Publications by authors named "Jacqueline García"

35 Publications

A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival.

Leuk Res 2021 May 2;104:106555. Epub 2021 Mar 2.

Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Université de Paris, Paris, France.

The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations.
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http://dx.doi.org/10.1016/j.leukres.2021.106555DOI Listing
May 2021

Reconstructing the Lineage Histories and Differentiation Trajectories of Individual Cancer Cells in Myeloproliferative Neoplasms.

Cell Stem Cell 2021 Mar 22;28(3):514-523.e9. Epub 2021 Feb 22.

Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Some cancers originate from a single mutation event in a single cell. Blood cancers known as myeloproliferative neoplasms (MPNs) are thought to originate when a driver mutation is acquired by a hematopoietic stem cell (HSC). However, when the mutation first occurs in individuals and how it affects the behavior of HSCs in their native context is not known. Here we quantified the effect of the JAK2-V617F mutation on the self-renewal and differentiation dynamics of HSCs in treatment-naive individuals with MPNs and reconstructed lineage histories of individual HSCs using somatic mutation patterns. We found that JAK2-V617F mutations occurred in a single HSC several decades before MPN diagnosis-at age 9 ± 2 years in a 34-year-old individual and at age 19 ± 3 years in a 63-year-old individual-and found that mutant HSCs have a selective advantage in both individuals. These results highlight the potential of harnessing somatic mutations to reconstruct cancer lineages.
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http://dx.doi.org/10.1016/j.stem.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939520PMC
March 2021

Protocol for outpatient management in cleft lip and palate repair.

Int J Pediatr Otorhinolaryngol 2021 Mar 11;142:110592. Epub 2021 Jan 11.

Fundación Gantz Hospital Del Niño con Fisuras, Santiago, Chile; Plastic Surgery Unit, Surgery Department, Clínica Alemana, Santiago, Chile.

Cleft lip is a common malformation in Chile. The standard care for cleft lip and palate repair is inpatient admission; this is mainly to observe complications and administer intravenous fluids, antibiotics, and analgesics. In our center, however, a strict selection of patients undergo ambulatory surgeries. In this paper, we illustrate our experience managing outpatient cleft lip and palate repair and show that it is possible to carry out a successful ambulatory surgery with few to no complications in children and adults with cleft lip and palate.
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http://dx.doi.org/10.1016/j.ijporl.2020.110592DOI Listing
March 2021

Does patient fitness play a role in determining first-line treatment of acute myeloid leukemia?

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):41-50

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

The treatment choice for newly diagnosed patients with acute myeloid leukemia (AML) is no longer straightforward. Historically, patient fitness has been a major driver of the initial therapy decision based on the belief that intensive chemotherapy would be the optimal choice if a patient were "fit" enough to receive it. Tools based on chronological age, performance status, and comorbidities have been developed to help estimate patient fitness. With newer approved therapies that include nonintensive options such as IDH1 inhibition or less intensive options such as hypomethylating agent (HMA)- or low-dose cytarabine (LDAC)-based combinations with venetoclax, the choice of frontline AML therapy places more emphasis on disease-specific features, including cytogenetics and mutational profile. Moreover, newer treatments have higher response rates than what has been expected with older nonintensive options such as LDAC or HMA monotherapy. We present cases of three patients with AML with varying cytogenetic and molecular risks to demonstrate the important but changing role of patient fitness in the current era of expanding therapeutic options.
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http://dx.doi.org/10.1182/hematology.2020000087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727557PMC
December 2020

Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia.

Cancer Cell 2020 Dec 19;38(6):872-890.e6. Epub 2020 Nov 19.

