Publications by authors named "Matthew D Hall"

248 Publications

Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: an observational cohort.

Elife 2021 Nov 23;10. Epub 2021 Nov 23.

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, London, United Kingdom.

There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high density unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics.

We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay.

Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors.

Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly-evolving situation.

This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill and Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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http://dx.doi.org/10.7554/eLife.70970DOI Listing
November 2021

Impact of MRI timing on tumor volume and anatomic displacement for brain metastases undergoing stereotactic radiosurgery.

Neurooncol Pract 2021 Dec 28;8(6):674-683. Epub 2021 Jul 28.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, Florida, USA.

Background: The objective of this study was to evaluate the impact of the time interval between planning imaging and stereotactic radiosurgery (SRS) delivery on tumor volumes and spatial anatomic displacements of brain metastases (BM).

Methods: Consecutive patients diagnosed with BM treated with SRS over a 3-year period were evaluated. Only patients who underwent an institutionally standardized diagnostic MRI (MRI-1) and a treatment planning MRI (MRI-2) were included. The impact of histology, inter-scan time interval, lesion location, tumor volume, and diameter were evaluated on final lesion diameter, volume, anatomic displacement, and ultimate need for change in management (ie, expanding margins, rescanning).

Results: 101 patients (531 lesions) with a median inter-scan time interval of 8 days (range: 1-42 days) met the inclusion criteria. The median percentage increase in BM diameter and volume were 9.5% (IQR: 2.25%-24.0%) and 20% (IQR: 0.7%-66.7%). Overall, 147 lesions (27.7%) in 57 patients (56.4%) required a change in management. There was a statistically significant relationship between initial tumor diameter (cm) and change in management (OR: 2.69, 95% CI: 1.93-3.75; < .001). Each day between MRI-1 and MRI-2 was associated with a change in management with an OR of 1.05 (95% CI: 1.03-1.07; < .001).

Conclusions: Changes in tumor diameter, volume, and spatial position occur as a function of time. Planning imaging for SRS is recommended to occur in close temporal proximity to treatment; for those with delays, a larger setup margin may need to be used to ensure tumor coverage and account for positional changes.
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http://dx.doi.org/10.1093/nop/npab047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579090PMC
December 2021

Factors associated with unplanned readmissions and costs following resection of brain metastases in the United States.

Sci Rep 2021 Nov 12;11(1):22152. Epub 2021 Nov 12.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Office 1R203, Miami, FL, 33176, USA.

The purpose of this study was to critically analyze the risk of unplanned readmission following resection of brain metastasis and to identify key risk factors to allow for early intervention strategies in high-risk patients. We analyzed data from the Nationwide Readmissions Database (NRD) from 2010-2014, and included patients who underwent craniotomy for brain metastasis, identified using ICD-9-CM diagnosis (198.3) and procedure (01.59) codes. The primary outcome of the study was unplanned 30-day all-cause readmission rate. Secondary outcomes included reasons and costs of readmissions. Hierarchical logistic regression model was used to identify the factors associated with 30-day readmission following craniotomy for brain metastasis. During the study period, 44,846 index hospitalizations occurred for patients who underwent resection of brain metastasis. In this cohort, 17.8% (n = 7,965) had unplanned readmissions within the first 30 days after discharge from the index hospitalization. The readmission rate did not change significantly during the five-year study period (p-trend = 0.286). The median per-patient cost for 30-day unplanned readmission was $11,109 and this amounted to a total of $26.4 million per year, which extrapolates to a national expenditure of $269.6 million. Increasing age, male sex, insurance status, Elixhauser comorbidity index, length of stay, teaching status of the hospital, neurological complications and infectious complications were associated with 30-day readmission following discharge after an index admission for craniotomy for brain metastasis. Unplanned readmission rates after resection of brain metastasis remain high and involve substantial healthcare expenditures. Developing tools and interventions to prevent avoidable readmissions could focus on the high-risk patients as a future strategy to decrease substantial healthcare expense.
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http://dx.doi.org/10.1038/s41598-021-01641-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589950PMC
November 2021

The humanized nanobody RBD-1-2G tolerates the spike N501Y mutation to neutralize SARS-CoV-2.

bioRxiv 2021 Oct 24. Epub 2021 Oct 24.

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.

One-sentence Summary: A cost-effective, high-throughput, adaptable pipeline capable of identifying effective humanized nanobodies against SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.10.22.465476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562546PMC
October 2021

Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties.

