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  • 1
    In: JAMA, American Medical Association (AMA), Vol. 329, No. 22 ( 2023-06-13), p. 1934-
    Abstract: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID . Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure SARS-CoV-2 infection. Main Outcomes and Measures PASC and 44 participant-reported symptoms (with severity thresholds). Results A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%] ) were PASC positive at 6 months. Conclusions and Relevance A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.
    Type of Medium: Online Resource
    ISSN: 0098-7484
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    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 2
    In: Blood, American Society of Hematology, Vol. 98, No. 1 ( 2001-07-01), p. 201-209
    Abstract: The (11;19)(q23;p13.1) translocation in acute leukemia leads to the generation of a chimeric protein that fuses MLL to the transcriptional elongation factor ELL. A novel protein was isolated from a yeast 2-hybrid screen with ELL that was named EAF1 for ELL-associated factor 1. Using specific antibodies, the endogenous EAF1 and ELL proteins were coimmunoprecipitated from multiple cell lines. In addition, endogenous EAF1 also exhibited the capacity to interact with ELL2. Database comparisons with EAF1 identified a region with a high content of serine, aspartic acid, and glutamic acid residues that exhibited homology with the transcriptional activation domains of several translocation partner proteins of MLL, including AF4, LAF4, and AF5q31. A similar transcriptional activation domain has been identified in this region of EAF1. By confocal microscopy, endogenous EAF1 and ELL colocalized in a distinct nuclear speckled pattern. Transfection of theMLL-ELL fusion gene delocalized EAF1 from its nuclear speckled distribution to a diffuse nucleoplasmic pattern. In leukemic cell lines derived from mice transplanted withMLL-ELL–transduced bone marrow, EAF1 speckles were not detected. Taken together, these data suggest that expression of the MLL-ELL fusion protein may have a dominant effect on the normal protein-protein interactions of ELL.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2001
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 6524-6524
    Abstract: 6524^ Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. Most tumor cells use glycolysis even under aerobic conditions (the Warburg effect). This altered metabolism is a possible therapeutic target. The novel lipoate derivative CPI-613 is a first-in-class agent that targets a key mitochondrial enzyme, pyruvate dehydrogenase complex (PDH). Methods: CPI-613 was tested against leukemia cell lines in vitro and in vivo. It is also the subject of a phase I clinical trial for patients with hematologic malignancies. Results: CPI-613 was active against HL60, Jurkat, and K562 cells, with an average IC50 value of 14 μM (range 12.2 – 16.4). CPI-613 was synergistic with doxorubicin, with Combinatorial Index (CI) values of 0.478 to 0.765. CPI-613 sensitivity increased with knockdown of p53 or MN1 expression, despite their increased resistance to standard therapy. CPI-613 was synergistic with nilotinib against BCR-ABL-expressing cells and with sorafenib against Flt3 ITD-expressing cells. CI values for nilotinib + CPI was 0.059 (+/-0.002) and for sorafenib + CPI was 0.581 (+/-0.052). In vivo, CPI-613 synergized with doxorubicin; median survival improved from 12 days with doxorubicin to 16 days with CPI-613 plus doxorubicin (p=0.0001). In the phase I clinical trial, 7 of 13 evaluable patients had a response of stable disease or better, for an overall response rate of 54% (see table). CPI-613 was well tolerated, with no evidence of marrow suppression and no dose limiting toxicity identified. Conclusions: The novel agent CPI-613 has activity against a variety of hematological malignancies, including acute leukemias. The therapeutic index appears high, with only minor toxicities observed. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3618-3618
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3618-3618
    Abstract: Abstract 3618 Acute leukemias are aggressive malignancies of the bone marrow. In adults these diseases disproportionally affect the elderly with a median age of onset of 72 for acute myeloid leukemia (AML) and 60 for acute lymphoblastic leukemia (ALL). Patients over the age of 60 have less than 10% survival at 5 years. This is the result of a combination of increased primary resistant disease and comorbidities that lead to treatment related mortality. Despite decades of research for the majority of AML and ALL patients, therapies have remained unchanged. There is a desperate need for novel agents with acceptable toxicities. Altered metabolism is a hallmark of cancer including the acute leukemias. Nearly all tumor cells will preferentially utilize anaerobic glycolysis even under aerobic conditions, a phenomenon known as the Warburg