tbuckley/cabot-search huggingface dataset:
Abstract 14580: Methodological Challenges Conducting In Vitro Ischemia and Reperfusion: A Fundamental Problem in Cell Viability Determination
Authors: Santiago J Miyara, Muhammad Shoaib, Yusuke Endo, Rishabh C Choudhary, Kei Hayashida, Koichiro Shinozaki, Tomoaki Aoki, Junhwan Kim, Mitsuaki Nishikimi, Sara Guevara, Ernesto P Molmenti, Linda Shore-lesserson, Judith Aronsohn, Lance B Becker
Journal: Circulation (2021)

Background: Oxygen &amp; Glucose Deprivation (OGD) and Reperfusion (OGD-R) is considered one of the best models for studying ischemia and reperfusion injury (IRI) in vitro. Cell viability (CV) experimentation can aid in estimating cell survival after IRI insults and potential benefits from therapeutic attempts. However, the different metabolites used in various CV assays may compromise the usefulness and validity of various CV tools. We conducted two independent cell viability assays (WST-8 &amp; ATP) after OGD and OGD-R on neurons (NE) and astrocytes (AS). Methods: NE (HT-22) and AS (C8-D1A) were subjected to 6h OGD only and 6h OGD followed by 20h Reperfusion (OGD-R). OGD is based on the combination of chemical ischemia (standard culture media depleted of glucose and other energy sources) and severe hypoxia (O2 ~1.4 to 1.8%) for 6h, while 20h reperfusion consists of readdition of standard culture media and conditions (21% O2, 5% CO2, 37°C). CV was determined by WST-8 and ATP “CellTiter-Glo 2.0” assays. Results: By WST-8 assay, OGD decreased CV in NE (Fig. 1A, P value = 0.0121), but increased CV in AS (Fig. 1A, P value = 0.0079). OGD-R decreased CV in NE and AS (Fig. 2A, P value = 0.0010, 0.0146, respectively). By ATP assay, OGD decreased CV in NE (Fig. 1B, P value &lt;0.0001) and AS (Fig. 1C, P value &lt;0.0001). OGD-R also decreased CV in NE (Fig. 2B, P value &lt;0.0001) and AS (Fig. 2C, P value = 0.0001). Conclusions: The current data reveals opposite CV results after OGD in AS when comparing WST-8 and ATP assays; OGD caused CV decrease in NE but increased in AS, which constitutes a paradoxical response based on previous literature. However, OGD-R caused similar injury patterns in NE and AS from WST-8 and ATP assays. It is unknown why OGD increased CV in AS through WST-8 after OGD, however, it can potentially occur due to AS hypermetabolism leading to increased NADPH+ production, which is the main substrate in this CV estimation. We conclude that CV should be carefully assessed with multiple, independent CV assays.
Impact of COVID-19 in patients with multiple myeloma based on a global data network
Authors: J. Martinez-Lopez, G. Hernandez-Ibarburu, R. Alonso, J. M. Sanchez-Pina, I. Zamanillo, N. Lopez-Muñoz, Rodrigo Iñiguez, C. Cuellar, M. Calbacho, M. L. Paciello, R. Ayala, N. García-Barrio, D. Perez-Rey, L. Meloni, J. Cruz, M. Pedrera-Jiménez, P. Serrano-Balazote, J. de la Cruz
Journal: Blood Cancer Journal (2021)

