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  • 1
    Language: English
    In: Science (American Association for the Advancement of Science), 2013-07-26, Vol.341 (6144), p.399-402
    Description: Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576—amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses.
    Subject(s): Proteins ; Phosphatases ; HEK293 cells ; B lymphocytes ; REPORTS ; Stem cells ; Cell lines ; Antibodies ; Amino acids ; Cellular immunity ; Tumors ; Phosphorylation ; Humans ; PTEN Phosphohydrolase - pharmacology ; Molecular Sequence Data ; Peptide Chain Initiation, Translational ; RNA, Messenger - metabolism ; HEK293 Cells ; Glioblastoma - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Phosphatidylinositol 3-Kinase - metabolism ; Amino Acid Sequence ; PTEN Phosphohydrolase - genetics ; Cell Survival ; RNA, Messenger - genetics ; PTEN Phosphohydrolase - metabolism ; Xenograft Model Antitumor Assays ; Animals ; Signal Transduction - drug effects ; Mice, Nude ; Glioblastoma - pathology ; Cell Line, Tumor ; Mice ; Embryonic Stem Cells ; Mutation ; Glioblastoma - drug therapy ; PTEN Phosphohydrolase - chemistry ; Cancer cells ; Tumor suppressor genes ; Genetic aspects ; Research ; Properties ; Genetic translation ; Index Medicus
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: Single Journals
    Source: Academic Search Ultimate
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: Cancer, 2017-10-01, Vol.123 (19), p.3781-3790
    Description: BACKGROUND: Pediatric oncology patients are at an increased risk of invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count ≥ 500/μL) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical usefulness. METHODS: A 6-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia: the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding 2 less clinically reliable variables also was created using the initial EsVan model derivative cohort, and was validated using all 5 external validation cohorts. One data set was used only in sensitivity analyses due to missing some variables. RESULTS: From the 5 primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C statistic for predicting bacteremia was 0.695, with a calibration slope of 0.50 for the original model and a calibration slope of 1.0 when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (gram-negative or Staphylococcus aureus infection) versus BSI alone, with a C statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across data sets with a C statistic of 0.733 for predicting BSI and a C statistic of 0.841 for high-risk BSI. CONCLUSIONS: The results of this external validation demonstrated that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and, once validated and implemented prospectively, could assist in decision making in clinical practice. Cancer 2017;123:3781–3790.
    Subject(s): health services research ; pediatric oncology ; risk prediction ; supportive care ; Oncology ; Cancer Research ; febrile neutropenia ; Predictive Value of Tests ; Uncertainty ; Datasets as Topic ; Humans ; Child, Preschool ; Risk ; Bacteremia - diagnosis ; Models, Statistical ; Neoplasms ; Staphylococcal Infections - diagnosis ; Gram-Negative Bacterial Infections - diagnosis ; Retrospective Studies ; Immunocompromised Host ; Febrile Neutropenia - microbiology ; Child ; Staphylococcus aureus ; Decision-making ; Care and treatment ; Bacterial infections ; Analysis ; Research ; Risk factors ; Neutropenia ; Index Medicus ; Abridged Index Medicus
    ISSN: 0008-543X
    E-ISSN: 1097-0142
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: Pediatric blood & cancer, 2018-07, Vol.65 (7), p.e27062-n/a
    Description: Background We sought to determine the feasibility of co‐administering everolimus with a four‐drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. Procedure This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring 〉18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2/day). Additional patients were enrolled at the 3‐ and 5 mg/m2/day DLs to further evaluate toxicity (dose expansion). Results Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose‐limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2/day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end‐reinduction minimal residual disease (MRD) level (≤10−3 by polymerase chain reaction–based assay). The CR2 rate for patients with B‐cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. Conclusions Everolimus combined with four‐drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end‐reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four‐drug reinduction is 5 mg/m2/day. This promising combination should be further evaluated in a larger patient cohort.
    Subject(s): relapsed acute lymphoblastic leukemia ; mTOR inhibitor ; developmental therapeutics ; Anthracyclines ; Relapse ; Chemotherapy ; Corticosteroids ; Clinical trials ; Product development ; Acute lymphocytic leukemia ; Diseases ; Cancer
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: JAMA : the journal of the American Medical Association, 2021-03-02, Vol.325 (9), p.830-832
    Subject(s): Young Adult ; Disease-Free Survival ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Recurrence ; Antibodies, Bispecific ; Humans ; Adolescent ; B-Lymphocytes ; Child ; Index Medicus ; Abridged Index Medicus
    ISSN: 0098-7484
    E-ISSN: 1538-3598
    Source: American Medical Association Journals Backfile (through 1997)
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 5
    Language: English
    In: Nature medicine, 2007-10, Vol.13 (10), p.1203-1210
    Description: Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.
