tbuckley/cabot-search huggingface dataset:
CDK2-Mediated Upregulation of TNFα as a Mechanism of Selective Cytotoxicity in Acute Leukemia
Authors: Husheng Ding, Nicole D. Vincelette, Cordelia D. McGehee, Mira A. Kohorst, Brian D. Koh, Annapoorna Venkatachalam, X. Wei Meng, Paula A. Schneider, Karen S. Flatten, Kevin L. Peterson, Cristina Correia, Sun-Hee Lee, Mrinal Patnaik, Jonathan A. Webster, Gabriel Ghiaur, B. Douglas Smith, Judith E. Karp, Keith W. Pratz, Hu Li, Larry M. Karnitz, Scott H. Kaufmann
Journal: Cancer Research (2021)

Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro, including TP53-null acute myeloid leukemia (AML) and BCR/ABL-positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFα production, and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically resistant to CHK1 inhibition exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2-AP1-TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo. Collectively, these observations not only identify new contributors to the antileukemic cell action of CHK1, ATR, and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand-induced killing that can potentially be exploited for acute leukemia treatment. SIGNIFICANCE: This study demonstrates that replication checkpoint inhibitors can kill AML cells through a pathway involving AP1-mediated TNF gene activation and subsequent TP53-independent, TNFα-induced apoptosis, which can potentially be exploited clinically.
Noninvasive Detection of Ischemic Vascular Damage in a Pig Model of Liver Donation After Circulatory Death
Authors: Katherine J.I. Ember, Fiona Hunt, Lauren E. Jamieson, John M. Hallett, Hannah Esser, Timothy J. Kendall, R. Eddie Clutton, Rachael Gregson, Karen Faulds, Stuart J. Forbes, Gabriel C. Oniscu, Colin J. Campbell
Journal: Hepatology (2021)

Background and Aims Liver graft quality is evaluated by visual inspection prior to transplantation, a process highly dependent on the surgeon’s experience. We present an objective, noninvasive, quantitative way of assessing liver quality in real time using Raman spectroscopy, a laser‐based tool for analyzing biomolecular composition. Approach and Results A porcine model of donation after circulatory death (DCD) with normothermic regional perfusion (NRP) allowed assessment of liver quality premortem, during warm ischemia (WI) and post‐NRP. Ten percent of circulating blood volume was removed in half of experiments to simulate blood recovery for DCD heart removal. Left median lobe biopsies were obtained before circulatory arrest, after 45 minutes of WI, and after 2 hours of NRP and analyzed using spontaneous Raman spectroscopy, stimulated Raman spectroscopy (SRS), and staining. Measurements were also taken in situ from the porcine liver using a handheld Raman spectrometer at these time points from left median and right lateral lobes. Raman microspectroscopy detected congestion during WI by measurement of the intrinsic Raman signal of hemoglobin in red blood cells (RBCs), eliminating the need for exogenous labels. Critically, this microvascular damage was not observed during WI when 10% of circulating blood was removed before cardiac arrest. Two hours of NRP effectively cleared RBCs from congested livers. Intact RBCs were visualized rapidly at high resolution using SRS. Optical properties of ischemic livers were significantly different from preischemic and post‐NRP livers as measured using a handheld Raman spectrometer. Conclusions Raman spectroscopy is an effective tool for detecting microvascular damage which could assist the decision to use marginal livers for transplantation. Reducing the volume of circulating blood before circulatory arrest in DCD may help reduce microvascular damage.
Increased focus on non-animal models for COVID-19 and non-COVID lung research
Authors: Laura Gribaldo, Killian Hurley, Pieter Hiemstra, Catherine Greene
Journal: European Respiratory Journal (2021)

<b>A recent report from the European Commission highlights strategies for the development of safe and efficacious therapies for respiratory diseases, especially those that exploit non-animal methods and recapitulate the mechanistic basis of human disease</b>https://bit.ly/2Vk3xfA
Burden of Ocular Comorbidities in Patients With Hidradenitis Suppurativa
Authors: Rosalynn R. Z. Conic, Gabriella Fabbrocini, Claudio Marasca, Nicola L. Bragazzi, Abdulla Watad, Mohammad Adawi, Giovanni Damiani
Journal: JAMA Dermatology (2021)