Department of Medical Oncology, Dana-Farber Cancer Institute, 440 Brookline Avenue, M430, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Acquired resistance to BH3 mimetic antagonists of BCL-2 and MCL-1 is an important clinical problem. Using acute myelogenous leukemia (AML) patient-derived xenograft (PDX) models of acquired resistance to BCL-2 (venetoclax) and MCL-1 (S63845) antagonists, we identify common principles of resistance and persistent vulnerabilities to overcome resistance. BH3 mimetic resistance is characterized by decreased mitochondrial apoptotic priming as measured by BH3 profiling, both in PDX models and human clinical samples, due to alterations in BCL-2 family proteins that vary among cases, but not to acquired mutations in leukemia genes. BCL-2 inhibition drives sequestered pro-apoptotic proteins to MCL-1 and vice versa, explaining why in vivo combinations of BCL-2 and MCL-1 antagonists are more effective when concurrent rather than sequential. Finally, drug-induced mitochondrial priming measured by dynamic BH3 profiling (DBP) identifies drugs that are persistently active in BH3 mimetic-resistant myeloblasts, including FLT-3 inhibitors and SMAC mimetics.
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http://dx.doi.org/10.1016/j.ccell.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988687PMC
December 2020

Differences Between Attached and Detached Cadaveric Prosections on Students' Identification Ability During Practical Examinations.

Anat Sci Educ 2020 Oct 9. Epub 2020 Oct 9.

Department of Ecology and Evolutionary Biology, College of Liberal Arts and Sciences, University of Kansas, Lawrence, Kansas.

Cadaveric prosections are effective learning tools in anatomy education. They range from a fully dissected, sometimes plastinated, complete cadaver (in situ prosections), to a single, carefully dissected structure detached from a cadaver (ex situ prosections). While most research has focused on the advantages and disadvantages of dissection versus prosection, limited information is available on the instructional efficacy of different prosection types. This contribution explored potential differences between in situ and ex situ prosections regarding the ability of undergraduate students to identify anatomical structures. To determine if students were able to recognize the same anatomical structure on both in situ and ex situ prosections, or on either one individually, six structures were tagged on both prosection types as part of three course summative examinations. The majority of students (61%-68%) fell into one of the two categories: those that recognized or failed to recognize the same structure on both in situ and ex situ prosections. The percentage of students who recognized a selected structure on only one type of prosection was small (1.6%-31.6%), but skewed in favor of ex situ prosections (P ≤ 0.01). These results suggest that overall students' identification ability was due to knowledge differences, not the spatial or contextual challenges posed by each type of prosection. They also suggest that the relative difficulty of either prosection type depends on the nature of the anatomical structure. Thus, one type of prosection might be more appropriate for teaching some structures, and therefore the use of both types is recommended.
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http://dx.doi.org/10.1002/ase.2023DOI Listing
October 2020

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia.

N Engl J Med 2020 08;383(7):617-629

From the Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (C.D.D., M.K.); the Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento (B.A.J.), the Department of Hematology and Hematopoietic Cell Transplantation and Gehr Family Center for Leukemia Research, City of Hope Comprehensive Cancer Center, Duarte (V. Pullarkat), and Genentech, South San Francisco (W.-J.H.) - all in California; the Section of Hematology and Oncology, Department of Medicine, University of Chicago Medicine, Chicago (M.J.T.), and AbbVie, North Chicago (Y.Z., J.P.) - both in Illinois; the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston (J.S.G., A.L.); the Australian Centre for Blood Diseases, Alfred Hospital and Monash University, Melbourne, VIC (A.H.W.); the Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany (H.D.); Hôpital St. Louis, Assistance Publique-Hôpitaux de Paris and Université de Paris, Paris (P.F.); the Third Medical Department for Hematology and Oncology, Hanusch Hospital, Vienna (E.K.); the Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels (V.H.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (B.L.); the Department of Hematology, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute, Barcelona (J.E.); the Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China (J.W.); the Department of Hematology, University Hospital Dubrava, University of Zagreb School of Medicine, Zagreb, Croatia (V. Pejsa); the Department of Clinic Subjects, University Hospital Ostrava-Poruba, Ostrava, Czech Republic (R.H.); Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki (K.P.); the Faculty of Medicine, Department of Hematology, University of Debrecen, Debrecen, Hungary (A.I.); Hadassah Medical Center, Jerusalem (D.L.); the Clinic of Hematology, Department of Internal Medicine, University of Genoa, and San Martino Hospital IRCCS - both in Genoa, Italy (R.M.L.); the Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan (K.Y.); the Department of Internal Medicine, Seoul National University College of Medicine (S.-S.Y.), and the Department of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-H.J.) - both in Seoul, South Korea; the Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan (S.-P.Y.); the Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ondokuz Mayıs University, Samsun, Turkey (M.T.); and Abramson Cancer Center, University of Pennsylvania, Philadelphia (K.W.P.).

