-18, CARD8 and NF-κB) in 267 CML patients and 344 healthy controls. We found that the AT genotype of CARD8 (rs2043211) was significantly higher compared to TT genotype in high and intermediate risk CML patients. IL-1β (rs16944) polymorphism in early molecular response at 6 months was marginally different, with more GG and less AA genotype in BCR-ABL IS >1% group. IL-18 (rs1946518) polymorphism was significantly different with more GG genotype in BCR-ABL IS >1% group at 6 months. We also demonstrated that WBC count of newly diagnosed patients carrying AG genotype was significantly higher than that of GG or AA genotype of IL-1β (rs16944). The onset age of patients carrying ins/ins genotype of NF-κB (rs28362491) was significantly older than that of ins/del and del/del genotype. Moreover, IL-1β or NLRP3 mRNA expression was decreased and IL-18 mRNA expression was increased significantly in CML patients compared with controls. In conclusion, the genetic polymorphisms of NLRP3 inflammasome may be served as potential predictors for CML. [ABSTRACT FROM AUTHOR]

DEX-Induced SREBF1 Promotes BMSCs Differentiation into Adipocytes to Attract and Protect Residual T-Cell Acute Lymphoblastic Leukemia Cells After Chemotherapy (Adv. Sci. 19/2023) Last, an SREBF1 inhibitor demonstrates superior improvement on therapeutic effect of dexamethason by reducing adipogenesis and provides a feasible strategy to solve the dilemma of recurrence. B T-Cell Acute Lym-phoblastic Leukemia b In article number 2205854, Jingjing Ye, Min Ji, Chunyan Ji, and co-workers observed aberrant adipogenesis in the bone marrow of chemotherapy-treated T-cell acute lymphoblastic leukemia (T-ALL) patients, and the differentiated-adipocytes attract and support residual T-ALL cells. [Extracted from the article]

Background: Though the pathogenesis of AML is still unknown, accumulating evidence revealed that immune response plays a vital part in it. NLRP3 inflammasome as a component of immune system has been found related to several cancers. The single nucleotide polymorphisms (SNPs) of NLRP3 inflammasome genes may be related to pathogenesis and prognosis of AML. Methods and results: We determined polymorphisms of NLRP3 (rs35829419), CARD8 (rs2043211), IL-1β (rs16944), IL-18 (rs1946518) and NF-κB −94 ins/del ATTG in de novo AML patients to find out whether they play roles in the susceptibility and severity of AML. In our study, 383 AML cases and 300 randomly selected healthy individuals were examined for the polymorphisms and expression of NLRP3 genes. IL-1β (rs16944) polymorphism in different risk AML subgroups was found statistically different, with more GA genotype in favorable-risk cytogenetics group. We also demonstrated that the bone marrow blasts of patients carrying IL-18 (rs1946518) GG or GT genotype were higher than patients of TT genotype. IL-18 plasma level of patients with IL-18 (rs1946518) GT or TT genotype was higher than GG genotype. Moreover, the GT genotype of IL-18 (rs1946518) led to statistically poorer AML-specific survival. Conclusion: IL-1β (rs16944) and IL-18 (rs1946518) may be served as potential predictors for AML. [ABSTRACT FROM AUTHOR]

Genetic factors have been shown to be associated with Myelodysplastic syndromes (MDS) susceptibility. In recent years, the role of inflammation in the promotion of tumor growth is supported by a broad range of experimental and clinical evidence. But the relationship between polymorphisms in NOD-like receptor protein 3 (NLRP3) inflammasome and MDS is rarely reported. Thus, we conducted a case-control study, and genotyped five single nucleotide polymorphisms (SNPs) (NLRP3, IL-1β, IL-18, CARD8, and NF-κB) in MDS patients and healthy controls. The association of different genotypes with patient characteristics was analyzed. Comparing MDS patients with controls, GG genotype of IL-1β (rs16944) was observed to be associated with a significantly increased risk of MDS 78/166 (48.8%) vs 26/96 (27.0%), OR = 2.1, CI (1.0–4.4). No significant association was identified regarding the rest of investigated polymorphisms and MDS susceptibility. Complex karyotypes were more frequent in patients with GG genotype of IL-1β (rs16944). Patients with IL-1β polymorphisms (rs16944) GG and GA had lower hemoglobin than those without. Patients with IL-1β polymorphisms (rs16944) GG had higher IPSS scores than those without IL-1β polymorphisms. In conclusion, our present data shows that the IL-1β polymorphisms (rs16944) GG were frequently occurred in MDS. IL-1β (rs16944) GG genotype might serve as a novel biomarker and potential targets for MDS. [ABSTRACT FROM AUTHOR]