Chem Sci 2021 Oct 26;12(38):12600-12609. Epub 2021 Aug 26.

Department of Mathematics and Computer Science, Freie Universität Berlin Berlin Germany

SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host cell proteins for viral entry into human lung cells. One of them, the protease TMPRSS2, is required to activate the viral spike protein (S). Even though two inhibitors, camostat and nafamostat, are known to inhibit TMPRSS2 and block cell entry of SARS-CoV-2, finding further potent therapeutic options is still an important task. In this study, we report that a late-stage drug candidate, otamixaban, inhibits SARS-CoV-2 cell entry. We show that otamixaban suppresses TMPRSS2 activity and SARS-CoV-2 infection of a human lung cell line, although with lower potency than camostat or nafamostat. In contrast, otamixaban inhibits SARS-CoV-2 infection of precision cut lung slices with the same potency as camostat. Furthermore, we report that otamixaban's potency can be significantly enhanced by (sub-) nanomolar nafamostat or camostat supplementation. Dominant molecular TMPRSS2-otamixaban interactions are assessed by extensive 109 μs of atomistic molecular dynamics simulations. Our findings suggest that combinations of otamixaban with supplemental camostat or nafamostat are a promising option for the treatment of COVID-19.
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http://dx.doi.org/10.1039/d1sc01494cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494051PMC
October 2021

Systematic evaluation and plan quality assessment of the Leksell® gamma knife® lightning dose optimizer.

Med Dosim 2021 Oct 22. Epub 2021 Oct 22.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176 USA; Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199 USA. Electronic address:

To compare stereotactic radiosurgery (SRS) plan quality metrics of manual forward planning (MFP) and Elekta Fast Inverse Planning™ (FIP)-based inversely optimized plans for patients treated with Gamma Knife®. Clinically treated, MFP SRS plans for 100 consecutive patients (115 lesions; 67 metastatic and 48 benign) were replanned with the FIP dose optimizer based on a convex linear programming formulation. Comparative plans were generated to match or exceed the following metrics in order of importance: Target Coverage (TC), Paddick Conformity Index (PCI), beam-on time (BOT), and Gradient Index (GI). Plan quality metrics and delivery parameters between MFP and FIP were compared for all lesions and stratified into subgroups for further analysis. Additionally, performance of FIP for multiple punctate (<4 mm) metastatic lesions on a subset of cases was investigated. A Wilcoxon signed-rank test for non-normal distributions was used to assess the statistical differences between the MFP and FIP treatment plans. Overall, 76% (87/115) of FIP plans showed a statistically significant improvement in plan quality compared to MFP plans. As compared to MFP, FIP plans demonstrated an increase in the median PCI by 1.1% (p<0.01), a decrease in GI by 3.7% (p< 0.01), and an increase in median number of shots by 74% (p< 0.01). TC and BOT were not statistically significantly different between MFP and FIP plans (p>0.05). FIP plans showed a statistically significant increase in use of 16 mm (p< 0.01) and blocked shots (p< 0.01), with a corresponding decrease in 4 mm shots (p< 0.01). Use of multiple shots per coordinate was significantly higher in FIP plans (p<0.01). The FIP optimizer failed to generate a clinically acceptable plan in 4/115 (3.5%) lesions despite optimization parameter changes. The mean optimization time for FIP plans was 5.0 min (Range: 1.0 - 10.0 min). In the setting of multiple punctate lesions, PCI for FIP was significantly improved (p<0.01) by changing the default low-dose/BOT penalty optimization setting from a default of 50/50 to 75-85/40. FIP offers a significant reduction in manual effort for SRS treatment planning while achieving comparable plan quality to an expert planner-substantially improving overall planning efficiency. FIP plans employ a non-intuitive increased use of blocked sectors and shot-in-shot technique to achieve high quality plans. Several FIP plans failed to achieve clinically acceptable treatments and warrant further investigation.
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http://dx.doi.org/10.1016/j.meddos.2021.08.006DOI Listing
October 2021

Development of therapies for rare genetic disorders of GPX4: roadmap and opportunities.

Orphanet J Rare Dis 2021 10 23;16(1):446. Epub 2021 Oct 23.

CureGPX4.org, Seattle, WA, USA.

Background: Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming.

Main Body: The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies.