    Subject(s): Phosphorylation ; Humans ; Phosphatidylinositol 3-Kinases - metabolism ; Drosophila Proteins - metabolism ; Proto-Oncogene Proteins c-akt - genetics ; Gene Expression Regulation, Leukemic - genetics ; DNA Mutational Analysis ; Leukemia, T-Cell - metabolism ; Female ; Proto-Oncogene Proteins c-akt - metabolism ; Transgenes ; Disease Models, Animal ; Drosophila - genetics ; PTEN Phosphohydrolase - genetics ; Signal Transduction ; PTEN Phosphohydrolase - metabolism ; Receptor, Notch1 - metabolism ; Pregnancy ; Animals ; Leukemia, T-Cell - genetics ; Mice ; Models, Genetic ; Drosophila - metabolism ; Drosophila Proteins - genetics ; Mutation ; Receptor, Notch1 - antagonists & inhibitors ; Receptor, Notch1 - genetics ; Index Medicus
    ISSN: 1078-8956
    E-ISSN: 1546-170X
    Source: Single Journals
    Source: Academic Search Ultimate
    Source: Nature Journals Online
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 6
    Language: English
    In: Science (American Association for the Advancement of Science), 2009-09-04, Vol.325 (5945), p.1261-1265
    Description: PTEN (phosphatase and tensin homolog on chromosome 10) is a tumor suppressor whose cellular regulation remains incompletely understood. We identified phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (P-REX2a) as a PTEN-interacting protein. P-REX2a mRNA was more abundant in human cancer cells and significantly increased in tumors with wild-type PTEN that expressed an activated mutant of PIK3CA encoding the p110 subunit of phosphoinositide 3-kinase subunit α (PI3Kα). P-REX2a inhibited PTEN lipid phosphatase activity and stimulated the PI3K pathway only in the pretence of PTEN. P-REX2a stimulated cell growth and cooperated with a PIK3CA mutant to promote growth factor-independent proliferation and transformation. Depletion of P-REX2a reduced amounts of phosphorylated AKT and growth in human cell lines with intact PTEN. Thus, P-REX2a is a component of the PI3K pathway that can antagonize PTEN in cancer cells.
    Subject(s): Proteins ; Cell growth ; Phosphatases ; HEK293 cells ; Cell lines ; Cell cycle ; Cellular senescence ; Reports ; Chromosomes ; Tumors ; Cancer ; Neoplasms - metabolism ; Phosphorylation ; Cell Proliferation ; Humans ; Male ; Phosphatidylinositol 3-Kinases - metabolism ; GTPase-Activating Proteins - metabolism ; Breast Neoplasms - metabolism ; PTEN Phosphohydrolase - antagonists & inhibitors ; Neoplasms - genetics ; Female ; Proto-Oncogene Proteins c-akt - metabolism ; Protein Structure, Tertiary ; Cell Line ; PTEN Phosphohydrolase - genetics ; Signal Transduction ; PTEN Phosphohydrolase - metabolism ; Guanine Nucleotide Exchange Factors ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Protein Binding ; GTPase-Activating Proteins - genetics ; Mutation ; Neoplasms - pathology ; PTEN Phosphohydrolase - chemistry ; Phosphatidylinositol ; Development and progression ; Tumor suppressor genes ; Genetic aspects ; Health aspects ; Index Medicus ; Clinical Medicine ; Medical and Health Sciences ; Klinisk medicin ; Cancer and Oncology ; Medicin och hälsovetenskap ; Cancer och onkologi
    ISSN: 0036-8075
    ISSN: 1095-9203
    E-ISSN: 1095-9203
    Source: Single Journals
    Source: Academic Search Ultimate
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 7
    Language: English
    In: Nature (London), 2018, Vol.553 (7689), p.511-+
    Description: Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2 mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.