Non-Hodgkin’s lymphomas (NHLs) are a heterogeneous group of neoplasm in which 90% are B-cell lymphomas and 10% T-cell lymphomas. Although T-helper 17 (Th17) cells have been implicated to be essential in the pathogenesis of autoimmune and inflammatory diseases, its role in B-cell non-Hodgkin’s lymphoma (B-NHL) remains unknown. In this study, we observed a significantly decreased frequency of Th17 cells in peripheral blood from B-NHL patients compared with healthy individuals, accompanied with increased Th1 cells. IL-17AF plasma levels were remarkably decreased in B-NHL patients, accompanied with undetectable IL-17FF and unchangeable IL-17AA. Moreover, Th17 and Th1 cells became normalized after one or two cycles of chemotherapy. Interestingly, in B-NHL, circulating Th17 cells frequencies were significantly higher in relapsed patients than those in untreated patients or normal individuals. Meanwhile, there was no statistical difference regarding the frequencies of Th1 cells between relapsed and untreated patients. Taken these data together, circulating Th17 subset immune response may be associated with the response of patients to treatment and with different stages of disease. [ABSTRACT FROM AUTHOR]

Background Aplastic anemia (AA) is an immune-mediated disorder and mainly related to active destruction of hematopoietic cells by effector T lymphocytes. T helper (Th) 22 cells characterized as a novel subset of CD4 + T cells participate in the pathogenesis of autoimmune and hematological diseases. However, the role of Th22 subset in AA remains unknown. Methods 31 untreated AA patients and 30 healthy controls were included in this study. The percentages of Th22, Th17 and pure Th17 cells in peripheral blood were detected by flow cytometry. ELISA to measure interleukin (IL)-22 and IL-17A plasma levels and qRT-PCR for the mRNA levels of Th22 and Th17 related molecules were performed. Results The proportions of Th22, pure Th17, Th17 cells and plasma levels of IL-22 were significantly lower in untreated AA patients than those in normal controls. A positive correlation was found between Th22 and pure Th17 cells in AA. Moreover, percentages of Th22 cells correlated positively with reticulocyte counts and percentages. In addition, STAT3/STAT5 mRNA expression ratio was elevated in AA patients. Conclusion Together, our results showed Th22 cells correlating with clinical characteristics of AA patients, indicating a possible role of Th22 immune response in the pathogenesis and therapeutic intervention of AA. [ABSTRACT FROM AUTHOR]

Background: T helper (Th) cells immune regulation is important for the pathogenesis of acute myeloid leukemia (AML). Recurrent Th abnormalities in AML peripheral blood were reported, while the comprehensive status of various Th subsets is rarely investigated in bone marrow (BM) microenvironment which is the origin of AML leukemic blast cells. Methods: BM was extracted from 48 newly-diagnosed (ND), 34 complete-remission (CR), 19 relapsed-refractory AML patients and 15 controls. Slight iron deficiency anemia patients were used as controls. Th subsets frequencies were examined by flow cytometry. BM plasma Th-associated cytokines levels were determined by ELISA. The expression of key transcription factor was examined by RT-PCR. Results: Th22, Th17, Th1, Th2 cells, IL-22 and RORC expression were significantly decreased, while Treg cells, related cytokine IL-10 and transcription factor Foxp3 were markedly elevated in ND compared to CR patients or controls. Meanwhile, the imbalanced Th1/Th2 and Th17/Treg ratio were observed in ND and relapsed-refractory patients. Negative correlation between Th1 or Th2 and peripheral WBC, between Th17/Treg or Th1/Th2 and leukemic blast existed in ND patients. Moreover, chemotherapy ameliorated these variations. Conclusion: Th subsets in BM are distinct for different stages of AML and chemotherapy partly ameliorates the abnormality. Our findings suggest that these cells and cytokines may be implicated in AML pathogenesis and provided therapeutic insights. [ABSTRACT FROM AUTHOR]