Abstract The COVID-19 pandemic has represented a major cause of morbidity/mortality worldwide, overstressing health systems. Multiple myeloma (MM) patients show an increased risk for infections and they are expected to be particularly vulnerable to SARS-CoV-2 infection. Here we have obtained a comprehensive picture of the impact of COVID-19 in MM patients on a local and a global scale using a federated data research network (TriNetX) that provided access to Electronic Medical Records (EMR) from Health Care Organizations (HCO) all over the world. Through propensity score matched analyses we found that the number of new diagnoses of MM was reduced in 2020 compared to 2019 (RR 0.86, 95%CI 0.76–0.96) and the survival of newly diagnosed MM cases decreased similarly (HR 0.61, 0.38–0.81). MM patients showed higher risk of SARS-CoV-2 infection (RR 2.09, 1.58–2.76) and a higher excess mortality in 2020 (difference in excess mortality 9%, 4.4–13.2) than non-MM patients. By interrogating large EMR datasets from HCO in Europe and globally, we confirmed that MM patients have been more severely impacted by COVID-19 pandemic than non-MM patients. This study highlights the necessity of extending preventive measures worlwide to protect vulnerable patients from SARS-CoV-2 infection by promoting social distancing and an intensive vaccination strategies.
Corrigendum to: Proton and carbon ion radiotherapy in skull base chordomas: a prospective study based on a dual particle and a patient-customized treatment strategy
Authors: Alberto Iannalfi, Emma D’Ippolito, Giulia Riva, Silvia Molinelli, Sara Gandini, Gisela Viselner, Maria Rosaria Fiore, Barbara Vischioni, Viviana Vitolo, Maria Bonora, Sara Ronchi, Rachele Petrucci, Amelia Barcellini, Alfredo Mirandola, Stefania Russo, Alessandro Vai, Edoardo Mastella, Giuseppe Magro, Davide Maestri, Mario Ciocca, Lorenzo Preda, Francesca Valvo, Roberto Orecchia
Journal: Neuro-Oncology (2021)
Hepatology Highlights
Authors: Giovanna Codispodo, Robert S. Brown, Amneet Hans, Giorgio Roccaro, Enis Kostallari, Robert E. Schwartz, Adebowale O. Bamidele, Robert E. Schwartz, Adam Buckholz, Robert S. Brown, Anthony J. Choi, Robert S. Brown, Davide Povero, Robert E. Schwartz, Nidhi Jalan‐Sakrikar, Robert E. Schwartz, Nathan K Sairam, Chandur Bhan, Daryl T.Y. Lau, Wei Zhang, Robert S. Brown
Journal: Hepatology (2021)