effect. Additionally, cancer cells can also increase lipid anabolism and upregulate fatty acid synthase (FASN). These alterations in metabolism represent a possible therapeutic target. The novel lipoate derivative CPI-613 is a first in class agent that targets a key mitochondrial enzyme involved in aberrant metabolism, pyruvate dehydrogenase complex (PDH). PDH is required for the conversion of pyruvate to acetyl-CoA, which then enters into the tricarboxylic acid cycle (TCA). TCA intermediates are utilized as biosynthetic precursors for the production of a variety of molecules, including fatty acids. To determine if leukemic blasts upregulate FASN we performed western blots on leukemic cell lines and primary patient samples and compared levels to normal hematopoietic precursor cells. We found all cell lines and many primary AML samples had increased levels of FASN when compared to controls implying an upregulation of fatty acid synthesis. Consistent with this, inhibition of fatty acid synthesis with the FASN inhibitor orlistat or acetyl-CoA carboxylase inhibitor TOFA resulted in loss of viability of HL60, Jurkat and K562 cells. To determine if PDH inhibition by CPI-613 has activity in the acute leukemias, we tested it against several human and murine acute leukemia cell lines in vitro and in vivo. CPI-613 was active against HL60, Jurkat and K562 cells with an average IC50 value of 14 μM (range 12.2 – 16.4). CPI-613 was found to be synergistic with doxorubicin with Combinatorial Index (CI) values between 0.478 and 0.765. Sensitivity to CPI-613 in a genetically defined murine AML cell line was increased with shRNA mediated knockdown of p53 or expression of MN1 despite their increased resistance to standard therapy. Intriguingly, in preliminary studies, CPI-613 appeared to be highly synergistic with the tyrosine kinase inhibitor nilotinib in Baf-3 cells transduced to express the p210 BCR-ABL kinase with CI values of 0.073–0.059. In vivo, CPI-613 was found to synergize with doxorubicin when these cells were injected into syngeneic Balb/c mice with an extension of median survival from 12 days with doxorubicin alone to 16 days with the combination of CPI-613 and doxorubicin (p=0.0001). In addition to these studies, CPI-631 is also the subject of a phase I clinical trial for patients with relapsed and refractory hematologic malignancies at the Wake Forest University Comprehensive Cancer Center. To date, ten patients have been treated. CPI-613 appears to be well tolerated with no adverse events 〉 grade 1 attributed as probably associated with drug. Four patients had a diagnosis of relapsed or refractory AML. CPI-613 at the initial dosing level concurrent with hydroxyurea resulted in a transient reduction in peripheral blood blasts in the first AML patient. Treatment at the next dosing level resulted in a hematologic improvement leading to transfusion independence and transient decrease in the 7q minus clone in the second AML patient. He maintains transfusion independence after 7 cycles and continues on therapy to date. The third patient with refractory AML had an increase in neutrophil count but no reduction in peripheral blood blasts. Taken together, these data suggest that altered lipid and mitochondrial metabolism are viable targets in the acute leukemias. The novel agent CPI-613 has activity against several acute leukemia cell lines in vitro and in vivo and may have activity in patients with relapsed disease. The therapeutic index appears quite high with only minor toxicities seen. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4869-4869
    Abstract: Abstract 4869 Background: Despite advances in treatment, adult patients with ALL (acute lymphocytic leukemia) have lower cure rates and decreased survival compared to children. These differences in outcome are partially attributed to unfavorable cytogenetic mutations that are more prevalent in adults than children, including the Philadelphia chromosome (Ph+). Some studies of pediatric ALL patients indicate the presence of racial disparities in outcomes and response to therapy which may be associated with genotypic variance across racial groups. There is limited published data of prevalence of cytogenetic abnormalities in adult ALL patients according to race, gender, and age. In our study, we evaluated the association of the incidence of recurrent cytogenetic abnormalities with race, gender, and age in adult patients with ALL. Methods: 275 patients (aged 17–95yo) diagnosed with ALL at Wake Forest University within the past 25 yrs were identified by reviewing the Cancer Registry database. Cytogenetics from patients' initial diagnostic bone marrow were reviewed and grouped by prognostic significance. Genotypes were sorted into normal (no abnormalities), Philadelphia chromosome t(9;22), hyperdiploid ( 〉 50), hypodiploid (30-39), t(4;11), t(8;14), and other (including tetrasomy 13 and multiple rearrangements). Genotypes were further grouped into normal, favorable (hyperdiploidy), or unfavorable (Ph+, hypodiploidy, t(4;11), t(8;14), other). Associations of prevalence of cytogenetic groups with race, age and gender were analyzed with Chi- squared tests. Results: This study included 275 patients, sorted by gender (114 women, 161 men); by race (233 white, 31 black, 11 other non-black minorities); and by age (33 patients 〈 30 yo, 87 patients 30–55 yo, and 155 patients 〉 55 yo). There was a statistically significant difference in age distribution across genders, with a higher percentage of women in older age groups than men, p=0.039. Overall, cytogenetics were distributed as follows: 41.5% (114) normal; 18.5% (51) Ph+, 6.2% (17) hyperdiploid, 2.2%(6) with t(4;11), 1.8% (5) Ph+ and hyperdiploid, 1.5%(4) hypodiploid, and 1.1%(3) with t(8;14). These genotypes are more broadly categorized as 41.5 % normal, 6.2% favorable, and 52.4% unfavorable. Between racial groups, there was no statistically significant difference in the distribution of Ph+ and hyperdiploidy or normal, favorable, or unfavorable cytogenetic groups. However, between genders, there was a statistically significant difference in the distribution of incidence of normal, favorable, and unfavorable cytogenetic groups, p=0.015. There was a greater incidence of favorable hyperdiploidy in men, 9.3% (15), compared to women, 1.8% (2), p=0.010. There was a greater incidence of unfavorable Ph+ in women, 26.3% (30), compared to men, 16.1% (26), p=0.039. Furthermore, between age groups, there was a statistically significant difference in the distribution of incidence of normal, favorable, and unfavorable cytogenetic groups, p=0.020. There was a higher incidence of Ph+ in patients age 30–55yo, p=0.010, with 12.1% (4) patients age 〈 30 yo, 31% (27) patients age 30–55yo, and 16.1% (25) patients age 〉 55 yo. Also, there was a trend toward higher incidence of favorable hyperdiploid mutation in older patients, p=0.082, with 9.0% (14) patients age 〉 55 yo. Conclusion: Our data indicate statistically significant differences in incidence of cytogenetic abnormalities across gender and age groups, but not across racial groups. By prognostic significance, there were increased incidences of unfavorable Ph+ mutations in both women and older patients, and favorable hyperdiploidy in men. Women were more prevalent in older age cohorts, which may partially account for an increased incidence of Ph+ in older patients in this study. Between racial groups, there was no difference in incidences of normal, favorable hyperdiploidy, unfavorable Ph+ and other unfavorable cytogenetics. While our ability to detect differences is limited by the relatively few minorities within the dataset, our findings suggest that differences in outcome between races may not be driven by cytogenetic risk. Disparities in response to therapy and outcomes in adult ALL patients may be related to age and gender, in addition to other factors. Further validation with a larger, more diverse patient population may enable us to identify risk factors of prognostic significance and target therapy. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 2516-2516
    Abstract: 2516^ Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. This altered metabolism is a possible therapeutic target. The lipoate derivative CPI-613 is a first in class agent that targets pyruvate dehydrogenase complex.This trial was designed to determine the maximally tolerated dose (MTD), safety, and efficacy of CPI-613 given as a single agent by IV infusion. Methods: CPI-613 was given over a 2 hour infusion on days 1 and 4 for 3 weeks every 28 days with a starting dose of 420 mg/m 2 . The dose was escalated in 6 cohorts to a final dose of 3780 mg/m 2 . Treatment could be continued if the patient experienced clinical benefit. Results: A total of 26 patients with advanced relapsed or refractory hematologic malignancies were enrolled. Patients were heavily pretreated with a median of 3 previous therapies (range 1-11). CPI-613 was well tolerated when infused over 2 hours, with no worsening of cytopenias at any dose level. After the dose was escalated to 2940 mg/m 2 the protocol was amended to a 1 hour infusion. When infused over 1 hour, 2 patients developed grade 3 renal failure. Infusion time was then returned to 2 hours and dose escalation resumed. At a dose of 3780 mg/m 2 , one patient experienced prolonged grade 3 nausea and one patient grade 3 renal failure, defining this dose as above the MTD. Renal failure resolved in all but one patient who opted for hospice care. A total of 6 patients were treated at a dose of 2940 mg/m 2 over 2 hours with no DLTs observed, establishing this as the MTD. Of the 21 patients evaluable for a response, eight achieved a response of stable disease or better for a response rate of 38%. Responses included a complete remission maintained over 27 cycles in one AML patient and clearance of marrow blasts in another, sustained partial response in both a Burkitt's and a cutaneous T cell lymphoma patient maintained over 17 and 8 cycles respectively, and stable disease in 2 multiple myeloma and 2 myelodysplasia patients. Conclusions: To our knowledge this is the first report of an agent with activity in aggressive hematological malignancies that is not myelosuppressive. The therapeutic index appears high suggesting CPI-613 should be further studied in phase II trials. Clinical trial information: NCT01034475.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 7