Conclusion: The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.
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http://dx.doi.org/10.1186/s13023-021-02048-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542321PMC
October 2021

Hybrid Approach Reveals Novel Inhibitors of Multiple SARS-CoV-2 Variants.

ACS Pharmacol Transl Sci 2021 Oct 17;4(5):1675-1688. Epub 2021 Sep 17.

National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.gov/covid19/). Here, we provide a hybrid approach that utilizes NCATS screening data from the SARS-CoV-2 cytopathic effect reduction assay to build predictive models, using both machine learning and pharmacophore-based modeling. Optimized models were used to perform two iterative rounds of virtual screening to predict small molecules active against SARS-CoV-2. Experimental testing with live virus provided 100 (∼16% of predicted hits) active compounds (efficacy > 30%, IC ≤ 15 μM). Systematic clustering analysis of active compounds revealed three promising chemotypes which have not been previously identified as inhibitors of SARS-CoV-2 infection. Further investigation resulted in the identification of allosteric binders to host receptor angiotensin-converting enzyme 2; these compounds were then shown to inhibit the entry of pseudoparticles bearing spike protein of wild-type SARS-CoV-2, as well as South African B.1.351 and UK B.1.1.7 variants.
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http://dx.doi.org/10.1021/acsptsci.1c00176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482323PMC
October 2021

Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors.

J Med Chem 2021 09 7;64(18):13551-13571. Epub 2021 Sep 7.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that generates galactose-1 phosphate, has been proposed as a novel strategy for treating classic galactosemia. Our previous work identified a highly selective unique dihydropyrimidine inhibitor against GALK1. With the determination of a co-crystal structure of this inhibitor with human GALK1, we initiated a structure-based structure-activity relationship (SAR) optimization campaign that yielded novel analogs with potent biochemical inhibition (IC < 100 nM). Lead compounds were also able to prevent gal-1P accumulation in patient-derived cells at low micromolar concentrations and have pharmacokinetic properties suitable for evaluation in rodent models of galactosemia.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00945DOI Listing
September 2021

Minimal information for chemosensitivity assays (MICHA): a next-generation pipeline to enable the FAIRification of drug screening experiments.

Brief Bioinform 2021 Sep 1. Epub 2021 Sep 1.

Research Program in Systems Oncology, Faculty of medicine, University of Helsinki, Finland.

Chemosensitivity assays are commonly used for preclinical drug discovery and clinical trial optimization. However, data from independent assays are often discordant, largely attributed to uncharacterized variation in the experimental materials and protocols. We report here the launching of Minimal Information for Chemosensitivity Assays (MICHA), accessed via https://micha-protocol.org. Distinguished from existing efforts that are often lacking support from data integration tools, MICHA can automatically extract publicly available information to facilitate the assay annotation including: 1) compounds, 2) samples, 3) reagents and 4) data processing methods. For example, MICHA provides an integrative web server and database to obtain compound annotation including chemical structures, targets and disease indications. In addition, the annotation of cell line samples, assay protocols and literature references can be greatly eased by retrieving manually curated catalogues. Once the annotation is complete, MICHA can export a report that conforms to the FAIR principle (Findable, Accessible, Interoperable and Reusable) of drug screening studies. To consolidate the utility of MICHA, we provide FAIRified protocols from five major cancer drug screening studies as well as six recently conducted COVID-19 studies. With the MICHA web server and database, we envisage a wider adoption of a community-driven effort to improve the open access of drug sensitivity assays.
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http://dx.doi.org/10.1093/bib/bbab350DOI Listing
September 2021

PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia.

Cancer Discov 2021 Aug 20. Epub 2021 Aug 20.

Cancer Center, University of Florida

Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2 mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2 mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. While H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1/(GR) promoter. Pre-treatment of NSD2 p.E1099K cell lines and PDX samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo. PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of pro-apoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1771DOI Listing
August 2021

Effect of Postoperative Radiation Therapy Timing on Survival in Pediatric and Young Adult Ependymoma.

Adv Radiat Oncol 2021 Jul-Aug;6(4):100691. Epub 2021 Mar 26.

Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, Florida.

Purpose: Postoperative radiation therapy (RT) is commonly used for World Health Organization grade II-III intracranial ependymoma. Clinicians generally aim to begin RT ≤5 weeks after surgery, but postoperative recovery and need for second look surgery can delay the initiation of adjuvant therapy. On ACNS 0831, patients were required to enroll ≤8 weeks after initial surgery and begin adjuvant therapy within 3 weeks after enrollment. The purpose of this study was to determine the optimal timing of RT after surgery.