Codispodo, Giovanna; Brown, Robert S. Jr; Hans, Amneet; Roccaro, Giorgio; Kostallari, Enis; Schwartz, Robert E.; Bamidele, Adebowale O.; Schwartz, Robert E.; Buckholz, Adam; Brown, Robert S. Jr; Choi, Anthony J.; Brown, Robert S. Jr; Povero, Davide; Schwartz, Robert E.; Jalan‐Sakrikar, Nidhi; Schwartz, Robert E.; Sairam, Nathan K; Bhan, Chandur; Lau, Daryl T.Y.; Zhang, Wei; Brown, Robert S. Jr Author Information
Incidence and Expected Probability of Liver Cirrhosis and Hepatocellular Carcinoma After Fontan Operation
Authors: Masaki Nii, Ryo Inuzuka, Kei Inai, Eriko Shimada, Tokuko Shinohara, Tomomi Kogiso, Hiroshi Ono, Shinichi Ootsuki, Yoshihiko Kurita, Atsuhito Takeda, Keiichi Hirono, Kota Takei, Satoshi Yasukochi, Tadahiro Yoshikawa, Yoshiyuki Furutani, Tomohiro Shinozaki, Yutaka Matsuyama, Hideaki Senzaki, Katsutoshi Tokushige, Toshio Nakanishi
Journal: Circulation (2021)
PORT (OP-109): Phase 2, Randomized, Pharmacokinetic (PK), Cross-over Study of Peripheral Vs Central Intravenous Administration of Melflufen in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Jiri Minarik, Ilina Micheva, Ganna Usenko, Gabor Mikala, Kameliya Simeonova, Marcus Thuresson, Markus Jerling, Hanjing Xie, Ludek Pour
Journal: Blood (2021)
Anticancer Drugs Approved by the US Food and Drug Administration From 2009 to 2020 According to Their Mechanism of Action
Authors: Timothée Olivier, Alyson Haslam, Vinay Prasad
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Both novel and next-in-class cancer drugs have a role in oncology, but the relative development of each is understudied. <h3>Objective</h3> To characterize the mechanisms of action of anticancer drugs approved by the US Food and Drug Administration (FDA) between 2009 and 2020, noting how many approvals were based on a new mechanism of action vs next-in-class approvals. <h3>Design, Study, and Participants</h3> This cross-sectional study included all anticancer drugs approved by the FDA from January 2009 to December 2020. The mechanism of action of each drug was extracted from FDA labels. Supportive-care treatments were excluded. <h3>Exposures</h3> Name of drug approved, date of approval, indication, tumor type, mechanism of action, broad pharmaceutical class, and biological target. Approvals considering all tumor types and each tumor type separately were classified in 3 nonoverlapping categories: new mechanism of action, next in class, or subsequent approval. <h3>Main Outcomes and Measures</h3> The number of all approvals each year; the number of approvals based on a new mechanism of action, either by drug (considering all tumor types) or by indication (considering tumor types separately); and the frequency of these numbers over time. <h3>Results</h3> Overall, 332 approvals were included. Between 2009 and 2020, there was an increase in the total number of approvals from 8 to 57. We found that 209 approvals (63%) were for a next-in-class indication in a new tumor type (84 [25%]) or a subsequent indication of the same drug in the same tumor type (195 [59%]). When considering each tumor type separately, 123 approvals (37%) were based on a new mechanism of action. <h3>Conclusions and Relevance</h3> In this study, approvals based on a new mechanism of action represented a minority of all approvals. Further consideration of incentives for drug development are needed to prioritize novel or highly innovative and transformative anticancer drugs.
Understanding Barriers to Adherence to Optimal Treatment of Elevated Blood Pressure and Hypertension—Insights From Primary Care
Authors: Harry H. X. Wang, Stewart W. Mercer
Journal: JAMA Network Open (2021)

Yishu Liu, MSc; Hongling Chu, PhD; Ke Peng, PhD; Xuejun Yin, MPH; Liping Huang, PhD; Yangfeng Wu, MD, PhD; Sallie-Anne Pearson, PhD; Nicole Li, MD, PhD; Paul Elliott, MB, PhD; Lijing L. Yan, PhD; Darwin R. Labarthe, PhD; Zhixin Hao, MD; Xiangxian Feng, PhD; Jianxin Zhang, PhD; Yuhong Zhang, MMed; Ruijuan Zhang, MSc; Bo Zhou, PhD; Zhifang Li, MSc; Jixin Sun, MSc; Yi Zhao, PhD; Yan Yu, PhD; Maoyi Tian, PhD; Bruce Neal, MB, ChB, PhD; Hueiming Liu, PhD
Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization
Authors: Jiang-Hui Wang, Ching-Li Tseng, Fan-Li Lin, Jinying Chen, Erh-Hsuan Hsieh, Suraj Lama, Yu-Fan Chuang, Satheesh Kumar, Linxin Zhu, Myra B. McGuinness, Jessika Hernandez, Leilei Tu, Peng-Yuan Wang, Guei-Sheung Liu
Journal: Theranostics (2021)

