Publications by authors named "Lauren Brown"

144 Publications

NMR-Based Serum and Urine Metabolomic Profile Reveals Suppression of Mitochondrial Pathways in Experimental Sepsis-Associated Acute Kidney Injury.

Am J Physiol Renal Physiol 2021 Apr 12. Epub 2021 Apr 12.

Chemistry and Biochemistry, Miami University, United States.

Sepsis-associated acute kidney injury (SA-AKI) is a significant problem in the critically ill that causes increased death. Emerging understanding of this disease implicates metabolic dysfunction in its pathophysiology. This study sought to identify specific metabolic pathways amenable to potential therapeutic intervention. Using a murine model of sepsis, blood and tissue samples were collected for assessment of systemic inflammation, kidney function, and renal injury. Nuclear magnetic resonance (NMR)-based metabolomics quantified dozens of metabolites in serum and urine which were subsequently submitted to pathway analysis. Kidney tissue gene expression analysis confirmed implicated pathways. Septic mice had elevated circulating levels of inflammatory cytokines and increased levels of blood urea nitrogen and creatinine, indicating both systemic inflammation and poor kidney function. Renal tissue showed only mild histologic evidence of injury in sepsis. NMR metabolomic analysis identified the involvement of mitochondrial pathways associated with branched-chain amino acid (BCAA) metabolism, fatty acid oxidation, and de novo nicotinamide adenine dinucleotide (NAD) biosynthesis in SA-AKI. Renal cortical gene expression of enzymes associated with those pathways was predominantly suppressed. Similar to humans, septic mice demonstrate renal dysfunction without significant tissue disruption, pointing to metabolic derangement as an important contributor to SA-AKI pathophysiology. Metabolism of BCAAs and fatty acids and NAD synthesis, which all center on mitochondrial function, appear to be suppressed. Developing interventions to activate these pathways may provide new therapeutic opportunities for SA-AKI.
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http://dx.doi.org/10.1152/ajprenal.00582.2020DOI Listing
April 2021

Pediatric Education Discharge Support Strategies for Newly Diagnosed Children With Cancer.

Cancer Nurs 2021 Mar 27. Epub 2021 Mar 27.

Author Affiliations: Duke University School of Nursing, Durham, North Carolina (Drs Hockenberry and Hatch and Ms Arthur); Ann & Robert H. Lurie Children's Hospital of Chicago, Illinois (Ms Haugen and Ms Coyne); Cohen Children's Medical Center, New Hyde Park, New York (Ms Slaven); Nationwide Children's Hospital, Columbus, Ohio (Dr Skeens); Children's Health System of Texas Children's Medical Center, Dallas, Texas (Ms Patton); American Family Children's Hospital, University of Wisconsin Health, Madison (Dr Montgomery); Northwestern Medicine Central DuPage Hospital, Chicago, Illinois (Ms Trimble); St Jude Children's Hospital, Memphis, Tennessee (Ms Hancock); King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia (Mr Ahmad); St Louis Children's Hospital, Washington University School of Medicine, Missouri (Ms Daut and Ms Glover); Levine Children's Hospital, Charlotte, North Carolina (Ms Brown); The Barbara Bush Children's Hospital at Maine Medical Center, Portland, Maine (Ms St Pierre); West Virginia University Medicine, Morgantown (Ms Shay); St Peter's University Hospital, New Brunswick, New Jersey (Ms Maloney); Nicklaus Children's Hospital, Miami, Florida (Ms Burke).

Background: Discharge education practices vary among institutions and lack a standardized approach for newly diagnosed pediatric oncology patients and their parents.

Objective: The purpose of this American Nurses Credentialing Center-supported pediatric multisite trial was to determine the feasibility and effectiveness of 2 nurse-led Parent Education Discharge Support Strategies (PEDSS) for families with a child who is newly diagnosed with cancer.

Interventions/methods: A cluster randomized clinical trial design assigned 16 Magnet-designated sites to a symptom management PEDSS intervention or parent support and coping PEDSS intervention. Outcome measures evaluated at baseline, 1, and 2 months after diagnosis include symptom experiences, parent perceptions of care, unplanned service utilization, and parent evaluation of the PEDSS interventions.

Results: There were 283 newly diagnosed children and their parent participating in this study. Linear mixed models revealed pain differed over time by the intervention; children in the symptom management group had a greater decrease in pain. Greater nausea and appetite disturbances were experienced by older children in both groups. Fatigue and sleep disturbance showed a significant decrease over time in both groups. The symptom management group reported significantly greater satisfaction with the PEDSS intervention.

Conclusions: This study is among the first to examine the effects of 2 different early-discharge planning strategies for families of a newly diagnosed child with cancer. The evidence supports a standardized discharge education strategy that can be successfully implemented across institutions.

Implications For Practice: Nurses play a major role in the educational preparation and discharge of newly diagnosed pediatric cancer patients and their families.
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http://dx.doi.org/10.1097/NCC.0000000000000947DOI Listing
March 2021

Employing telehealth within HIV care: Advantages, challenges, and recommendations.

