myeloid

摘要： Pathogenesis of chronic myeloid leukemia(CML)has mostly been studied with regard to the oncogenic role of BCR/ABL fusion,however,recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored.Given the involvement of cyclin-dependent kinases(CDKs)in the pathogenesis of CML,the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells.Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27.The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity,suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor,at least partly,through a c-Mycdependent mechanism.To the best of our knowledge,to date,no study has addressed the effect of autophagy on CML cell response to AT7519,and,herein,we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562.Overall,we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.

摘要： Myeloid sarcoma occurs in 1% - 9% of patients with myelogenous leukemia. Spinal epidural myeloid sarcoma is particularly rare, and its treatment has not been established. A 27-year-old woman complained of pain on her left chest, back around the scapula, and neck. Magnetic resonance imaging (MRI) showed a thoracic epidural tumor. One week after her visit, she developed motor weakness of her lower extremities and dysuria, and she was diagnosed with acute myelogenous leukemia (AML) on peripheral blood analysis. The epidural tumor was strongly suspected to be myeloid sarcoma. The paralysis of the lower extremities and bladder dysfunction were not progressive, and chemotherapy and local radiation therapy to the spine were performed. Improvement of paralysis and complete reduction of tumor volume were achieved by the combination of local low-dose radiation therapy and chemotherapy.

摘要： Bone marrow microenvironment (BMM) is the main sanctuary of leukemic stem cells (LSCs) and protects these cells against conventional therapies. However, it may open up an opportunity to target LSCs by breaking the close connection between LSCs and the BMM. The elimination of LSCs is of high importance, since they follow cancer stem cell theory as a part of this population. Based on cancer stem cell theory, a cell with stem cell-like features stands at the apex of the hierarchy and produces a heterogeneous population and governs the disease. Secretion of cytokines, chemokines, and extracellular vesicles, whether through autocrine or paracrine mechanisms by activation of downstream signaling pathways in LSCs, favors their persistence and makes the BMM less hospitable for normal stem cells. While all details about the interactions of the BMM and LSCs remain to be elucidated, some clinical trials have been designed to limit these reciprocal interactions to cure leukemia more effectively. In this review, we focus on chronic myeloid leukemia and acute myeloid leukemia LSCs and their milieu in the bone marrow, how to segregate them from the normal compartment, and finally the possible ways to eliminate these cells.

摘要： Mutations in the Sfpi1 gene are essential for the development of radia-tion-induced acute myeloid leukemia. In this study, we investigated long-term interaction among immature hematopoietic cell number, intra-cellular reactive oxygen species contents, and oxidative DNA damage fre-quency after irradiation. Lin-/Sca-1+ cells were isolated from C3H/HeN mice on days 1 - 400 after 0 - 3 Gy total body irradiation. On days 1 - 7, the number of surviving cells decreased and reached a minimum;however, the number of cells gradually recovered until day 200. Intracellular reactive oxygen species contents significantly increased from day 1 to day 30. In addition, the frequency of oxidative DNA damage tended to increase from day 1 and day 30, and that at day 30 was significantly increased in the 3 Gy group compared with that in the control group. In contrast, decreased cell number, increased intracellular reactive oxygen species content, and decreased oxidative DNA damage frequency were observed on day 400. These results suggested that oxidative DNA damage was involved in intracellular reactive oxygen species generation induced by cell proliferation to compensate for cell death after irradiation.

摘要： While chemotherapy remains to be one of the main using approaches in the clinical treatment of acute myeloid leukemia (AML), multidrug resistance (MDR) is considered the major obstacle that limits the therapeutic efficacy. Nowadays, Herbal therapy as an adjuvant therapy has been used for many health problems. Ginger (Zingiber officinale) is considering one of the promising herbal spices showing high therapeutic and preventive effects against many disorders specially cancer. In the current work, we focused on the role of ginger crude extract in fighting drug resistant AML. MTT assay showed a significant decrease in cell viability and clear cytotoxic effect on HL60/ADR and HL60 cell under the high concentrations (100 and 1000 μg/Ml) of ginger extract. The flow cytometry results showed a significant apoptotic cell death by ginger in HL60 and ADR/Hl60 and also confirmed by immunostaining of nucleus by DAPI which showed apoptotic nuclei. Our data clearly declared that the high concentration of ginger extract is promising anticancer drug by induction of apoptotic cell death in HL60/ADR cells especially in drug resistant AML.