Background: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study.

Methods: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival.

Results: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively.

Conclusions: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).
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http://dx.doi.org/10.1056/NEJMoa2012971DOI Listing
August 2020

Prospects for Venetoclax in Myelodysplastic Syndromes.

Hematol Oncol Clin North Am 2020 04 11;34(2):441-448. Epub 2019 Dec 11.

Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Dana 2054, Boston, MA 02215, USA. Electronic address:

BCL-2 is an antiapoptotic protein that plays a critical role acute and chronic leukemias. Venetoclax is an orally selective BCL-2 inhibitor and BH3 mimetic approved in chronic lymphocytic leukemia and in combination with low dose cytarabine or hypomethylating agent in acute myeloid leukemia for the treatment of patients unfit for intensive chemotherapy. This article reviews the biology of BCL-2, focusing on its relationship to the myeloid microenvironment, and discusses the rationale for BCL-2 inhibition in myelodysplastic syndrome (MDS). Clinical trials testing venetoclax in MDS patients are under way. Potential biomarkers for clinical response to BCL-2 inhibition are discussed. Therapeutic opportunities for venetoclax in the therapeutic landscape of MDS are explored.
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http://dx.doi.org/10.1016/j.hoc.2019.10.005DOI Listing
April 2020

Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial.

Lancet Haematol 2020 Feb 11;7(2):e122-e133. Epub 2019 Dec 11.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Background: Increased aurora A kinase (AAK) expression occurs in acute myeloid leukaemia; AAK inhibition is a promising therapeutic target in this disease. We therefore aimed to assess the activity of alisertib combined with 7 + 3 induction chemotherapy in previously untreated patients with high-risk acute myeloid leukaemia.

Methods: We did a single-arm, phase 2 trial of patients recruited from the Dana-Farber/Harvard Cancer Center in the USA. Eligible patients had previously untreated acute myeloid leukaemia, an Eastern Cooperative Oncology Group performance status of 0-2, and were at high risk of disease as defined by the presence of an adverse-risk karyotype, the presence of secondary acute myeloid leukaemia arising from previous myelodysplastic syndrome or myeloproliferative neoplasm, the presence of therapy-related acute myeloid leukaemia, or being 65 years or older. Enrolled patients received 7 + 3 induction chemotherapy of continuous infusion of cytarabine (100 mg/m per day on days 1-7) and intravenous bolus of idarubicin (12 mg/m per day on days 1-3). Oral alisertib (30 mg) was given twice per day on days 8-15. Patients could receive up to four consolidation cycles with cytarabine and alisertib, and alisertib maintenance for 12 months. The primary endpoint was a composite including the proportion of patients achieving complete remission and those with a complete remission with incomplete neutrophil or platelet count recovery. Analyses were per-protocol. This study is registered with Clinicaltrials.gov, number NCT02560025, and has completed enrolment.

Findings: Between Dec 31, 2015, and Aug 1, 2017, we enrolled a total of 39 eligible patients. 19 (49%) of 39 patients had secondary acute myeloid leukaemia and three (8%) had therapy-related acute myeloid leukaemia. At mid-induction, 33 (85%) of 39 patients showed marrow aplasia, six (15%) received re-induction. The median follow-up was 13·7 months (IQR 12·7-14·4). Composite remission was 64% (two-stage 95% CI 48-79), with 20 (51%) of 39 patients achieving complete remission and five (13%) achieving complete remission with incomplete neutrophil or platelet count recovery. The most common grade 3 or 4 adverse events included febrile neutropenia (16 [41%] of 39), neutropenia (12 [31%]), thrombocytopenia (13 [33%]), anaemia (11 [28%]), anorexia (nine [23%]), and oral mucositis (four [10%]). No treatment-related deaths were observed.