AIDS 2021 Mar 22. Epub 2021 Mar 22.

Legacy Counseling Center, Dallas, TX USA Department of Psychiatry & Behavioral Sciences, School of Medicine, Meharry Medical College, Nashville, TN, USA Infectious Disease Division, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN USA Department of Behavioral Science, University of Kentucky, Lexington, KY, USA Department of Public Administration and Policy, Rockefeller College of Public Affairs and Policy, University at Albany, Albany, NY, USA Center for Collaborative HIV Research in Practice and Policy, School of Public Health, University at Albany Community Health and Implementation Research Program, RTI International, Research Triangle Park, NC, USA.

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http://dx.doi.org/10.1097/QAD.0000000000002892DOI Listing
March 2021

Molecular Biomarkers for Contemporary Therapies in Hormone Receptor-Positive Breast Cancer.

Genes (Basel) 2021 Feb 17;12(2). Epub 2021 Feb 17.

Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.

Systemic treatment of hormone receptor-positive (HR+) breast cancer is undergoing a renaissance, with a number of targeted therapies including CDK4/6, mTOR, and PI3K inhibitors now approved for use in combination with endocrine therapies. The increased use of targeted therapies has changed the natural history of HR+ breast cancers, with the emergence of new escape mechanisms leading to the inevitable progression of disease in patients with advanced cancers. The identification of new predictive and pharmacodynamic biomarkers to current standard-of-care therapies and discovery of new therapies is an evolving and urgent clinical challenge in this setting. While traditional, routinely measured biomarkers such as estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) still represent the best prognostic and predictive biomarkers for HR+ breast cancer, a significant proportion of patients either do not respond to endocrine therapy or develop endocrine resistant disease. Genomic tests have emerged as a useful adjunct prognostication tool and guide the addition of chemotherapy to endocrine therapy. In the treatment-resistant setting, mutational profiling has been used to identify , , and mutations as predictive molecular biomarkers to newer therapies. Additionally, pharmacodynamic biomarkers are being increasingly used and considered in the metastatic setting. In this review, we summarise the current state-of-the-art therapies; prognostic, predictive, and pharmacodynamic molecular biomarkers; and how these are impacted by emerging therapies for HR+ breast cancer.
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http://dx.doi.org/10.3390/genes12020285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922594PMC
February 2021

Application of the Consolidated Framework for Implementation Research to Facilitate Delivery of Trauma-Informed HIV Care.

Ethn Dis 2021 21;31(1):109-118. Epub 2021 Jan 21.

Emory University, Rollins School of Public Health, Department of Behavioral Sciences and Health Education, Atlanta, GA.

Background: The high prevalence of trauma and its negative impact on health among people living with HIV underscore the need for adopting trauma-informed care (TIC), an evidence-based approach to address trauma and its physical and mental sequelae. However, virtually nothing is known about factors internal and external to the clinical environment that might influence adoption of TIC in HIV primary care clinics.

Methods: We conducted a pre-implementation assessment consisting of in-depth interviews with 23 providers, staff, and administrators at a large urban HIV care center serving an un-/under-insured population in the southern United States. We used the Consolidated Framework for Implementation Research (CFIR) to guide qualitative coding to ascertain factors related to TIC adoption.

Results: Inner setting factors perceived as impacting TIC adoption within HIV primary care included relative priority, compatibility, available resources, access to knowledge and information (ie, training), and networks and communications. Relevant outer setting factors included patient needs/resources and cosmopolitanism (ie, connections to external organizations). Overall, the HIV care center exhibited high priority and compatibility for TIC adoption but displayed a need for system strengthening with regard to available resources, training, communications, cosmopolitanism, and patient needs/resources.

Conclusions: Through identification of CFIR inner and outer setting factors that might influence adoption of TIC within an HIV primary care clinic, our findings begin to fill key knowledge gaps in understanding barriers and facilitators for adopting TIC in HIV primary care settings and highlight implementation strategies that could be employed to support successful TIC implementation.
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http://dx.doi.org/10.18865/ed.31.1.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843045PMC
January 2021

Bitter taste receptor agonists regulate epithelial two-pore potassium channels via cAMP signaling.

Respir Res 2021 Jan 28;22(1):31. Epub 2021 Jan 28.

Department of Otorhinolaryngology-Head and Neck Surgery, Division of Rhinology, University of Pennsylvania Medical Center, Perelman School of Medicine, 5th Floor Ravdin Building, 3400 Spruce Street, Philadelphia, PA, USA.

Background: Epithelial solitary chemosensory cell (tuft cell) bitter taste signal transduction occurs through G protein coupled receptors and calcium-dependent signaling pathways. Type II taste cells, which utilize the same bitter taste signal transduction pathways, may also utilize cyclic adenosine monophosphate (cAMP) as an independent signaling messenger in addition to calcium.

