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  • 1
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    Syngeneic Blood and Marrow Transplantation: A Report of 94 Cases From Chinese Society of Blood and Marrow Transplantation (CSBMT).
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4295-4295
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4295-4295
    Abstract: Abstract 4295 Syngeneic blood and marrow transplantation (BMT) has been applied in the treatment of many malignant or nonmalignant hematologic disorders with no or minimal and transient graft-versus-host disease (GVHD), much less transplant-related mortality (TRM) in contrast to allogeneic BMT, and lower relapse rate compared with autologous BMT. However, limited data in a single BMT center is not sufficient for statistical analysis. To evaluate the clinical outcomes of syngeneic BMT, CSBMT has performed a cooperative survey among BMT centers in mainland, Taiwan, and Hong Kong. From January 1964 to May 2009, 94 transplants from syngeneic donors have been performed in 32 BMT centers. The median age was 20 (1.5 to 51) years old. The diagnosis included AML (29 cases), SAA (26 cases), ALL (17 cases), CML (12 cases), lymphoma (3 cases), MDS (4 cases), neuroblastoma (2 cases), and large granular lymphocytosis (1 case). The main conditioning regimens were CYTBI or BUCY for malignant diseases, none or CY plus ATG for SAA. Bone marrow (BM, 34) or peripheral blood (PB, 49) or both BM and PB (11) as grafts were used. Five patients (SAA 2, AML 3) underwent the same donor's syngeneic BMT twice. One patient with large granular lymphocytosis and 1 case with SAA underwent the same donor's syngeneic BMT thrice. The median follow-up time was 28 months (1 month to 45 years). The median time for white blood cells 〉 1.0 × 109/L, and platelets 〉 20 × 109/L was 11 (2-30) days, 13 (0-122) days, respectively. Two patients (2.1%) had grade I acute GVHD (aGVHD), and 4 cases (4.3%) had grade II aGVHD. However, only one patient's specimen was consulted by pathologist. All aGVHD was controlled easily with low-dose steroid. No chronic GVHD was noted. Three-year disease-free survival (DFS) for the patients with nonmalignant disorders was 88.5%. Among them, the longest survivor was living and well for 45 years after transplant. Three-year DFS for the patients with malignant diseases was 62.9%. The overall survival rates at 3 years were 87.9%, and 69.5% for nonmalignant, and malignant diseases, respectively. 22 of 94 patients died after BMT (nonmalignant 3, malignant 19). The only cause of death for the patients with nonmalignant disorders was rejection. Relapse was the main cause of death in patients with malignancies (17/19). TRM was 2.1%. In conclusion, syngeneic BMT is a safe and effective therapeutic option for both nonmalignant and malignant hematologic disorders. Syngeneic donor, if available, should be the first choice in all cases of AA and hematological malignancies in general. The longest survivor of 45 years post-BMT is presented in this series. The good results and advantage of syngeneic BMT cast light on the potential utility of stored autologous placental-cord blood which is shared by the identical twin through the same placenta. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4295.4295
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
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    Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing granulocytopenia in sarcoma patients receiving doxorubicin combined with ifosfamide: A prospective, randomized, non-inferiority phase II study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e24173-e24173
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e24173-e24173
    Abstract: e24173 Background: Prophylactic use of rhG-CSF is routinely recommended in patients with a high risk of febrile neutropenia (FN) after chemotherapy. Currently, rhG-CSF is mostly used in clinical practice. However, PEG-rhG-CSF tends to be a substitute due to its convenience and long-acting effect. Regarding concerns about its efficacy and safety, whether PEG-rhG-CSF could be prophylactically used after these regimens with a high risk of FN is still in doubt. Doxorubicin combined with ifosfamide is commonly applied in sarcoma patients and is one of the most serious myelosuppressive chemotherapy regimens in solid tumors. We compared the efficacy and safety of PEG-rhG-CSF with rhG-CSF in the prevention of severe granulocytopenia and FN, in patients receiving this representative regimen. Methods: This was a single-center, prospective, randomized, crossover, non-inferiority phase II trial. Patients with sarcoma suitable for