tbuckley/cabot-search huggingface dataset:
Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development
Authors: Yurong Lai, Xiaoyan Chu, Li Di, Wei Gao, Yingying Guo, Xingrong Liu, Chuang Lu, Jialin Mao, Hong Shen, Huaping Tang, Cindy Q. Xia, Lei Zhang, Xinxin Ding
Journal: Acta Pharmaceutica Sinica B (2022)

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.
Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways
Authors: Peter P. Zandi, Andrew E. Jaffe, Fernando S. Goes, Emily E. Burke, Leonardo Collado-Torres, Louise Huuki-Myers, Arta Seyedian, Yian Lin, Fayaz Seifuddin, Mehdi Pirooznia, Christopher A. Ross, Joel E. Kleinman, Daniel R. Weinberger, Thomas M. Hyde
Journal: Nature Neuroscience (2022)
Association of Medication Treatment for Opioid Use Disorder With Suicide Mortality
Authors: Bradley V. Watts, Daniel J. Gottlieb, Natalie B. Riblet, Jiang Gui, Brian Shiner
Journal: American Journal of Psychiatry (2022)

Understanding the effectiveness of medication treatment for opioid use disorder to decrease the risk of suicide mortality may inform clinical and policy decisions. The authors sought to describe the effect of medications for opioid use disorder (MOUD) on risk of suicide mortality.This was a retrospective cohort study in Department of Veterans Affairs (VA) patients from 2003 to 2017. The authors linked three data sources: the VA Corporate Data Warehouse, Centers for Medicare and Medicaid Services Claims Data, and the VA-Department of Defense Mortality Data Repository. The exposure of interest was MOUD, including starting periods (first 14 days on treatment), stopping periods (first 14 days off treatment), stable time on treatment, and stable time off treatment (reference category). The main outcome measures included suicide mortality, external-cause mortality, and all-cause mortality in the 5 years following initiation of MOUD.Over 60,000 VA patients received MOUD. Patients were typically male (92.8%) and their mean age was 46.5 years (SD=13.1). After adjusting for demographic characteristics, mental health and physical health conditions, and health care utilization, the adjusted hazard ratio during stable MOUD was 0.45 (95% CI=0.32, 0.63) for suicide mortality, 0.35 (95% CI=0.31, 0.40) for external-cause mortality, and 0.34 (95% CI=0.31, 0.37) for all-cause mortality. MOUD starting periods were associated with an adjusted hazard ratio for suicide mortality of 0.55 (95% CI=0.25, 1.21), and MOUD stopping periods were associated with an adjusted hazard ratio for suicide mortality of 1.38 (95% CI=0.82, 2.34).Treatment with MOUD was associated with a substantial reduction in suicide mortality as well external causes of mortality and all-cause mortality.
Concurrent silencing of TBCE and drug delivery to overcome platinum-based resistance in liver cancer
Authors: Senlin Li, Siyu Chen, Zhihui Dong, Xingdong Song, Xiuling Li, Ziqi Huang, Huiru Li, Linzhuo Huang, Ganyuan Zhuang, Ran Lan, Mingyan Guo, Wende Li, Phei Er Saw, Lei Zhang
Journal: Acta Pharmaceutica Sinica B (2022)

Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma (HCC). Herein, RNAseq analysis revealed that elevated tubulin folding cofactor E (TBCE) expression is associated with platinum-based chemotherapy resistance. High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients. Mechanistically, TBCE silencing significantly affects cytoskeleton rearrangement, which in turn increases cisplatin-induced cycle arrest and apoptosis. To develop these findings into potential therapeutic drugs, endosomal pH-responsive nanoparticles (NPs) were developed to simultaneously encapsulate TBCE siRNA and cisplatin (DDP) to reverse this phenomena. NPs (siTBCE + DDP) concurrently silenced TBCE expression, increased cell sensitivity to platinum treatment, and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft (PDX) models. Taken together, NP-mediated delivery and the co-treatment of siTBCE + DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.
