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Article ; Online: Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines.

Wang, Wentian / Ranjan, Alok / Zhang, Wei / Liang, Qiren / MacMillan, Karen S / Chapman, Karen / Wang, Xiaoyu / Chandrasekaran, Preethi / Williams, Noelle S / Rosenbaum, Daniel M / De Brabander, Jef K

Bioorganic & medicinal chemistry letters

2024 Volume 99, Page(s) 129624

Abstract: A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for ... ...

Abstract	A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for G
MeSH term(s)	Orexin Receptors/agonists ; Imines/pharmacology ; Imidazoles/pharmacology ; Pyridines ; Ethers
Chemical Substances	Orexin Receptors ; Imines ; Imidazoles ; Pyridines ; Ethers
Language	English
Publishing date	2024-01-23
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2024.129624
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Article ; Online: The structure of importin α and the nuclear localization peptide of ChREBP, and small compound inhibitors of ChREBP-importin α interactions.

Jung, Hunmin / Takeshima, Tomomi / Nakagawa, Tsutomu / MacMillan, Karen S / Wynn, R Max / Wang, Hanzhi / Sakiyama, Haruhiko / Wei, Shuguang / Li, Yang / Bruick, Richard K / Posner, Bruce A / De Brabander, Jef K / Uyeda, Kosaku

The Biochemical journal

2020 Volume 477, Issue 17, Page(s) 3253–3269

Abstract: The carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in glucose-mediated induction of genes involved in hepatic glycolysis and lipogenesis. In response to fluctuating blood ... ...

Abstract	The carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in glucose-mediated induction of genes involved in hepatic glycolysis and lipogenesis. In response to fluctuating blood glucose levels ChREBP activity is regulated mainly by nucleocytoplasmic shuttling of ChREBP. Under high glucose ChREBP binds to importin α and importin β and translocates into the nucleus to initiate transcription. We have previously shown that the nuclear localization signal site (NLS) for ChREBP is bipartite with the NLS extending from Arg158 to Lys190. Here, we report the 2.5 Å crystal structure of the ChREBP-NLS peptide bound to importin α. The structure revealed that the NLS binding is monopartite, with the amino acid residues K171RRI174 from the ChREBP-NLS interacting with ARM2-ARM5 on importin α. We discovered that importin α also binds to the primary binding site of the 14-3-3 proteins with high affinity, which suggests that both importin α and 14-3-3 are each competing with the other for this broad-binding region (residues 117-196) on ChREBP. We screened a small compound library and identified two novel compounds that inhibit the ChREBP-NLS/importin α interaction, nuclear localization, and transcription activities of ChREBP. These candidate molecules support developing inhibitors of ChREBP that may be useful in treatment of obesity and the associated diseases.
MeSH term(s)	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/chemistry ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Crystallography, X-Ray ; Hep G2 Cells ; Humans ; Nuclear Localization Signals/chemistry ; Nuclear Localization Signals/genetics ; Nuclear Localization Signals/metabolism ; alpha Karyopherins/chemistry ; alpha Karyopherins/genetics ; alpha Karyopherins/metabolism
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; MLXIPL protein, human ; Nuclear Localization Signals ; alpha Karyopherins
Language	English
Publishing date	2020-07-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20200520
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Article ; Online: Pilot Study of Donor-Engrafted Clonal Hematopoiesis Evolution and Clinical Outcomes in Allogeneic Hematopoietic Cell Transplantation Recipients Using a National Registry.

Gillis, Nancy / Padron, Eric / Wang, Tao / Chen, Karen / DeVos, Jakob D / Spellman, Stephen R / Lee, Stephanie J / Kitko, Carrie L / MacMillan, Margaret L / West, Jeffrey / Tang, Yi-Han / Teng, Mingxiang / McNulty, Samantha / Druley, Todd E / Pidala, Joseph A / Lazaryan, Aleksandr

Transplantation and cellular therapy

2023 Volume 29, Issue 10, Page(s) 640.e1–640.e8

Abstract: Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling ... ...

Abstract	Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. We aimed to determine the prevalence of CH in older HLA-matched sibling donors pretransplantation and to assess the clinical impact of donor-engrafted CH on HCT outcomes. This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (Protocol 1202) were included. Older donors and patients (both ≥55 years) receiving first RIC HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), overall survival, relapse, nonrelapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency (VAF) ≥2%, there were 44 CH mutations in 13.7% (41 of 299) of HLA-matched sibling donors. CH mostly involved DNMT3A (n = 27; 61.4%) and TET2 (n= 9; 20.5%). Post-HCT samples from 13 recipients were also sequenced, of whom 7 had CH
Language	English
Publishing date	2023-07-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2023.07.021
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Article: Group plus "mini" individual pre-test genetic counselling sessions for hereditary cancer shorten provider time and improve patient satisfaction.