doxorubicin combined with ifosfamide treatment were enrolled. All patients received 2 cycles of chemotherapy and were randomly assigned to either the AOB group (PEG-rhG-CSF used in 1st cycle and rhG-CSF in 2nd cycle) or BOA group (rhG-CSF used in 1st cycle and PEG-rhG-CSF in 2nd cycle). Blood monitoring every other day until ANC ≥ 2×10 9 /L in two consecutive tests. The primary endpoints were the frequency and duration of grade 4 granulocytopenia after prophylactic use of PEG-rhG-CSF and rhG-CSF respectively, the secondary endpoints were the frequency and duration of febrile neutropenia, and proportion of antibiotic use. Results: From Jan 1, 2018 to Aug 31, 2021, 70 patients were enrolled, 35 each in AOB and BOA. There were no statistical differences in the incidence and duration of grade 4 granulocytopenia (85.7% vs. 77.0%, p = 0.1; 1.34d vs. 1.41d, p = 0.70), the proportion and duration of febrile neutropenia (12.8% vs. 8.2%, p = 0.77; 0.6d vs. 0.8d, p = 0.74), and the proportion of antibiotics used (19.1% vs. 14.9%, p = 0.79) when comparing PEG-rhG-CSF vs. rhG-CSF in prophylactical use. The incidence of grade 4 granulocytopenia in both groups was comparable in 1st cycle (90.9% vs. 96.0%, p = 0.47), but in 2nd cycle it was significantly lower in AOB than that in BOA (54.5% vs. 88.0%, p = 0.01). The lowest value of ANC was higher in AOB in 2nd cycle (0.32G/L vs. 0.12G/L, p = 0.03). Conclusions: This study demonstrated PEG-rhG-CSF could prevent granulocytopenia and FN in sarcoma patients receiving doxorubicin combined with ifosfamide, with comparable efficacy and toxicities as rhG-CSF. Considering the convenience in use and patient compliance, PEG-rhG-CSF could be an effective and reasonable alternative to rhG-CSF. Clinical trial information: ChiCTR1900021945 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e24173
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Pegylated liposomal doxorubicin combined with ifosfamide for advanced soft tissue sarcomas: A phase I dose-escalation study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e23525-e23525
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e23525-e23525
    Abstract: e23525 Background: Doxorubicin combined with ifosfamide (IFO) is one of the preferred treatment options for non-specific soft tissue sarcomas (STS), but is limited by cumulative cardiotoxicity and severe myelosuppression. Pegylated liposomal doxorubicin (PLD) provides an effective alternative to conventional anthracyclines with reduced toxicity. However, there is no standard dose recommendation for PLD combined with IFO for STS. The present study aimed to investigate the maximum tolerated dose (MTD) of PLD combined with IFO in advanced STS patients. Methods: This was a phase I, open-label, single-center, dose-escalation study. Patients with locally advanced or metastatic STS were enrolled, except for gastrointestinal stromal tumors, Ewing's sarcomas, embryonal rhabdomyosarcomas, and alveolar rhabdomyosarcomas. We used a standard 3 + 3 dose-escalation design with progressively increasing PLD and IFO (3 g/m 2 per day for 3 days, q3w) for one cycle, with a dose escalation ranged from 30 to 70 mg/m 2 (5mg/m 2 increment per step). The primary endpoint was determination of the MTD, and the secondary endpoint was the incidence/severity of adverse events (AEs). Results: From January 2020 to September 2022, 23 patients were enrolled in this study, including 3 patients at doses 30-45 mg/m 2 , 6 patients at dose 50 mg/m 2 , and 5 patients at 55 mg/m 2 . The median age was 49 years (ranges from 30 to 68 years), the male/female ratio was 12/11, and 22 (95.65%) patients had stage IV disease (AJCC staging system). Initially, no DLT was observed at doses of 30-50 mg/m 2 , with 3 patients in each dose phase. Two patients developed DLTs at the 55 mg/m 2 dose, resulting in the 50 mg/m 2 dose extending to a total of 6 patients who completed treatment without DLT. The DLTs at dose 55 mg/m 2 of the first patient were grade 4 neutropenia lasting ≥ 5 days and grade 3 thrombocytopenia with hemorrhage tendency; the second patient had grade 4 neutropenia lasting ≥ 5 days, grade 4 thrombocytopenia relapsed after platelet transfusion, and grade 3 increased alanine aminotransferase. Therefore, the MTD of PLD was 50 mg/m 2 . The most common (≥ 10%) grade 3-4 AEs in all patients were lymphopenia (56.52%), neutropenia (82.61%), leukopenia (86.96%), and thrombocytopenia (13.04%). Conclusions: For patients with locally advanced or metastatic STS, single cycle PLD combined with IFO had a tolerable AE profile, with an MTD of 50 mg/m 2 for PLD. Further researches are needed to confirm the multi-cycle recommendation. Clinical trial information: ChiCTR1900028270 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e23525