Performance Comparison of Computational Methods for the Prediction of the Function and Pathogenicity of Non-Coding Variants
Authors: Zheng Wang, Guihu Zhao, Bin Li, Zhenghuan Fang, Qian Chen, Xiaomeng Wang, Tengfei Luo, Yijing Wang, Qiao Zhou, Kuokuo Li, Lu Xia, Yi Zhang, Xun Zhou, Hongxu Pan, Yuwen Zhao, Yige Wang, Lin Wang, Jifeng Guo, Beisha Tang, Kun Xia, Jinchen Li
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Non-coding variants in the human genome significantly influence human traits and complex diseases via their regulation and modification effects. Hence, an increasing number of computational methods are developed to predict the effects of variants in human non-coding sequences. However, it is difficult for inexperienced users to select appropriate computational methods from dozens of available methods. To solve this issue, we assessed 12 performance metrics of 24 methods on four independent non-coding variant benchmark datasets: (1) rare germline variants from clinical relevant sequence variants (ClinVar), (2) rare somatic variants from Catalogue Of Somatic Mutations In Cancer (COSMIC), (3) common regulatory variants from curated expression quantitative trait locus (eQTL) data, and (4) disease-associated common variants from curated genome-wide association studies (GWAS). All 24 tested methods performed differently under various conditions, indicating varying strengths and weaknesses under different scenarios. Importantly, the performance of existing methods was acceptable for rare germline variants from ClinVar with the area under the receiver operating characteristic curve (AUROC) of 0.4481–0.8033 and poor for rare somatic variants from COSMIC (AUROC = 0.4984–0.7131), common regulatory variants from curated eQTL data (AUROC = 0.4837–0.6472), and disease-associated common variants from curated GWAS (AUROC = 0.4766–0.5188). We also compared the prediction performance of 24 methods for non-coding de novo mutations in autism spectrum disorder, and found that the combined annotation-dependent depletion (CADD) and context-dependent tolerance score (CDTS) methods showed better performance. Summarily, we assessed the performance of 24 computational methods under diverse scenarios, providing preliminary advice for proper tool selection and guiding the development of new techniques in interpreting non-coding variants.
Comparison of Long-term Performance of Bioprosthetic Aortic Valves in Sweden From 2003 to 2018
Authors: Michael Persson, Natalie Glaser, Johan Nilsson, Örjan Friberg, Anders Franco-Cereceda, Ulrik Sartipy
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The performance of bioprosthetic aortic valves is usually assessed in single valve models or head-to-head comparisons. National databases or registries offer the opportunity to investigate all available valve models in the population and allows for a comparative assessment of their performance. <h3>Objective</h3> To analyze the long-term rates of reintervention, all-cause mortality, and heart failure hospitalization associated with commonly used bioprosthetic aortic valves and to identify valve model groups with deviation in clinical performance. <h3>Design, Setting, and Participants</h3> This population-based, nationwide cohort study included all adult patients who underwent surgical aortic valve replacement (with or without concomitant coronary artery bypass surgery or ascending aortic surgery) in Sweden between January 1, 2003, and December 31, 2018. Patients were identified from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry. Patients with concomitant valve surgery, previous cardiac surgery, and previous transcatheter valve replacement were excluded. Follow-up was complete for all participants. Data were analyzed from March 9, 2020, to October 12, 2021. <h3>Exposures</h3> Primary surgical aortic valve replacement with the Perimount, Mosaic/Hancock, Biocor/Epic, Mitroflow/Crown, Soprano, and Trifecta valve models. <h3>Main Outcomes and Measures</h3> The primary outcome was cumulative incidence of reintervention, defined as a subsequent aortic valve operation or transcatheter valve replacement. Secondary outcomes were all-cause mortality and heart failure hospitalization. Regression standardization and flexible parametric survival models were used to account for intergroup differences. Mean follow-up time was 7.1 years, and maximum follow-up time was 16.0 years. <h3>Results</h3> A total of 16 983 patients (mean [SD] age, 72.6 [8.5] years; 10 685 men [62.9%]) were included in the analysis. The Perimount valve model group had the lowest and the Mitroflow/Crown valve model group had the highest cumulative incidence of reintervention. The estimated cumulative incidence of reintervention at 10 years was 3.6% (95% CI, 3.1%-4.2%) in the Perimount valve model group and 12.2% (95% CI, 9.8%-15.1%) in the Mitroflow/Crown valve model group. The estimated incidence of reintervention at 10 years was 9.3% (95% CI, 7.3%-11.3%) in the Soprano valve model group. <h3>Conclusions and Relevance</h3> Results of this study showed that the Perimount valve was the most commonly used and had the lowest incidence of reintervention, all-cause mortality, and heart failure hospitalization, whereas the Mitroflow/Crown valve had the highest rates. These findings highlight the need for clinical vigilance in patients who receive either a Soprano or Mitroflow/Crown aortic bioprosthesis.