Rationale: Corneal neovascularization (CoNV) is a severe complication of various types of corneal diseases, that leads to permanent visual impairment.Current treatments for CoNV, such as steroids or anti-vascular endothelial growth factor agents, are argued over their therapeutic efficacy and adverse effects.Here, we demonstrate that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) plays an important role in the pathogenesis of CoNV.Methods: Angiogenic activities were assessed in ex vivo and in vitro models subjected to TAK1 inhibition by 5Z-7-oxozeaenol, a selective inhibitor of TAK1.RNA-Seq was used to examine pathways that could be potentially affected by TAK1 inhibition.A gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol was developed as the eyedrop to treat CoNV in a rodent model. Results:We showed that 5Z-7-oxozeaenol reduced angiogenic processes through impeding cell proliferation.Transcriptome analysis suggested 5Z-7-oxozeaenol principally suppresses cell cycle and DNA replication, thereby restraining cell proliferation.In addition, inhibition of TAK1 by 5Z-7-oxozeaenol blocked TNFα-mediated NFκB signalling, and its downstream genes related to angiogenesis and inflammation.5Z-7-oxozeaenol also ameliorated pro-angiogenic activity, including endothelial migration and tube formation.Furthermore, topical administration of the gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol led to significantly greater suppression of CoNV in a mouse model compared to the free form of 5Z-7-oxozeaenol, likely due to extended retention of 5Z-7-oxozeaenol in the cornea. Conclusion:Our study shows the potential of TAK1 as a therapeutic target for pathological angiogenesis, and the gelatin nanoparticle coupled with 5Z-7-oxozeaenol as a promising new eyedrop administration model in treatment of CoNV.
163P Health-related quality of life (HRQoL) with pembrolizumab (pembro) vs chemotherapy (chemo) in platinum-pretreated recurrent or metastatic (R/M) nasopharyngeal cancer (NPC): Phase III KEYNOTE-122 study
Authors: A.T.C. Chan, H.F.V. Lee, R-L. Hong, M-J. Ahn, W.Q. Chong, S-B. Kim, H.G. Fuang, P.B. Caguioa, N. Ngamphaiboon, C. Ho, M.A.S. Abdul Aziz, Q.S. Ng, C.J. Yen, N. Soparattanapaisarn, R. Ngan, S.K. Kho, L. Wang, R. Swaby, S. Saraf, L.L. Siu
Journal: Annals of Oncology (2021)
A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer
Authors: Andrew W. Chung, Kartik Anand, Ann C. Anselme, Alfred A. Chan, Nakul Gupta, Luz A. Venta, Mary R. Schwartz, Wei Qian, Yitian Xu, Licheng Zhang, John Kuhn, Tejal Patel, Angel A. Rodriguez, Anna Belcheva, Jorge Darcourt, Joe Ensor, Eric Bernicker, Ping-Ying Pan, Shu Hsia Chen, Delphine J. Lee, Polly A. Niravath, Jenny C. Chang
Journal: Science Translational Medicine (2021)

A phase 1/2 clinical trial in patients with chemoresistant triple-negative breast cancer targets the inducible nitric oxide signaling pathway.
Digging Deeper for the Truth of a STEMI Mimic
Authors: Wen-Biao Chen, Zhuo-Yu An
Journal: JAMA Internal Medicine (2021)

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PTC923 (sepiapterin) lowers elevated blood phenylalanine in subjects with phenylketonuria: a phase 2 randomized, multi-center, three-period crossover, open-label, active controlled, all-comers study
Authors: Drago Bratkovic, Lali Margvelashvili, Michel C. Tchan, Janelle Nisbet, Neil Smith
Journal: Metabolism (2021)