    Subject(s): 5'-Nucleotidase - genetics ; Mercaptopurine - pharmacology ; Recurrence ; Cell Proliferation ; Guanosine - biosynthesis ; Humans ; Gain of Function Mutation - genetics ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Mercaptopurine - therapeutic use ; HEK293 Cells ; Female ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Disease Models, Animal ; Purines - metabolism ; Receptor, Notch1 - metabolism ; Mutation - genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Xenograft Model Antitumor Assays ; IMP Dehydrogenase - metabolism ; Drug Resistance, Neoplasm - genetics ; Animals ; IMP Dehydrogenase - antagonists & inhibitors ; Mice ; 5'-Nucleotidase - metabolism ; Clonal Evolution ; Relapse ; Genetic aspects ; Acute lymphocytic leukemia ; Gene mutations ; Health aspects ; Diseases ; Index Medicus
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 8
    Language: English
    In: Pediatric pulmonology, 2017-06, Vol.52 (6), p.820-826
    Description: Summary Background The diagnostic yield of bronchoalveolar lavage (BAL) in the Immunocompromised pediatric population has ranged from 28% to 68%. We hypothesized that the diagnostic yield of BALs would be higher in more recent years due to new diagnostic assays. Methods A retrospective case series was performed among immunocompromised children ≤18 years old who underwent BALs from 2001 to 2012, to assess the yield of microbiologic diagnostic studies and to determine the impact of BAL findings on antimicrobial management. Results In all, 123 subjects underwent 174 BALs (mean age 9.9 years). Underlying diagnoses included both malignant (n = 79) and non‐malignant (n = 44) disorders, and 75 (61.0%) subjects were hematopoietic stem cell transplant (HSCT) recipients. Fifty‐four (31.0%) of 174 BAL were positive for ≥1 potential pathogen (n = 58 microorganisms). The diagnostic yield of BALs performed from 2001 to 2006 versus2007–2012 was similar (40.5% vs. 26.6%, respectively, P = 0.07). Most subjects (86.2%) were on ≥1 antimicrobial at the time of BAL. Most (65.8%) negative BALs were associated with narrowing antimicrobial therapy, while most (74.1%) positive BALs were associated with continuing or changing to targeted antimicrobial therapy. Conclusions In this study population, the diagnostic yield of BAL was similar to that previously described and unchanged in more recent years. Both negative and positive BALs were associated with changes in antimicrobial management. Summary A 10‐year retrospective review of bronchoalveolar lavage in 123 immunocompromised children determined that the rate of isolation of potential pathogens was 31% in this population. The majority of BAL was associated with a change in antimicrobial therapy. Pediatr Pulmonol. 2017;52:820–826. © 2017 Wiley Periodicals, Inc.
    Subject(s): BMT ; gram positive cocci ; mold ; fungi ; virus ; gram negative bacilli ; Humans ; Neoplasms - microbiology ; Anti-Infective Agents - therapeutic use ; Bronchoalveolar Lavage ; Child, Preschool ; Infant ; Male ; Neoplasms - diagnosis ; Bronchoalveolar Lavage Fluid - microbiology ; Adolescent ; Female ; Retrospective Studies ; Immunocompromised Host ; Child ; Transplantation ; Hematopoietic stem cells ; Index Medicus ; Original
    ISSN: 8755-6863
    E-ISSN: 1099-0496
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 9
    Language: English
    In: Leukemia, 2018-11, Vol.32 (11), p.2316-2325
    Description: The survival of pediatric patients with multiply relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia has historically been very poor; however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply R/R childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean ± SE) were 51 ± 4% for patients with bone marrow R/R B-ALL who underwent a second salvage attempt, 37 ± 6% for a third attempt, and 31 ± 6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41 ± 6%, 13 ± 7%, and 27 ± 13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 10
    Language: English
    In: Nature medicine, 2010-11-01, Vol.16 (11), p.1321-1327
    Description: textabstractThe TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.
    Subject(s): Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Homeodomain Proteins - metabolism ; Molecular Sequence Data ; Aneuploidy ; Gene Expression Profiling ; Cell Transformation, Neoplastic - genetics ; DNA Mutational Analysis ; Base Sequence ; Gene Deletion ; Tumor Suppressor Proteins - genetics ; Thymus Gland - pathology ; Spectral Karyotyping ; Thymus Gland - growth & development ; T-Lymphocytes - pathology ; Proto-Oncogene Proteins - metabolism ; Organ Size ; Repressor Proteins - genetics ; Mice, Transgenic ; Proto-Oncogene Proteins - genetics ; Gene Expression Regulation, Leukemic ; Homeodomain Proteins - genetics ; Animals ; Trisomy - genetics ; Comparative Genomic Hybridization ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Chromosome Aberrations ; Mice ; Index Medicus
    ISSN: 1078-8956
    E-ISSN: 1546-170X
    Source: Single Journals
    Source: Academic Search Ultimate
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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