Damage Mechanism of CK2 and IKAROS in Philadelphia Like Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is characterized by immature and poorly differentiated B lymphocytes in large numbers in the blood. B cells are distinct from the cell types involved in their development (common lymphoid progenitor cells, pro-B cells, pre-B cells, and mature cells). The process of B cell maturation depends on precise communication within the cell: signals activate specific genes that are essential for proper development. Errors in this intricate signaling network can lead to issues with B cell function and contribute to disease. B-lineage acute lymphoid leukemias, malignancies of precursor-stage B lymphoid cells inhibit lymphoid differentiation, leading to abnormal cell proliferation and survival. The process of developing leukemia (leukemogenesis) can be triggered by an overproduction of both hematopoietic stem cells (the cells that form all blood cells) and the immature versions of white blood cells called lymphoblasts. Acute lymphoblastic leukemia (ALL) with the presence of the Philadelphia chromosome (ALL Ph) is classified as a high-risk manifestation of the disease, this chromosome is the product of the reciprocal translocation, whose product is a BCR-ABL fusion protein. It is a highly active tyrosine kinase that can transform hematopoietic cells into cytokine-independent. Hyperphosphorylation cascades inhibit the differentiating function of IKZF1 as a tumor suppressor gene which leads to an abnormal proliferation of B cells due to the presence of the Philadelphia chromosome;it inhibits the differentiating process, leukemogenesis involving immature B cells in the bloodstream can result from the uncontrolled growth and division of hematopoietic stem cells and immature lymphoblasts (the precursors to B cells).

Philadelphia chromosome-positive leukemia stem cells in acute lymphoblastic leukemia and tyrosine kinase inhibitor therapy

Leukemia stem cells(LSCs),which constitute a minority of the tumor bulk,are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal.The presence of LSCs has been demonstrated in acute lymphoblastic leukemia(ALL),of which ALL with Philadelphia chromosome-positive(Ph+).The use of imatinib,a tyrosine kinase inhibitor(TKI),as part of front-line treatment and in combination with cytotoxic agents,has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph+ ALL.New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations.An important recent addition to the arsenal against Ph+ leukemias in general was the development of novel TKIs,such as nilotinib and dasatinib.However,in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells.None of the TKIs in clinical use target the LSC.Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs.Allogeneic stem cell transplantation(SCT) remains the only curative treatment available for these patients.Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations.Hence,TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy.Better understanding the biology of Ph+ ALL will open new avenues for effective management.In this review,we highlight recent findings relating to the question of LSCs in Ph+ ALL.

The Philadelphia chromosome in leukemogenesis

The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.

Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs:A literature review

Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly―the presence of the Philadelphia chromosome.The advances in cytogenetic and molecular assays are of great importance to the diagnosis,prognosis,treatment,and monitoring of CML.The discovery of the breakpoint cluster region(BCR)-Abelson murine leukemia(ABL)1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein.Tyrosine kinase inhibitors(known as TKIs)are the standard therapy for CML and greatly increase the survival rates,despite adverse effects and the odds of residual disease after discontinuation of treatment.As therapeutic alternatives,the subsequent TKIs lead to faster and deeper molecular remissions;however,with the emergence of resistance to these drugs,immunotherapy appears as an alternative,which may have a cure potential in these patients.Against this background,this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.

Efficacy of Nilotinib versus Imatinib in Philadelphia Positive Patients with Chronic Myeloid Leukemia in Early Chronic Phase Who Have a Warning Molecular Response to Imatinib

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.

China Tourism Goes to Philadelphia Travel & Adventure Show

The Sixth Philadelphia Travel & Adventure Show took place at Pennsylvania Convention Center in Philadelphia, the USA, from March 9 to 1 0. China National Tourist Office, New York, used pandas and Peking Opera symbolic meaning as the key visual style,"Beautiful China" national tourism brand as the theme to present "China Beyond Imaginations , in Philadelphia, delivered news about tourism in China and caught attention of lots of participants.

NCPA May Festival 2019 Closing Concert: The Philadelphia Orchestra

Date: May 17-18, 2019 Venue: National Center for the Performing Arts Prices: RMB 280, 480, 600, 780, 900, 1080, 1280 The Philadelphia Orchestra is one of the preeminent orchestras in the world, renowned for its distinctive sound, desired for its keen ability to capture the hearts and imaginations of audiences, and admired for a legacy of imagination and innovation on and off the concert stage.

Unusual cytogenetic abnormalities associated with Philadelphia chromosome

Cytogenetic abnormalities are the hallmark of leukemias. We report here two cases of unusual cytogenetic abnormalities associated with Philadelphia chromosome, one with mixed phenotypic acute leukemia showing monosomy 7 and t(9;22)(q34;q11.2) and the other with chronic myeloid leukemia and additional translocation involving chromosomes 10 and 13. Both patients achieved complete remission following imatinib based treatment.

