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1.
BMC Med Educ ; 24(1): 482, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38693525

ABSTRACT

PURPOSE: To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities. METHOD: Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content. RESULTS: Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6-16 h, p < 0.0001). Two UME institutions (2.4%; 95% CI, 0.0%-5.8%) reported 0 h during the pre-clerkship phase; 21 institutions (24.7%; CI, 15.5%-33.9%) reported 0 h during the clerkship phase; and 1 institution (1.2%; CI, 0%-3.5%) reported 0 h across the curriculum. Median US allopathic clerkship hours were significantly different from US osteopathic clerkship hours (4 h [IQR, 1-6 h] versus 0 h [IQR, 0-0 h]; p = 0.01). Suggested strategies to increase content included more curricular material focusing on LGBTQI + health and health disparities at 55 schools (64.7%; CI, 54.6%-74.9%), more faculty willing and able to teach LGBTQI + -related content at 49 schools (57.7%; CI, 47.1%-68.2%), and more evidence-based research on LGBTQI + health and health disparities at 24 schools (28.2%; CI, 18.7%-37.8%). CONCLUSION: Compared to a 2011 study, the median reported time dedicated to LGBTQI + health-related topics in 2022 increased across US and Canadian UME institutions, but the breadth, efficacy, or quality of instruction continued to vary substantially. Despite the increased hours, this still falls short of the number of hours based on recommended LGBTQI + health competencies from the Association of American Medical Colleges. While most deans of medical education reported their institutions' coverage of LGBTQI + health as 'fair,' 'good,' or 'very good,' there continues to be a call from UME leadership to increase curricular content. This requires dedicated training for faculty and students.


Subject(s)
Curriculum , Education, Medical, Undergraduate , Sexual and Gender Minorities , Humans , Canada , United States , Education, Medical, Undergraduate/standards , Surveys and Questionnaires , Male , Female
2.
Blood ; 2024 Feb 16.
Article in English | MEDLINE | ID: mdl-38437498

ABSTRACT

BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/co-factors to access enhancers/promoter and modulate gene-expressions responsible for cell growth and differentiation of AML stem/progenitor cells. In AML with MLL1r (MLL1 rearrangement) or mutant (mt) NPM1, although Menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring Menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1 and CDK4/6. Co-treatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In patient-derived xenograft (PDX) models of AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared to each drug, co-treatment with FHD-286 and BETi, MI, decitabine or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with MLL1r or mtNPM1.

3.
Blood Cancer J ; 14(1): 25, 2024 02 05.
Article in English | MEDLINE | ID: mdl-38316746

ABSTRACT

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.


Subject(s)
Blood Platelet Disorders , Leukemia, Myeloid, Acute , Humans , Animals , Mice , Core Binding Factor Alpha 2 Subunit/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Homoharringtonine , Blood Platelets/pathology , Blood Platelet Disorders/complications , Blood Platelet Disorders/genetics , Blood Platelet Disorders/pathology , Proto-Oncogene Proteins c-bcl-2
4.
LGBT Health ; 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38301142

ABSTRACT

Purpose: The "one-liner," commonly used in clinical communications, summarizes a patient's identity, presenting condition, medical history, and clinical findings. Imprecise, inconsistent use of gender and sex information in one-liners threatens the provision of affirming care to transgender, nonbinary, gender-expansive, and intersex patients and may exacerbate health care disparities. This study aimed to generate guidance for communicating gender and sex information in one-liners. Methods: This is an explanatory sequential, equal status mixed methods study of transgender, nonbinary, gender-expansive, and intersex people and clinicians caring for this population. Survey participants rated one-liners on a five-point Likert-type scale of appropriateness, considering affirmation and clinical utility, and provided open-ended comments. We conducted two focus groups with survey respondents to explore survey results and performed a thematic analysis of survey comments and focus group transcripts. Results: Survey respondents included 57 clinicians and 80 nonclinicians. One-liners containing patient pronouns were rated most appropriate, and appropriate patient descriptors included self-described gender identity or gender-neutral terms. In scenarios where patient sex information was not pertinent to the chief concern (CC), one-liners containing no sex information were rated most appropriate. Four themes were identified: inclusion of sex information based on relevance to the CC, accurate patient representation, influence of clinical setting, and risk of harm from inaccurate one-liners. Conclusion: This study generated data to support the appropriate use of gender and sex language in one-liners. Clinicians, educators, and trainees may use these findings to compose one-liners that are affirming and clinically useful for patients of diverse gender and sex identities.

