tbuckley/cabot-search huggingface dataset:
Abstract PO-60: The stage-specific roles of radiotherapy and chemotherapy in nodular lymphocyte-predominant Hodgkin lymphoma patients: A propensity-matched analysis of the Surveillance, Epidemiology, and End Results database
Authors: Shijie Wang, Mingfang Jia, Jianglong Han, Rui Zhang, Kejie Huang, Yunfeng Qiao, Ping Chen, Zhenming Fu
Journal: Blood Cancer Discovery (2020)

Abstract Background: The stage-specific roles of radiotherapy (RT) alone, chemotherapy alone, and chemoradiotherapy (CRT) for patients with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) have not been adequately evaluated. Methods: We analyzed patients with NLPHL in all stages enrolled from the Surveillance, Epidemiology, and End Results (SEER) registry from January 2000 to December 2015. Propensity score (PS) analysis with 1:1 matching was performed to ensure well-balanced characteristics between the comparison groups. Kaplan-Meier and Cox proportional hazards models were used to evaluate the overall survival (OS), cancer-specific survival (CSS), the hazard ratio (HR), and corresponding 95% confidence intervals (95% CI). Restricted mean survival times (RMST) were also used for the survival analyses. Results: For early-stage patients, RT alone was found to be associated with the improved survival of 10 months to 15 months and the deceased HR of 60% to 80%. Chemotherapy alone also had survival benefits (improved OS = 12.1 months; improved CSS = 5.3 months). However, not all of these improvements were statistically significant. CRT was associated with the best survival: the mean OS was significantly improved by 20 months and the HR was reduced by more than 80%, both before and after PS matching (PSM) (P &amp;lt; 0.05). For advanced-stage patients, none of RT alone, chemotherapy alone, and CRT had a significant effect on survival. Chemotherapy alone and CRT might be more beneficial for long-term survival (RMST120m: neither RT nor chemotherapy vs. chemotherapy alone vs. CRT = 104m vs. 111m vs. 108m). Subgroup analysis showed that the efficacy of RT alone in patients with early-stage NLPHL was significantly different between younger people and older people (age &amp;lt; 40: HR, 95% CI = 5.70, 0.34 - 94.2, P = 0.224; age ≧ 40: HR, 95% CI = 0.06, 0.01 - 0.32, P = 0.001; P for interaction = 0.005). Conclusions: The results from the large SEER database suggested that CRT was associated with the best survival of patients with the early-stage NLPHL. More effective treatment strategies for patients with advanced-stage NLPHL remain to be further studied. Citation Format: Shijie Wang, Mingfang Jia, Jianglong Han, Rui Zhang, Kejie Huang, Yunfeng Qiao, Ping Chen, Zhenming Fu. The stage-specific roles of radiotherapy and chemotherapy in nodular lymphocyte-predominant Hodgkin lymphoma patients: A propensity-matched analysis of the Surveillance, Epidemiology, and End Results database [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-60.
Pathogenesis of Experimental Viral Hepatitis
Authors: Seymour M. Sabesin, Raymond S. Koff
Journal: New England Journal of Medicine (1974)

Pathology of Viral HepatitisIn reviewing some aspects of the histopathology of experimental and human viral hepatitis, we shall refer particularly to ultrastructural studies of MHV that have revealed information concerning the role of specific subcellular organelles in hepatitis-virus replication and cell injury.MHVThe first microscopical evidence of infection in mouse liver after intraperitoneal injection of MHV is enlargement of Kupffer cells.86 , 87 The earliest necrotic areas are localized to the vicinity of injured Kupffer cells, many of which develop into acidophilic bodies similar to those seen in human viral hepatitis.86 The rapidity of development of the liver lesions depends . . .
Differential Synaptic Input to External Globus Pallidus Neuronal Subpopulations In Vivo
Authors: Maya Ketzef, Gilad Silberberg
Journal: Neuron (2020)

