Ratio of hemoglobin to mean corpuscular volume: A new index for discriminating between iron deficiency anemia and thalassemia trait.

BACKGROUND: Iron deficiency anemia (IDA) and thalassemia trait (TT) are the most common microcytic and hypochromic anemias. Differentiation between mild TT and early IDA is still a clinical challenge. AIM: To develop and validate a new index for discriminating between IDA and TT. METHODS: Blood count data from 126 patients, consisting of 43 TT patients and 83 IDA patients, was retrospectively analyzed to develop a new index formula. This formula was further validated in another 61 patients, consisting of 48 TT patients and 13 IDA patients. RESULTS: The new index is the ratio of hemoglobin to mean corpuscular volume. Its sensitivity, specificity, accuracy, Youden's Index, area under the receiver operating characteristic curve, and Kappa coefficient in discriminating between IDA and TT were 93.5%, 78.4%, 83.3%, 0.72, 0.97, and 0.65, respectively. CONCLUSION: This new index has good diagnostic performance in discriminating between mild TT and early IDA. It requires only two results of complete blood count, which can be a very desirable feature in under-resourced scenarios.

The novel HLA-DPB1*02:02:07 allele identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*02:02:07 differs from HLA-DPB1*02:02:01:01 by one nucleotide in exon 2.

CAPN1 is a novel biomaker of patients with AML based on comprehensive analysis.

Acute myeloid leukemia (AML) is a common hematologic malignancy in adults. Recent studies investigating the potential pathogenesis of AML have significantly advanced our understanding of this disease. While cytogenetics and molecular abnormalities are crucial for confirming chemotherapy response and long-term outcomes, there are additional potential therapeutic targets and prognostic factors. The CAPN1 gene, which encodes a large subunit of the ubiquitous enzyme calpain, has not been extensively studied in hematological diseases. In this study, we used data from the TCGA public database to perform a bioinformatic analysis and found that CAPN1 is differentially expressed in multiple cancers and is associated with an unfavorable prognosis in AML. We employed R software and websites such as David and STRING to conduct differential analysis, GO and KEGG analysis, and explore the correlation between CAPN1 and physiological processes and key pathways. Our findings suggest that CAPN1 is significantly associated with the structure of the extracellular matrix and receptor-ligand interactions, indicating its potential role in disease progression. Additionally, we used CYBERSORT and ssGSEA to analyze the immune environment of CAPN1 and found that it is associated with most immune components, particularly CD56 cells and neutrophils. In conclusion, CAPN1 is a key prognostic gene in AML that is significantly correlated with disease progression, clinical features, and immune invasion.

A novel silicone derivative of natural osalmid (DCZ0858) exerts anti-multiple myeloma activity by promoting cell apoptosis and inhibiting cell cycle and mTOR signaling.

Multiple myeloma (MM) is a malignant disease characterized by abnormal proliferation of clonal plasma cells. Based on the organic drug osalmid, the novel small molecule compound DCZ0858 was designed and synthesized for treating MM. DCZ0858 inhibited the proliferation and activity of MM cells and reduced colony formation. It also promoted the apoptosis of primary cells from patients with MM and cultured MM cell lines but had little effect on peripheral blood mononuclear cells in healthy people. Simultaneously, DCZ0858 activated caspase family proteins, blocked MM cells in G0/G1 phase, and reduced the expression of related cyclins CDK4/6 and CyclinD1. Moreover, DCZ0858 overcame the protective effect of the bone marrow microenvironment and effectively inhibited the activity of mTORC1 and mTORC2. Further, xenograft model experiments in mice showed that DCZ0858 significantly inhibited the proliferation and growth of tumors, with low drug toxicity. These results indicate that DCZ0858 has marked anti-MM activity and little effect on normal cells and tissues, making it a new candidate clinical drug for the treatment of MM.

Quercetin inhibits the proliferation of multiple myeloma cells by upregulating PTPRR expression.