MULTIPLE ANTI-ARRHYTHMIC DRUGS DID NOT LEAD TO REDUCTION IN ICD SHOCKS IN A CONTINUOUS FLOW LVAD POPULATION: A SINGLE CENTER EXPERIENCE
Authors: Peter Rothstein, Summit Pandat, Rachel Laird, Amy Truman, Momin Islam, Syed Zaid, Arvind Bhimaraj, Rayan Yousefzai, Paul Schurmann, Amish S. Dave, Miguel Valderrabano, Nilesh Mathuria
Journal: Journal of the American College of Cardiology (2022)
DEEP LEARNING-BASED CLASSIFICATION OF DIASTOLIC FUNCTION USING 2D ECHOCARDIOGRAPHIC IMAGES
Authors: Ali Sadeghi, Lucas Oliveira, Nils Gessert, Jin Liu, Simon Wehle, Mathieu De Craene, David Prabhu, Parastou Eslami, Irina Waechter, Victor Mor-Avi, Amita Singh, Roberto M. Lang
Journal: Journal of the American College of Cardiology (2022)
Treatment patterns and outcomes of patients with relapsed or refractory follicular lymphoma receiving three or more lines of systemic therapy (LEO CReWE): a multicentre cohort study
Authors: Carla Casulo, Melissa C Larson, Julianne J Lunde, Thomas M Habermann, Izidore S Lossos, Yucai Wang, Loretta J Nastoupil, Christopher Strouse, Dai Chihara, Peter Martin, Jonathon B Cohen, Brad S Kahl, W Richard Burack, Jean L Koff, Yong Mun, Anthony Masaquel, Mei Wu, Michael C Wei, Ashwini Shewade, Jia Li, James Cerhan, Christopher R Flowers, Brian K Link, Matthew J Maurer
Journal: The Lancet Haematology (2022)
Abstract P4-01-18: Acquired sensitivity strategies in ER+ breast cancer progressing on CDK4/6 and mTOR inhibitors
Authors: Eleni Farmaki, Rena Emond, Patrick Cosgrove, Andrea Bild
Journal: Cancer Research (2022)

Abstract Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and mammalian target of rapamycin (mTOR) inhibitors have become important components of the clinical management of metastatic ER+ breast cancer. Despite the benefit of these treatments, progression and resistance will still develop in the majority of patients. Therefore, it is important to research strategies that can increase response durability and effectiveness of these therapies. The aim of our study is to use the identified acquired resistance targets in progressing patients for treatment approaches. Our previous studies on the evolution of resistance using transcriptomic analysis in earlier stage patients as they progress on therapy identified resistance pathways that include the MAPK, AKT, and survival signaling pathways. We used isogenic breast cancer cell lineages sensitive and resistant to CDK4/6 inhibitors, ribociclib and abemaciclib, and the mTOR inhibitor, everolimus, to determine the efficacy of drug combinations targeting the acquired resistance JNK, MAPK and AKT pathways. The effect of the pathways’ inhibition in the resistant cells was examined in vitro, in 2D drug response assays, and in 3D spheroid assays. Our results indicate increased potency in the resistant cells to the combination therapies with JNK and TIC10/ONC201 inhibitors which are currently seeing promise in clinical trials. These findings were validated in 2D and 3D in vitro studies with patient derived breast cancer cells under the same combination treatments, recapitulating the increased response to combination therapy and further supporting clinical relevance. In conclusion, our study leveraged our patient data cohorts as well as pre-clinical models to identify acquired sensitivity to JNK, MAPK and AKT inhibition. With the linking of both patient derived data with isogenic cell line driven experiments, our study provides validated findings in various settings strengthening the potential of clinical applications of these targetable pathways. Citation Format: Eleni Farmaki, Rena Emond, Patrick Cosgrove, Andrea Bild. Acquired sensitivity strategies in ER+ breast cancer progressing on CDK4/6 and mTOR inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-18.