T helper- (Th-) cell immunodeficiency plays important roles in tumor development and their effects in chronic myeloid leukemia (CML) remain unclear. In the present study, we mainly investigated the role of Th22, Th17, and Th1 cell and their related cytokines (IL-22, IL-17, and IFN-r) in the pathophysiology of CML. Bone marrow (BM) and peripheral blood (PB) were extracted from newly diagnosed (ND), chronic phase- (CP-) CML patients, and controls. Th subsets were examined by flow cytometry. Plasma IL-22, IL-17, and IFN-r concentrations were measured by ELISA. AHR and RORC mRNA expressions were examined by RT-PCR. The frequencies of Th22, Th17, and Th1 cells, along with the expression of specific transcription factors RORC and AHR, were significantly decreased in ND patients compared with healthy controls, while all these abnormality recovered in CP patients. In addition, there existed a significantly positive relationship between Th22 and Th17 cells in PB or BM. A significantly negative relationship was found between Th cells (Th22, Th17, or Th1) and BCR-ABL (%) IS or the number of PB white blood cells. All these results demonstrated that Th22, Th17, and Th1 cells might be important therapeutic targets in CML and could facilitate a better outcome for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Extra-medullary infiltration is still one of the main causes of recurrence and treatment failure of T-cell acute lymphoblastic leukemia (T-ALL). Intensive studies revealed that Notch pathway plays an important role in the invasion of tumor cells. Notch pathway can be triggered by binding of Notch receptors on T-ALL cells to their ligands on bone marrow stromal cells (BMSCs), which contributes to the development of T-ALL. However, the effect and molecular mechanisms of BMSCs in invasion of T-ALL cells remain unclear. To explore the effect of Notch-1 on the invasiveness of T-ALL cells, we co-cultured T-ALL cells with BMSCs (from healthy donors)/BMSCs ⁎ (from newly diagnosed T-ALL patients). The results demonstrated that BMSCs/BMSCs ⁎ promoted invasion of T-ALL cells through activating Notch-1 signaling. In particular, T-ALL cells showed a higher invasive potential in the presence of BMSCs ⁎ than BMSCs. Knockdown of Notch-1 prevented the positive effect of stromal cells-mediated invasion. Our study also showed that BMSCs/BMSCs ⁎ -induced Notch-1 activation increased the expression of matrix metalloprote inase-2 (MMP-2) and matrix metalloprote inase-9 (MMP-9), which increased invasiveness. These results provided theoretical and laboratory basis for the prevention and treatment of extra-medullary infiltration of T-ALL cells. [ABSTRACT FROM AUTHOR]

The proto-oncogene c-Myc plays critical roles in human malignancies including chronic myeloid leukemia (CML), suggesting that the discovery of specific agents targeting c-Myc would be extremely valuable for CML treatment. Nitidine Chloride (NC), a natural bioactive alkaloid, is suggested to possess anti-tumor effects. However, the function of NC in leukemia and the underlying molecular mechanisms have not been established. In this study, we found that NC induced erythroid differentiation, accompanied by increased expression of erythroid differentiation markers, e. g. α-, ε-, γ-globin, CD235a, CD71 and α-hemoglobin stabilizing protein (AHSP) in CML cells. We also observed that NC induced apoptosis and upregulated cleaved caspase-3 and Parp-1 in K562 cells. These effects were associated with concomitant attenuation of c-Myc. Our study showed that NC treatment in CML cells enhanced phosphorylation of Thr58 residue and subsequently accelerated degradation of c-Myc. A specific group of miRNAs, which had been reported to be activated by c-Myc, mediated biological functions of c-Myc. We found that most of these miRNAs, especially miR-17 and miR-20a showed strong decrement after NC treatment or c-Myc interference. Furthermore, overexpression of c-Myc or miR-17/20a alleviated NC induced differentiation and apoptosis in K562 cells. More importantly, NC enhanced the effects of imatinib in K562 and primary CML cells. We further found that even imatinib resistant CML cell line (K562/G01) and CML primary cells exhibited high sensitivity to NC, which showed potential possibility to overcome imatinib resistance. Taken together, our results clearly suggested that NC promoted erythroid differentiation and apoptosis through c-Myc-miRNAs regulatory axis, providing potential possibility to overcome imatinib resistance. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia (T-ALL) is a serious hematologic malignancy and glucocorticoid resistance is the main recurrent cause for a high relapsed and death rate. Here, we proposed an effective therapeutic regimen of combining gamma-secretase inhibitors (GSIs) with dexamethasone (DEX) to overcome glucocorticoid resistance. Moreover, the bone marrow targeting DT7 peptide-modified lecithin nanoparticles co-loaded with DEX and GSI (TLnp/D&G) were developed to enhance T-ALL cells recognition and endocytosis. In vitro cytotoxicity studies showed that TLnp/D&G significantly inhibited cell survival and promoted apoptosis of T-ALL cells. Mechanically, we found that GSIs promoted DEX-induced cell apoptosis by two main synergetic mechanisms: 1) GSIs significantly upregulated glucocorticoid receptor (GR) expression in T-ALL and restored the glucocorticoid-induced pro-apoptotic response. 2) Both DEX and GSI synergistically inhibited BCL2 and suppressed the survival of T-ALL cells. Furthermore, in vivo studies demonstrated that TLnp/D&G showed high bone marrow accumulation and better antileukemic efficacy both in leukemia bearing models and in systemic Notch1-induced T-ALL models, with excellent biosafety and reduced gastrointestinal toxicity. Overall, our study provides new strategies for the treatment of T-ALL and promising bone marrow targeting systems with high transformation potential. [ABSTRACT FROM AUTHOR]