Methods And Materials: The National Cancer Database was queried for patients (aged 1-39 years) with localized World Health Organization grade II-III intracranial ependymoma treated with surgery and postoperative RT. Overall survival (OS) curves were plotted based on RT timing (≤5 weeks, 5-8 weeks, and >8 weeks after surgery) and were compared by log-rank test. Factors associated with OS were identified by multivariate analysis. After 2009, complete data were available on whether patients underwent gross total resection or subtotal resection. Planned subset analysis was performed to examine the effect of RT timing on OS in patients with known extent of resection.

Results: In the final analytical data set of 1043 patients, no difference in 3-year OS was observed in patients who initiated RT ≤5 weeks, 5 to 8 weeks, and >8 weeks after surgery (89.8% vs 89.1% vs 88.4%;  = .796). On multivariate analysis, grade III tumors (hazard ratio, 2.752; 95% confidence interval, 1.969-3.846, < .001) and subtotal resection (hazard ratio, 2.253; 95% confidence interval, 1.405-3.611, < .001) were significantly associated with reduced OS. Timing of RT, total RT dose, age, and other factors were not significant. These findings were affirmed in the subset of patients treated between 2010 and 2016, when extent of resection was routinely recorded.

Conclusions: Delayed postoperative RT was not associated with inferior survival in patients with intracranial ependymoma. Delayed RT initiation may be acceptable in patients who require longer postoperative recovery or referral to an appropriate RT center, but should be minimized whenever practical.
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http://dx.doi.org/10.1016/j.adro.2021.100691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360936PMC
March 2021

The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia.

Sci Transl Med 2021 08;13(607)

Department of Neurology, Duke University Medical Center, Durham, NC 27715, USA.

Dystonias are a group of chronic movement-disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, ∆E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging signals when delivered during a discrete early developmental window. Mechanistically, we found that, across the family of HIV protease inhibitors, efficacy correlated with integrated stress response activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential.
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http://dx.doi.org/10.1126/scitranslmed.abd3904DOI Listing
August 2021

SARS-CoV-2 Seroprevalence and Drug Use in Trauma Patients from Six Sites in the United States.

medRxiv 2021 Aug 11. Epub 2021 Aug 11.

In comparison to the general patient population, trauma patients show higher level detections of bloodborne infectious diseases, such as Hepatitis and Human Immunodeficiency Virus. In comparison to bloodborne pathogens, the prevalence of respiratory infections such as SARS-CoV-2 and how that relates with other variables, such as drug usage and trauma type, is currently unknown in trauma populations. Here, we evaluated SARS-CoV-2 seropositivity and antibody isotype profile in 2,542 trauma patients from six Level-1 trauma centers between April and October of 2020 during the first wave of the COVID-19 pandemic. We found that the seroprevalence in trauma victims 18-44 years old (9.79%, 95% confidence interval/CI: 8.33 11.47) was much higher in comparison to older patients (45-69 years old: 6.03%, 4.59-5.88; 70+ years old: 4.33%, 2.54 - 7.20). Black/African American (9.54%, 7.77 - 11.65) and Hispanic/Latino patients (14.95%, 11.80 - 18.75) also had higher seroprevalence in comparison, respectively, to White (5.72%, 4.62 7.05) and Non-Latino patients (6.55%, 5.57 - 7.69). More than half (55.54%) of those tested for drug toxicology had at least one drug present in their system. Those that tested positive for narcotics or sedatives had a significant negative correlation with seropositivity, while those on anti-depressants trended positive. These findings represent an important consideration for both the patients and first responders that treat trauma patients facing potential risk of respiratory infectious diseases like SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.08.10.21261849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366813PMC
August 2021

Discovery of Small Molecule Entry Inhibitors Targeting the Fusion Peptide of SARS-CoV-2 Spike Protein.