Multiple myeloma (MM) is an incurable disease characterized by malignant plasma cell clonal expansion in the bone marrow; therefore, inhibiting the proliferation of plasma cells is an important approach to overcome the progression of MM. Quercetin (Que) is a promising flavonoid with broad-spectrum anti-tumor activity against various cancers, including MM; however, the underlying mechanism is not yet understood. The present study aimed to reveal the gene expression profile of Que-treated MM cells and clarify its potential mechanism. The 30% inhibitory concentration (IC30) of Que against MM cells was calculated, and the proliferation rate was significantly reduced after Que treatment. Next, 495 dysregulated genes were identified via RNA sequencing in Que-treated MM cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses indicated that the dysregulated genes were enriched in various apoptosis-related GO terms and amino acid metabolism-related pathways. qPCR validation showed that protein tyrosine phosphatase receptor-type R (PTPRR) had the highest verified log2 FC (abs) among the top 15 dysregulated genes. Overexpression of PTPRR increased the sensitivity of MM cells against Que, significantly inhibiting their proliferation and colony formation ability; silencing of PTPRR showed the opposite results. Furthermore, bioinformatics analyses and PPI network construction of PTPRR indicated that dephosphorylation of ERK might be the potential pathway for the PTPRR-induced inhibition of MM cell proliferation. In summary, our study identified the gene expression profile in Que-treated MM cells and demonstrated that the upregulation of PTPRR was one of the important mechanisms for the Que-induced inhibition of MM cell proliferation.

Establishment of epidemic early warning index system and optimization of infectious disease model: Analysis on monitoring data of public health emergencies.

The ability to mitigate the damages caused by emergencies is an important symbol of the modernization of an emergency capability. When responding to emergencies, government agencies and decision makers need more information sources to estimate the possible evolution of the disaster in a more efficient manner. In this paper, an optimization model for predicting the dynamic evolution of COVID-19 is presented by combining the propagation algorithm of system dynamics with the warning indicators. By adding new parameters and taking the country as the research object, the epidemic situation in countries such as China, Japan, Korea, the United States and the United Kingdom was simulated and predicted, the impact of prevention and control measures such as effective contact coefficient on the epidemic situation was analyzed, and the effective contact coefficient of the country was analyzed. The paper strives to provide early warning of emergencies scientifically and effectively through the combination of these two technologies, and put forward feasible references for the implementation of various countermeasures. Judging from the conclusion, this study reaffirmed the importance of responding quickly to public health emergencies and formulating prevention and control policies to reduce population exposure and prevent the spread of the pandemic.

A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway.

BACKGROUND: Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. METHODS: We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. RESULTS: The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. CONCLUSION: The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.

A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe.

BACKGROUND: DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown. METHODS: We generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models. RESULTS: DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G2/M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933. CONCLUSIONS: Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.

Dihydrocelastrol exerts potent antitumor activity in mantle cell lymphoma cells via dual inhibition of mTORC1 and mTORC2.

Mantle cell lymphoma (MCL) is a distinct and highly aggressive subtype of B-cell non-Hodgkin lymphoma. Dihydrocelastrol (DHCE) is a dihydro-analog of celastrol, which is isolated from the traditional Chinese medicinal plant Tripterygium wilfordii. The present study aimed to investigate the effects of DHCE treatment on MCL cells, and to determine the mechanism underlying its potent antitumor activity in vitro and in vivo using the Cell Counting kit-8 assay, clonogenic assay, apoptosis assay, cell cycle analysis, immunofluorescence staining, western blotting and tumor xenograft models. The results demonstrated that DHCE treatment exerted minimal cytotoxic effects on normal cells, but markedly suppressed MCL cell proliferation by inducing G0/G1 phase cell cycle arrest, and inhibited MCL cell viability by stimulating apoptosis via extrinsic and intrinsic pathways. In addition, the results revealed that DHCE suppressed cell growth and proliferation by inhibiting mammalian target of rapamycin complex (mTORC)1-mediated phosphorylation of ribosomal protein S6 kinase and eukaryotic initiation factor 4E binding protein. Simultaneously, DHCE induced apoptosis and inhibited cell survival by suppressing mTORC2-mediated phosphorylation of protein kinase B and nuclear factor-κB activity. In addition to in vitro findings, DHCE treatment reduced the MCL tumor burden in a xenograft mouse model, without indications of toxicity. Furthermore, combined treatment with DHCE and bortezomib, a proteasome inhibitor, induced a synergistic cytotoxic effect on MCL cells. These findings indicated that DHCE may have the potential to serve as a novel therapeutic agent for the treatment of MCL through dually inhibiting mTORC1 and mTORC2.

DCZ3301, a novel aryl-guanidino inhibitor, induces cell apoptosis and cell cycle arrest via suppressing the PI3K/AKT pathway in T-cell leukemia/lymphoma.

