tbuckley/cabot-search huggingface dataset:
Trends in Drug Overdose Mortality Rates in Kentucky, 2019-2020
Authors: Svetla Slavova, Dana Quesinberry, Sarah Hargrove, Peter Rock, Candace Brancato, Patricia R. Freeman, Sharon L. Walsh
Journal: JAMA Network Open (2021)

In April 2020, early signals from emergency medical services data raised concerns for increasing numbers of drug overdoses during the emerging COVID-19 pandemic in Kentucky.1 Subsequently, provisional national data for the 12-month period ending May 2020 showed accelerated drug overdose deaths, resulting in a Health Alert Network Advisory calling for expanded prevention efforts.2 This cross-sectional study evaluates the changes in drug overdose mortality rates for Kentucky residents between 2019 and 2020.
Abstract 2568: Use of kinase inhibitors in Fanconi anemia oral cancercell lines
Authors: Walter N. Jungbauer, Mustafa M. Ali, Beverly R. Wuertz, Frank G. Ondrey
Journal: Cancer Research (2021)

Abstract Successful Fanconi anemia (FA) treatment allows greater longevity for these patients. However, there is a greatly increased risk of squamous malignancies of the head and neck which are quite deadly in these young patients. There is an unmet need for non DNA damaging therapies for this malignancy which could augment surgery. Our approach has been to examine potential treatments based on known pathophysiology of the disease which would be acceptable for this population so we examined the effects of metformin and pioglitazone, as well as two cell cycle kinase inhibitors, in FA and leukoplakia cell lines. We examined dose-dependent and combination effects on cell proliferation, as judged by MTT assay. We examined metformin, pioglitazone, the polo-like kinase 1 inhibitor, GSK461364, and Wee1 kinase inhibitor, AZD1775.In single agent studies, we observed dose-dependent decreases in cell proliferation with all 4 single agents. We observed decreased cell proliferation in all cell lines at 72 hours at clinically achievable serum levels of 85% to 55% of control levels (P&amp;lt;0.0001). Additionally, we found decreases beyond single agent treatment levels when cells were treated with metformin combined with GSK461364 or AZD1775 and similarly, with combination therapies of pioglitazone and GSK461364 or AZD1775. Our current data demonstrate feasibility and preclinical efficacy of a combined agent approach for FA associated head and neck cancer. The low reported toxicity of these agents clinically allows for all of these agents to potentially move forward clinically, once additional experiments are conducted in mechanistic and animal studies. Citation Format: Walter N. Jungbauer, Mustafa M. Ali, Beverly R. Wuertz, Frank G. Ondrey. Use of kinase inhibitors in Fanconi anemia oral cancercell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2568.
Abstract 197: The Calcium Sensitizer Levosimendan Improves Long-Term Neurological Outcome After Experimental Cardiac Arrest
Authors: Robert F Kelm, Sarah Stebner, Andrea Ullrich, Irene Schmidtmann, Christian Werner, Kristin Engelhard, Rüdiger R Noppens
Journal: Circulation (2011)

Introduction: Neurological disorder after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is common in human survivors. Impaired cerebral blood flow (CBF) and myocardial dysfunction after successful CPR possibly affect neurological outcome. Levosimendan (Orion Corporation, Finland) improves myocardial function and enhances CBF after experimental CA and CPR. The present study investigated the effect of levosimendan on mortality and neurological outcome 7 d after experimental CA and CPR in rats. Methods: After governmental animal care committee approval (Koblenz, Germany) 80 male Sprague-Dawley rats (330 - 390 g) were included. In 64 animals asphyxial CA and CPR was achieved, randomized to a group with levosimendan treatment (Levo, n = 32, bolus [12 µg/kg] and infusion for 3 h [0.3 µg/min/kg]), or normal saline treatment (Vehicle, n = 32, bolus and infusion for 3 h [equivalent fluid volume]). For technical control 16 animals received surgical intervention and treatment without CA and CPR (sLevo, n = 8; sVehicle, n = 8). After 9 min of asphyxia and CA, CPR was initiated and experimental treatment was started. Survival, neurological assessment (neuro-deficit-score, NDS) and motor function were evaluated over a 7-d-observation period. Histopathological neuronal injury was assessed using HE-staining (expressed as numbers of viable neurons in cortex and hippocampal formation). Results: Survival showed no differences between the CA-groups after 7 d (Levo vs. Vehicle: 25 vs. 28 animals, p = 0.5092). All animals survived in sham-groups. NDS (Group comparison Levo vs. Vehicle: p = 0.003; day 7 of observation period: 13.4 ± 0.6 vs. 14.2 ± 1.4 [mean ± SD]) and cortical neuronal injury (Levo vs. Vehicle: 401 ± 87 vs. 343 ± 57 viable neurons, p = 0.007) were reduced in the Levo-group compared to Vehicle-group. Improved motor function was detected in animals treated with levosimendan (Group comparison Levo vs. Vehicle: p = 0.0091). Conclusion: In this model of CA and CPR treatment with levosimendan reduced cortical neuronal injury and ameliorated neurological performance after 7 d of survival. Based on previously demonstrated findings, the improvement of myocardial function and cerebral blood flow during reperfusion by levosimendan may cause this result.
Abstract 998: Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of cancer
Authors: Caroline Phillips, Simon Woodcock, Catherine Eagle, Andrew Saunders, Craig Tilston, Inder Bhamra, Richard Armer
Journal: Cancer Research (2021)