Hynes, Jaclyn / MacMillan, Andrée / Fernandez, Sara / Jacob, Karen / Carter, Shannon / Predham, Sarah / Etchegary, Holly / Dawson, Lesa

Hereditary cancer in clinical practice

2020 Volume 18, Page(s) 3

Abstract: Background: Genetic counselling (GC) is an integral component in the care of individuals at risk for hereditary cancer predisposition syndromes (CPS). In many jurisdictions, access to timely counselling and testing is limited by financial constraints, ... ...

Abstract	Background: Genetic counselling (GC) is an integral component in the care of individuals at risk for hereditary cancer predisposition syndromes (CPS). In many jurisdictions, access to timely counselling and testing is limited by financial constraints, by the shortage of genetics professionals and by labor-intensive traditional models of individual pre and post-test counselling. There is a need for further research regarding alternate methods of GC service delivery and implementation. This quality improvement project was initiated to determine if pretest group GC followed immediately by a 'mini' individual session, would be acceptable to patients at risk for hereditary breast and colon cancer. Methods: Patients on waitlists for GC at the Provincial Medical Genetics Program in St. John's, NL, Canada ( Results: Sixty participants completed questionnaires. The majority of participants strongly agreed that they were comfortable with the group session (58/60); the explanation of cancer genetics was clear (54/59); they understood their cancer risks (50/60); and they would recommend such a session to others (56/59). 38/53 respondents disagreed or strongly disagreed that they would prefer to wait for a traditional private appointment. All 5 participating genetic counselors reported a preference for this model. At the end of the pilot project, the waitlist for counselling/testing was reduced by 12 months. Conclusions: Group pre-test genetic counselling combined with immediate "mini" individual session is strongly supported by patients and reduces wait times. Additional formal investigation of this approach in larger numbers of patients is warranted.
Language	English
Publishing date	2020-02-19
Publishing country	Poland
Document type	Journal Article
ZDB-ID	2252512-9
ISSN	1897-4287 ; 1731-2302
ISSN (online)	1897-4287
ISSN	1731-2302
DOI	10.1186/s13053-020-0136-2
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Article: An additional spirocyclization for duocarmycin SA.

MacMillan, Karen S / Boger, Dale L

Journal of the American Chemical Society

2009 Volume 130, Issue 49, Page(s) 16521–16523

MeSH term(s)	Alkylation ; Antineoplastic Agents/chemistry ; Cyclization ; Duocarmycins ; Hydrogen-Ion Concentration ; Indoles/chemistry ; Kinetics ; Pyrroles/chemistry
Chemical Substances	Antineoplastic Agents ; Duocarmycins ; Indoles ; Pyrroles ; duocarmycin SA (130288-24-3)
Language	English
Publishing date	2009-06-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja806593w
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Article ; Online: Fundamental relationships between structure, reactivity, and biological activity for the duocarmycins and CC-1065.

MacMillan, Karen S / Boger, Dale L

Journal of medicinal chemistry

2009 Volume 52, Issue 19, Page(s) 5771–5780

MeSH term(s)	Alkylating Agents/chemistry ; Alkylating Agents/pharmacology ; Antibiotics, Antineoplastic/chemistry ; Antibiotics, Antineoplastic/pharmacology ; Duocarmycins ; Indoles/chemistry ; Indoles/pharmacology ; Molecular Structure ; Pyrroles/chemistry ; Pyrroles/pharmacology ; Structure-Activity Relationship
Chemical Substances	Alkylating Agents ; Antibiotics, Antineoplastic ; Duocarmycins ; Indoles ; Pyrroles ; duocarmycin SA (130288-24-3) ; CC 1065 (69866-21-3)
Language	English
Publishing date	2009-07-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm9006214
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Article ; Online: Chronic Graft-versus-Host Disease, Nonrelapse Mortality, and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis.

Transplantation and cellular therapy

2021 Volume 28, Issue 1, Page(s) 34–42

Abstract: The effect of chronic graft-versus-host disease (cGVHD) on the risk of nonrelapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and ... ...