Burden of Ocular Comorbidities in Patients With Hidradenitis SuppurativaHidradenitis suppurativa (HS) is a chronic systemic inflammatory disorder of the terminal follicular epithelium in the apocrine gland-bearing skin.Clinically, it is characterized by lesions, including comedones, papules, pustules, nodules, and fistulas, that are mainly concentrated in axillae, perineal, and submammary areas. 1 Other autoimmune diseases are associated with ocular comorbidities; however, there is a paucity of data on ocular comorbidities in HS. [1][2][3][4] In this article, we aim to quantify the burden of ocular comorbidities in patients with HS.
Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease
Authors: Kun Leng, Emmy Li, Rana Eser, Antonia Piergies, Rene Sit, Michelle Tan, Norma Neff, Song Hua Li, Roberta Diehl Rodriguez, Claudia Kimie Suemoto, Renata Elaine Paraizo Leite, Alexander J. Ehrenberg, Carlos A. Pasqualucci, William W. Seeley, Salvatore Spina, Helmut Heinsen, Lea T. Grinberg, Martin Kampmann
Journal: Nature Neuroscience (2021)
Erratum for Research Article “Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis” by C. Carmona-Rivera, P. M. Carlucci, E. Moore, N. Lingampalli, H. Uchtenhagen, E. James, Y. Liu, K. L. Bicker, H. Wahamma, V. Hoffman, A. I. Catrina, P. Thompson, J. H. Buckner, W. H. Robinson, D. A. Fox, M. J. Kaplan
Journal: Science Immunology (2020)
Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation
Authors: Jiro Ikeda, Corey A. Scipione, Sharon J. Hyduk, Marwan G. Althagafi, Jawairia Atif, Sarah A. Dick, Maneesha Rajora, Erika Jang, Takuo Emoto, Junichi Murakami, Noriko Ikeda, Hisham M. Ibrahim, Chanele K. Polenz, Xiaotang Gao, Kelly Tai, Jenny Jongstra-Bilen, Ryota Nakashima, Slava Epelman, Clinton S. Robbins, Gang Zheng, Warren L. Lee, Sonya A. MacParland, Myron I. Cybulsky
Journal: Circulation Research (2021)

Rationale: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. Objective: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. Methods and Results: Ldlr −/− mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr −/− relative to Ldlr +/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT. Conclusions: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.
Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19
Authors: Michael J Joyner, Rickey E Carter, Jonathon W Senefeld, Stephen A Klassen, John R Mills, Patrick W Johnson, Elitza S Theel, Chad C Wiggins, Katelyn A Bruno, Allan M Klompas, Elizabeth R Lesser, Katie L Kunze, Matthew A Sexton, Juan C Diaz Soto, Sarah E Baker, John R A Shepherd, Noud van Helmond, Nicole C Verdun, Peter Marks, Camille M van Buskirk, Jeffrey L Winters, James R Stubbs, Robert F Rea, David O Hodge, Vitaly Herasevich, Emily R Whelan, Andrew J Clayburn, Kathryn F Larson, Juan G Ripoll, Kylie J Andersen, Matthew R Buras, Matthew N P Vogt, Joshua J Dennis, Riley J Regimbal, Philippe R Bauer, Janis E Blair, Nigel S Paneth, DeLisa Fairweather, R Scott Wright, Arturo Casadevall
Journal: New England Journal of Medicine (2021)

BackgroundConvalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown.MethodsIn a retrospective study based on a U.S. national registry, we determined the anti–SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti–SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis.ResultsOf the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti–SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32).ConclusionsAmong patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti–SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.) Visual Abstract Convalescent Plasma Antibody Levels and Covid-19 Mortality
PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates
Authors: Darren R. Veach, Claire M. Storey, Katharina Lückerath, Katharina Braun, Christian von Bodman, Urpo Lamminmäki, Teja Kalidindi, Sven-Erik Strand, Joanna Strand, Mohamed Altai, Robert Damoiseaux, Pat Zanzonico, Nadia Benabdallah, Dmitry Pankov, Howard I. Scher, Peter Scardino, Steven M. Larson, Hans Lilja, Michael R. McDevitt, Daniel L.J. Thorek, David Ulmert
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA (KLK3). Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3_Hi-Myc transgenic mice were imaged with 89Zr- or treated with 90Y- or 225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in nonhuman primates (NHP) were determined using PET. Results: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (P ≤ 0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, P &amp;lt; 0.0001) but less sustained (TTP, P &amp;lt; 0.0001). Complete responses were observed in 7 of 18 [225Ac]hu5A10 and 1 of 9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period. Conclusions: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.
Bacteria-specific phototoxic reactions triggered by blue light and phytochemical carvacrol
Authors: Min Lu, Shen Wang, Tao Wang, Sisi Hu, Brijesh Bhayana, Momoko Ishii, Yifei Kong, Yuchen Cai, Tianhong Dai, Wenguo Cui, Mei X. Wu
Journal: Science Translational Medicine (2021)