Abstract Background: RXC004 is a porcupine inhibitor, and thus a potent and selective inhibitor of Wnt ligand-dependent signalling. RXC004 is currently being investigated in a safety and tolerability study in cancer patients with solid tumours (NCT03447470). Certain Wnt pathway alterations, including loss-of-function RNF43 mutations and RSPO gene fusions, result in higher levels of the Wnt receptor Fzd on the cell surface increasing Wnt-ligand dependent signalling. These alterations are implicated in colorectal and pancreatic cancer. We present pre-clinical data on the effects of RXC004 in genetically defined models of cancer. Methods: RXC004 in vitro effects on the metabolic activity of both sensitive (genetically selected RNF43 mutant or RSPO fusion models) and insensitive (beta-catenin mutant model) colorectal and pancreatic tumour cells lines were assessed. To test if these effects translated in vivo, RXC004 was also evaluated in an in vivo FDG-PET study in an RSPO fusion tumour cell line. In addition, as we had previously noted that RXC004 caused cell differentiation in an RSPO fusion model, we studied if pre-treatment with RXC004 would affect subsequent tumour growth post RXC004 induced cell differentiation in vivo. Results: In tumour cell lines in vitro, RXC004 significantly reduced glucose uptake only in genetically selected tumour cell lines. In vivo FDG-PET studies also showed a reduction in FDG-PET signals post 7 days treatment of 5mg/kg QD RXC004. Imaging demonstrated that MaxSUV (maximum standardised uptake value) decreased by 31% in RXC004 treated versus vehicle treated tumours, furthermore biodistribution of PET ligand was significantly inhibited in tumours post 7 days RXC004 treatment. Pre-treatment of RXC004 in an in vivo mouse xenograft model for 7 days resulted in a significant reduction in tumour growth when tumour fragments from these pre-treated mice were re-implanted into naïve mice (P&amp;lt;0.05). Conclusion: These data demonstrate that RXC004 monotherapy results in tumour cell differentiation accompanied by reduced metabolic activity in genetically selected tumours. RXC004-induced cell differentiation may therefore continue to provide patient benefit even post dosing. Moreover, FDG-PET imaging in clinical studies may allow early detection of the positive effects of RXC004 in a non-invasive manner, and prior to any changes in tumour volume by conventional RECIST measurements. Citation Format: Caroline Phillips, Simon Woodcock, Catherine Eagle, Andrew Saunders, Craig Tilston, Inder Bhamra, Richard Armer. Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 998.
Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study
Authors: Stephen T J Ray, Omar Abdel-Mannan, Mario Sa, Charlotte Fuller, Greta K Wood, Karen Pysden, Michael Yoong, Helen McCullagh, David Scott, Martin McMahon, Naomi Thomas, Micheal Taylor, Marjorie Illingworth, Nadine McCrea, Victoria Davies, William Whitehouse, Sameer Zuberi, Keira Guthrie, Evangeline Wassmer, Nikit Shah, Mark R Baker, Sangeeta Tiwary, Hui Jeen Tan, Uma Varma, Dipak Ram, Shivaram Avula, Noelle Enright, Jane Hassell, Amy L Ross Russell, Ram Kumar, Rachel E Mulholland, Sarah Pett, Ian Galea, Rhys H Thomas, Laura A Benjamin, Ming Lim, Yael Hacohen, Tom Solomon, Michael J Griffiths, Benedict D Michael, Rachel Kneen, Gerome Breen, Hannah Castell, Ceryce Collie, Lilly George, Monika Hartmann, Marc Henrion, Maria Kinali, Christina Petropoulos, Sithara Ramdas, Victoria Vlachou, Brigitte Vollmer, Bethany Facer, Cordelia Dunai, Laura Benjamin
Journal: The Lancet Child & Adolescent Health (2021)
Lack of intrafollicular memory CD4 + T cells is predictive of early clinical failure in newly diagnosed follicular lymphoma
Authors: Patrizia Mondello, Angelo Fama, Melissa C. Larson, Andrew L. Feldman, Jose C. Villasboas, Zhi-Zhang Yang, Ilia Galkin, Viktor Svelolkin, Ekaterina Postovalova, Alexander Bagaev, Pavel Ovcharov, Arina Varlamova, Sarah Huet, Bruno Tesson, Kaitlyn R. McGrath, Susan Slager, Brian K. Link, Sergei Syrbu, Anne J. Novak, Thomas M. Habermann, Thomas E. Witzig, Grzegorz S. Nowakowski, Gilles Salles, James R. Cerhan, Stephen M. Ansell
Journal: Blood Cancer Journal (2021)