ACS Med Chem Lett 2021 Aug 28;12(8):1267-1274. Epub 2021 Jul 28.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

SARS-CoV-2 entry into host cells relies on the spike (S) protein binding to the human ACE2 receptor. In this study, we investigated the structural dynamics of the viral S protein at the fusion peptide (FP) domain and small molecule binding for therapeutics development. Following comparative modeling analysis and docking studies of our previously identified fusion inhibitor chlorcyclizine, we performed a pharmacophore-based virtual screen and identified two novel chemotypes of entry inhibitors targeting the FP. The compounds were evaluated in the pseudoparticle viral entry assay and SARS-CoV-2 cytopathic effect assay and showed single-digital micromole inhibition against SARS-CoV-2 as well as SARS-CoV-1 and MERS. The characterization of the FP binding site of SARS-CoV-2 S protein provides a promising target for the structure-based development of small molecule entry inhibitors as drug candidates for the treatment of COVID-19.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353886PMC
August 2021

Microbes increase thermal sensitivity in the mosquito Aedes aegypti, with the potential to change disease distributions.

PLoS Negl Trop Dis 2021 07 22;15(7):e0009548. Epub 2021 Jul 22.

Department of Entomology & The Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.

The mosquito Aedes aegypti is the primary vector of many disease-causing viruses, including dengue (DENV), Zika, chikungunya, and yellow fever. As consequences of climate change, we expect an increase in both global mean temperatures and extreme climatic events. When temperatures fluctuate, mosquito vectors will be increasingly exposed to temperatures beyond their upper thermal limits. Here, we examine how DENV infection alters Ae. aegypti thermotolerance by using a high-throughput physiological 'knockdown' assay modeled on studies in Drosophila. Such laboratory measures of thermal tolerance have previously been shown to accurately predict an insect's distribution in the field. We show that DENV infection increases thermal sensitivity, an effect that may ultimately limit the geographic range of the virus. We also show that the endosymbiotic bacterium Wolbachia pipientis, which is currently being released globally as a biological control agent, has a similar impact on thermal sensitivity in Ae. aegypti. Surprisingly, in the coinfected state, Wolbachia did not provide protection against DENV-associated effects on thermal tolerance, nor were the effects of the two infections additive. The latter suggests that the microbes may act by similar means, potentially through activation of shared immune pathways or energetic tradeoffs. Models predicting future ranges of both virus transmission and Wolbachia's efficacy following field release may wish to consider the effects these microbes have on host survival.
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http://dx.doi.org/10.1371/journal.pntd.0009548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297775PMC
July 2021

Thermal limits in the face of infectious disease: How important are pathogens?

Glob Chang Biol 2021 10 14;27(19):4469-4480. Epub 2021 Jul 14.

School of Biological Sciences, Monash University, Melbourne, Vic., Australia.

The frequency and severity of both extreme thermal events and disease outbreaks are predicted to continue to shift as a consequence of global change. As a result, species persistence will likely be increasingly dependent on the interaction between thermal stress and pathogen exposure. Missing from the intersection between studies of infectious disease and thermal ecology, however, is the capacity for pathogen exposure to directly disrupt a host's ability to cope with thermal stress. Common sources of variation in host thermal performance, which are likely to interact with infection, are also often unaccounted for when assessing either the vulnerability of species or the potential for disease spread during extreme thermal events. Here, we describe how infection can directly alter host thermal limits, to a degree that exceeds the level of variation commonly seen across species large geographic distributions and that equals the detrimental impact of other ecologically relevant stressors. We then discuss various sources of heterogeneity within and between populations that are likely to be important in mediating the impact that infection has on variation in host thermal limits. In doing so we highlight how infection is a widespread and important source of variation in host thermal performance, which will have implications for both the persistence and vulnerability of species and the dynamics and transmission of disease in a more thermally extreme world.
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http://dx.doi.org/10.1111/gcb.15761DOI Listing
October 2021

The potential role of MR-guided adaptive radiotherapy in pediatric oncology: Results from a SIOPE-COG survey.

Clin Transl Radiat Oncol 2021 Jul 4;29:71-78. Epub 2021 Jun 4.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background And Purpose: Magnetic resonance guided radiotherapy (MRgRT) has been successfully implemented for several routine clinical applications in adult patients. The purpose of this study is to map the potential benefit of MRgRT on toxicity reduction and outcome in pediatric patients treated with curative intent for primary and metastatic sites.