5.
LGBT Health ; 11(2): 131-142, 2024.
Article in English | MEDLINE | ID: mdl-38052073

ABSTRACT

Purpose: The study was designed to evaluate whether an educational intervention to train the health center (HC) staff to optimize care for sexual and gender minority (SGM) patients could improve documentation of sexual orientation and gender identity (SOGI) and increase preventive screenings. Methods: Twelve HCs were matched and randomized to either receive a tailored, multicomponent educational intervention or a 1-hour prerecorded webinar. Documentation of SGM status and clinical testing was measured through analysis of data that HCs report annually. Nonparametric statistics were used to assess associations between baseline HC characteristics and outcome measures. Results: The HCs were geographically, racially, and ethnically diverse. In all but one HC, <10% of the patients were identified as SGM. Intervention HCs underwent between 3 and 10 trainings, which were highly acceptable. In 2018, 9 of 12 HCs documented SO and 11 of 12 documented GI for at least 50% of their patients. Five of 6 intervention HCs increased SO documentation by 2020, compared to 3 of 6 control HCs (nonsignificant, NS). Five intervention HCs increased GI documentation, although generally by less than 10%, compared to 2 of the controls (NS). Intervention HCs tended to increase documentation of preventive services more than control HCs, but the changes were NS. Conclusions: An educational intervention designed to train the HC staff to provide culturally responsive services for SGM patients was found to be acceptable, with favorable, but nonsignificant changes. Further refinement of the intervention using a larger sample of HCs might demonstrate the effectiveness of this approach. Clinical trial registration #: NCT03554785.


Subject(s)
Gender Identity , Sexual and Gender Minorities , Humans , Female , Male , Sexual Behavior
6.
Leukemia ; 38(3): 545-556, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38086946

ABSTRACT

AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear ß-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-ß signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.


Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Humans , Animals , Mice , Transcription Factors/genetics , Transcription Factors/metabolism , MDS1 and EVI1 Complex Locus Protein/genetics , MDS1 and EVI1 Complex Locus Protein/metabolism , Nuclear Proteins/genetics , Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Epigenesis, Genetic , Proto-Oncogenes , Bromodomain Containing Proteins , Cell Cycle Proteins/genetics
7.
BMC Med Educ ; 23(1): 955, 2023 Dec 13.
Article in English | MEDLINE | ID: mdl-38093220

ABSTRACT

BACKGROUND: Multiple duty hour reforms have been implemented to optimize resident wellness through increasing opportunities for sleep recovery, but few studies have recorded objectively measured sleep or shown direct sleep and wellness benefits from such interventions. This study seeks to determine whether mandatory post-call relief policies with a partial night float system improved resident sleep, activity, and burnout among ophthalmology residents taking home call. METHODS: We conducted a two group cohort study of ophthalmology residents at the University Washington comparing post graduate year-2 (PGY-2) resident sleep, activity, and burnout between the optional post-call relief group from July 1, 2017 to June 30, 2019 to the mandatory post-call relief group from July 1, 2019 to June 30, 2021. RESULTS: Of twenty total residents participating in the survey portion, 18 residents participated in the sleep and activity tracking portion of the study, 9 in in the optional post-call relief cohort, and 9 in the mandatory post-call relief cohort. The mandatory post-call relief group recorded longer total sleep on call than the optional post-call relief group (p < 0.001). There was no difference in overnight sleep recorded on call (median 3.4 h), but residents recorded more time napping in the mandatory post-call relief cohort (p < 0.001). There was no significant difference between cohorts in amount of sleep while not on call. Residents in the mandatory post-call relief cohort recorded higher average daily steps, higher exercise time, and lower sedentary time than residents in the optional post-call relief cohort (p < 0.001). They also recorded lower median emotional exhaustion on the Maslach Burnout Inventory and lower stress in the Depression and Anxiety Stress Scale in the mandatory post-call relief cohort (p = 0.008). CONCLUSIONS: Implementation of mandatory post-call relief policies with a partial night-float system among PGY-2 residents was associated with more post-call naps with more overall physical activity, lower emotional exhaustion scores, and lower stress scores, despite no changes to overnight sleep on call or total sleep. Although sample size limits interpretation of data, implementation of mandatory post call relief could be considered to improve post-call sleep in programs with home call.