Abstract Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Cells in the microenvironment may be a key contributor to treatment failure. We used a discovery and validation study design to identify microenvironmental determinants of early failure and then integrated these results into the FLIPI. In total, 496 newly diagnosed FL grade 1–3 A patients who were prospectively enrolled into the MER cohort from 2002 to 2012 were evaluated. Tissue microarrays were stained for CD4, CD8, FOXP3, CD32b, CD14, CD68, CD70, SIRP-α, TIM3, PD-1, and PD-L1. Early failure was defined as failing to achieve event-free survival at 24 months (EFS24) in immunochemotherapy-treated patients and EFS12 in all others. CyTOF and CODEX analysis were performed to characterize intratumoral immunophenotypes. Lack of intrafollicular CD4 expression was the only predictor of early failure that replicated with a pooled OR 2.37 (95%CI 1.48–3.79). We next developed a bio-clinical risk model (BioFLIPI), where lack of CD4 intrafollicular expression moved patients up one FLIPI risk group, adding a new fourth high-risk group. Compared with BioFLIPI score of 1, patients with a score of 2 (OR 2.17; 95% CI 1.08–4.69), 3 (OR 3.53; 95% CI 1.78–7.54), and 4 (OR 8.92; 95% CI 4.00–21.1) had increasing risk of early failure. The favorable intrafollicular CD4 T cells were identified as activated central memory T cells, whose prognostic value was independent from genetic features. In conclusion, lack of intrafollicular CD4 expression predicts early failure in FL and combined with FLIPI improves identification of high-risk patients; however, independent validation is warranted.
Abstract 1156: The integrated stress response (ISR) is involved in the synergistic combinatorial efficacy of ONC201 and epigenetic modulators in brain tumor cell lines
Authors: Yiqun Zhang, Lanlan Zhou, Varun V. Prabhu, Joshua E. Allen, Attila A. Seyhan, Wafik S. El-Deiry
Journal: Cancer Research (2021)

Abstract First-in-class small molecule ONC201 is an anti-cancer agent that activates the TRAIL pathway through ATF4 and the integrated stress response (ISR). ONC201 demonstrated durable tumor regressions and prolonged disease stabilization in some patients with histone H3K27M-mutated diffuse midline glioma (DMG). The H3K27M-mutation reduces H3K27 methylation. EZH2 inhibitors (EZH2i) reduce global H3K27 methylation. We hypothesized that ONC201 sensitivity and tumor cell death may be enhanced by reducing H3K27 methylation with EZH2i as a mimic of the H3K27M-mutation, particularly in tumor types beyond DMG. We treated cancer cells from different tissue origins including breast cancer, pancreatic cancer, colorectal cancer, glioblastoma, and DMG with single agent ONC201, EZH2 inhibitor EPZ-6438 or PF-06821497, or the combination of ONC201 plus EPZ-6438 or ONC201 plus PF-06821497. Cell viability was determined with the Cell Titer-Glo assay. Integrated stress response (ISR) activation widely observed in ONC201-treated tumor cells was evaluated using Western blot analysis of ATF4. We determined TRAIL pathway activity by analysis of DR5, and apoptosis by analysis of PARP cleavage. The effect of EPZ-6438 or PF-06821497on the target was validated by immunoblotting of H3K27me3. We knocked down ATF4 with siRNA to evaluate the role of ISR in cell death. Our results demonstrate that ONC201 synergistically reduced cell viability in combination with EZH2i, induced integrated stress response and apoptosis in combination with EZH2i. There was greater induction of ATF4 and DR5 in combinatorial therapy-treated tumor cells versus monotherapy. Knockdown of ATF4 reduced the apoptosis induced by combination therapy. EPZ-6438 or PF-06821497 decreased H3K27 tri-methylation. Our study results unravel potent synergy between ONC201 and EZH2i, highlight the role of ISR in the synergy, and provide further insights into the role of H3K27me3 in ONC201 drug sensitivity. Citation Format: Yiqun Zhang, Lanlan Zhou, Varun V. Prabhu, Joshua E. Allen, Attila A. Seyhan, Wafik S. El-Deiry. The integrated stress response (ISR) is involved in the synergistic combinatorial efficacy of ONC201 and epigenetic modulators in brain tumor cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1156.
Abstract 1159: Hexamethylene bisacetamide (HMBA) inhibits the induction of alkaline phosphatase by butyrate in some bladder and colon cancer cell lines
Authors: Michael A. Lea
Journal: Cancer Research (2021)