DCZ3301, a novel aryl-guanidino compound, was previously found to have potent anti-tumor activity in myeloma and B-cell lymphoma. In the present study, we investigated the effects of DCZ3301 on T-cell leukemia/lymphoma cells both in vitro and in vivo via cell proliferation, cell cycle analysis, apoptosis assay, mitochondrial membrane potential (MMP) assay, western blot analysis and tumor xenograft models. We found that DCZ3301 inhibited the viability of T-cell leukemia/lymphoma cells in a dose- and time-dependent manner. DCZ3301-induced G2/M cell cycle arrest, associated with downregulation of CDK1, cyclin B1, and cdc25C. DCZ3301 also induced cell apoptosis by decreasing MMP in T-cell leukemia/lymphoma cells, but had no significant pro-apoptotic effect on normal peripheral blood mononuclear cells (PBMCs). In addition, DCZ3301-induced apoptosis may be mediated by the caspase-dependent pathway and suppressing the phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we showed that DCZ3301 treatment effectively inhibited tumor growth, with no significant side effects, in xenograft mouse models. In conclusion, these results suggest that DCZ3301 may be regarded as a new therapeutic strategy for T-cell leukemia/lymphoma patients.

Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma.

We synthesized a novel aryl-guanidino compound, DCZ3301, and found that it has potent cytotoxicity against multiple human cancer cell lines. The anticancer activity was most potent against multiple myeloma (MM). DCZ3301 induced cytotoxicity in MM cell lines, as well as patient myeloma cells, in part by decreasing mitochondrial membrane potential to induce apoptosis. In contrast, DCZ3301 had no cytotoxic effect on normal cells. DCZ3301 also inhibited cell cycling and caused a G2/M accumulation that corresponded with downregulation of Cdc25C, CDK1, and Cyclin B1. DCZ3301 retained its activity against MM cells in the presence of exogenous cytokines (IL-6 or VEGF) or bone marrow stromal cells (BMSCs) and reduced activity of multiple signaling pathways (STAT3, NFκB, AKT, ERK1/2) in MM but not normal cells. The STAT3 pathway played an important role in modulating DCZ3301-mediated cytotoxicity. Knockdown of STAT3 using siRNA in MM cells enhanced DCZ3301-induced cytotoxicity, whereas overexpression of STAT3 in MM cells partially protected them from apoptosis. In addition, DCZ3301 inhibited VEGF and IL-6 secretion in a dose-dependent fashion in a co-culture of MM cells and BMSCs. Combining DCZ3301 with bortezomib induced synergistic cytotoxicity in MM cell lines and primary MM cells. Finally, in vivo efficacy of DCZ3301 was confirmed in an MM xenograft mouse model. Together, these results provide a rationale for translation of this small-molecule inhibitor, either alone or in combination, to the clinic against MM.

DCZ3301, a novel cytotoxic agent, inhibits proliferation in diffuse large B-cell lymphoma via the STAT3 pathway.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults, characterized by a rapidly increasing painless mass. A novel compound, DCZ3301, was synthesized that exerted direct cytotoxicity against DLBCL cell lines. The effects of DCZ3301 on DLBCL cells in vitro and in vivo and the associated mechanisms were investigated. DCZ3301 inhibited the viability of DLBCL cell lines, even in the presence of protumorigenesis cytokines. Additionally, the compound induced apoptosis and cell cycle arrest at the G2/M phase by reducing mitochondrial membrane potential. DCZ3301 exerted an antitumor effect through modulation of Akt, extracellular signal-regulated kinases 1/2 (ERK1/2) and janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. Furthermore, DCZ3301 downregulates STAT3 phosphorylation by inhibiting Lck/Yes-related novel protein tyrosine kinase (Lyn) activation in DLBCL. A synergistic cytotoxic effect on DLBCL cells was observed upon combination of DCZ3301 with panobinostat. In vivo, intraperitoneal injection of xenograft mice with DCZ3301 resulted in reduced tumor volume. Our preliminary results collectively support the utility of the small-molecule inhibitor DCZ3301 as an effective novel therapeutic option for DLBCL that requires further clinical evaluation.

TRIP13 impairs mitotic checkpoint surveillance and is associated with poor prognosis in multiple myeloma.