The Philadelphia Orchestra’s Triumphal Return to China

MUSIC is an internationalart,enabling people allover the world to com-municate with and understand eachother.The first cultural troupe sentby the American government to visitChina 20 years ago was the Philadel-phia Orchestra.Their perform-ances contributed greatly to Sino-American cultural exchange andpromoted friendship between theAmerican and Chinese people.InMay 1993 the Philadelphia Orches-tra came to China again as theAmerican people’s cultural

Administration of imatinib in the first 90 days after allogeneic hematopoietic cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Background Relapse happens frequently after allogeneic hematopoietic cell transplantation （alIo-HCT） in the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph^＋ ALL）. Detection of the minimal residual disease （MRD） before and after alIo-HCT is associated with higher relapse rate. Early administration of imatinib after alIo-HCT may prevent recurrent Ph^＋ ALL. The aim of this study was to evaluate the safety and efficacy of imatinib in preventing hematological relapse when imatinib was administrated in the first 90 days after alIo-HCT. Methods Patients with Ph^＋ ALL that underwent alIo-HCT were enrolled in a prospective study. A TaqMan-based real-time quantitative polymerase chain reaction （RQ-PCR） technique was used to detect the MRD （bcr-abl transcript levels）. Imatinib therapy was initiated prior to 90 days after alIo-HCT if the patient＇s absolute neutrophil count （ANC） was above 1.0×10^9/L （without granulocyte colony-stimulating factor （G-CSF） administration） and the platelet count was greater than 50.0×10^9/L, or if the bcr-abl transcript levels were elevated in two consecutive tests, or if the bcr-abl transcript levels were 〉10.2 after the initial engraftment. The initial daily dose of imatinib was 400 mg/d for adults and 260 mg/m^2 for children （younger than 17 years）. Imatinib was administered for at least I month and the bcr-abl TaqMan results were negative for 3 consecutive tests, or complete molecular remission （CR^mol） was sustained for at least 3 months. Results From May 2005 to October 2008, 29 patients were enrolled in this study, of whom, 19 patients were male and 10 were female. The median age of the enrolled patients was 33 years （range 6-50 years）. Imatinib therapy was started at a median time of 60 days （range 20-122 days） post HCT （only one patient started Imatinib therapy at 122nd day after HCT）. Twenty-five adult patients could tolerate a dose of 300-400 mg/d of imatinib, and three children tolerated a dose of 260 mg·m^2·d^-1. Sixty-eight percent of the patients experienced various adverse events during imatinib therapy, hematological toxicity being the most common adverse event. The median duration of imatinib treatment was 3 months （range 7 days-18 months）. During the median follow-up of 24 months （range 16.0-54.5 months）, 3 out of 27 patients that could be evaluated for efficacy died from relapse. The 3-year probability of relapse for the evaluated patients was （11.34-0.61）%. The relapse rates among the subgroup of positive and negative bcr-abl patients before allo-HCT were 13.6% and 0, respectively （P 〉0.05）. The relapse rates among the subgroups of bcr-abl positive and negative patients after alIo-HCT were 20.0% and 5.9%, respectively （P 〉0.05）. The relapse rates among the patients in first complete remission （CR1） and second complete remission/non-remission （CR2/NR） before transplantation were 0 and 31.4%, respectively （P 〈0.05）. The 3-year probability of overall survival （OS） and disease-free survival （DFS） for the all enrolled patients were （75.3±8.1）%. The 3-year probabilities for OS and DFS among the subgroup of patients in CR1 and CR2/NR before transplantation were （87.7±8.2）% and （54.6±15.0）%, respectively （P 〈0.05）. Conclusions Administration of irnatinib at a dose of 300-400 mg/d in the first 90 days after allo-HCT is feasible in Ph^＋ ALL patients. With this treatment, bcr-abl positive patients before or after transplantation do not have a higher relapse rate after allo-HCT compared with the bcr-abl negative patients. Because of lower relapse rate and better OS and DFS, we recommend that Ph^＋ ALL patients receive allo-HCT in CRI.

Efficacy and prognostic factors of imatinib plus CALLG2008 protocol in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia

A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia （ALL）. We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome （Ph）-positive ALL enrolled into imatinib （400 mg/d） plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years （range, 18-68 years）, with 81 （52.3%） males. The overall hematologic complete remission （CR） rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3-year overall survival （OS） and event-free survival （EFS） rates were 49.5% （95% confidence interval （CI）： 38.5%-59.5%） and 49.2% （95% CI： 38.3%-59.2%）, respectively. Fifty-eight （36 with haploidentical donor） patients underwent allogeneic hematopoietic stem call transplantation （allo-HSCT） in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without alIo-HSCT group （73.2%, 95% CI： 58.3%-83.5% vs. 22.2%, 95% CI： 8.7%-39.6% and 66.5%, 95% CI： 50.7%-78.2% vs. 16.1%, 95% CI： 5.1%-32.7%, respectively）. Multivariate analysis showed that alIo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the alIo-HSCT cohort, the donor type （haploidentical versus matched donors） had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool.