Methods: In this work we utilized specific pharmacologic inhibitors to interrogate the short circuit current (Isc) of polarized nasal epithelial cells mounted in Ussing chambers to assess the electrophysiologic changes associated with bitter agonist (denatonium) treatment. We also assessed release of human β-defensin-2 from polarized nasal epithelial cultures following treatment with denatonium benzoate and/or potassium channel inhibitors.

Results: We demonstrate that the bitter taste receptor agonist, denatonium, decreases human respiratory epithelial two-pore potassium (K2P) current in polarized nasal epithelial cells mounted in Ussing chambers. Our data further suggest that this occurs via a cAMP-dependent signaling pathway. We also demonstrate that this decrease in potassium current lowers the threshold for denatonium to stimulate human β-defensin-2 release.

Conclusions: These data thus demonstrate that, in addition to taste transducing calcium-dependent signaling, bitter taste receptor agonists can also activate cAMP-dependent respiratory epithelial signaling pathways to modulate K2P currents. Bitter-agonist regulation of potassium currents may therefore serve as a means of rapid regional epithelial signaling, and further study of these pathways may provide new insights into regulation of mucosal ionic composition and innate mechanisms of epithelial defense.
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http://dx.doi.org/10.1186/s12931-021-01631-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844973PMC
January 2021

Tumor-Infiltrating Lymphocyctes in Triple-Negative Breast Cancer: Update for 2020.

Cancer J 2021 Jan-Feb 01;27(1):25-31

From the Peter MacCallum Cancer Centre, Victoria, Australia.

Abstract: Triple-negative breast cancer (TNBC) continues to represent an unmet need because of its significantly poorer outcomes, including higher relapse rates following early-stage disease and dismal survival times in the advanced setting, when compared with other breast cancer subtypes (Cancer 2012;118:5463-5472). Furthermore, there remains a lack of established systemic treatment options beyond conventional cytotoxic chemotherapy, with the exception of PARP inhibitors in the small subset of patients who harbor a BRCA mutation (N Engl J Med 2018;379:753; Lancet Oncol 2020;21:1269-1282; Ann Oncol 2019;30:558-566) and recently the use of immunotherapy in the first-line metastatic setting in those who are programmed death ligand 1-positive (Lancet Oncol 2020;21(1):44-59; N Engl J Med 2018;379(22):2108-2121). Suitable biomarkers for improving prognostication and directing therapy in both the early and advanced TNBC settings are required in order for improvements in survival outcomes to be continued to be attained. Tumor-infiltrating lymphocytes are gaining increasing relevance as an immunological biomarker in this arena.
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http://dx.doi.org/10.1097/PPO.0000000000000501DOI Listing
January 2021

The Importance of Air Quality Policy for Older Adults and Diverse Communities.

Public Policy Aging Rep 2021 9;31(1):33-37. Epub 2020 Dec 9.

Division of Health Management & Policy, School of Public Health, San Diego State University, San Diego, California, USA.

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http://dx.doi.org/10.1093/ppar/praa036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799383PMC
December 2020

Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity.

J Med Chem 2021 01 14;64(2):1139-1169. Epub 2021 Jan 14.

Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, United States.

The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many of which govern thermotolerance, virulence, and drug resistance in fungal species. However, use of Hsp90 inhibitors as antifungal therapeutics has been precluded by human host toxicities and suppression of immune responses. We recently described resorcylate aminopyrazoles (RAPs) as the first class of Hsp90 inhibitors capable of discriminating between fungal (, ) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure-property optimization toward RAPs capable of inhibiting growth in culture. In addition, we report the first X-ray crystal structures of Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01777DOI Listing
January 2021

Sources of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Other Dioxins in Lower Passaic River, New Jersey, Sediments.

Environ Toxicol Chem 2021 May 5;40(5):1499-1519. Epub 2021 Apr 5.

Ramboll, Portland, Maine, USA.

Elevated levels of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and other contaminants have been reported in lower Passaic River, New Jersey, USA, sediments since the 1980s. Nearly 8000 surficial and buried sediment samples have been collected along the 17 miles (27.4 km) of river and analyzed for various contaminants, including the seventeen 2,3,7,8-substituted PCDD/F congeners. Principal component analysis and hierarchical cluster analysis reveal spatial heterogeneity in the distribution of dioxin congeners, with respect to both sediment depth and river mile. Polytopic vector analysis resolved 11 unique 2,3,7,8-substituted dioxin congener profiles in the river sediment. The profiles were consistent with multiple dioxin source types, including manufacture of certain dyes and pigments, chlorinated industrial chemicals, hexachlorophene, polychlorinated biphenyls, waste disposal and incineration, the production and use of 2,4,5-trichorophenol (2,4,5-TCP), and other industrial processes. The distribution of dioxin profiles in surface and buried river sediments is indicative of multiple inputs of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and other dioxins at different locations along the lower Passaic River. These findings are inconsistent with historical claims that a former herbicide manufacturing plant in the lower reach of the river is the only significant 2,3,7,8-TCDD source and consistent with evidence of several different inputs associated with the production, use, and/or disposal of 2,4,5-TCP at several locations along the lower Passaic River. Environ Toxicol Chem 2021;40:1499-1519. © 2020 SETAC.
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http://dx.doi.org/10.1002/etc.4974DOI Listing
May 2021

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris.