Highlights: [•] We construct a novel chronic myeloid leukemia polyepitope dentritic cell (DC) vaccine (DC-BCR/ABL*WT1). [•] DC-BCR/ABL*WT1 is more specific to Chinese population. [•] DC-BCR/ABL*WT1 demonstrates strong immune response to BCR/ABL(+) patients. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: T helper 17 (Th17), T cytotoxic 17 (Tc17) and regulatory T (Treg) cells are important factors in the pathogenesis of inflammatory and autoimmune diseases. However, information concerning the roles of these cells in antitumor immunity or endometrial tumorigenesis remains limited. In this study, we aimed to describe the distribution of Th17, Tc17 and Treg cells in endometrial carcinoma patients, and elucidate the probable role of these effector T cells. Methods: We assessed the expression of interleukin (IL)-17 and Foxp3 in the peripheral blood of endometrial carcinoma patients and healthy controls by flow cytometry to determine the relative numbers of Th17, Tc17 and Treg cells. Th17 cells and Tc17 cells were counted as percentages of the total number of CD3+ T cells; Treg cells were counted as a percentage of the total number of CD4+ T cells. We also evaluated Th17 and Tc17 cells in tumor tissue by immunohistochemical staining. IL-17 and IL-10, dominant products of these three cell types, were detected by using enzyme-linked immunosorbent assays. Results: The frequencies of Th17, Tc17 and Treg cells, as well as the serum level of IL-10, were significantly elevated in endometrial carcinoma patients compared to healthy controls. The Th17/Tc17 and Th17/Treg ratios were also observed to change significantly. However, there was no significant difference on the IL-17 levels in the serum. Additionally, immunohistochemistry performed on tumor tissues indicated that the amounts of Th17 and Tc17 increased in the cancer patients. Conclusions: Our data suggests a probable involvement of Th17, Tc17 and Treg cells in the pathogenesis of endometrial carcinoma. Restoring the balance of these cells may help with the research and development of immunotherapies for endometrial carcinoma. [Copyright &y& Elsevier]

Background: The existence of Tc17 cells was recently shown in several types of infectious and autoimmune diseases, but their distribution and functions in uterine cervical cancer (UCC) have not been fully elucidated. Methods: The frequency of Tc17 cells in peripheral blood samples obtained from UCC patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls was determined by flow cytometry. Besides, the prevalence of Tc17 cells and their relationships to Th17 cells and Foxp3-expressing T cells as well as microvessels in tissue samples of the patients were assessed by immunohistochemistry staining. Results: Compared to controls, patients with UCC or CIN had a higher proportion of Tc17 cells in both peripheral blood and cervical tissues, but the level of Tc17 cells in UCC tissues was significantly higher than that in CIN tissues. Besides, the increased level of Tc17 in UCC patients was associated with the status of pelvic lymph node metastases and increased microvessel density. Finally, significant correlations of infiltration between Tc17 cells and Th17 cells or Foxp3-expressing T cells were observed in UCC and CIN tissues. Conclusions: This study indicates that Tc17 cell infiltration in cervical cancers is associated with cancer progression accompanied by increased infiltrations of Th17 cells and regulatory T cells as well as promoted tumor vasculogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Immune regulation is important for the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Th22 cells are recently-identified CD4+ T cells that implicated in the pathogenesis of many hematological diseases, such as AML. However, the role of Th22 cells in the pathophysiology of T-ALL remains unclear. We examined the Th22, Th17 and Th1 cell frequencies in peripheral blood of T-ALL patients. Methods: We studied 24 newly-diagnosed (ND), 17 morphologic complete remission (CR) T-ALL patients and 30 healthy controls. Th subsets were examined by flow cytometry. Plasma IL-22 and IL-17 concentrations were measured by ELISA. Transcription factor RORC, T-bet and AHR mRNA expressions were examined by RT-PCR. Results: Th22, Th17 frequencies, plasma IL-22 concentration and AHR expression were significantly increased in ND or CR T-ALL patients compared with controls. Moreover, Th22 showed positive correlation with Th17 or Th1 cells in T-ALL patients. However, a significant decrease of IL-17 concentration, Th1 frequency and T-bet expression was found in ND or CR ALL patients compared with controls. Furthermore, Th17 cells showed positive correlation but Th1 cells showed negative correlation with white blood cell counts. Conclusion: The profile of Th subsets was distinct for T-ALL patients and showed some correlations with clinical index, which suggest that these Th subsets may be implicated in the pathogenesis of T-ALL and be reasonable targets for therapeutic intervention. [Copyright &y& Elsevier]