摘要： Background: There are very few publications on synchronous presentation of dual malignancies in the literature. Occurrence of second malignancy in a patient with a known malignant tumor is not uncommon, though synchronous primary malignancies are unusual. Case Presentation: A 77-year-old man was diagnosed elsewhere as squamous cell carcinoma of lung came to our oncology department for further management. He underwent bone marrow evaluation with the suspicious of metastasis in view of pancytopenia. On bone marrow evaluation, found to have prominence of blasts more than 20%, which were CD34 positive and CD117 positive and. Conclusion: Here we describe an unusual rare combination of synchronous presentation of acute myeloid leukemia and squamous cell carcinoma of lung.

摘要： BACKGROUND Genomic profiling of tumors has contributed to the understanding of colorectal cancer(CRC), facilitating diagnosis, prognosis and selection of treatments,including targeted regimens. A report suggested that a 19-gene-based risk classifier(TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging.AIM To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology.METHODS A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival(PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction(qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry(IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte in vitro.RESULTS In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen(P = 0.041).In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7(SLAMF7) and triggering receptor expressed on myeloid cells 1(TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR,and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD73 were significantly lower at day 5 of co-culture than at day 0.CONCLUSION The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.

摘要： Background and Objectives: Chronic myeloid leukemia (CML) accounts for approximately 15% of newly diagnosed cases of leukemia in adults. In this study, the efficacy of nilotinib at 400 mg BID is compared with imatinib at 400 mg BID in CML patients with suboptimal molecular response after at least 12 months of daily dose 400 mg of imatinib therapy. Patients and Methods: This study included a total number of 50 patients, divided into two groups (25 patients each). The first group (Group I): Patients received imatinib at 400 mg BID, second group (Group II): Patients had a suboptimal molecular response to imatinib and received nilotinib at 400 mg BID in early chronic phase. During the two years period of data collection, the primary end included median survival. The secondary end included response rate, type of response, duration of response and progression free survival. Also side effects were recorded. Patients were followed up every month by complete and differential blood counts, liver function test, renal function test and (PCR) every three months for two year. Results: Nilotinib group had significantly higher frequency of major molecular response (MMR) where 23 (92%) patients achieved it while only 16 (64%) patients in Imatinib group achieved MMR (P = 0.01). Nilotinib had better toxicities profile than Imatinib. Conclusion: Both Nilotinib and high dose Imatinib achieved response in CML patients with suboptimal response with rapid and deeper molecular response, better survival outcomes and less side effects in nilotinib.

摘要： OBJECTIVE To investigate the role of triggering receptor expressed on myeloid cells-2(TREM2) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) model mice with Parkinson disease(PD) and explore the underlying signaling pathway that mediate TREM2 function.METHODS TREM2 adenovirus were stereologically injected into the right striatum.Two weeks later,MPTP was intraperitoneally injected to produce the acute MPTP mouse model of PD.Mice were sacrificed at different time points following MPTP for biochemical or histological study.RESULTS Overexpression of TREM2 remarkably reduced MPTP-induced neuropathology including the dopaminergic neurodegeneration and neuroinflammation in vivo.Further study revealed that TREM2 may inhibit neuroinflammation by negatively regulating the TRAF6/TLR4-mediated activation of the MAPK and NF-κB signaling pathways.CONCLUSION TREM2 may have important neuroprotective effects against PD by critical y modulating neuroinflammatory responses.

摘要： Acute myeloid leukemia(AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells(LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to in-troduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models.