Nat Commun 2020 12 22;11(1):6429. Epub 2020 Dec 22.

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.
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http://dx.doi.org/10.1038/s41467-020-20183-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755909PMC
December 2020

Air sampling for detection of infectious laryngotracheitis (ILT) in commercial poultry flocks.

BMC Res Notes 2020 Dec 9;13(1):556. Epub 2020 Dec 9.

Department of Animal, Plant and Soil Science and Centre for AgriBioscience (AgriBio), La Trobe University, Bundoora, Melbourne, VIC, Australia.

Objective: Infectious laryngotracheitis (ILT) is an acute and highly contagious viral respiratory disease of poultry, caused by gallid herpesvirus 1 (ILTV), which causes significant economic losses. Due to recent outbreaks of ILT in Australia, it has been proposed that ILT could be transmitted between poultry sheds by airborne transmission; however, there has never been direct detection of ILTV from air samples. We aimed to optimize a sampling system for the detection of airborne ILTV in poultry sheds.

Results: Poultry farms with a known outbreaks of ILT were used for detection of airborne ILTV. Infected chickens were verified by detection of ILTV nucleic acid in feather shafts with all farms being positive. Using a liquid cyclonic impinging device, it was found that recovery and detection of airborne ILTV was possible in alkaline PEG buffer. Additional sampling was performed at different heights to determine the presence of ILTV in the air. In farm 3, all three air samples at both heights were positive for ILTV while at farm 2 only one sample at 45 cm was positive. We envisaged in the future air sampling will be able to detect and track potential transmission of ILTV both inside and outside of the poultry shed.
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http://dx.doi.org/10.1186/s13104-020-05399-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727125PMC
December 2020

Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer.

Nat Commun 2020 12 7;11(1):6245. Epub 2020 Dec 7.

Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel.

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.
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http://dx.doi.org/10.1038/s41467-020-20054-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721883PMC
December 2020

Recurrent fusions in pediatric sarcoma and brain tumors.

Cold Spring Harb Mol Case Stud 2020 Dec 17;6(6). Epub 2020 Dec 17.

Children's Cancer Institute, University of New South Wales, Randwick, 2031, Australia.

The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase () family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the fusion directly from a patient sample and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by expression are sensitive to a TRK inhibitor drug. We report here that fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect fusions, these techniques may be of benefit when fusions are not suspected on clinical grounds or not identified by other methods.
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http://dx.doi.org/10.1101/mcs.a005710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784491PMC
December 2020

Measuring More Than Exposure: Does Stress Appraisal Matter for Black-White Differences in Anxiety and Depressive Symptoms Among Older Adults?

Innov Aging 2020 7;4(5):igaa040. Epub 2020 Sep 7.

Leonard Davis School of Gerontology, University of Southern California, Los Angeles.

Background And Objectives: Prior research and theory suggest that exposure to objectively stressful events contributes to mental health disparities. Yet, blacks report higher cumulative stress exposure than whites but lower levels of common psychiatric disorders. In order to understand why blacks bear disproportionate stress exposure but similar or better mental health relative to whites, we need to consider race differences in not only stress exposure, but also stress appraisal-how upsetting stress exposures are perceived to be.

Research Design And Methods: We examine whether race differences in the number of reported chronic stressors across 5 domains (health, financial, residential, relationship, and caregiving) and their appraised stressfulness explain black-white differences in anxiety and depressive symptoms. Data come from 6019 adults aged older than 52 from the 2006 Health and Retirement Study.

Results: Older blacks in this sample experience greater exposure to chronic stressors but appraise stressors as less upsetting relative to whites. In fully adjusted models, stress exposure is related to higher levels of anxiety and depressive symptoms, and perceiving stress as upsetting is associated with higher symptomology for whites and blacks. We also find that blacks report greater anxiety symptoms but fewer depressive symptoms with more stress exposure relative to whites. Stress appraisal partially explains race differences in the association between stress exposure and anxiety symptoms and fully explains race differences in the association between exposure and depressive symptoms.

Discussion And Implications: The relationship between race, chronic stress exposure, and mental health is mediated by stress appraisal. Stress appraisal provides insight on important pathways contributing to black-white mental health disparities in older adulthood.
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http://dx.doi.org/10.1093/geroni/igaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580160PMC
September 2020

Developing a Health Impact Model for Adult Lead Exposure and Cardiovascular Disease Mortality.

Environ Health Perspect 2020 09 23;128(9):97005. Epub 2020 Sep 23.

Abt Associates Inc., Rockville, Maryland, USA.