Subject(s)
Burnout, Professional , Internship and Residency , Ophthalmology , Humans , Cohort Studies , Sleep , Surveys and Questionnaires , Burnout, Professional/prevention & control
8.
J Acad Ophthalmol (2017) ; 15(2): e204-e208, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37744316

ABSTRACT

Purpose This article aims to compare resident sleep while on night float with a traditional home call. Methods We conducted a crossover observational study assessing sleep patterns of seven postgraduate year-2 ophthalmology residents at the University of Washington from 2019 to 2021 using the Fitbit Alta HR device. Overnight call was scheduled from 5 p.m. to 8 a.m. on weekdays, and 8 a.m. to 8 a.m. on weekends. The residency program implemented a partial night float rotation, during which two to three nights of consecutive call were assigned to a resident without other clinical duties. Sleep was recorded using the Fitbit Alta HR for residents while on a 5-week partial night float rotation, on 10-week home call rotations, with postcall relief, and for stretches of seven or more days without call responsibilities. Mixed model regression analysis was used to compare average sleep on home call, night float, and periods without call. Results Sleep data were recorded for a total of 1,015 nights, including 503 nights on home call rotation and 230 nights on night float rotation. Residents slept more during periods away from call compared to either night float or home call rotations ( p < 0.001). Residents experienced increased average overall sleep during 10-week rotations on night float compared to home call ( p = 0.008). While there was no difference in overnight sleep on call between night float and home call ( p = 0.701), residents experienced more sleep overall while on call on night float compared to home call due to more sleep being recorded during postcall naps ( p = 0.016). Conclusion Implementing a night float system can increase resident sleep by allowing for more sleep recovery during time away from clinical duties.

9.
AIDS Educ Prev ; 35(3): 247-253, 2023 06.
Article in English | MEDLINE | ID: mdl-37410373

ABSTRACT

HIV pre-exposure prophylaxis (PrEP) is highly effective, but PrEP use has been suboptimal. We describe a telementoring program for clinics in high-HIV burden areas, focusing on systems-level practice transformation and care for populations disproportionately affected by HIV. We developed and delivered a telementoring program for U.S. health centers. We analyzed participants' baseline and post-session surveys to ascertain experiences providing PrEP and caring for people disproportionately affected by HIV, comparing responses between medical and behavioral health clinicians. Forty-eight people from 16 health centers participated. Medical clinicians were more likely than behavioral health clinicians to care for people taking PrEP, but the groups did not differ in self-rated capacity to counsel about PrEP or care for populations disproportionately affected by HIV. Virtual training on practice transformation for PrEP, involving medical and behavioral health clinicians, is feasible and acceptable. PrEP training and delivery efforts should include behavioral health clinicians.


Subject(s)
Anti-HIV Agents , HIV Infections , Pre-Exposure Prophylaxis , Humans , HIV Infections/prevention & control
10.
Blood Cancer J ; 13(1): 53, 2023 04 13.
Article in English | MEDLINE | ID: mdl-37055414

ABSTRACT

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse.


Subject(s)
Leukemia, Myeloid, Acute , Myeloid-Lymphoid Leukemia Protein , Humans , Cell Cycle Proteins/genetics , Epigenesis, Genetic , Histone Demethylases/genetics , Histone-Lysine N-Methyltransferase/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Myeloid-Lymphoid Leukemia Protein/genetics , Myeloid-Lymphoid Leukemia Protein/metabolism , Neoplasm Recurrence, Local/genetics , Nuclear Proteins/genetics , Proto-Oncogene Proteins/metabolism , Transcription Factors/genetics
11.
Leukemia ; 37(6): 1336-1348, 2023 06.
Article in English | MEDLINE | ID: mdl-36977823

ABSTRACT

In AML with NPM1 mutation causing cytoplasmic dislocation of NPM1, treatments with Menin inhibitor (MI) and standard AML chemotherapy yield complete remissions. However, the causal and mechanistic linkage of mtNPM1 to the efficacy of these agents has not been definitively established. Utilizing CRISPR-Cas9 editing to knockout (KO) or knock-in a copy of mtNPM1 in AML cells, present studies demonstrate that KO of mtNPM1 from AML cells abrogates sensitivity to MI, selinexor (exportin-1 inhibitor), and cytarabine. Conversely, the knock-in of a copy of mtNPM1 markedly sensitized AML cells to treatment with MI or cytarabine. Following AML therapy, most elderly patients with AML with mtNPM1 and co-mutations in FLT3 suffer AML relapse with poor outcomes, creating a need for novel effective therapies. Utilizing the RNA-Seq signature of CRISPR-edited AML cells with mtNPM1 KO, we interrogated the LINCS1000-CMap data set and found several pan-HDAC inhibitors and a WEE1 tyrosine kinase inhibitor among the top expression mimickers (EMs). Additionally, treatment with adavosertib (WEE1 inhibitor) or panobinostat (pan-HDAC inhibitor) exhibited synergistic in vitro lethal activity with MI against AML cells with mtNPM1. Treatment with adavosertib or panobinostat also reduced AML burden and improved survival in AML xenograft models sensitive or resistant to MI.