Abstract	The effect of chronic graft-versus-host disease (cGVHD) on the risk of nonrelapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research (CIBMTR) analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (age ≥60 years). We included 4429 adults age ≥40 years who underwent a first HLA-matched peripheral blood stem cell alloHCT for acute myelogenous leukemia or myelodysplastic syndrome between 2008 and 2017. We compared outcomes of 4 groups-older adults (≥60 years) and younger adults (40 to 59 years) with cGVHD and older and younger adults without cGVHD-to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse, and overall survival (OS). We treated cGVHD as a time-dependent covariate. The severity of cGVHD was based on the CIBMTR clinical definitions. cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher for older adults versus younger adults. Adults who developed cGVHD as a group had longer OS compared with age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild to moderate cGVHD was associated with longer OS. Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse, and longer OS. Older adults had a higher risk of NRM, but the increased risk of NRM associated with cGVHD did not differ based on age. The development of mild to moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing the risk of relapse. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
MeSH term(s)	Adult ; Aged ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Middle Aged ; Myelodysplastic Syndromes/therapy ; Recurrence ; Transplantation Conditioning ; United States
Language	English
Publishing date	2021-10-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2021.10.002
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Book ; Online: Galaxy Zoo DECaLS

Walmsley, Mike / Lintott, Chris / Geron, Tobias / Kruk, Sandor / Krawczyk, Coleman / Willett, Kyle W. / Bamford, Steven / Keel, William / Kelvin, Lee S. / Fortson, Lucy / Masters, Karen L. / Mehta, Vihang / Simmons, Brooke D. / Smethurst, Rebecca / Baeten, Elisabeth M. / Macmillan, Christine

Detailed Visual Morphology Measurements from Volunteers and Deep Learning for 314,000 Galaxies

2021

Abstract: We present Galaxy Zoo DECaLS: detailed visual morphological classifications for Dark Energy Camera Legacy Survey images of galaxies within the SDSS DR8 footprint. Deeper DECaLS images (r=23.6 vs. r=22.2 from SDSS) reveal spiral arms, weak bars, and tidal ...

Abstract	We present Galaxy Zoo DECaLS: detailed visual morphological classifications for Dark Energy Camera Legacy Survey images of galaxies within the SDSS DR8 footprint. Deeper DECaLS images (r=23.6 vs. r=22.2 from SDSS) reveal spiral arms, weak bars, and tidal features not previously visible in SDSS imaging. To best exploit the greater depth of DECaLS images, volunteers select from a new set of answers designed to improve our sensitivity to mergers and bars. Galaxy Zoo volunteers provide 7.5 million individual classifications over 314,000 galaxies. 140,000 galaxies receive at least 30 classifications, sufficient to accurately measure detailed morphology like bars, and the remainder receive approximately 5. All classifications are used to train an ensemble of Bayesian convolutional neural networks (a state-of-the-art deep learning method) to predict posteriors for the detailed morphology of all 314,000 galaxies. When measured against confident volunteer classifications, the networks are approximately 99% accurate on every question. Morphology is a fundamental feature of every galaxy; our human and machine classifications are an accurate and detailed resource for understanding how galaxies evolve. Comment: First review received from MNRAS. Data at https://zenodo.org/record/4196267. Temporary interactive viewer at https://share.streamlit.io/mwalmsley/galaxy-poster/gz_decals_mike_walmsley.py
Keywords	Astrophysics - Astrophysics of Galaxies ; Computer Science - Computer Vision and Pattern Recognition
Subject code	520
Publishing date	2021-02-16
Publishing country	us
Document type	Book ; Online
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Article ; Online: Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811, or AbeAdo) - An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity.

Brockway, Anthony J / Volkov, Oleg A / Cosner, Casey C / MacMillan, Karen S / Wring, Stephen A / Richardson, Thomas E / Peel, Michael / Phillips, Margaret A / De Brabander, Jef K

Bioorganic & medicinal chemistry

2017 Volume 25, Issue 20, Page(s) 5433–5440

Abstract: ... inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential ...