Background: Lead (Pb) is a highly toxic pollutant. Evidence suggests it is associated with cardiovascular disease (CVD)-related mortality.

Objectives: We present a rigorous approach for identifying concentration-response functions that relate adult Pb exposures to CVD mortality to inform a health impact model (HIM). We then use the model in a proof-of-concept example.

Methods: Building on previously conducted government literature reviews and a supplemental literature review, we compiled and evaluated the available data on Pb and CVD mortality in humans. We applied a set of predefined selection criteria to identify studies that would be most useful in understanding the impact of Pb exposure on CVD mortality risk in adults. Once we identified the studies, we derived a HIM and used each study's concentration-response function in a proof-of-concept example.

Results: Our literature search identified 15 studies for full-text review. Of those 15 studies, 4 fit our criteria for use in the HIM. Using population and CVD mortality rates for 40- to 80-y-olds in 2014, we estimated that 34,000-99,000 deaths have been avoided due to the lowering of blood Pb levels from 1999 to 2014. Based on these values we estimated that approximately 16%-46% of the decreased CVD-related death rate from 1999 to 2014 may be attributable to decreased blood Pb levels.

Conclusion: Our results demonstrate that decreases in Pb exposure can result in large benefits for the adult population. We have provided a HIM that can be used in a variety of applications from burden-of-disease estimates to regulatory impact assessments and have demonstrated its sensitivity to the choice of concentration-response function. https://doi.org/10.1289/EHP6552.
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http://dx.doi.org/10.1289/EHP6552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510336PMC
September 2020

The Effects of Perceived Stress and Cortisol Concentration on Antiretroviral Adherence When Mediated by Psychological Flexibility Among Southern Black Men Living with HIV.

AIDS Behav 2021 Feb;25(2):645-652

Department of Family and Community Medicine, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN, 37208-359, USA.

This pilot study investigates the correlation between psychological stress and antiretroviral therapy (ART) adherence and plasma HIV RNA (viral load) as mediated by psychological flexibility among Black men in the south. Data were collected from 48 HIV-positive, low income Black men. Results indicate a strong positive correlation between perceived stress and psychological inflexibility (adjusted for age and income r = 0.67; p < 0.001), a negative correlation between psychological inflexibility and ART adherence (adjusted r = - 0.32; p = 0.03), a negative correlation between perceived stress and ART adherence (adjusted r = - 0.45; p = 0.006), and a negative correlation between ART adherence and viral load (adjusted r = - 0.37; p = 0.04). Our findings suggest stress decreases adherence to ART and viral suppression among Black men living with HIV. However, psychological flexibility did not mediate the relationship between stress and treatment adherence. Hair cortisol concentrations were high (mean of 34.2 pg/mg), but uncorrelated with adherence.
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http://dx.doi.org/10.1007/s10461-020-03016-8DOI Listing
February 2021

When Is Hope Enough? Hopefulness, Discrimination and Racial/Ethnic Disparities in Allostatic Load.

Behav Med 2020 Jul-Sep;46(3-4):189-201

Jack, Joseph and Morton Mandel School of Applied Social Sciences, Case Western Reserve University.

Hopefulness is associated with better health and may be integral for stress adaptation and resilience. Limited research has prospectively examined whether hopefulness protects against physiological dysregulation or does so similarly for U.S. whites, blacks and Hispanics. We examined the association between baseline hopefulness and future allostatic load using data from the Health and Retirement Study (n = 8,486) and assessed differences in this association by race/ethnicity and experiences of discrimination. Four items measured hopefulness and allostatic load was a count of seven biomarkers for which a respondent's measured value was considered high-risk for disease. A dichotomous variable assessed whether respondents experienced at least one major act of discrimination in their lifetime. We used Poisson regression to examine the association between hopefulness and allostatic load and included a multiplicative interaction term to test racial/ethnic differences in this association. Subsequent analyses were stratified by race/ethnicity and tested the interaction between hopefulness and discrimination within each racial/ethnic group. Hopefulness was associated with lower allostatic load scores, but its effects varied significantly by race/ethnicity. Race-stratified analyses suggested that hopefulness was protective among whites and not associated with allostatic load among Hispanics irrespective of experiencing discrimination. Hopefulness was associated with lower allostatic load among blacks reporting discrimination but associated with higher allostatic load among those who did not. Findings suggest that hopefulness plays differing roles for older whites, blacks and Hispanics and, for blacks, its protective effects on physiological dysregulation are intricately tied to their experiences of discrimination.
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http://dx.doi.org/10.1080/08964289.2020.1729086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458691PMC
July 2021

Cotargeting BCL-2 and MCL-1 in high-risk B-ALL.

Blood Adv 2020 06;4(12):2762-2767

Centre for Cancer Research, University of Melbourne, Parkville, Melbourne, Australia.

Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.
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http://dx.doi.org/10.1182/bloodadvances.2019001416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322969PMC
June 2020

The EXTrauterine Environment for Neonatal Development Supports Normal Intestinal Maturation and Development.