PTC923 (formerly CNSA-001), an oral formulation of sepiapterin, a natural precursor of intracellular tetrahydrobiopterin (BH4), has been shown in humans to induce larger increases in circulating BH4 vs. sapropterin dihydrochloride. Sapropterin reduces blood phenylalanine (Phe) by ≥20-30% in a minority of subjects with PKU. This was a Phase 2 randomized, multicenter, three-period crossover, open-label, active controlled, all-comers [regardless of phenylalanine hydroxylase (PAH) variants] comparison of PTC923 60 mg/kg, PTC923 20 mg/kg and sapropterin 20 mg/kg in 24 adults with phenylketonuria (PKU) and hyperphenylalaninemia.Eligible subjects were adult men or women (18-60 y) with PKU. Subjects enrolled received 7 days of once-daily oral treatment with PTC923 20 mg/kg/day, PTC923 60 mg/kg/day and sapropterin dihydrochloride 20 mg/kg/day each in a random order. Treatments were separated by a 7-day washout. Subjects maintained their usual pre-study diet, including consumption of amino acid mixtures. Blood Phe was measured on Day 1 (predose baseline), Day 3, Day 5, and Day 7 of each treatment period.Least squares mean changes (SE) from baseline in blood Phe were: -206.4 (41.8) μmol/L for PTC923 60 mg/kg (p < 0.0001); -146.9 (41.8) μmol/L for PTC923 20 mg/kg (p = 0.0010); and - 91.5 (41.7) μmol/L for sapropterin (p = 0.0339). Effects of PTC923 60 mg/kg on blood Phe vs. sapropterin were significantly larger (p = 0.0098) and faster in onset with a significantly larger mean reduction in blood Phe at day 3 of treatment, p = 0.0135 (20 mg/kg) and p = 0.0007 (60 mg/kg). Only PTC923 60 mg/kg reduced blood Phe in classical PKU subjects (n = 11, p = 0.0287). The mean blood Phe reduction (PTC923 60 mg/kg) in a cofactor responder analysis (n = 8; baseline Phe ≥300 μmol/L and blood Phe reduction ≥30%) was -463.3 μmol/L (SE 51.5) from baseline. Adverse events were mostly mild to moderate, transient, and similar across treatment groups with no serious adverse events or discontinuations.The substantially significantly better effect of PTC923 60 mg/kg on blood Phe reduction vs. sapropterin supports further clinical development of PTC923 for PKU; ANZCTR number, ACTRN12618001031257.
Health-related quality of life (HRQOL) in patients (pts) with advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC): Results of nivolumab plus chemotherapy (NIVO+chemo) versus chemo from CheckMate 649.
Authors: Elena Elimova, Lucjan Wyrwicz, Steven I. Blum, Hong Xiao, Mingshun Li, Kaoru Kondo, Eric Davenport, Jinyi Wang, Shannon Hunter, Markus H. Moehler
Journal: Journal of Clinical Oncology (2021)

167 Background: CheckMate 649 (NCT02872116) is a randomized, open label phase 3 study in first line (1L) treatment of pts with advanced GC/GEJC/EAC. Primary analysis results showed statistically significant improvement in overall survival (OS) for NIVO+chemo vs. chemo in all randomized pts. We present HRQOL results for these pts, included as an exploratory study objective. Methods: HRQOL was assessed using EQ-5D-3L (EQ-5D) and Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga). Assessments were performed at baseline (BL), every 6 weeks during treatment and during follow-up. Change from BL EQ-5D Visual Analog Scale (VAS), Utility Index (UI) and FACT-Ga scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement was based on prespecified meaningful change thresholds. Results: 1581 pts were randomized to NIVO+chemo (n = 789) or chemo (n = 792). Among 1359 pts with BL and post-BL patient-reported outcomes (NIVO+chemo, n = 693; chemo, n = 666), BL scores for FACT-Ga total were similar between treatment groups. Least squares mean differences from BL favored NIVO+chemo at most visits for EQ-5D, FACT-Ga total, and Gastric Cancer Subscale (GaCS), and were comparable for other subscales (not shown). TTI generally favored NIVO+chemo (most HR &gt; 1) but was not significantly different between arms. TTSD was longer in NIVO+chemo arm compared with chemo alone (all HRs &lt; 1), except for Emotional Well-Being (WB); only GaCS and FACT-Ga total were significantly different between arms. TuDD showed statistically significant delays in deterioration (HR with CI &lt; 1) for all scores expect Social WB. Conclusions: Compared with chemo alone, the addition of NIVO to chemo maintained HRQoL with a decreased risk of symptom deterioration in patients with previously untreated advanced or metastatic GC/GEJC/EAC. Together with improved OS, these data support NIVO+chemo as a new 1L standard treatment for GC/GEJC/EAC. Clinical trial information: NCT02872116. [Table: see text]
Dodging blood brain barrier with “nano” warriors: Novel strategy against ischemic stroke
Authors: Suhel Parvez, Medha Kaushik, Mubashshir Ali, Mohammad Mumtaz Alam, Javed Ali, Heena Tabassum, Pooja Kaushik
Journal: Theranostics (2021)