The rodent external globus pallidus (GPe) contains two main neuronal subpopulations, prototypic and arkypallidal cells, which differ in their cellular properties. Their functional synaptic connectivity is largely unknown. Here we studied the membrane properties, synaptic inputs, and sensory responses of these subpopulations in the mouse GPe. We performed in vivo whole-cell recordings in GPe neurons and used optogenetic stimulation to dissect their afferent inputs from the striatum and subthalamic nucleus (STN). Both GPe subpopulations received barrages of excitatory and inhibitory inputs during slow wave activity and responded to sensory stimulation with distinct multiphasic patterns. Prototypic cells synaptically inhibited arkypallidal and prototypic cells. Both GPe subpopulations received synaptic input from STN and striatal medium spiny neurons (MSNs). Although STN and indirect pathway MSNs strongly targeted prototypic cells, direct pathway MSNs selectively inhibited arkypallidal cells. We show that GPe subtypes have distinct connectivity patterns that underlie their respective functional roles.
T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies
Authors: Valentina Cordo', Jordy C.G. van der Zwet, Kirsten Canté-Barrett, Rob Pieters, Jules P.P. Meijerink
Journal: Blood Cancer Discovery (2020)

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with T-ALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent T-ALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of T-ALL and gives a comprehensive overview of the novel treatments for patients with T-ALL that are currently under clinical investigation or that are emerging from preclinical research. SIGNIFICANCE: T-ALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.
104P Safety and efficacy of HLX04 versus reference bevacizumab in combination with XELOX or mFOLFOX6 as first-line treatment for metastatic colorectal cancer: A randomised, double-blind phase III study
Authors: S. Qin, J. Li, Y. Bai, Y. Shu, W. Li, X. Yin, Y. Cheng, G. Sun, Y. Deng, H. Zhong, Y. Li, X. Qian, L. Zhang, J. Zhang, K. Chen, L. Zhang, W. Li, W. Jiang, S. Liu, K. Chai
Journal: Annals of Oncology (2020)
Cell-ECM contact-guided intracellular polarization is mediated via lamin A/C dependent nucleus-cytoskeletal connection
Authors: Geonhui Lee, Seong-Beom Han, Dong-Hwee Kim
Journal: Biomaterials (2020)