Abstract	We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood-brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5'-amine, the ribose, and the purine fragments. Although we gained valuable structure-activity insights from this comprehensive dataset, we did not gain traction on improving the prospects for CNS penetration while retaining the potent antiparasitic activity and metabolic stability of the lead compound 1.
MeSH term(s)	Adenosylmethionine Decarboxylase/antagonists & inhibitors ; Adenosylmethionine Decarboxylase/metabolism ; Animals ; Deoxyadenosines/chemical synthesis ; Deoxyadenosines/chemistry ; Deoxyadenosines/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Mice ; Molecular Conformation ; Parasitic Sensitivity Tests ; Structure-Activity Relationship ; Trypanocidal Agents/chemical synthesis ; Trypanocidal Agents/chemistry ; Trypanocidal Agents/pharmacology ; Trypanosoma brucei brucei/drug effects ; Trypanosomiasis, African/drug therapy
Chemical Substances	Deoxyadenosines ; Enzyme Inhibitors ; Trypanocidal Agents ; MDL 73811 (7GI49JB39O) ; Adenosylmethionine Decarboxylase (EC 4.1.1.50)
Language	English
Publishing date	2017-08-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2017.07.063
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Article ; Online: Severity of Chronic Graft-versus-Host Disease and Late Effects Following Allogeneic Hematopoietic Cell Transplantation for Adults with Hematologic Malignancy.

Lee, Catherine J / Wang, Tao / Chen, Karen / Arora, Mukta / Brazauskas, Ruta / Spellman, Stephen R / Kitko, Carrie / MacMillan, Margaret L / Pidala, Joseph A / Badawy, Sherif M / Bhatt, Neel / Bhatt, Vijaya R / DeFilipp, Zachariah / Diaz, Miguel A / Farhadfar, Nosha / Gadalla, Shahinaz / Hashmi, Shahrukh / Hematti, Peiman / Hossain, Nasheed M /

Inamoto, Yoshihiro / Lekakis, Lazaros J / Sharma, Akshay / Solomon, Scott / Lee, Stephanie J / Couriel, Daniel R

Transplantation and cellular therapy

2023 Volume 30, Issue 1, Page(s) 97.e1–97.e14

Abstract: The study aimed to determine the association of chronic graft-versus-host disease (cGVHD) diagnosis and severity with the development of subsequent neoplasms (SN) and nonmalignant late effects (NM-LE) in 2-year disease-free adult survivors following ... ...

Abstract	The study aimed to determine the association of chronic graft-versus-host disease (cGVHD) diagnosis and severity with the development of subsequent neoplasms (SN) and nonmalignant late effects (NM-LE) in 2-year disease-free adult survivors following hematopoietic cell transplantation (HCT) for a hematologic malignancy. To do so, we conducted a retrospective analysis of 3884 survivors of HCT for hematologic malignancy in the Center of International Blood and Marrow Transplant Research database. We conducted a landmark analysis at the 2-year post-transplantation date, comparing first SN and NM-LE in survivors with and without cGVHD. The cumulative incidence (CuI) of SN and NM-LE were estimated through 10 years post-HCT in both groups, with death or disease relapse as a competing risk. Cox proportional hazards models were used to evaluate the associations of cGVHD and its related characteristics with the development of SN and NM-LE. The estimated 10-year CuI of SN in patients with GVHD (n = 2669) and patients without cGVHD (n = 1215) was 15% (95% confidence interval [CI], 14% to 17%) versus 9% (7.2% to 11%) (P < .001). cGVHD by 2 years post-HCT was independently associated with SN (hazard ratio [HR], 1.94; 95% CI, 1.53 to 2.46; P < .0001) with a standardized incidence ratio of 3.2 (95% CI, 2.9 to 3.5; P < .0001). Increasing severity of cGVHD was associated with an increased risk of SN. The estimated 10-year CuI of first NM-LE in patients with and without cGVHD was 28 (95% CI, 26% to 30%) versus 13% (95% CI, 11% to 15%) (P < .001). cGVHD by 2 years post-HCT was independently associated with NM-LE (HR, 2.23; 95% CI, 1.81 to 2.76; P < .0001). Multivariate analysis of cGVHD-related factors showed that increasing severity of cGVHD, extensive grade, having both mucocutaneous and visceral involvement, and receiving cGVHD treatment for >12 months were associated with the greatest magnitude of risk for NM-LE. cGVHD was closely associated with both SN and NM-LE in adult survivors of HCT for hematologic malignancy. Patients identified as having more severe involvement and both mucocutaneous and visceral organ involvement may warrant enhanced monitoring and screening for SNs and NM-LEs. However, caution is warranted when interpreting these results, as patients with cGVHD may have more vigilant post-transplantation health care and surveillance for late effects.
MeSH term(s)	Adult ; Humans ; Bronchiolitis Obliterans Syndrome ; Retrospective Studies ; Graft vs Host Disease/epidemiology ; Graft vs Host Disease/etiology ; Allografts/pathology ; Neoplasm Recurrence, Local/complications ; Hematologic Neoplasms/complications ; Hematologic Neoplasms/epidemiology ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Disease Progression
Language	English
Publishing date	2023-10-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2023.10.010
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