AAA-ATPase TRIP13 is one of the chromosome instability gene recently established in multiple myeloma (MM), the second most common and incurable hematological malignancy. However, the specific function of TRIP13 in MM is largely unknown. Using sequential gene expression profiling, we demonstrated that high TRIP13 expression levels were positively correlated with progression, disease relapse, and poor prognosis in MM patients. Overexpressing human TRIP13 in myeloma cells prompted cell growth and drug resistance, and overexpressing murine TRIP13, which shares 93% sequence identity with human TRIP13, led to colony formation of NIH/3T3 fibroblasts in vitro and tumor formation in vivo. Meanwhile, the knockdown of TRIP13 inhibited myeloma cell growth, induced cell apoptosis, and reduced tumor burden in xenograft MM mice. Mechanistically, we observed that the overexpression of TRIP13 abrogated the spindle checkpoint and induced proteasome-mediated degradation of MAD2 primarily through the Akt pathway. Thus, our results demonstrate that TRIP13 may serve as a biomarker for MM disease development and prognosis, making it a potential target for future therapies.

Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma.

We previously showed that the proteasome inhibitor carfilzomib and the histone deacetylase inhibitor (HDACI) vorinostat cooperated to induce cell apoptosis in one T-cell leukemia cell line in vitro, implying the possibility of the combination treatment of carfilzomib and vorinostat as a potential therapeutic strategy in human T-cell leukemia/lymphoma. Here we report that combination treatment of carfilzomib and vorinostat enhanced cell apoptosis and induced a marked increase in G2-M arrest, reactive oxygen species (ROS) generation, and activated the members of mitogen-activated protein kinases (MAPK) family, including the stress-activated kinases JNK, p38MAPK, and ERK1/2. Carfilzomib/vorinostat-mediated apoptosis was blocked by the ROS scavenger N-acetylcysteine (NAC). The JNK inhibitor SP600125 and the p38MAPK inhibitor SB203580 but not the MEK1/2 inhibitor U0126 significantly attenuated carfilzomib/vorinostat-induced apoptosis, suggesting that p38MAPK and JNK activation contribute to carfilzomib and vorinostat-induced apoptosis. This was further confirmed via short hairpin (shRNA) RNA knockdown of p38MAPK and JNK. Interestingly, the ROS scavenger NAC attenuated carfilzomib/vorinostat-mediated activation of p38MAPK and JNK. However, p38MAPK shRNA but not JNK shRNA diminished carfilzomib/vorinostat-mediated ROS generation. In contrast, overexpression of p38MAPK significantly increased carfilzomib/vorinostat-mediated ROS generation, suggesting that an amplification loop exists between ROS and p38MAPK pathway. Combination treatment of carfilzomib and vorinostat enhanced their individual antitumor activity in both a human xenograft model as well as human primary T-cell leukemia/lymphoma cells. These data suggest the potential clinical benefit and underlying molecular mechanism of combining carfilzomib with vorinostat in the treatment of human T-cell leukemia/lymphoma.

Overexpression of RPS27a contributes to enhanced chemoresistance of CML cells to imatinib by the transactivated STAT3.

STAT3 plays a pivotal role in the hematopoietic system, which constitutively activated by BCR-ABL via JAK and Erk/MAP-kinase pathways. Phospho-STAT3 was overexpressed in imatinib-resistant CML patients as relative to imatinib responsive ones. By activation of the STAT3 pathway, BCR-ABL can promote cell cycling, and inhibit differentiation and apoptosis. Ribosomal protein S27a (RPS27a) performs extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. RPS27a can promote proliferation, regulate cell cycle progression and inhibit apoptosis of leukemia cells. However, the relationship between STAT3 and RPS27a has not been reported. In this study, we detected a significantly increased expression of STAT3 and RPS27a in bone marrow samples from CML-AP/BP patients compared with those from CML-CP. In addition, we also demonstrated that it was a positive correlation between the level of STAT3 and that of RPS27a. Imatinib-resistant K562/G01 cells expressed significantly higher levels of STAT3 and RPS27a compared with those of K562 cells. RPS27a could be transactivated by p-STAT3 through the specific p-STAT3-binding site located nt -633 to -625 and -486 to -478 of the RPS27a gene promoter in a dose-dependent manner. The transactivated RPS27a could decrease the percentage of apoptotic CML cells induced by imatinib. And the effect of STAT3 overexpression could be counteracted by the p-STAT3 inhibitor WP1066 or RPS27a knockdown. These results suggest that drugs targeting STAT3/p-STAT3/RPS27a combining with TKI might represent a novel therapy strategy in patients with TKI-resistant CML.