Materials And Methods: Between May and August 2020, a survey was distributed among SIOPE- and COG-affiliated radiotherapy departments, treating at least 25 pediatrics patients annually and being (candidate) users of a MRgRT system. The survey consisted of a table with 45 rows (clinical scenarios for primary (n = 28) and metastatic (n = 17) tumors) and 7 columns (toxicity reduction, outcome improvement, PTV margin reduction, target volume daily adaptation, online re-planning, intrafraction motion compensation and on-board functional imaging) and the option to answer by 'yes/no' . Afterwards, the Dutch national radiotherapy cohort was used to estimate the percentage of pediatric treatments that may benefit from MRgRT.

Results: The survey was completed by 12/17 (71% response rate) institutions meeting the survey inclusion criteria. Responders indicated an 'expected benefit' from MRgRT for toxicity/outcome in 7% (for thoracic lymphomas and abdominal rhabdomyosarcomas)/0% and 18% (for mediastinal lymph nodes, lymph nodes located in the liver/splenic hilum, and liver metastases)/0% of the considered scenarios for the primary and metastatic tumor sites, respectively, and a 'possible benefit' was estimated in 64%/46% and 47%/59% of the scenarios. When translating the survey outcome into a clinical perspective a toxicity/outcome benefit, either expected or possible, was anticipated for 55%/24% of primary sites and 62%/38% of the metastatic sites.

Conclusion: Although the benefit of MRgRT in pediatric radiation oncology is estimated to be modest, the potential role for reducing toxicity and improving clinical outcomes warrants further investigation. This fits best within the context of prospective studies or registration trials.
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http://dx.doi.org/10.1016/j.ctro.2021.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202186PMC
July 2021

Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States.

Sci Transl Med 2021 07 22;13(601). Epub 2021 Jun 22.

Clinical Studies Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.

Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates in the United States and elsewhere. To address this, we analyzed seropositivity in 9089 adults in the United States who had not been diagnosed previously with COVID-19. Individuals with characteristics that reflected the U.S. population ( = 27,716) were selected by quota sampling from 462,949 volunteers. Enrolled participants ( = 11,382) provided medical, geographic, demographic, and socioeconomic information and dried blood samples. Survey questions coincident with the Behavioral Risk Factor Surveillance System survey, a large probability-based national survey, were used to adjust for selection bias. Most blood samples (88.7%) were collected between 10 May and 31 July 2020 and were processed using ELISA to measure seropositivity (IgG and IgM antibodies against SARS-CoV-2 spike protein and the spike protein receptor binding domain). The overall weighted undiagnosed seropositivity estimate was 4.6% (95% CI, 2.6 to 6.5%), with race, age, sex, ethnicity, and urban/rural subgroup estimates ranging from 1.1% to 14.2%. The highest seropositivity estimates were in African American participants; younger, female, and Hispanic participants; and residents of urban centers. These data indicate that there were 4.8 undiagnosed SARS-CoV-2 infections for every diagnosed case of COVID-19, and an estimated 16.8 million infections were undiagnosed by mid-July 2020 in the United States.
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http://dx.doi.org/10.1126/scitranslmed.abh3826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432952PMC
July 2021

Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles.

J Biol Chem 2021 07 16;297(1):100881. Epub 2021 Jun 16.

Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address:

GPR17 is a G-protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Such evidence is primarily drawn from mouse knockout studies and suggests GPR17 as a potential novel therapeutic target for the treatment of metabolic diseases. However, links between human GPR17 genetic variants, downstream cellular signaling, and metabolic diseases have yet to be reported. Here, we analyzed GPR17 coding sequences from control and disease cohorts consisting of individuals with adverse clinical metabolic deficits including severe insulin resistance, hypercholesterolemia, and obesity. We identified 18 nonsynonymous GPR17 variants, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, membrane localization, and downstream signaling profiles of nine GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). These nine GPR17 variants had similar protein expression and subcellular localization as wild-type GPR17; however, they showed diverse downstream signaling profiles. GPR17-G136S lost the capacity for agonist-mediated cAMP, Ca, and β-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT, but showed impaired Ca and β-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca signaling, but unaffected agonist-stimulated β-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with diverse signaling profiles, including differential signaling perturbations that resulted in GPCR signaling bias. Our findings provide a framework for structure-function relationship studies of GPR17 signaling and metabolic disease.
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http://dx.doi.org/10.1016/j.jbc.2021.100881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267566PMC
July 2021

Discovery of TMPRSS2 Inhibitors from Virtual Screening as a Potential Treatment of COVID-19.