Interpretation: These results suggest that alisertib combined with induction chemotherapy is active and safe in previously untreated patients with high-risk acute myeloid leukaemia. This study met criteria to move forward to a future randomised trial.

Funding: Millennium Pharmaceuticals.
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http://dx.doi.org/10.1016/S2352-3026(19)30203-0DOI Listing
February 2020

Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy.

Am J Hematol 2020 03 22;95(3):245-250. Epub 2019 Dec 22.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.
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http://dx.doi.org/10.1002/ajh.25692DOI Listing
March 2020

Clinical, immunophenotypic, and genomic findings of acute undifferentiated leukemia and comparison to acute myeloid leukemia with minimal differentiation: a study from the bone marrow pathology group.

Mod Pathol 2019 09 18;32(9):1373-1385. Epub 2019 Apr 18.

Department of Pathology and Laboratory Medicine, University of Chicago, Chicago, IL, USA.

Acute undifferentiated leukemia is a rare type of acute leukemia that shows no evidence of differentiation along any lineage. Clinical, immunophenotypic and genetic data is limited and it is uncertain if acute undifferentiated leukemia is biologically distinct from acute myeloid leukemia with minimal differentiation, which also shows limited myeloid marker expression and has been reported to have a poor prognosis. We identified 92 cases initially diagnosed as acute undifferentiated leukemia or acute myeloid leukemia with minimal differentiation from pathology databases of nine academic institutions with available diagnostic flow cytometric data, cytogenetic findings, mutational and clinical data. Outcome analysis was performed using Kaplan Meier test for the 53 patients who received induction chemotherapy. Based on cytogenetic abnormalities (N = 30) or history of myelodysplastic syndrome (N = 2), 32 cases were re-classified as acute myeloid leukemia with myelodysplasia related changes. The remaining 24 acute undifferentiated leukemia patients presented with similar age, blood counts, bone marrow cellularity, and blast percentage as the remaining 30 acute myeloid leukemia with minimal differentiation patients. Compared to acute myeloid leukemia with minimal differentiation, acute undifferentiated leukemia cases were characterized by more frequent mutations in PHF6 (5/15 vs 0/19, p = 0.016) and more frequent expression of TdT on blasts (p = 0.003) while acute myeloid leukemia with minimal differentiation cases had more frequent CD123 expression (p = 0.042). Outcome data showed no difference in overall survival, relapse free survival, or rates of complete remission between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation groups (p > 0.05). Acute myeloid leukemia with myelodysplasia-related changes patients showed shorter survival when censoring for bone marrow transplant as compared to acute undifferentiated leukemia (p = 0.03) and acute myeloid leukemia with minimal differentiation (p = 0.002). In this largest series to date, the acute undifferentiated leukemia group shows distinct characteristics from acute myeloid leukemia with minimal differentiation, including more frequent PHF6 mutations and expression of TdT.
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http://dx.doi.org/10.1038/s41379-019-0263-3DOI Listing
September 2019

Genomic and clinical characterization of B/T mixed phenotype acute leukemia reveals recurrent features and T-ALL like mutations.

Am J Hematol 2018 11 26;93(11):1358-1367. Epub 2018 Sep 26.

Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.