Thalidomide treatment for patients with previously untreated multiple myeloma: a meta-analysis of randomized controlled trials.

The efficacy and safety of thalidomide as an initial treatment in myeloma patients who were unsuitable for autologous stem cell transplantation (ASCT), as induction treatment prior to ASCT, or as a maintenance treatment was unclear. The purpose of this study was to assess the benefits and risks of thalidomide for previously untreated myeloma patients. MEDLINE, EMBASE, and Cochrane Library were searched for randomized controlled trials (RCTs) of thalidomide used in either induction or maintenance therapy for previously untreated myeloma patients. Twenty-two RCTs enrolling 9098 patients were identified, including 15 RCTs of induction thalidomide, 6 RCTs of maintenance thalidomide, and 1 RCT of induction and maintenance thalidomide. Induction thalidomide improved overall response rate (ORR) (risk ratio (RR) 1.54, 95 % confidence interval (CI) 1.30-1.83), complete response rate (CRR) (RR 3.03, 95 % CI 1.91-4.80), progression-free survival (PFS) (hazard ratio (HR) 0.65, 95 % CI 0.56-0.76), and overall survival (OS) (HR 0.78, 95 % CI 0.67-0.91) in patients who were not allowed to receive ASCT. Induction thalidomide improved pre-ASCT ORR (RR 1.20, 95 % CI 1.11-1.30), pre-ASCT and post-ASCT CRR (RR 1.47, 95 % CI 1.12-1.93 and RR 1.23, 95 % CI 1.00-1.50, respectively), and PFS (HR 0.73, 95 % CI 0.59-0.91) in patients who were allowed to receive ASCT, but it did not improve post-ASCT ORR (RR 1.04, 95 % CI 0.99-1.09) and OS (HR 0.91, 95 % CI 0.79-1.05). Improved PFS and prolonged OS were observed (HR 0.61, 95 % CI 0.53-0.70 and HR 0.77, 95 % CI 0.62-0.95, respectively) when thalidomide was added to maintenance therapy. More patients experienced venous thromboembolism (VTE) of grade 3/4 when thalidomide was added to induction or maintenance therapy (HR 2.15, 95 % CI 1.58-2.92 and RR 1.96, 95 % CI 1.13-3.40, respectively). Induction thalidomide still increased the risk of VTE (RR 1.53, 95 % CI 1.12-2.08) after VTE prophylaxis was used. Induction thalidomide effectively improved CRR, ORR, and PFS (except post-ASCT ORR). Notably, induction thalidomide improved OS in patients who were not allowed to receive ASCT but not in patients who were allowed to receive ASCT. The addition of thalidomide to maintenance therapy improved both PFS and OS. However, thalidomide led to a greater risk of VTE with grade 3/4. This risk did not disappear after VTE prophylaxis was used in induction therapy with thalidomide.

[Silence potentiates chemosensitivity of K562 cells to SAHA].

Ribosomal protein S27a (RPS27a) can perform extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. The RPS27a gene has been reported to be over-expressed in breast fibroadenomas, colorectal and renal cancers, advanced-phase chronic myeloid leukemia (CML) and acute leukemia (AL) patients. This study was purposed to explore the function of RPS27a in CML-erythroleukemia cell line K562 cells. RPS27a was silenced by short hairpin RNA (shRNA) in K562 cells. Furthermore, the proliferation changes of K562 cells was detected by MTT method after silencing the RPS27a with suberoylanilide hydroxamic acid (SAHA), then the IC50 of K562-sh1/sh2 and K562-scr cells to SAHA was measured. The results indicated that compared with K562-scr cells, the IC50 of K562-sh1/sh2 to SAHA at 24 h and 48 h decreased (P < 0.01); RPS27a silence significantly increased the percentage of apoptotic K562-sh1/sh2 cells after incubation with 1 µmol/L, 2 µmol/L and 5 µmol/L SAHA for 24 h and 48 h as compared with that of K562-scr cells (P < 0.01). K562-sh1, K562-sh2 and K562-scr cells after incubation with or without 2 µmol/L SAHA for 48 h presented apoptosis features: i. e. chromatin condensation, nucleic fragmentation and apoptotic body formation. It is concluded that RPS27a can inhibit the apoptosis of K562 cells and RPS27a silence can potentiate sensitivity of K562 cells to SAHA.

RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells.