ACS Pharmacol Transl Sci 2021 Jun 2;4(3):1124-1135. Epub 2021 Apr 2.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has prompted researchers to pivot their efforts to finding antiviral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received attention for the development of drugs against SARS and Middle East respiratory syndrome. Starting with comparative structural modeling and a binding model analysis, we developed an efficient pharmacophore-based approach and applied a large-scale in silico database screening for small-molecule inhibitors against TMPRSS2. The hits were evaluated in the TMPRSS2 biochemical assay and the SARS-CoV-2 pseudotyped particle entry assay. A number of novel inhibitors were identified, providing starting points for the further development of drug candidates for the treatment of coronavirus disease 2019.
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http://dx.doi.org/10.1021/acsptsci.0c00221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043206PMC
June 2021

Temperature and pathogen exposure act independently to drive host phenotypic trajectories.

Biol Lett 2021 06 16;17(6):20210072. Epub 2021 Jun 16.

School of Biological Sciences, Monash University, Melbourne, VIC 3800, Australia.

Natural populations are experiencing an increase in the occurrence of both thermal stress and disease outbreaks. How these two common stressors interact to determine host phenotypic shifts will be important for population persistence, yet a myriad of different traits and pathways are a target of both stressors, making generalizable predictions difficult to obtain. Here, using the host and its bacterial pathogen , we tested how temperature and pathogen exposure interact to drive shifts in multivariate host phenotypes. We found that these two stressors acted mostly independently to shape host phenotypic trajectories, with temperature driving a faster pace of life by favouring early development and increased intrinsic population growth rates, while pathogen exposure impacted reproductive potential through reductions in lifetime fecundity. Studies focussed on extreme thermal stress are increasingly showing how pathogen exposure can severely hamper the thermal tolerance of a host. However, our results suggest that under milder thermal stress, and in terms of life-history traits, increases in temperature might not exacerbate the impact of pathogen exposure on host performance, and vice versa.
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http://dx.doi.org/10.1098/rsbl.2021.0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205525PMC
June 2021

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit.

J Infect Dis 2021 Jul;224(Supplement_1):S1-S21

University of Massachusetts Medical School, Worcester, Massachusetts, USA.

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.
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http://dx.doi.org/10.1093/infdis/jiab305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280938PMC
July 2021

A Universal and High-Throughput Proteomics Sample Preparation Platform.

Anal Chem 2021 06 10;93(24):8423-8431. Epub 2021 Jun 10.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Major advances have been made to improve the sensitivity of mass analyzers, spectral quality, and speed of data processing enabling more comprehensive proteome discovery and quantitation. While focus has recently begun shifting toward robust proteomics sample preparation efforts, a high-throughput proteomics sample preparation is still lacking. We report the development of a highly automated universal 384-well plate sample preparation platform with high reproducibility and adaptability for extraction of proteins from cells within a culture plate. Digestion efficiency was excellent in comparison to a commercial digest peptide standard with minimal sample loss while improving sample preparation throughput by 20- to 40-fold (the entire process from plated cells to clean peptides is complete in ∼300 min). Analysis of six human cell types, including two primary cell samples, identified and quantified ∼4,000 proteins for each sample in a single high-performance liquid chromatography (HPLC)-tandem mass spectrometry injection with only 100-10K cells, thus demonstrating universality of the platform. The selected protein was further quantified using a developed HPLC-multiple reaction monitoring method for HeLa digests with two heavy labeled internal standard peptides spiked in. Excellent linearity was achieved across different cell numbers indicating a potential for target protein quantitation in clinical research.
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http://dx.doi.org/10.1021/acs.analchem.1c00265DOI Listing
June 2021

The synergy of BET inhibitors with aurora A kinase inhibitors in MYCN-amplified neuroblastoma is heightened with functional TP53.

Neoplasia 2021 06 7;23(6):624-633. Epub 2021 Jun 7.