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 4
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    Abstract 997: Oncogenic tyrosine kinases are localized to mitochondria and regulate cancer metabolism by phosphorylating key components of pyruvate dehydrogenase kinase complex
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 997-997
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 997-997
    Abstract: The Warburg effect describes the observation that cancer cells take up more glucose than normal tissue and favor aerobic glycolysis. Many tumor cells rely on aerobic glycolysis instead of mitochondrial oxidative phosphorylation for their continued proliferation and survival. This may be, in part, due to attenuated mitochondrial function, which is suggested to be achieved through inhibition of pyruvate dehydrogenase complex (PDC) in cancer cells. Pyruvate dehydrogenase (PDH) is the first and most important enzyme component of PDC, which catalyzes the conversion of pyruvate to acetyl-CoA that subsequently enters into the Krebs cycle to produce ATP and electron donors including NADH. PDH activity is negatively regulated by phosphorylation at several serine sites. Phosphorylation of PDH by PDH kinase (PDHK) results in the inactivation of PDC, while dephosphorylation by pyruvate dehydrogenase phosphatase (PDP) restores PDC activity. Thus, PDHK and PDP coordinate to regulate the phosphorylation and consequently activation status of PDH. In cancer cells, c-Myc and HIF-1alpha are believed to promote inhibition of PDC by, in part, upregulating gene expression of PDHK. However, how oncogenic signals regulate PDH, and/or coordinate PDHK and PDP activity to inhibit PDH and ultimately attenuate PDC activity in cancer metabolism still remains unclear. We recently reported that, surprisingly, functional PDC can form in mitochondria outside of matrix in some cancer cells. Moreover, several oncogenic tyrosine kinases including FGFR1, FGFR1 fusion tyrosine kinase, and FLT3-ITD mutant, as well as BCR-ABL and JAK2 V617F mutants, are localized to different mitochondrial compartments including outer membrane and matrix, respectively, in cancer cells, where they phosphorylate PDHK1, PDP1 and PDHA. Our studies demonstrate that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding, which promotes cancer cell metabolism, proliferation and tumor growth. In consonance with these findings, we found that tyrosine phosphorylation attenuates PDP1 phosphatase activity but inhibits PDHA enzyme activity. These data suggest that mitochondrial oncogenic tyrosine kinases regulate PDC activity by inhibiting PDHA1 enzyme activity directly through tyrosine phosphorylation and indirectly by enhancing and attenuating PDHK1 and PDP1 activity, respectively. These findings represent an acute mechanism underlying the Warburg effect, in addition to the long-term regulation that is believed to be regulated by c-Myc and HIF-1alpha. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 997. doi:1538-7445.AM2012-997
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-997
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 5
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    Abstract 3362: Tyr-phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate pyruvate dehydrogenase complex and promote the Warburg effect
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3362-3362
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3362-3362
    Abstract: Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homoeostasis in mammalian cells. The current understanding of PDC regulation involves serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDHK), which inhibits PDH and subsequently PDC, whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here we report that lysine acetylation of PDHA1 and PDP1 is induced by EGF-stimulation in human cells, and is common in diverse human cancer cells. We found that K321 acetylation inhibits PDHA1 by recruiting PDHK1 and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important for the metabolic switch to glycolysis in cancer cells and promote tumor growth. Moreover, we identified mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) as the upstream acetyltransferase of PDHA1 and PDP1 using a novel shRNA library that targets the majority of acetyltransferases in the human genome, and SIRT3 as the deacetylase. Knockdown of ACAT1 results in decreased cancer cell proliferation and tumor growth. Furthermore, we found that EGFR and other tyrosine kinases including FGFR1 that are frequently dysregulated