Cell polarization plays a crucial role in dynamic cellular events, such as cell proliferation, differentiation, and directional migration in response to diverse extracellular and intracellular signals. Although it is well known that cell polarization entails highly orchestrated intracellular molecular reorganization, the underlying mechanism of repositioning by intracellular organelles in the presence of multiple stimuli is still unclear. Here, we show that front-rear cell polarization based on the relative positions of nucleus and microtubule organizing center is precisely controlled by mechanical interactions including cellular adhesion to extracellular matrix and nucleus-cytoskeletal connections. By modulating the size and distribution of fibronectin-coated adhesive spots located in the polarized cell shape mimicking micropatterns, we monitored the alterations in cell polarity. We found that the localization of individual adhesive spots is more dominant than the cell shape itself to induce intracellular polarization. Further, the degree of cell polarization was diminished significantly by disrupting nuclear lamin A/C. We further confirm that geometrical cue-guided intracellular polarization determines directional cell migration via local activation of Cdc42. These findings provide novel insights into the role of nucleus-cytoskeletal connections in single cell polarization under a combination of physical, molecular, and genetic cues, where lamin A/C acts as a critical molecular mediator in ECM sensing and signal transduction via nucleus-cytoskeletal connection.
Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1–mediated immunoescape via STING-IFN signaling and extracellular vesicles
Authors: An Ning Cheng, Li-Chun Cheng, Cheng-Liang Kuo, Yu Kang Lo, Han-Yu Chou, Chung-Hsing Chen, Yi-Hao Wang, Tsung-Hsien Chuang, Shih-Jung Cheng, Alan Yueh-Luen Lee
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Mitochondrial Lon is a chaperone and DNA-binding protein that functions in protein quality control and stress response pathways. The level of Lon regulates mitochondrial DNA (mtDNA) metabolism and the production of mitochondrial reactive oxygen species (ROS). However, there is little information in detail on how mitochondrial Lon regulates ROS-dependent cancer immunoescape through mtDNA metabolism in the tumor microenvironment (TME). Methods We explored the understanding of the intricate interplay between mitochondria and the innate immune response in the inflammatory TME. Results We found that oxidized mtDNA is released into the cytosol when Lon is overexpressed and then it induces interferon (IFN) signaling via cGAS-STING-TBK1, which upregulates PD-L1 and IDO-1 expression to inhibit T-cell activation. Unexpectedly, upregulation of Lon also induces the secretion of extracellular vehicles (EVs), which carry mtDNA and PD-L1. Lon-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME. Conclusions The levels of mtDNA and PD-L1 in EVs in patients with oral cancer function as a potential diagnostic biomarker for anti-PD-L1 immunotherapy. Our studies provide an insight into the immunosuppression on mitochondrial stress and suggest a therapeutic synergy between anti-inflammation therapy and immunotherapy in cancer.
139P An intraoperative model for predicting survival and deciding therapeutic schedules: A comprehensive analysis of peritoneal metastasis in patients with advanced gastric cancer
Authors: Z-Y. Liu, S-J. Que, J-P. Lin, Q-Y. Chen, C-H. Zheng, P. Li, J-W. Xie, J-B. Wang, J-X. Lin, J. Lu, L-L. Cao, M. Lin, R-H. Tu, Z-N. Huang, J-L. Lin, H-L. Zheng, C. Huang
Journal: Annals of Oncology (2020)
Engineering approaches for effective therapeutic applications based on extracellular vesicles
Authors: Seunglee Kwon, Sol Shin, Minjae Do, Byeong Hoon Oh, Yeari Song, Van Dat Bui, Eun Sook Lee, Dong-Gyu Jo, Yong Woo Cho, Deok-Ho Kim, Jae Hyung Park
Journal: Journal of Controlled Release (2020)
Tumor Size Differences Between Preoperative Endoscopic Ultrasound and Postoperative Pathology for Neoadjuvant-Treated Pancreatic Ductal Adenocarcinoma Predict Patient Outcome
Authors: Rohit Das, Kevin McGrath, Natalie Seiser, Katelyn Smith, Shikhar Uttam, Randall E. Brand, Kenneth E. Fasanella, Asif Khalid, Jennifer S. Chennat, Savreet Sarkaria, Harkirat Singh, Adam Slivka, Herbert J. Zeh, Amer H. Zureikat, Melissa E. Hogg, Kenneth K. Lee, Alessandro Paniccia, Melanie C. Ongchin, James F. Pingpank, Brian A. Boone, Anil K. Dasyam, Nathan Bahary, Vikram C. Gorantla, John C. Rhee, Roby Thomas, Susannah Ellsworth, Michael S. Landau, N. Paul Ohori, Patrick Henn, Susan Shyu, Brian K. Theisen, Aatur D. Singhi
Journal: Clinical Gastroenterology and Hepatology (2020)
14998 Reductions in absolute PASI over 144 weeks of treatment with certolizumab pegol in patients with plaque psoriasis: Pooled analysis from two phase 3 trials (CIMPASI-1 and CIMPASI-2)
Authors: Alice Gottlieb, Andrew Blauvelt, Diamant Thaci, Yves Poulin, Fiona Brock, Catherine Arendt, Marion Boehnlein, Kristian Reich
Journal: Journal of the American Academy of Dermatology (2020)
First flare of ACPA-positive rheumatoid arthritis after SARS-CoV-2 infection
Authors: Lea Perrot, Marie Hemon, Jean-Marc Busnel, Olivier Muis-Pistor, Christophe Picard, Christine Zandotti, Thao Pham, Jean Roudier, Sophie Desplat-Jego, Nathalie Balandraud
Journal: The Lancet Rheumatology (2020)
Nuclear localization of dUTPase is regulated by phosphorylation and modulates chemosensitivity to 5-fluorouracil
Authors: Nicole Rubin, Peter Wilson, Robert Ladner
Journal: Cancer Research (2007)