Department of Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA. Electronic address:

Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance. We previously performed a viability screen of ∼1,900 oncology-focused compounds combined with BET bromodomain inhibitors against MYCN-amplified NBL cell lines. Reanalysis of our screening results prominently identified inhibitors of aurora kinase A (AURKAi) to be highly synergistic with BETi. We confirmed the anti-proliferative effects of several BETi+AURKAi combinations in MYCN-amplified NBL cell lines. Compared to single agents, these combinations cooperated to decrease levels of N-myc. We treated both TP53-wild type and mutant, MYCN-amplified cell lines with the BETi JQ1 and the AURKAi Alisertib. The combination had improved efficacy in the TP53-WT context, notably driving apoptosis in both genetic backgrounds. JQ1+Alisertib combination treatment of a MYCN-amplified, TP53-null or TP53-restored genetically engineered mouse model of NBL prolonged survival better than either single agent. This was most profound with TP53 restored, with marked tumor shrinkage and apoptosis induction in response to combination JQ1+Alisertib. BETi+AURKAi in MYCN-amplified NBL, particularly in the context of functional TP53, provided anti-tumor benefits in preclinical models. This combination should be studied more closely in a pediatric clinical trial.
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http://dx.doi.org/10.1016/j.neo.2021.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192452PMC
June 2021

Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor.

EMBO J 2021 06 1;40(11):e107226. Epub 2021 May 1.

Malaria Biochemistry Laboratory, The Francis Crick Institute, London, UK.

Malaria parasite egress from host erythrocytes (RBCs) is regulated by discharge of a parasite serine protease called SUB1 into the parasitophorous vacuole (PV). There, SUB1 activates a PV-resident cysteine protease called SERA6, enabling host RBC rupture through SERA6-mediated degradation of the RBC cytoskeleton protein β-spectrin. Here, we show that the activation of Plasmodium falciparum SERA6 involves a second, autocatalytic step that is triggered by SUB1 cleavage. Unexpectedly, autoproteolytic maturation of SERA6 requires interaction in multimolecular complexes with a distinct PV-located protein cofactor, MSA180, that is itself a SUB1 substrate. Genetic ablation of MSA180 mimics SERA6 disruption, producing a fatal block in β-spectrin cleavage and RBC rupture. Drug-like inhibitors of SERA6 autoprocessing similarly prevent β-spectrin cleavage and egress in both P. falciparum and the emerging zoonotic pathogen P. knowlesi. Our results elucidate the egress pathway and identify SERA6 as a target for a new class of antimalarial drugs designed to prevent disease progression.
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http://dx.doi.org/10.15252/embj.2020107226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167364PMC
June 2021

Discovery and Optimization of 2-1λ-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer.

J Med Chem 2021 04 6;64(8):4913-4946. Epub 2021 Apr 6.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2-1λ-quinoline-2,5(6)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (-, ). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
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http://dx.doi.org/10.1021/acs.jmedchem.1c00019DOI Listing
April 2021

Hospitalization rates for complications due to systemic therapy in the United States.

Sci Rep 2021 04 1;11(1):7385. Epub 2021 Apr 1.

Florida International University, Miami, FL, USA.

The aim of this study was to estimate the trends and burdens associated with systemic therapy-related hospitalizations, using nationally representative data. National Inpatient Sample data from 2005 to 2016 was used to identify systemic therapy-related complications using ICD-9 and ICD-10 external causes-of-injury codes. The primary outcome was hospitalization rates, while secondary outcomes were cost and in-hospital mortality. Overall, there were 443,222,223 hospitalizations during the study period, of which 2,419,722 were due to complications of systemic therapy. The average annual percentage change of these hospitalizations was 8.1%, compared to - 0.5% for general hospitalizations. The three most common causes for hospitalization were anemia (12.8%), neutropenia (10.8%), and sepsis (7.8%). Hospitalization rates had the highest relative increases for sepsis (1.9-fold) and acute kidney injury (1.6-fold), and the highest relative decrease for dehydration (0.21-fold) and fever of unknown origin (0.35-fold). Complications with the highest total charges were anemia ($4.6 billion), neutropenia ($3.0 billion), and sepsis ($2.5 billion). The leading causes of in-hospital mortality associated with systemic therapy were sepsis (15.8%), pneumonia (7.6%), and acute kidney injury (7.0%). Promoting initiatives such as rule OP-35, improving access to and providing coordinated care, developing systems leading to early identification and management of symptoms, and expanding urgent care access, can decrease these hospitalizations and the burden they carry on the healthcare system.
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http://dx.doi.org/10.1038/s41598-021-86911-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016938PMC
April 2021

Optimization of ether and aniline based inhibitors of lactate dehydrogenase.

Bioorg Med Chem Lett 2021 06 24;41:127974. Epub 2021 Mar 24.

Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, United States. Electronic address:

Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.
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http://dx.doi.org/10.1016/j.bmcl.2021.127974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113097PMC
June 2021
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