in human cancers phosphorylate PDP1 at Y381, which dissociates SIRT3 and recruits ACAT1 to PDC. Our findings suggest a novel mechanism where lysine acetylation of PDHA1 and PDP occurs in both normal and cancer cells, and contributes to inhibitory regulation of PDC, providing complementary insight into the current understanding of PDHA1 regulation. We also demonstrate that hierarchical, distinct post-translational modifications crosstalk to regulate PDC by controlling its molecular composition. Moreover, our findings for the first time link a mitochondrial acetyltransferase, ACAT1, to the Warburg effect and tumor growth, suggesting that the ACAT1-PDP1-PDHA axis represents a promising anti-cancer target. Citation Format: Jun Fan, Ting-Lei Gu, Titus Boggon, Sumin Kang, Jing Chen. Tyr-phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate pyruvate dehydrogenase complex and promote the Warburg effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2014-3362
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-3362
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract 2798: Tyrosine phosphorylation of LDH-A is important for cancer cell redox homeostasis and tumor growth
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2798-2798
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2798-2798
    Abstract: Cancer cells take up more glucose than normal tissue and favor aerobic glycolysis, generating lactate through a NADH-dependent enzyme, lactate dehydrogenase A (LDH-A). This is the last step of glycolysis that permits the regeneration of NAD+, which is needed as an electron acceptor to maintain cytosolic glucose catabolism. Therefore, most tumor cells are reliant on lactate production for their survival. LDH-A gene expression is believed to be upregulated by both HIF and Myc in cancer cells to achieve increased lactate production, and expression of LDH-A was previously implicated to be involved in tumour initiation and growth. However, how oncogenic signals activate LDH-A to regulate cancer cell metabolism remains unclear. Our phospho-proteomics studies revealed that oncogenic fibroblast growth factor (FGF) receptor type 1 (FGFR1) tyrosine kinase directly phosphorylates LDH-A. Structural and biochemical studies revealed that phosphorylation at Y10 and Y83 activates LDH-A by promoting the formation of active, tetrameric LDH-A and binding of LDH-A substrate NADH, respectively. Moreover, we found that LDH-A is commonly phosphorylated at Y10 in diverse human cancer cells by multiple oncogenic tyrosine kinases including BCR-ABL, FLT3 and JAK2, which represents an acute molecular mechanism underlying increased lactate production in cancer cells. Furthermore, cancer cells with stable knockdown of endogenous LDH-A and rescue expression of a catalytic hypomorph LDH-A mutant, Y10F, show decreased cell proliferation and ATP levels under hypoxia, increased mitochondrial respiration to sustain glycolysis by providing NAD+, and reduced tumor growth in xenograft nude mice. Our findings suggest that tyrosine phosphorylation activates LDH-A to promote the Warburg effect and tumor growth by regulating NADH/NAD+ redox homeostasis in cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2798. doi:10.1158/1538-7445.AM2011-2798
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2798
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    detail.hit.zdb_id: 410466-3
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  • 7
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    Differential usage of transcriptional repressor Zeb2 enhancers distinguishes adult and embryonic hematopoiesis
    Elsevier BV ; 2021
    In:  Immunity Vol. 54, No. 7 ( 2021-07), p. 1417-1432.e7
    Details
    In: Immunity, Elsevier BV, Vol. 54, No. 7 ( 2021-07), p. 1417-1432.e7
    Type of Medium: Online Resource
    ISSN: 1074-7613
    URL: Article
    DOI: 10.1016/j.immuni.2021.04.015
    RVK:
    XA 48754.8
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2001966-X
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  • 8
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    Platelet decline rate as the indication of using recombinant human thrombopoietin to prevent chemotherapy induced thrombocytopenia: A prospective, randomized, controlled study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e24171-e24171
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e24171-e24171