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 486-486
    Abstract: Altered metabolism is a hallmark of cancer, including hematologic malignancies. Cancer cells alter the normally catabolic role of their mitochondria to produce biosynthetic precursors to more efficiently generate additional cancer cells. This altered metabolism is a possible therapeutic target. The lipoate derivative CPI-613 is a first in class agent that targets the mitochondrial enzyme pyruvate dehydrogenase complex (PDH). This trial was designed to determine the maximally tolerated dose (MTD), pharmacokinetics, safety, and efficacy of CPI-613 given as a single agent. Methods CPI-613 was given over a 2 hour infusion on days 1 and 4 for 3 weeks every 28 days with a starting dose of 420 mg/m2. The dose was escalated in 6 cohorts to a final dose of 3780 mg/m2. Treatment was continued if the patient experienced clinical benefit. Pharmacokinetic samples were analyzed to determine the half-life of CPI-613. Results A total of 26 patients with advanced relapsed or refractory hematologic malignancies were enrolled. Patients were heavily pretreated with a median of 3 previous therapies (range 1-11). CPI-613 was well tolerated when infused over 2 hours, with no worsening of cytopenias at any dose level. After the dose was escalated to 2940 mg/m2 the protocol was amended to a 1 hour infusion. When infused over 1 hour, 2 of 3 patients developed grade 3 renal failure. Infusion time was then returned to 2 hours and dose escalation resumed. At a dose of 3780 mg/m2, one patient experienced prolonged grade 3 nausea and one patient grade 3 renal failure, defining this dose as above the MTD. Renal failure resolved in all but one patient who opted for hospice care. A total of 6 patients were treated at a dose of 2940 mg/m2 over 2 hours with no DLTs observed, establishing this as the MTD. CPI-613 was eliminated from the plasma in a triphasic pattern. The α-phase occurred during the first 6-8 hrs post-administration and was associated with a relatively rapid decline in the mean plasma CPI-613 concentrations with a T1/2 of ∼1.3 hrs. The β-phase occurred from 6-8 hrs to 24 hrs post-administration and was associated with a modest increase in CPI-613 concentration, from ∼0.5 to 4 μM when averaged across all dose levels. The γ- or final phase started from 24 hrs until 72 hrs post-administration and was associated with a very slow decline in mean plasma CPI-613 values consistent with high plasma protein binding. Upon repeat dosing there was no evidence of significant accumulation of CPI-613. Of the 21 patients evaluable for a response, eight achieved a response of stable disease or better for a response rate of 38%. All three MDS patients had a response, including one therapy-related MDS patient with deletion 7q who achieved a complete remission and continues on therapy for over 31 cycles. One refractory AML patient had clearance of marrow blasts, allowing for a subsequent allogeneic stem cell transplant. A Burkitt's and a cutaneous T cell lymphoma patient each achieved a partial response, maintained over 17 and 14 cycles respectively. The Burkitt’s patient had her only site of disease resected, and currently has no evidence of disease more than 6 months post resection. Conclusions CPI-613 is a non-myelosuppressive PDH inhibitor with activity against aggressive hematological malignancies. The therapeutic index appears high, warranting further studies of CPI-613 in phase II trials. Disclosures: Pardee: Cornerstone Pharmaceuticals: Honoraria. Lee:Cornerstone Pharmaceuticals: Employment. Luddy:Cornerstone Pharmaceuticals: Employment. Maturo:Cornerstone Pharmaceuticals: Employment. Rodriguez:Cornerstone Pharmaceuticals: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 8
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 4, No. S1 ( 2016-11)
    Type of Medium: Online Resource
    ISSN: 2051-1426
    Language: English
    Publisher: BMJ
    Publication Date: 2016
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  • 9
    In: The Journal of Thoracic and Cardiovascular Surgery, Elsevier BV, ( 2022-3)
    Type of Medium: Online Resource
    ISSN: 0022-5223
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2007600-9
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  • 10
    In: Journal of the American College of Cardiology, Elsevier BV, Vol. 77, No. 6 ( 2021-02), p. 713-724
    Type of Medium: Online Resource
    ISSN: 0735-1097
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1468327-1
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