Cell Mol Gastroenterol Hepatol 2020 28;10(3):623-637. Epub 2020 May 28.

Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background And Aims: The Extra-Uterine Environment for Neonatal Development (EXTEND) aims to avoid the complications of prematurity, such as NEC. Our goal was to determine if bowel development occurs normally in EXTEND-supported lambs, with specific emphasis on markers of immaturity associated with NEC.

Methods: We compared terminal ileum from 17 pre-term lambs supported on EXTEND for 2- 4 weeks to bowel from age-matched fetal lambs that developed in utero. We evaluated morphology, markers of epithelial integrity and maturation, enteric nervous system structure, and bowel motility.

Results: EXTEND-supported lamb ileum had normal villus height, crypt depth, density of mucin-containing goblet cells, and enteric neuron density. Expression patterns for I-FABP, activated caspase-3 and EGFR were normal in bowel epithelium. Transmural resistance assessed in Ussing chambers was normal. Bowel motility was also normal as assessed by ex vivo organ bath and video imaging. However, Peyer's patch organization did not occur normally in EXTEND ileum, resulting in fewer circulating B cells in experimental animals.

Conclusion: EXTEND supports normal ileal epithelial and enteric nervous system maturation in pre-term lambs. The classic morphologic changes and cellular expression profiles associated with NEC are not seen. However, immune development within the EXTEND supported lamb bowel does not progress normally.
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http://dx.doi.org/10.1016/j.jcmgh.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408362PMC
May 2020

Posttraumatic stress disorder and breast cancer: Risk factors and the role of inflammation and endocrine function.

Cancer 2020 Jul 6;126(14):3181-3191. Epub 2020 May 6.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.

A breast cancer diagnosis can be a life-changing and stressful experience that can lead to chronic mental health conditions such as posttraumatic stress disorder (PTSD). Greater than one-third of patients initially diagnosed with PTSD after a diagnosis of breast cancer continue to have persistent or worsening PTSD symptoms after 4 years. An emerging body of literature has indicated several key environmental and biological risk factors for PTSD among survivors of breast cancer. Well-recognized risk factors include having a history of childhood trauma, being nonwhite, obesity, younger age at the time of diagnosis, diagnosis with a higher stage of breast cancer, and short time since treatment. Of the emerging risk factors related to fear circuitry in the brain, 2 pathways of particular importance are the stress-driven activation of inflammatory pathways and the long-term effect of antiendocrine therapies. These central and peripheral responses during and after stress exposure are important because increased fear and anxiety can lead to the maintenance of PTSD and worse patient outcomes. Given the poor outcomes associated with PTSD and the high prevalence of breast cancer in women, more research to identify those women at heightened risk of PTSD after breast cancer is warranted to reduce the number of diagnoses and lessen the negative impact of this chronic mental health condition.
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http://dx.doi.org/10.1002/cncr.32934DOI Listing
July 2020

Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris.

mBio 2020 03 10;11(2). Epub 2020 Mar 10.

Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

Fungal infections are a major contributor to infectious disease-related deaths worldwide. Recently, global emergence of the fungal pathogen has caused considerable concern because most isolates are resistant to fluconazole, the most commonly administered antifungal, and some isolates are resistant to drugs from all three major antifungal classes. To identify novel agents with bioactivity against , we screened 2,454 compounds from a diversity-oriented synthesis collection. Of the five hits identified, most shared a common rocaglate core structure and displayed fungicidal activity against These rocaglate hits inhibited translation in but not in its pathogenic relative Species specificity was contingent on variation at a single amino acid residue in Tif1, a fungal member of the eukaryotic initiation factor 4A (eIF4A) family of translation initiation factors known to be targeted by rocaglates. Rocaglate-mediated inhibition of translation in activated a cell death program characterized by loss of mitochondrial membrane potential, increased caspase-like activity, and disrupted vacuolar homeostasis. In a rocaglate-sensitized mutant engineered to express translation initiation factor 1 (Tif1) with the variant amino acid that we had identified in , translation was inhibited but no programmed cell death phenotypes were observed. This surprising finding suggests divergence between these related fungal pathogens in their pathways of cellular responses to translation inhibition. From a therapeutic perspective, the chemical biology that we have uncovered reveals species-specific vulnerability in and identifies a promising target for development of new, mechanistically distinct antifungals in the battle against this emerging pathogen. Emergence of the fungal pathogen has ignited intrigue and alarm within the medical community and the public at large. This pathogen is unusually resistant to antifungals, threatening to overwhelm current management options. By screening a library of structurally diverse molecules, we found that is surprisingly sensitive to translation inhibition by a class of compounds known as rocaglates (also known as flavaglines). Despite the high level of conservation across fungi in their protein synthesis machinery, these compounds inhibited translation initiation and activated a cell death program in but not in its relative Our findings highlight a surprising divergence across the cell death programs operating in species and underscore the need to understand the specific biology of a pathogen in attempting to develop more-effective treatments against it.
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http://dx.doi.org/10.1128/mBio.03329-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064782PMC
March 2020

The application of RNA sequencing for the diagnosis and genomic classification of pediatric acute lymphoblastic leukemia.