Moving Beyond Race-Based Medicine
Authors: Ashok V. Daftary
Journal: Annals of Internal Medicine (2022)

LettersMarch 2022Moving Beyond Race-Based MedicineAshok V. Daftary, MDAshok V. Daftary, MDStockton, CaliforniaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L21-0777 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: Jones (1) is correct that our crude categorizations of race are not always relevant. As an Asian Indian, how would I be categorized? I am neither White nor Black and not Hispanic.It would have been impossible to separate every thread from Joseph's coat. The uniqueness of the United States, like that of Joseph's coat, is defined by its myriad colors. Any move to separate them would destroy the fabric of the nation as it would have destroyed Joseph's coat.Recent demands for a special place for critical race theories that postulate that a particular race (or ...Reference1. Jones DS. Moving beyond race-based medicine. Ann Intern Med. 2021;174:1745-6. [PMID: 34662149] doi:10.7326/M21-3804 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Stockton, CaliforniaDisclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L21-0777. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoMoving Beyond Race-Based Medicine David S. Jones Moving Beyond Race-Based Medicine Mack Roach III Moving Beyond Race-Based Medicine David S. Jones Metrics March 2022Volume 175, Issue 3Page: W20KeywordsMammographyRacial and ethnic issuesRacismResearch designStructural racism ePublished: 15 March 2022 Issue Published: March 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and <i>FLT3</i>-Internal Tandem Duplication
Authors: Hiroto Inaba, Jolieke G. van Oosterwijk, John C. Panetta, Lie Li, Daelynn R. Buelow, James S. Blachly, Sheila Shurtleff, Ching-Hon Pui, Raul C. Ribeiro, Jeffrey E. Rubnitz, Stanley Pounds, Sharyn D. Baker
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To evaluate the safety, activity, and emergence of FLT3-kinase domain (KD) mutations with combination therapy of crenolanib and sorafenib in acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD). Patients and Methods: After in vitro and xenograft efficacy studies using AML cell lines that have FLT3-ITD with or without FLT3-KD mutation, a pilot study was performed with crenolanib (67 mg/m2/dose, three times per day on days 1–28) and two dose levels of sorafenib (150 and 200 mg/m2/day on days 8–28) in 9 pediatric patients with refractory/relapsed FLT3-ITD–positive AML. Pharmacokinetic, pharmacodynamic, and FLT3-KD mutation analysis were done in both preclinical and clinical studies. Results: The combination of crenolanib and sorafenib in preclinical models showed synergy without affecting pharmacokinetics of each agent, inhibited p-STAT5 and p-ERK for up to 8 hours, and led to significantly better leukemia response (P &amp;lt; 0.005) and survival (P &amp;lt; 0.05) compared with single agents. Fewer FLT3-KD mutations emerged with dose-intensive crenolanib (twice daily) and low-intensity sorafenib (three times/week) compared with daily crenolanib or sorafenib (P &amp;lt; 0.05). The crenolanib and sorafenib combination was tolerable without dose-limiting toxicities, and three complete remissions (one with incomplete count recovery) and one partial remission were observed in 8 evaluable patients. Median crenolanib apparent clearance showed a nonsignificant decrease during treatment (45.0, 40.5, and 20.3 L/hour/m2 on days 1, 7, and 14, respectively) without drug–drug interaction. Only 1 patient developed a FLT3-KD mutation (FLT3 F691L). Conclusions: The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.
Recommendations for the surveillance of mental health problems in childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group
Authors: Jordan Gilleland Marchak, Salome Christen, Renée L Mulder, Katja Baust, Johanna M C Blom, Tara M Brinkman, Iris Elens, Erika Harju, Nina S Kadan-Lottick, Joel W T Khor, Jurgen Lemiere, Christopher J Recklitis, Claire E Wakefield, Lori Wiener, Louis S Constine, Melissa M Hudson, Leontien C M Kremer, Roderick Skinner, Janine Vetsch, Jennifer L Lee, Gisela Michel
Journal: The Lancet Oncology (2022)
Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening
Authors: Haijiang Dong, Zequn Li, Suchen Bian, Guangyuan Song, Wenfeng Song, Mingqi Zhang, Haiyang Xie, Shusen Zheng, Xuxu Yang, Tiefeng Li, Penghong Song
Journal: Bioactive Materials (2022)

A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening. The economical and high-efficiency simulation of the liver tumor microenvironment (TME) in a drug-screening model has high value yet challenging to accomplish. Herein, we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters, and the culture of patient-derived tumor organoids(PDTOs) for personalized pre-clinical drug screening. The hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in vivo. As a result, 18 of the 28 patient-derived multicellular clusters were successfully cultured as PDTOs. These PDTOs, along with hepatocyte growth factor (HGF) of non-cellular components, preserve stromal cells, including cancer-associated fibroblasts (CAFs) and vascular endothelial cells (VECs). They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver tumors. Drugs, including cabazitaxel, oxaliplatin, and sorafenib, were tested in PDTOs. The sensitivity of PDTOs to these drugs differs between individuals. The sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging (MRI) and biochemical tests after oxaliplatin clinical treatment of the corresponding patient. Therefore, this approach is promising for economical, accurate, and high-throughput drug screening for personalized treatment.