The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified nine cases of B/T MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data. We report that B/T MPAL commonly presents with lymphadenopathy in adolescence and young adulthood. While the tumors have diverse cytogenetic and genomic perturbations, recurrent acquired aberrations include mutations in the putative transcriptional regulator PHF6 and the JAK-STAT and Ras signaling pathways. Alterations were also identified in genes encoding hematopoietic transcription factors, cell cycle regulators/tumor suppressors, and chromatin modifying enzymes. The genomic landscape of B/T MPAL strongly resembles that of T-ALL subgroups associated with early developmental arrest, while genetic alterations that are common in B-ALL were rarely seen. Two-thirds of the patients responded to ALL-based chemotherapy with or without stem cell transplantation. Our observations lay the groundwork for further study of the unique biology and clinical trajectory of B/T MPAL.
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http://dx.doi.org/10.1002/ajh.25256DOI Listing
November 2018

Brd4 regulates the expression of essential autophagy genes and Keap1 in AML cells.

Oncotarget 2018 Feb 7;9(14):11665-11676. Epub 2018 Feb 7.

Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, California, USA.

We have recently reported that activation of Brd4 is associated with the presence of autophagy in NPMc+ and MLL AML cells. In order to determine the mechanisms underlying this relationship, we have examined the role of Brd4 in regulating the expression of several genes that are central to the process of autophagy. We found that Brd4 binds to the promoters of ATG 3, 7 and CEBPβ, and expression of these genes is markedly reduced by inhibitors of Brd4, as well as by Brd4-shRNA and depletion of CEBPβ. Inhibitors of Brd4 also dramatically suppress the transcription of Keap1, thereby increasing the expression of anti-oxidant genes through the Nrf2 pathway and reducing the cytotoxicity induced by Brd4 inhibitors. Elimination of ATG3 or KEAP1 expression using CRISPR-cas9 mediated genomic editing markedly reduced autophagy. We conclude that Brd4 plays a significant role in autophagy activation through the direct transcriptional regulation of genes essential for it, as well as through the Keap1-Nrf2 axis in NPMc+ and MLL-fusion AML cells.
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http://dx.doi.org/10.18632/oncotarget.24432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837743PMC
February 2018

Moving Away from the Tip of the Pyramid: Screening and Brief Intervention for Risky Alcohol and Opioid Use in Underserved Patients.

J Am Board Fam Med 2018 Mar-Apr;31(2):243-251

From the Department of Psychology and Center on Alcoholism Substance Abuse, and Addiction (KLV), College of Population Health (VS), Department of Family and Community Medicine (JG, RW, ALS), University of New Mexico, Albuquerque, NM.

Purpose: Rates of risky substance use and substance use disorders are high in primary-care practices, yet the adoption of universal screening and brief intervention (SBI) has been slow and uneven. This study aimed to describe SBI-related attitudes, practices, and perspectives regarding practice change among medical providers in a minority-majority state.

Methods: We conducted a cross-sectional, on-line survey of a practice-based research network of medical providers serving predominantly Hispanic/Latinx and Native American patients in rural and urban settings. The main variables were clinician 1) perspectives on the need to address substance use problems in primary care, 2) current screening and intervention practices, and 3) satisfaction with and willingness to make changes to their practices.

Results: Although providers endorsed alcohol and opiate misuse to be significant problems in their practices, only 25% conducted universal screening. Providers reported focusing most of their screening efforts on those with substance use dependence. In general, providers rated importance of and ability to make practice changes moderately high. There was high interest in practice coordination with the community followed by interest in a collaborative care approach.

Conclusions: Providers mainly focus efforts on the relatively few patients at the tip of the pyramid (substance use dependence) rather than on the majority of patients who comprise the middle of the pyramid (risky substance use). Practice change strategies are needed to increase universal screening with a focus on risky substance use, particularly in practices serving racial/ethnic communities.
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http://dx.doi.org/10.3122/jabfm.2018.02.170134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014597PMC
September 2019

The Development of FLT3 Inhibitors in Acute Myeloid Leukemia.

Hematol Oncol Clin North Am 2017 08 17;31(4):663-680. Epub 2017 May 17.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Dana 2058, Boston, MA 02215-5450, USA.