Philadelphia chromosome-positive acute myeloid leukemia with masses and osteolytic lesions： finding of 18F-FDG PET/CT

Philadelphia chromosome-positive acute myeloid leukemia is controversial and difficult to distinguish from the blast phase of chronic myeloid leukemia. As a myeloid neoplasm, rare cases of this leukemia manifest multiple soft-tissue tumors or bone lyric lesions. In this paper, we describe a 49-year-old male patient who had an abrupt onset with sharp chest pain, fever, fatigue, emaciation, and splenomegaly. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography （18F-FDG PET/CT） result showed diffuse and uneven hypermetabolic lesions in the bone marrow with peripheral bone marrow expansion, multiple soft tissue neoplasms with high 18F-FDG uptake, and lyric bone lesions. Bone marrow smear and biopsy detected aberrant blast cells expressing myeloid rather than lymphoid immunophenotype marker. For the existence of Philadelphia chromosome and BCR-ABL1 fusion gene together with complex chromosome abnormalities, a diagnosis of Philadelphia-positive acute myeloid leukemia was made, although the type （de novo or blast crisis） remained unclear.

JAK2 exon 12 mutations in patients with Philadelphia(Ph) chromosome-negative myeloproliferative neoplasms

Objective To investigate JAK2 exon 12 mutations in patients with Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms (MPN) and the clinical characteristics of patients with JAK2 exon 12 mutants. Methods Allele-specific PCR(AS-PCR) was applied to identify JAK2 V617F mutation.

Effect of VE-cadherin on sentitivity to Imatinib in Sup-B15 Philadelphia chromosome positive acute lymphoblastic leukemia cells

Objective To investigate the sensitivity of imatinib mesylate (IM) on Sup-B15 Ph+acute lymphoblastic leukemia (ALL) cells knockdown of VE-cadherin (CD144) ,and to further explore its mechanism.Methods CD144in Sup-B15 leukemia cells was stably knockdowned via lentivirus-mediated RNA interference (named

Philadelphia Water Bad for Elderly Health — Study

美国的环境保护工作无疑走在世界的前列。凡是到过美国的人都会被那里优美清洁的环境所倾倒。美国的自来水(tap water),可以直接饮用。…its tap water was filled with pathogens.这将是一个极为可怕的情景!本报道在肯定费城的tap water有问题时,振振有辞。而费城市长的发言人在驳斥这个结论的时候,也不乏根据:He noted that an EPA authorized peer review of the study found it flawed. 费城的市长发言人说过的一句话值得我们研究: No one has hinted that our water quality wasn't the best in the region. 初读此句,可能被句中的两个否定词所惑:no/not。其实,我们不能以“否定+否定=肯定”的公式来套用本句。本句的关键在于:wasn't the best。这里使用了一种被称为understatement的修辞,…our water quality wasn't the best in the region的弦外之音是:there was some problem in our water quality in the region. 形容词的比较级常常用在understatement中。另如,在《英语900句》中,有这样一个对话: What do you think of the performance? I think it could be better. 回答中的could be better即understatement,意思是:还可以更好些;不是很好。 No one has hinted that our water quality

Library of Congress/VOA/Philadelphia

【对美国国会图书馆的描绘虽然只有三言两语,倒也可读。既有所见,又有所感。作为世界上最大的图书馆之一,每日的进书量(7,000册)则让读者慨叹:吾生有限,知识无涯!古朴的塑像、拱形的屋顶、建筑的命名以及那叠叠书籍和缕缕书香,真是一个诱人的去处!而国会图书馆北侧的Supreme Court,其外表虽有浓重的文化色彩,让观众产生的却是一种别样的心情。足以称奇的是,美国的Supreme Court“凌驾”于宪法之上,有权对宪法作出解释。While studying American Politics, we went through a lot of court cases starting from very personal and local levels, but ending up triggering the amendment or clarification of the Constitution.这句话则让我们想起此间的一句名言:实践是检验真理的唯一标准。】

Philadelphia Girl Found Years after Thought Dead

故事虽短,但情节曲折,细节生动。文章的主题句把这个人间悲喜剧的梗概说得明明白白。但是,出人预料的是,失女6年的母亲对即将重逢的女儿竟然表态如下:Cuevas,who has three sons,said she did not try to reclaim(要求归还)the child until she had proof that Delimar was her daughter,故事的最后结局究竟如何?文章一个老词的新鲜用法,让我们一惊:consumed(毁灭)

费城图书馆公司及其历史意义

费城图书馆公司是1731年由本杰明·富兰克林创办的会员图书馆。费城图书馆公司实行会员管理制度,将学术研究类书籍作为图书馆收藏的重点,为会员和非会员提供差别化的服务。费城图书馆公司的创建在美国图书馆史乃至世界图书馆史上具有举足轻重的历史地位。费城图书馆公司是图书馆史上有据可考的第一所会员图书馆,是“北美所有会员图书馆之母”,是美国民主思想与文化的重要象征,它的建立为美国民主思想的传播和民主政治的发展作出了不可替代的历史贡献。