Development of alternatives to antibiotics is one of the top priorities in the battle against multidrug-resistant (MDR) bacterial infections. Here, we report that two naturally occurring nonantibiotic modalities, blue light and phytochemical carvacrol, synergistically kill an array of bacteria including their planktonic forms, mature biofilms, and persisters, irrespective of their antibiotic susceptibility. Combination but not single treatment completely or substantially cured acute and established biofilm-associated Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus infections of full thickness murine third-degree burn wounds and rescued mice from lethal Pseudomonas aeruginosa skin wound infections. The combined therapy diminished bacterial colony-forming units as high as 7.5 log10 within 30 min and introduced few adverse events in the survival of cocultured mammalian cells, wound healing, or host DNA. Mechanistic studies revealed that carvacrol was photocatalytically oxidized into a series of photoreactive substrates that underwent photolysis or additional photosensitization reactions in response to the same blue light, forming two autoxidation cycles that interacted with each other resulting in robust generation of cytotoxic reactive oxygen species. This phototoxic reaction took place exclusively in bacteria, initiated by blue light excitation of endogenous porphyrin-like molecules abundantly produced in bacteria compared with mammalian cells. Moreover, no bacterial resistance developed to the combined treatment after 20 successive passages. This highly selective phototoxic reaction confers a unique strategy to combat the growing threat of MDR bacteria.
Association of prenatal exposure to fine particulate matter pollution with childhood eczema
Authors: Tsung‐Chieh Yao, Hsin‐Yi Huang, Wen‐Chi Pan, Chao‐Yi Wu, Shun‐Yu Tsai, Chi‐Yen Hung, Kun‐Lin Lu, Ju Chang‐Chien, Chih‐Lin Tseng, Chih‐Da Wu, Yu‐Chen Chen, Yvonne J. Huang, Hui‐Ju Tsai
Journal: Allergy (2021)

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Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5α Promotes Cancer Invasion and Tumor Growth
Authors: Shinji Iizuka, Manuela Quintavalle, Jose C. Navarro, Kyle P. Gribbin, Robert J. Ardecky, Matthew M. Abelman, Chen-Ting Ma, Eduard Sergienko, Fu-Yue Zeng, Ian Pass, George V. Thomas, Shannon K. McWeeney, Christian A. Hassig, Anthony B. Pinkerton, Sara A. Courtneidge
Journal: Cancer Research (2021)

Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. In this study, we used our high-content screening assay to identify kinases whose activity affects invadopodia formation. Among the top hits selected for further analysis was TAO3, an STE20-like kinase of the GCK subfamily. TAO3 was overexpressed in many human cancers and regulated invadopodia formation in melanoma, breast, and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in three-dimensional matrices and in vivo. A novel, potent catalytic inhibitor of TAO3 was developed that inhibited invadopodia formation and function as well as tumor cell extravasation and growth. Treatment with this inhibitor demonstrated that TAO3 activity is required for endosomal trafficking of TKS5α, an obligate invadopodia scaffold protein. A phosphoproteomics screen for TAO3 substrates revealed the dynein subunit protein LIC2 as a relevant substrate. Knockdown of LIC2 or expression of a phosphomimetic form promoted invadopodia formation. Thus, TAO3 is a new therapeutic target with a distinct mechanism of action. SIGNIFICANCE: An unbiased screening approach identifies TAO3 as a regulator of invadopodia formation and function, supporting clinical development of this class of target.
Capsular Invasion Matters Also in “Papillary Patterned” Tumors: A Study on 121 Cases of Encapsulated Conventional Variant of Papillary Thyroid Carcinoma
Authors: Dilara Akbulut, Ezgi Dicle Kuz, Nazmiye Kursun, Serpil Dizbay Sak
Journal: Endocrine Pathology (2021)
Mortality Among Young Adults Born Preterm and Early Term in 4 Nordic Nations
Authors: Kari Risnes, Josephine Funck Bilsteen, Paul Brown, Anna Pulakka, Anne-Marie Nybo Andersen, Signe Opdahl, Eero Kajantie, Sven Sandin
Journal: JAMA Network Open (2021)