Blood Adv 2020 03;4(5):930-942

Murdoch Children's Research Institute, Parkville, VIC, Australia.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and implementation of risk-adapted therapy has been instrumental in the dramatic improvements in clinical outcomes. A key to risk-adapted therapies includes the identification of genomic features of individual tumors, including chromosome number (for hyper- and hypodiploidy) and gene fusions, notably ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1 in B-cell ALL (B-ALL). RNA-sequencing (RNA-seq) of large ALL cohorts has expanded the number of recurrent gene fusions recognized as drivers in ALL, and identification of these new entities will contribute to refining ALL risk stratification. We used RNA-seq on 126 ALL patients from our clinical service to test the utility of including RNA-seq in standard-of-care diagnostic pipelines to detect gene rearrangements and IKZF1 deletions. RNA-seq identified 86% of rearrangements detected by standard-of-care diagnostics. KMT2A (MLL) rearrangements, although usually identified, were the most commonly missed by RNA-seq as a result of low expression. RNA-seq identified rearrangements that were not detected by standard-of-care testing in 9 patients. These were found in patients who were not classifiable using standard molecular assessment. We developed an approach to detect the most common IKZF1 deletion from RNA-seq data and validated this using an RQ-PCR assay. We applied an expression classifier to identify Philadelphia chromosome-like B-ALL patients. T-ALL proved a rich source of novel gene fusions, which have clinical implications or provide insights into disease biology. Our experience shows that RNA-seq can be implemented within an individual clinical service to enhance the current molecular diagnostic risk classification of ALL.
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http://dx.doi.org/10.1182/bloodadvances.2019001008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065479PMC
March 2020

Rocaglates Induce Gain-of-Function Alterations to eIF4A and eIF4F.

Cell Rep 2020 02;30(8):2481-2488.e5

Department of Biochemistry, McGill University, Montreal, QC, Canada; Department of Oncology, McGill University, Montreal, QC, Canada; Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada. Electronic address:

Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.
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http://dx.doi.org/10.1016/j.celrep.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077502PMC
February 2020

Standardizing Multidisciplinary Rounds: Creation of an Efficient and Effective Process to Care for the Critically Ill.

J Nurs Adm 2020 Jan;50(1):5-8

Author Affiliations: Clinical Support Nurse (Ms Brown), Medical Director of Critical Care (Dr Saini), and Critical Care Pharmacist (Dr Carter), SSM Health St Clare Hospital-Fenton, Missouri.

Objective: To describe the impact of a standardized rounding process on rounding time and multidisciplinary member attendance.

Background: Rounding efficiency and effectiveness are often compromised by lack of standardization of important elements including start time and location, the attendance of multidisciplinary representatives, patient presentation highlights, and physician workflow. In 2017, the study authors noted inefficiencies and process failures in multidisciplinary rounds within our ICU.

Methods: We conducted a retrospective review of rounding data before and after the implementation of a simplified and streamlined rounding template for ICU nurses and measures to standardize rounding processes and attendance.

Results: Rounding time was decreased by 25% in postimplementation phase. Additionally, attendance of respiratory therapists, clinical dietitians, and case managers improved.

Conclusions: We suggest the piloting of these strategies in other ICUs that experience similar inefficiencies and process failures during multidisciplinary rounds.
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http://dx.doi.org/10.1097/NNA.0000000000000830DOI Listing
January 2020

eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma.

Nat Commun 2019 11 13;10(1):5151. Epub 2019 Nov 13.

Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.
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http://dx.doi.org/10.1038/s41467-019-13086-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853918PMC
November 2019

The KDEL receptor has a role in the biogenesis and trafficking of the epithelial sodium channel (ENaC).

J Biol Chem 2019 11 25;294(48):18324-18336. Epub 2019 Oct 25.

Division of Pulmonary Medicine and Cystic Fibrosis Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address:

Endoplasmic reticulum protein of 29 kDa (ERp29) is a thioredoxin-homologous endoplasmic reticulum (ER) protein that regulates the biogenesis of cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial sodium channel (ENaC). ERp29 may promote ENaC cleavage and increased open probability by directing ENaC to the Golgi via coat complex II (COP II) during biogenesis. We hypothesized that ERp29's C-terminal KEEL ER retention motif, a KDEL variant that is associated with less robust ER retention, strongly influences its regulation of ENaC biogenesis. As predicted by our previous work, depletion of Sec24D, the cargo recognition component of COP II that we previously demonstrated to interact with ENaC, decreases ENaC functional expression without altering β-ENaC expression at the apical surface. We then tested the influence of KDEL ERp29, which should be more readily retrieved from the proximal Golgi by the KDEL receptor (KDEL-R), and a KEEL-deleted mutant (ΔKEEL ERp29), which should not interact with the KDEL-R. ENaC functional expression was decreased by ΔKEEL ERp29 overexpression, whereas KDEL ERp29 overexpression did not significantly alter ENaC functional expression. Again, β-ENaC expression at the apical surface was unaltered by either of these manipulations. Finally, we tested whether the KDEL-R itself has a role in ENaC forward trafficking and found that KDEL-R depletion decreases ENaC functional expression, again without altering β-ENaC expression at the apical surface. These results support the hypothesis that the KDEL-R plays a role in the biogenesis of ENaC and in its exit from the ER through its association with COP II. The cleavage of the extracellular loops of the epithelial sodium channel (ENaC) α and γ subunits increases the channel's open probability and function. During ENaC biogenesis, such cleavage is regulated by the novel 29-kDa chaperone of the ER, ERp29. Our data here are consistent with the hypothesis that ERp29 must interact with the KDEL receptor to exert its regulation of ENaC biogenesis. The classically described role of the KDEL receptor is to retrieve ER-retained species from the proximal Golgi and return them to the ER via coat complex I machinery. In contrast, our data suggest a novel and important role for the KDEL receptor in the biogenesis and forward trafficking of ENaC.
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http://dx.doi.org/10.1074/jbc.RA119.008331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885628PMC
November 2019

Does Salivary Telomere Length Explain Race/Ethnic Differences in Aging?

Biodemography Soc Biol 2019 Oct-Dec;65(4):351-369. Epub 2020 Nov 26.

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.

Telomere length (TL) is a biomarker that can be used to characterize variability in aging and may explain race/ethnic differences in aging. Yet, it remains unclear if TL is related to aging-associated health risks in multi-ethnic populations or if it explains race/ethnic differences in health. We examine whether salivary TL (STL) explains any of the race/ethnic variability in 15 indicators of high-risk biological, physical and cognitive health among 4,074 white, black, and Latinx older adults ages 54+ in the 2008 Health and Retirement Study. TL was assayed from saliva using quantitative PCR (T/S ratio). Decomposition analyses from logistic regression models show variation in STL does not account for any of the observed race/ethnic differences health. In age-adjusted, race-stratified models, STL was associated with HDL, total cholesterol, and lung function among whites, but was not associated with any markers of health among black or Latinx groups. In this diverse national sample of older adults, STL does not account for race/ethnic differences in late life health, is associated with relatively few indicators of health among whites, and is not associated with indicators of health among black or Latinx groups. STL may not be a useful biomarker for understanding racial/ethnic differences in population aging among older adults.
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http://dx.doi.org/10.1080/19485565.2020.1798736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7740300PMC
November 2020

Amidino-Rocaglates: A Potent Class of eIF4A Inhibitors.

Cell Chem Biol 2019 11 10;26(11):1586-1593.e3. Epub 2019 Sep 10.

Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Oncology, McGill University, Montreal, Canada; Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada. Electronic address:

Rocaglates share a common cyclopenta[b]benzofuran core that inhibits eukaryotic translation initiation by modifying the behavior of the RNA helicase, eIF4A. Working as interfacial inhibitors, rocaglates stabilize the association between eIF4A and RNA, which can lead to the formation of steric barriers that block initiating ribosomes. There is significant interest in the development and expansion of rocaglate derivatives, as several members of this family have been shown to possess potent anti-neoplastic activity in vitro and in vivo. To further our understanding of rocaglate diversity and drug design, herein we explore the RNA clamping activity of >200 unique rocaglate derivatives. Through this, we report on the identification and characterization of a potent class of synthetic rocaglates called amidino-rocaglates. These compounds are among the most potent rocaglates documented to date and, taken together, this work offers important information that will guide the future design of rocaglates with improved biological properties.
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http://dx.doi.org/10.1016/j.chembiol.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874763PMC
November 2019

Design and Synthesis of Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors.

J Med Chem 2020 03 26;63(5):2139-2180. Epub 2019 Sep 26.

Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215, United States.

The molecular chaperone Hsp90, essential in all eukaryotes, plays a multifaceted role in promoting survival, virulence, and drug resistance across diverse pathogenic fungal species. The chaperone is also critically important, however, to the pathogen's human host, preventing the use of known clinical Hsp90 inhibitors in antifungal applications due to concomitant host toxicity issues. With the goal of developing Hsp90 inhibitors with acceptable therapeutic indices for the treatment of invasive fungal infections, we initiated a program to design and synthesize potent inhibitors with selective activity against fungal Hsp90 isoforms over their human counterparts. Building on our previously reported derivatization of resorcylate natural products to produce fungal-selective compounds, we have developed a series of synthetic aminopyrazole-substituted resorcylate amides with broad, potent, and fungal-selective Hsp90 inhibitory activity. Herein we describe the synthesis of this series, as well as biochemical structure-activity relationships driving selectivity for the Hsp90 isoforms expressed by and , two pathogenic fungi of major clinical importance.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069776PMC
March 2020