Abstract Induction of alkaline phosphatase in colon cancer cells by inhibitors of histone deacetylase activity has been widely used to monitor the induction of differentiation. We have previously identified three human bladder cancer cell lines in which alkaline phosphatase activity can be induced by inhibitors of histone deacetylase (5637, HT1197 and HT1376 cells). In earlier work it was observed that some bromodomain inhibitors inhibit growth and induction of alkaline phosphatase in these cells. After a recent report that HMBA acts as a bromodomain inhibitor, the effects of HMBA on growth and induction of alkaline phosphatase were investigated in two colon cancer cell lines (Caco-2 and HT29) and in 5637, HT1197 and HT1376 bladder cancer cells. Growth was monitored by staining with sulforhodamine B. Incubation with 2 mM butyrate for 72 hours caused induction of alkaline phosphatase in the five cell lines. In some cell lines there was inhibition of growth and of the induction of alkaline phosphatase activity by 2 mM HMBA. Increasing the HMBA concentration to 5 mM caused significant growth inhibition in all five cell lines and significant inhibition of induction of alkaline phosphatase activity by 2 mM butyrate in the 5637, Caco-2 and HT1376 cells, whether expressed as total activity or activity per unit protein. Although the effect of HMBA on induction of alkaline phosphatase in HT29 cells was not statistically significant there is evidence in the literature for inhibition with longer incubation times. The most marked effects on enzyme induction were seen with the HT1376 bladder cancer cells and this distinction was in line with previous studies on the combined effects of butyrate and the well-established bromodomain inhibitor, JQ1. HMBA has been found by several investigators to be an effective inducer of differentiation in erythroleukemia cells as judged by hemoglobin production. The lack of induction of alkaline phosphatase by HMBA as a single agent in any of the cell lines investigated in the present work suggests that different mechanisms of induction of differentiation operate in erythroleukemia cells than in bladder and colon cancer cells. Citation Format: Michael A. Lea. Hexamethylene bisacetamide (HMBA) inhibits the induction of alkaline phosphatase by butyrate in some bladder and colon cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1159.
The single-dose J&amp;J vaccine had 67% efficacy against moderate to severe-critical COVID-19 at ≥14 d
Authors: Henry S. Sacks
Journal: Annals of Internal Medicine (2021)

Sadoff J, Gray G, Vandebosch A, et al. Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19. N Engl J Med. 2021. [Epub ahead of print.] 33882225.
Abstract 504: NKG7 mRNA therapy increases the anti-tumor cytotoxicity of CD8 T cells
Authors: Whitney J. Barham, Ti Wen, Ying Li, Henan Zhang, Cindy Liu, Jacob Hirdler, Joanina Gicobi, Fabrice Lucien-Matteoni, Yiyi Yan, Haidong Dong
Journal: Cancer Research (2021)