Adverse long-term outcomes in individuals born before full gestation are not confined to individuals born at extreme gestational ages. Little is known regarding mortality patterns among individuals born in the weeks close to ideal gestation, and the exact causes are not well understood; both of these are crucial for public health, with the potential for modification of risk.To examine the risk of all-cause and noncommunicable diseases (NCD) deaths among young adults born preterm and early term.This multinational population-based cohort study used nationwide birth cohorts from Norway, Sweden, Denmark, and Finland for individuals born between 1967 and 2002. Individuals identified at birth who had not died or emigrated were followed up for mortality from age 15 years to 2017. Analyses were performed from June 2019 to May 2020.Categories of gestational age (ie, moderate preterm birth and earlier [23-33 weeks], late preterm [34-36 weeks], early term [37-38 weeks], full term [39-41 weeks] and post term [42-44 weeks]).All-cause mortality and cause-specific mortality from NCD, defined as cancer, diabetes, chronic lung disease, and cardiovascular disease (CVD).A total of 6 263 286 individuals were followed up for mortality from age 15 years. Overall, 339 403 (5.4%) were born preterm, and 3 049 100 (48.7%) were women. Compared with full-term birth, the adjusted hazard ratios (aHRs) for all-cause mortality were 1.44 (95% CI, 1.34-1.55) for moderate preterm birth and earlier; 1.23 (95% CI, 1.18-1.29) for late preterm birth; and 1.12 (95% CI, 1.09-1.15) for early-term birth. The association between gestational age and all-cause mortality were stronger in women than in men (P for interaction = .03). Preterm birth was associated with 2-fold increased risks of death from CVD (aHR, 1.89; 95% CI, 1.45-2.47), diabetes (aHR, 1.98; 95% CI, 1.44-2.73), and chronic lung disease (aHR, 2.28; 95% CI, 1.36-3.82). The main associations were replicated across countries and could not be explained by familial or individual confounding factors.The findings of this study strengthen the evidence of increased risk of death from NCDs in young adults born preterm. Importantly, the increased death risk was found across gestational ages up to the ideal term date and includes the much larger group with early-term birth. Excess mortality associated with shorter gestational age was most pronounced for CVDs, chronic lung disease, and diabetes.
New EULAR/ACR 2019 SLE Classification Criteria: defining ominosity in SLE
Authors: Laura P Whittall Garcia, Dafna D Gladman, Murray Urowitz, Zahi Touma, Jiandong Su, Sindhu R Johnson
Journal: Annals of the Rheumatic Diseases (2021)

To determine the ominosity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Systemic Lupus Erythematosus Classification Criteria by determining its predictive role for disease severity in the first 5 years following diagnosis.867 patients with systemic lupus erythematosus (SLE) from the Toronto Lupus Clinic were included (all first 12 months after SLE diagnosis). The EULAR/ACR criteria score was calculated based on baseline information. To determine disease severity in the first 5 years after diagnosis, adjusted mean SLE Disease Activity Index 2000 (AMS), flares, remission and immunosuppressive treatment were used as outcomes. The Systemic Lupus International Collaborating Clinics (SLICC) registry comprised the validation cohort.Based on receiver operating characteristic analysis, a EULAR/ACR score of 20 was used as a threshold to compare outcomes between groups. In the first 5 years of disease course, patients with a score of ≥20 had higher AMS scores (p<0.001) and were more likely to ever experience a flare (p<0.001). These patients had lower probabilities of achieving remission and higher requirements for immunosuppressives. Results were confirmed in the SLICC validation cohort. Patients with a score of ≥20 had higher AMS during the first 5 years of disease (5.4 vs 3.1% and ≥20 vs <20 respectively, p≤0.001). The score correlated with AMS (r=0.43, p≤0.001) in the same time frame.A EULAR/ACR score of ≥20 is an indicator of ominosity in SLE. Patients with a score of ≥20 were characterised by a more active disease course throughout the first 5 years. These criteria provide prognostic information regarding disease severity in the first 5 years following diagnosis.