Subject(s)
Leukemia, Myeloid, Acute , Nuclear Proteins , Humans , Aged , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Nucleophosmin , Panobinostat , Neoplasm Recurrence, Local , Mutation , Cytarabine/pharmacology , Cytarabine/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/therapeutic use
12.
Acad Med ; 98(1): 57-61, 2023 01 01.
Article in English | MEDLINE | ID: mdl-36222538

ABSTRACT

PROBLEM: Medical educators recognize that partnering actively with health system leaders closes significant health care experience, quality, and outcomes gaps. Medical schools have explored innovations training physicians to care for both individual patients and populations while improving systems of care. Yet, early medical student education fails to include systems improvement as foundational skills. When health systems science is taught, it is often separated from core clinical skills. APPROACH: The Clinical Microsystems Clerkship at the University of California, San Francisco School of Medicine, launched in 2016, integrates clinical skills training with health systems improvement from the start of medical school. Guided by communities of practice and workplace learning principles, it embeds first-year and second-year students in longitudinal clinical microsystems with physician coaches and interprofessional clinicians one day per week. Students learn medical history, physical examination, patient communication, interprofessional teamwork, and health systems improvement. Assessments include standardized patient examinations and improvement project reports. Program outcome measures include student satisfaction and attitudes, clinical skills performance, and evidence of systems improvement learning, including dissemination and scholarship. OUTCOMES: Students reported high satisfaction (first-year, 4.10; second-year, 4.29, on a scale of 1-5) and value (4.14) in their development as physicians. Clinical skills assessment accuracy was high (70%-96%). Guided by interprofessional clinicians across 15 departments, students completed 258 improvement projects in 3 health systems (academic, safety net, Veterans Affairs). Sample projects reduced disparities in hypertension, improved opiate safety, and decreased readmissions. Graduating students reported both clinical skills and health systems knowledge as important to physician success, patient experience, and clinical outcomes (4.73). Most graduates discussed their projects in residency applications (85%) and disseminated related papers and presentations (54%). NEXT STEPS: Integrating systems improvement, interprofessional teamwork, and clinical skills training can redefine early medical student education. Health system perspectives, long-term outcomes, and sustainability merit further exploration.


Subject(s)
Clinical Clerkship , Education, Medical, Undergraduate , Education, Medical , Students, Medical , Humans , Clinical Competence , San Francisco , Learning , Curriculum
14.
Med Sci Educ ; 32(6): 1313-1317, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36439405

ABSTRACT

In response to the COVID-19 pandemic, we developed and implemented a theory-informed process to adapt a comprehensive pre-clerkship medical school curriculum to run in the virtual learning environment utilizing sociocultural learning theory and cognitive load theory. Of 124 student respondents, 45% rated virtual learning as very or extremely effective, and 49% as moderately effective. Positive aspects of virtual learning included effectiveness of chat moderators, displaying pronouns on Zoom, active learning technology, and captioning and transcription. Negative aspects included access to technology and feeling isolated from community. Overall course ratings, examination performance, and work hours did not differ pre- and post-implementation.

16.
Nucleic Acids Res ; 50(11): 6020-6037, 2022 06 24.
Article in English | MEDLINE | ID: mdl-35687098

ABSTRACT

At the time of writing, although siRNA therapeutics are approved for human use, no official regulatory guidance specific to this modality is available. In the absence of guidance, preclinical development for siRNA followed a hybrid of the small molecule and biologics guidance documents. However, siRNA differs significantly from small molecules and protein-based biologics in its physicochemical, absorption, distribution, metabolism and excretion properties, and its mechanism of action. Consequently, certain reports typically included in filing packages for small molecule or biologics may benefit from adaption, or even omission, from an siRNA filing. In this white paper, members of the 'siRNA working group' in the IQ Consortium compile a list of reports included in approved siRNA filing packages and discuss the relevance of two in vitro reports-the plasma protein binding evaluation and the drug-drug interaction risk assessment-to support siRNA regulatory filings. Publicly available siRNA approval packages and the literature were systematically reviewed to examine the role of siRNA plasma protein binding and drug-drug interactions in understanding pharmacokinetic/pharmacodynamic relationships, safety and translation. The findings are summarized into two decision trees to help guide industry decide when in vitro siRNA plasma protein binding and drug-drug interaction studies are warranted.