FLT3 mutations, generally associated with a poor prognosis, are found in approximately one-third of patients with acute myeloid leukemia (AML) and represent an attractive therapeutic target. FLT3 inhibitors undergoing clinical evaluation include first-generation relatively non-specific small molecules and second-generation compounds with higher potency and selectivity against mutant FLT3. Recently presented results from a prospective randomized clinical trial will likely lead to a change in the standard of care for younger patients with FLT3-mutated AML: addition of the multi-targeted FLT3 inhibitor midostaurin to standard induction and consolidation chemotherapy. Thus, personalized therapies for this subset of AML will soon be possible.
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http://dx.doi.org/10.1016/j.hoc.2017.03.002DOI Listing
August 2017

Buffering the Uneven Impact of the Affordable Care Act: Immigrant-serving Safety-net Providers in New Mexico.

Med Anthropol Q 2018 06 9;32(2):233-253. Epub 2017 Jul 9.

Comprehensive Cancer Center, University of New Mexico.

We conducted a study in early 2014 to document how the initial implementation of the Affordable Care Act (ACA) affected health care provision to different categories of immigrants from the perspective of health care providers in New Mexico. Though ACA navigators led enrollment, a range of providers nevertheless became involved by necessity, expressing concern about how immigrants were faring in the newly configured health care environment and taking on advocacy roles. Providers described interpreting shifting eligibility and coverage, attending to vulnerable under/uninsured patients, and negotiating new bureaucratic barriers for insured patients. Findings suggest that, like past efforts, this recent reform to the fragmented health care system has perpetuated a condition in which safety-net clinics and providers are left to buffer a widening gap for immigrant patients. With possible changes to the ACA ahead, safety-net providers' critical buffering roles will likely become more crucial, underscoring the necessity of examining their experiences with past reforms.
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http://dx.doi.org/10.1111/maq.12391DOI Listing
June 2018

Effective Strategies for Affordable Care Act Enrollment in Immigrant-Serving Safety Net Clinics in New Mexico.

J Health Care Poor Underserved 2017 ;28(2):626-634

In the new Affordable Care Act (ACA) health care environment, safety-net institutions continue to serve as important sources of culturally appropriate care for different groups of immigrant patients. This article reports on a qualitative study examining the early ACA enrollment experiences of a range of health care providers (n = 29) in six immigrant-serving safety-net clinics in New Mexico. The six clinics configured their ACA enrollment strategies differently with regard to operations, staffing, and outreach. Providers reported a generally chaotic rollout overall and expressed frustration with strategies that did not accommodate patients, provided little training for providers, and engaged in minimal outreach. Conversely, providers lauded strategies that flexibly met patient needs, leveraged trust through strategic use of staff, and prioritized outreach. Findings underscore the importance of using and funding concerted strategies for future enrollment of immigrant patients, such as featuring community health workers and leveraging trust for outreach.
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http://dx.doi.org/10.1353/hpu.2017.0063DOI Listing
April 2018

Autophagy mediates proteolysis of NPM1 and HEXIM1 and sensitivity to BET inhibition in AML cells.

Oncotarget 2016 Nov;7(46):74917-74930

Stanford Cancer Institute, Stanford University, Stanford, California, USA.

The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells.
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http://dx.doi.org/10.18632/oncotarget.12493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342712PMC
November 2016

The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.

Cancer Cell 2016 04;29(4):574-586

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.
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http://dx.doi.org/10.1016/j.ccell.2016.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177991PMC
April 2016

Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species.

Clin Cancer Res 2016 Apr 3;22(8):1978-88. Epub 2015 Dec 3.

Division of Hematology, Department of Medicine, Stanford University, Stanford, California. Stanford Cancer Institute, Stanford University, Stanford, California.

Purpose: This study was performed to determine whether the investigational proteasome inhibitor ixazomib demonstrated selective antineoplastic activity against acute myelogenous leukemia cells expressing a mutated nucleophosmin-1 gene and to gain a better understanding of its mechanisms of action.

Experimental Design: The cytotoxic effects of ixazomib treatment were analyzed in human acute myelogenous leukemia (AML) cell lines and primary AML samples expressing wild-type or mutated NPM1 (NPMc(+)). The potential roles of oxidative stress in mediating cytotoxic activity were determined using flow cytometry, enzyme-based assays, and Western blots.