    Abstract: e24171 Background: Doxorubicin combined with ifosfamide is the common regimen for patients with sarcoma, which will induce severe thrombocytopenia. Sarcoma patients especially those with rapid platelet count decline after receiving this regimen could not avoid severe thrombocytopenia, even Recombinant Human Thrombopoietin(rhTPO) was used when the platelet count decreased to 75,000/μL according to current guidelines. The present study aimed to test the efficiency and safety of using rhTPO to prevent severe thrombocytopenia when rapid platelet count decline occurred. Methods: Our previous data showed those patients with rapid platelet count decline more than 40% within 3 days after administration of doxorubicin combined with ifosfamide were more likely to develop severe thrombocytopenia. In this prospective study, 53 patients with this characteristic were randomly assigned to prevention group (starting rhTPO immediately after enrollment) or treatment group (starting rhTPO when platelet count was less than 75,000/μL after chemotherapy). rhTPO was administrated with 300IU/kg·d until the platelet count increased to 100,000/μL or by 50,000/μL. Incidence and duration of grade 3 to 4 thrombocytopenia, proportion of platelet transfusion and adverse reactions were collected and analyzed. Results: The incidence of grade 3 to 4 thrombocytopenia in the prevention group and the treatment group was 63% and 81% respectively (p = 0.224), however the incidence of grade 4 thrombocytopenia in the former was significantly lower than that in the latter(22% versus 50% , p = 0.047).The duration of grade 3 to 4 thrombocytopenia in the prevention group had a declining trend compared with the treatment group( 2.6±2.8d versus 3.7±3.3d, p = 0.198). There was no difference in the proportion of platelet transfusion between the two groups. No rhTPO related toxicities of grade 3 to 4 were observed in both groups. Conclusions: For sarcoma patients treated with doxorubicin combined with ifosfamide, rapid platelet count decline more than 40% within 3 days after chemotherapy can be used as an indicator for the prophylactic administration of rhTPO, which can significantly reduce the probability of grade 4 thrombocytopenia without increasing toxicity. Clinical trial information: ChiCTR1900022667 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e24171
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 9
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    Abstract 1257: Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1257-1257
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1257-1257
    Abstract: Many tumor cells rely on aerobic glycolysis for their continued proliferation and survival, which is in part due to actively inhibited mitochondrial function. Myc and HIF-1 are believed to promote such inhibition by upregulating gene expression of pyruvate dehydrogenase kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial pyruvate dehydrogenase complex (PDC). However, how oncogenic signals activate PDHK1 to regulate cancer cell metabolism remains unclear. Here we report that oncogenic FGFR1 activates mitochondrial PDHK1 by tyrosine phosphorylation. FGFR1 directly phosphorylates PDHK1 at Y136, Y243 and Y244. Mutational, structural and biochemical studies revealed that phosphorylation at both Y243 and Y244, but not Y136 is required to promote ATP binding to PDHK1, which consequently facilitates PDHK1 binding to PDC scaffold to access substrate PDHA1. In contrast, Y136 phosphorylation may only function to enhance binding between PDHK1 and PDC. We also found that PDHK1 is commonly tyrosine phosphorylated by diverse oncogenic tyrosine kinases in different human cancers. Moreover, we generated cancer cells with stable knockdown of endogenous human PDHK1 and “rescue” expression of phosphorylation-deficient, catalytic hypomorph mouse PDHK1 mutants including Y134F and Y239/240F (mouse PDHK1 numberings correspond to human PDHK1 Y136F and Y243/244F, respectively). These “rescue” cancer cells demonstrated decreased cell proliferation under hypoxia, increased oxidative phosphorylation with decreased lactate production, and reduced tumor growth in xenograft nude mice. Our findings suggest that tyrosine phosphorylation activates PDHK1 to inhibit mitochondrial function, providing a metabolic advantage for tumor growth. This represents a common, short-term molecular mechanism underlying the active inhibition of mitochondrial function in tumor cells, in addition to the chronic changes that are believed to be regulated by Myc and HIF-1. Moreover, inhibition of PDHK1 attenuates tumor growth, suggesting that PDHK1 may serve as a therapeutic target in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1257. doi:10.1158/1538-7445.AM2011-1257
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1257
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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