Subject(s)
Blood Proteins , Drug Interactions , Biological Products , Blood Proteins/chemistry , Decision Trees , Humans , Protein Binding , RNA, Small Interfering/chemistry , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology
17.
Blood Cancer J ; 12(1): 5, 2022 01 11.
Article in English | MEDLINE | ID: mdl-35017466

ABSTRACT

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.


Subject(s)
Antineoplastic Agents/pharmacology , Histone-Lysine N-Methyltransferase/genetics , Leukemia, Myeloid, Acute/drug therapy , Myeloid-Lymphoid Leukemia Protein/genetics , Nucleophosmin/genetics , Proto-Oncogene Proteins/antagonists & inhibitors , Aminopyridines/pharmacology , Benzimidazoles/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Gene Expression Regulation, Leukemic/drug effects , Gene Rearrangement/drug effects , Humans , Leukemia, Myeloid, Acute/genetics , Mutation/drug effects , Proto-Oncogene Proteins/genetics , Sulfonamides/pharmacology
18.
Blood ; 139(6): 907-921, 2022 02 10.
Article in English | MEDLINE | ID: mdl-34601571

ABSTRACT

The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed enhancers and their BRD4 occupancy and was associated with reduced levels of c-Myc, c-Myb, MCL1, and Bcl-xL. Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared with each agent alone, cotreatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune-depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.


Subject(s)
Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Core Binding Factor Alpha 2 Subunit/genetics , Homoharringtonine/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Protein Synthesis Inhibitors/pharmacology , Sulfonamides/pharmacology , Cell Line, Tumor , Drug Synergism , Humans , Leukemia, Myeloid, Acute/genetics , Mutation/drug effects , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
19.
Acad Med ; 97(1): 93-104, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34232149

ABSTRACT

PURPOSE: Firearm injury is a leading cause of morbidity and mortality in the United States. However, many medical professionals currently receive minimal or no education on firearm injury or its prevention. The authors sought to convene a diverse group of national experts in firearm injury epidemiology, injury prevention, and medical education to develop consensus on priorities to inform the creation of learning objectives and curricula for firearm injury education for medical professionals. METHOD: In 2019, the authors convened an advisory group that was geographically, demographically, and professionally diverse, composed of 33 clinicians, researchers, and educators from across the United States. They used the nominal group technique to achieve consensus on priorities for health professions education on firearm injury. The process involved an initial idea-generating phase, followed by a round-robin sharing of ideas and further idea generation, facilitated discussion and clarification, and the ranking of ideas to generate a prioritized list. RESULTS: This report provides the first national consensus guidelines on firearm injury education for medical professionals. These priorities include a set of crosscutting, basic, and advanced learning objectives applicable to all contexts of firearm injury and all medical disciplines, specialties, and levels of training. They focus on 7 contextual categories that had previously been identified in the literature: 1 category of general priorities applicable to all contexts and 6 categories of specific contexts, including intimate partner violence, mass violence, officer-involved shootings, peer (nonpartner) violence, suicide, and unintentional injury. CONCLUSIONS: Robust, data- and consensus-driven priorities for health professions education on firearm injury create a pathway to clinician competence and self-efficacy. With an improved foundation for curriculum development and educational program-building, clinicians will be better informed to engage in a host of firearm injury prevention initiatives both at the bedside and in their communities.


Subject(s)
Firearms , Suicide Prevention , Wounds, Gunshot , Consensus , Humans , United States/epidemiology , Violence , Wounds, Gunshot/epidemiology , Wounds, Gunshot/prevention & control
20.
Acad Med ; 97(3S): S71-S81, 2022 Mar 01.
Article in English | MEDLINE | ID: mdl-34789658

ABSTRACT

Medical education exists to prepare the physician workforce that our nation needs, but the COVID-19 pandemic threatened to disrupt that mission. Likewise, the national increase in awareness of social justice gaps in our country pointed out significant gaps in health care, medicine, and our medical education ecosystem. Crises in all industries often present leaders with no choice but to transform-or to fail. In this perspective, the authors suggest that medical education is at such an inflection point and propose a transformational vision of the medical education ecosystem, followed by a 10-year, 10-point plan that focuses on building the workforce that will achieve that vision. Broad themes include adopting a national vision; enhancing medicine's role in social justice through broadened curricula and a focus on communities; establishing equity in learning and processes related to learning, including wellness in learners, as a baseline; and realizing the promise of competency-based, time-variable training. Ultimately, 2020 can be viewed as a strategic inflection point in medical education if those who lead and regulate it analyze and apply lessons learned from the pandemic and its associated syndemics.


Subject(s)
Change Management , Education, Medical/trends , COVID-19 , Forecasting , Humans , Pandemics , SARS-CoV-2 , United States
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