Ribosomal protein S27a (RPS27a) could perform extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. The high expression level of RPS27a was reported in solid tumors, and we found that the expression level of RPS27a was up-regulated in advanced-phase chronic myeloid leukemia (CML) and acute leukemia (AL) patients. In this study, we explored the function of RPS27a in leukemia cells by using CML cell line K562 cells and its imatinib resistant cell line K562/G01 cells. It was observed that the expression level of RPS27a was high in K562 cells and even higher in K562/G01 cells. Further analysis revealed that RPS27a knockdown by shRNA in both K562 and K562G01 cells inhibited the cell viability, induced cell cycle arrest at S and G2/M phases and increased cell apoptosis induced by imatinib. Combination of shRNA with imatinib treatment could lead to more cleaved PARP and cleaved caspase-3 expression in RPS27a knockdown cells. Further, it was found that phospho-ERK(p-ERK) and BCL-2 were down-regulated and P21 up-regulated in RPS27a knockdown cells. In conclusion, RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells. It appears that drugs targeting RPS27a combining with tyrosine kinase inhibitor (TKI) might represent a novel therapy strategy in TKI resistant CML patients.

Icaritin induces AML cell apoptosis via the MAPK/ERK and PI3K/AKT signal pathways.

Icaritin, a hydrolytic product of icaritin, is isolated from the traditional Chinese medicinal herb epimedium. Icaritin inhibits the proliferation of several tumor cell lines, but its effect on acute myeloid leukemia (AML) and underlying mechanisms remain to be identified. In the present study, we demonstrated that icaritin inhibits the proliferation of human AML cell lines NB4, HL60, and U937, in a dose- and time-dependent manner. Importantly, icaritin showed anti-leukemia activity on bone marrow mononuclear cells from 15 newly diagnosed AML patients. Flow cytometry analyses indicated that icaritin induces AML cells apoptosis. Icaritin induced activation of caspase-9, -3, -7 and the cleavage of PARP as measured by Western blotting. Icaritin downregulates p-ERK and p-AKT and inhibits the expression of c-myc. These results suggest that icaritin is a promising candidate drug for the treatment of AML. The underlying mechanisms of icaritin anti-AML activity are associated with inhibition of the MAPK/ERK and PI3K/AKT signals and downregulation of c-myc.

[The immunocyte subsets and their clinical significance in the peripheral blood of 35 patients with immune thrombocytopenic purpura].

OBJECTIVE: To explore the clinical significance of immunocyte subsets before and after immunosuppressive therapy in the peripheral blood of patients with immune thrombocytopenic purpura (ITP). METHODS: The percentages of immunocyte subsets in the peripheral blood of 35 patients with ITP and 20 healthy controls were detected by flow cytometry, including CD(3)(+), CD(4)(+), CD(8)(+), CD(+)(56), CD(19)(+) lymphocytes and CD(4)(+)/CD(8)(+). RESULTS: The percentages of CD(3)(+) T lymphocyte (61.58 ± 6.45)%, CD(4)(+) T lymphocyte (28.38 ± 4.89)% and the ratio of CD(4)(+)/CD(8)(+) 0.99 ± 0.22 in patients with ITP were lower than those in healthy controls [(67.85 ± 4.68)%, (38.00 ± 3.37)%, 1.54 ± 0.13, all P < 0.05]. After immunosuppressive therapy, the percentages of CD(3)(+)T lymphocyte (69.41 ± 5.03)%, CD(4)(+)T lymphocyte (38.17 ± 3.18)% and the ratio of CD(4)(+)/CD(8)(+) 1.60 ± 0.15 recovered to control levels. The percentages of CD(8)(+)T lymphocyte (29.20 ± 4.50)% and CD(19)(+)B lymphocyte (17.74 ± 4.14)% were higher than those in healthy controls [(24.82 ± 2.93)% and (12.09 ± 3.51)%, all P < 0.05]. After the immunosuppressive therapy, the percentages of CD(8)(+)T lymphocyte (24.06 ± 3.02)% and CD(19)(+)B lymphocyte (10.90 ± 3.55)% recovered to control levels. There were no significant difference of the percentage of CD(56)(+) lymphocyte among ITP patients (15.80 ± 2.85)%, ITP patients after immunosuppressive therapy (15.16 ± 2.77)% and healthy controls (16.36 ± 2.75)%. CONCLUSION: The aberrant immunocyte subsets are involved in the pathogenesis of ITP, and detection of immunocyte subsets might be helpful for the diagnosis and determination of therapeutic outcome of ITP.