Ischemic stroke (IS) is one of the leading causes of death and disability resulting in inevitable burden globally. Ischemic injury initiates cascade of pathological events comprising energy dwindling, failure of ionic gradients, failure of blood brain barrier (BBB), vasogenic edema, calcium over accumulation, excitotoxicity, increased oxidative stress, mitochondrial dysfunction, inflammation and eventually cell death. In spite of such complexity of the disease, the only treatment approved by US Food and Drug Administration (FDA) is tissue plasminogen activator (t-PA). This therapy overcome blood deficiency in the brain along with side effects of reperfusion which are responsible for considerable tissue injury. Therefore, there is urgent need of novel therapeutic perspectives that can protect the integrity of BBB and salvageable brain tissue. Advancement in nanomedicine is empowering new approaches that are potent to improve the understanding and treatment of the IS. Herein, we focus nanomaterial mediated drug delivery systems (DDSs) and their role to bypass and cross BBB especially via intranasal drug delivery. The various nanocarriers used in DDSs are also discussed. In a nut shell, the objective is to provide an overview of use of nanomedicine in the diagnosis and treatment of IS to facilitate the research from benchtop to bedside.
CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study
Authors: Krish Patel, Jeffrey A. Zonder, Dahlia Sano, Michael Maris, Alexander Lesokhin, Gottfried von Keudell, Catherine Lai, Rod Ramchandren, Tina Catalano, Gloria H. Y. Lin, Bob Uger, Penka S. Petrova, Naomi Molloy, Ingmar Bruns, Swaminathan P Iyer
Journal: Blood (2021)
Error in Abstract and Methods
Authors: Frans Van Workum, Moniek Verstegen, Camiel Rosman
Journal: JAMA Surgery (2021)

Douglas Zatzick, MD; Gregory Jurkovich, MD; Patrick Heagerty, PhD; Joan Russo, PhD; Doyanne Darnell, PhD; Lea Parker, BA; Michelle K. Roberts, MPH; Rddhi Moodliar, BA; Allison Engstrom, MSW; Jin Wang, PhD; Eileen Bulger, MD; Lauren Whiteside, MD; Deepika Nehra, MD; Lawrence A. Palinkas, PhD; Kathleen Moloney, BA; Ronald Maier, MD
Impact of Central Nervous System Involvement in Adult Patients with Acute Lymphoblastic Leukemia Treated in a Pediatrics-Inspired Protocol - a Graall Study
Authors: Corentin Orvain, Sylvain Chantepie, Xavier Thomas, Martine Escoffre-Barbe, Francoise Huguet, Yohan Desbrosses, Gaelle Guillerm, Thibaut Leguay, Sarah Barbieux, Norbert Vey, Patrice Chevallier, Jean Valere Malfuson, Stephane Lepretre, Jean Pierre Marolleau, Hacene Zerazhi, Diana Carp, Ambroise Marçais, Maria Pilar Gallego Hernanz, Iona Vaida, Florence Pasquier, Veronique Lheritier, Norbert Ifrah, Hervé Dombret, Nicolas Boissel, Hunault-Berger Mathilde
Journal: Blood (2021)
A gerophysiology perspective on healthy ageing
Authors: Ph. Kemoun, I. Ader, V. Planat-Benard, C. Dray, N. Fazilleau, P. Monsarrat, B. Cousin, J. Paupert, M. Ousset, A. Lorsignol, I. Raymond-Letron, B. Vellas, P. Valet, T. Kirkwood, J. Beard, L. Pénicaud, L. Casteilla
Journal: Ageing Research Reviews (2021)