Results: Apoptosis induced by ixazomib was abrogated by knockdown of NPM1/NPMc(+)expression using an inducible shRNA construct and enhanced by NPMc(+)overexpression. Cytotoxicity was associated with superoxide generation and was reduced by the addition of the antioxidant N-acetylcysteine. AML cells expressing NPMc(+)had significantly reduced levels of intracellular glutathione and NADPH associated with reduced antioxidant responses to drug treatment. Treatment of 3 patients with relapsed NPMc(+)AML resulted in an antileukemic effect in 1 patient as demonstrated by a marked reduction of leukemic blasts in the peripheral blood. Efficacy was associated with superoxide generation, reduced glutathione levels, and reduced mRNA and protein expression of antioxidant effectors in responding cells.

Conclusions: In this study, a direct association was observed between NPMc(+)expression in AML, reduced antioxidant responses, and enhanced sensitivity to an oral proteasome inhibitor that induces oxidative stress. These data suggest that intracellular determinants of antioxidant responses may be good predictors of therapeutic response to ixazomib.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1440DOI Listing
April 2016

Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome.

Leuk Lymphoma 2016 13;57(3):609-15. Epub 2015 Oct 13.

a Division of Hematology, Department of Medicine , Stanford University School of Medicine , Stanford , CA , USA .

The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). This study describes a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. The median number of treatment cycles on study was two (range = 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders vs non-responders was 9.8 vs 4.0 months, respectively (HR = 0.36, p = 0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.
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http://dx.doi.org/10.3109/10428194.2015.1091930DOI Listing
December 2016

Monosomal karyotype acute myeloid leukemia: tread lightly.

Acta Haematol 2015 4;133(4):324-6. Epub 2014 Dec 4.

Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, Calif., USA.

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http://dx.doi.org/10.1159/000368213DOI Listing
June 2015

Regulation of ribosomal gene expression in cancer.

J Cell Physiol 2015 Jun;230(6):1181-8

Departments of Medicine and Chemical and Systems Biology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.

The ability of a cell to undergo malignant transformation is both associated with and dependent on a concomitant increase in protein synthesis due to increased cell division rates and biosynthetic activities. Protein synthesis, in turn, depends upon the synthesis of ribosomes and thus ultimately on the transcription of ribosomal RNA by RNA polymerase I that occurs in the nucleolus. Enlargement of nucleoli has long been considered a hallmark of the malignant cell, but it is only recently that the rate of synthesis of rRNA in the nucleolus has been recognized as both a critical regulator of cellular proliferation and a potential target for therapeutic intervention. As might be expected, the factors regulating rRNA synthesis are both numerous and complex. It is the objective of this review to highlight recent advances in understanding how rRNA synthesis is perturbed in transformed mammalian cells and to consider the impact of these findings on the development of new approaches to the treatment of malignancies. In-depth analysis of the process of rRNA transcription itself may be found in several recently published reviews (Drygin et al., 2010, Annu Rev Pharmacol Toxicol 50:131-156; Bywater et al., 2013,Cancer Cell 22: 51-65; Hein et al., 2013,Trends Mol Med 19:643-654).
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http://dx.doi.org/10.1002/jcp.24854DOI Listing
June 2015

Comparative study of nasoalveolar molding methods: nasal elevator plus DynaCleft® versus NAM-Grayson in patients with complete unilateral cleft lip and palate.

Cleft Palate Craniofac J 2013 Sep 20;50(5):548-54. Epub 2012 Aug 20.