Abstract Cytotoxic T lymphocytes (CTL's) are capable of killing tumor cells throughout the body, and can be stimulated to do so by a form of immunotherapy known as PD-1 checkpoint blockade. However, the majority of patients given anti-PD-1 therapeutics do not respond to treatment. Thus, we sought to identify key factors associated with failure of PD-1 blockade in order to develop strategies that could significantly improve response rates. We performed single-cell RNA-seq analysis of peripheral CD8+ T cells from responding and non-responding patients and found that the non-responders had less NKG7 expression. Functional assays revealed that knock-down of NKG7 compromised cytolytic granule localization and trafficking within CTL's. Since decreasing NKG7 reduced the cytolytic efficiency of CD8+ T cells, we next hypothesized that by increasing expression of NKG7 we could promote better T cell killing of tumor and enhance the effects of immune checkpoint inhibitors. To test this, we utilized peripheral blood samples from melanoma patients who failed to respond to anti-PD-1 treatment and transfected the PBMC's with NKG7 mRNA. The addition of NKG7 mRNA significantly increased T cell killing of melanoma tumor cells in an in vitro cytotoxicity assay, and this effect was even more robust in combination with anti-PD-1 or anti-PD-L1 pre-treatment. To confirm that over-expression of NKG7 could improve CD8+ T cell killing in an antigen-specific manner, we transfected OT-1 transgenic T cells with murine sequence of NKG7 mRNA or control mRNA. OT-1 CD8+ T cells with increased NKG7 expression exhibited enhanced cytolytic ability when challenged with either EL4 cells pulsed with OVA peptide or B16-OVA tumor cells in vitro. In addition, NKG7 mRNA-transfected OT-1 CD8+ T cells suppressed the aggressive growth of B16-OVA cells in vivo significantly better than control OT-1 CD8+ T cells. These results indicate that deficits in a T cell-intrinsic cytolytic factor can lead to failure of PD-1/L1 blockade and establish NKG7 as a new therapeutic target for enhancing response to cancer immunotherapy. Citation Format: Whitney J. Barham, Ti Wen, Ying Li, Henan Zhang, Cindy Liu, Jacob Hirdler, Joanina Gicobi, Fabrice Lucien-Matteoni, Yiyi Yan, Haidong Dong. NKG7 mRNA therapy increases the anti-tumor cytotoxicity of CD8 T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 504.
Abstract 79: Crosstalk of PIM and LKB1 kinases in driving growth of prostate cancer cells
Authors: Kwan Long Mung, William Eccleshall, Niina M. Santio, Adolfo Rivero-Müller, Cecilia Sahlgren, Päivi J. Koskinen
Journal: Cancer Research (2021)

Abstract The oncogenic PIM kinases and the tumor-suppressive LKB1 kinase have been linked to regulation of cell growth and proliferation. Here we have investigated their potential interactions as well as their relative impacts on tumorigenic growth of prostate cancer cells. The cellular functions of PIM and LKB1 kinases were evaluated using either pan-PIM inhibitors or CRISPR/Cas9-based genomic editing, with which all three PIM family members and/or LKB1 were knocked out from PC3 prostate cancer cells. In addition to cell-based 2D proliferation assays, we examined tumor growth using the chick embryo chorioallantoic membrane (CAM) xenograft model. In this report, we show that inhibition of PIM expression or activity results in increased phosphorylation of AMPK at Thr172 in an LKB1-dependent fashion. With in vitro kinase assays, we demonstrate that LKB1 is a novel direct substrate for PIM kinases and that Ser334 is one of the PIM target sites in LKB1. Accordingly, wild-type LKB1, but not the phosphodeficient S334A mutant can restore PIM inhibitor-induced AMPK phosphorylation in LKB1 knock-out cells. Whereas loss of LKB1 exaggerates formation of PC3-based tumors in the CAM xenograft model, co-deletion of PIM kinases attenuates it. The impairment of cell proliferation and tumor growth in cells lacking both PIM and LKB1 kinases not only underscores the potential crosstalk in signaling between these kinases, but also suggest that PIM inhibitors could be used to restrain growth of LKB1-deficient tumors. Citation Format: Kwan Long Mung, William Eccleshall, Niina M. Santio, Adolfo Rivero-Müller, Cecilia Sahlgren, Päivi J. Koskinen. Crosstalk of PIM and LKB1 kinases in driving growth of prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 79.
Novel nomogram to identify patients candidate for extended pelvic lymph-node dissection during radical prostatectomy based on target biopsy findings only
Authors: E. Checcucci, C. Fiori, I. Stura, D. Amparore, S. De Cillis, A. Pecoraro, P. Alessio, A. Piana, F. Piramide, G. Volpi, P. Verri, S. Granato, B. Carbonaro, D. Zamengo, A. De Pascale, D. Gned, M. Manfredi, G. Migliaretti, F. Porpiglia
Journal: European Urology (2021)
たばこの煙による肺炎症およびCOPDにおけるIL-1αおよびNIrp3/カスパーゼ-1/IL-1β軸の役割
Authors: N S Pauwels, K R Bracke, L L Dupont, G R Van Pottelberge, S Provoost, Berghe T. Vanden, P Vandenabeele, B N Lambrecht, G F Joos, G G Brusselle
Journal: European Respiratory Journal (2011)