Objective : To compare nasoalveolar molding (NAM) effect employing a nasal elevator plus DynaCleft® and NAM-Grayson system in patients with complete unilateral cleft lip and palate. Method : Prospective study in two groups. Group A included 20 consecutive patients treated with DynaCleft® and a nasal elevator before lip surgery. Group B included 20 patients treated with NAM-Grayson system. Maxillary casts and standard view photographs were done before and after treatment. Columella deviation angle, soft tissue distance of the cleft, intercommisural distance, and nostril height and width were traced and measured on the printed photos; a ratio was obtained and compared before and after treatment. Cleft width, anterior width, and anteroposterior distances were measured on the maxillary cast. Results : Group A began treatment at an average age of 14.3 days and group B at an average age of 16.9 days; no complications were observed. For group A, the initial average alveolar cleft within the cast was 10.7 mm, and after treatment it was 6.6 mm. For group B, pretreatment width was 11.2 mm, and after treatment it was 5.9 mm. No differences were found on the anterior and posterior width, and A-P distance of both groups. The initial mean columellar angle in group A was 38.1°, and after treatment it was 61.5°; for group B the initial mean columellar angle was 33.6°, and after treatment it was 59.5°. Results of Mann-Whitney U and Student's t tests showed no differences (P > .05). Width and height dimensions of the nostril showed minor differences. Conclusions : Both methods significantly reduced the cleft width and improved the nasal asymmetry. Our findings show that both methods produced similar results.
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http://dx.doi.org/10.1597/11-245DOI Listing
September 2013

Blood consult: monosomal karyotype acute myeloid leukemia.

Blood 2012 Jun 12;119(24):5659-60. Epub 2012 Apr 12.

Stanford University School of Medicine, Stanford, CA 94305-5281, USA.

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http://dx.doi.org/10.1182/blood-2012-01-405225DOI Listing
June 2012

Mathematical modelling and assessment of the pH homeostasis mechanisms in Aspergillus niger while in citric acid producing conditions.

J Theor Biol 2011 Aug 3;282(1):23-35. Epub 2011 May 3.

Grupo de Tecnología Bioquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad de La Laguna, 38206, La Laguna, Tenerife, Islas Canarias, Spain.

In this work we introduce an extended model of the Aspergillus niger metabolism while in citrate production conditions. The model includes many recent findings related to various transport processes. It now considers a new information about the fructose uptake system and the proton and amino acids carriers between cytoplasm and the external medium. It also accounts for recent information about both the malate-citrate antiport between mitochondria and cytoplasm and the dihydrogen citrate ion excretion symport with protons. Finally, the model also accounts for new information about the glycerol-3-phosphate shuttle and pH buffering systems. Provided with this updated representation and after having assessed its quality and dynamic behaviour, we were able to explain the observed pH homoeostasis found in A. niger while in citrate producing conditions. The model also serves to enhance our comprehension of the molecular mechanisms operating in order to keep homoeostasis of pH in A. niger and other fungi, bacteria and yeast of biotechnological relevance.
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http://dx.doi.org/10.1016/j.jtbi.2011.04.028DOI Listing
August 2011

Biochemical systems analysis of signaling pathways to understand fungal pathogenicity.

Methods Mol Biol 2011 ;734:173-200

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.

Over the past decade, researchers have recognized the need to study biological systems as integrated systems. While the reductionist approaches of the past century have made remarkable advances of our understanding of life, the next phase of understanding comes from systems-level investigations. Additionally, biology has become a data-intensive field of research. The introduction of high throughput sequencing, microarrays, high throughput proteomics, metabolomics, and now lipidomics are producing significantly more data than can be interpreted using existing methods. The field of systems biology brings together methods from computer science, modeling, statistics, engineering, and biology to explore the volumes of data now being produced and to develop mathematical representations of metabolic, signaling, and gene regulatory systems. Advances in these methods are allowing biologists to develop new insights into the complexities of life, to predict cellular responses and treatment outcomes, and to effectively plan experiments that extend our understanding. In this chapter, we are providing the basic steps of developing and analyzing a small S-system model of a biochemical pathway related to sphingolipid metabolism in the regulation of virulence of the human fungal microbial pathogen Cryptococcus neoformans (Cn).
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http://dx.doi.org/10.1007/978-1-61779-086-7_9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155339PMC
July 2011