4755  For over forty years, 5-fluorouracil (5-FU) has remained the central therapeutic agent for the treatment of colorectal cancer (CRC). Progress in CRC treatment has resulted from the combination of 5-FU with additional drugs including oxaliplatin and irinotecan. However, response rates to combination chemotherapy remain below 50% and effective treatment is hindered by the high occurrence of drug resistance, tumor recurrence and mortality. Therefore, there is a great need to identify and exploit novel therapeutic targets and drug combinations to improve clinical efficacy.  5-FU exerts its cytotoxic activity primarily through inhibition of thymidylate synthase (TS), the sole de novo source of thymidylate required for DNA replication. Upon TS inhibition, TTP pools are depleted and in some cases, there is an accumulation of dUTP pools that result in the detrimental misincorporation of uracil into DNA during replication and repair. dUTP nucleotidohydrolase (dUTPase) is an essential enzyme in nucleotide metabolism that hydrolyzes dUTP, removing it from the DNA biosynthetic pathway. In a small retrospective study, overexpression of dUTPase in the nucleus of colon cancer cells was associated with resistance to 5-FU-based therapy.  In this study, we investigated the significance of dUTPase subcellular localization as a critical determinant of dUTPase-mediated resistance to 5-FU-based therapy. The dUTPase protein contains a monopartite nuclear localization sequence (NLS) located close its amino terminus. Directly adjacent to this NLS is Serine-11, a unique phosphorylation site of dUTPase. Site-directed mutagenesis of Serine-11 to the phoshomimetic aspartic acid residue (S11D) abrogates nuclear import as determined by fluorescence microscopy. In contrast, mutation of Serine-11 to alanine (S11A) did not influence nuclear import. To investigate the influence of dUTPase localization in modulating 5-FU sensitivity, we generated colon cancer cell lines that conditionally over-express the wild type dUTPase isoforms, a cytoplasmic-localized S11D mutant and a nuclear localized S11A mutant under the control of a tetracycline-inducible promoter. Thus far we have determined the critical residues required for nuclear and cytoplasmic localization of dUTPase. Ongoing research indicates the effects of differential localization of dUTPase on sensitivity to 5-FU as demonstrated by clonogenic cell survival and growth inhibition assays. Increased resistance is correlated with the abrogation of dUTP pool expansion following TS inhibition. Experiments proposed here will test the hypothesis that nuclear dUTPase is the key determinant in uracil mediated toxicity following TS inhibition. These findings provide scientific rationale highlighting dUTPase as a novel therapeutic target with the potential to improve the clinical efficacy of TS-directed chemotherapy.
Chronic embedded cortico-thalamic closed-loop deep brain stimulation for the treatment of essential tremor
Authors: Enrico Opri, Stephanie Cernera, Rene Molina, Robert S. Eisinger, Jackson N. Cagle, Leonardo Almeida, Timothy Denison, Michael S. Okun, Kelly D. Foote, Aysegul Gunduz
Journal: Science Translational Medicine (2020)

Effective tremor suppression in ET with half the energy requirements was achieved by on-demand DBS based on real-time cortical sensing.
In situ activation of STING pathway with polymeric SN38 for cancer chemoimmunotherapy
Authors: Jiayu Zhao, Sheng Ma, Yudi Xu, Xinghui Si, Haochen Yao, Zichao Huang, Yu Zhang, Haiyang Yu, Zhaohui Tang, Wantong Song, Xuesi Chen
Journal: Biomaterials (2020)
383MO Tepotinib in Asian patients (pts) with advanced NSCLC with MET exon 14 (METex14) skipping
Authors: J.C-H. Yang, X. Le, B.C. Cho, J-Y. Han, M. Morise, Y-M. Chen, J-H. Kang, T. Kato, H. Takeoka, K. Chikamori, H. Sakai, K. Park, Y-L. Wu, K. Schumacher, R. Bruns, J. Straub, P. Paik
Journal: Annals of Oncology (2020)
THU0027 Effects of leflunomide on cytokine production in cultured rheumatoid synovial cells
Authors: P Vergne, B Liagre, P Bertin, C Bonnet, M Rigaud, JL Beneytout
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Leflunomide (A 771726) has been shown recently to be effective in rheumatoid arthritis (RA). It inhibits cell proliferation in activated lymphocytes. Its faster onset of action could be due to both antiinflammatory and immunoregulatory properties. <h3>Objectives</h3> The present study evaluated the effects of the drug on cytokine production in cultured human rheumatoid synovial cells. <h3>Methods</h3> Adherent synovial cells were obtained by collagenase digestion of synovium, isolated from RA patients undergoing surgery. Between passages 4 and 6, cultured synovial cells were incubated with 6 different concentrations of leflunomide (10,20,40,60,80 and 100 μM) and dexamethasone for 24 h. Lipopolysaccharides (LPS) were or were not added for the last 6 h of incubation. Supernatants were assayed for IL-1 receptor antagonist (IL-1 RA), soluble type I receptor of tumour necrosis factor (sTNF RI) and interleukin-6 (IL-6) productions by ELISA. Statistical analysis of differences was carried out by analysis of variance (ANOVA). <h3>Results</h3> IL-1 RA and IL-6 production of LPS-stimulated synovial cells were respectively 2.4- and 1.7-fold higher than that of unstimulated cells. LPS did not enhance the production of sTNF RI. Leflunomide increased significantly (p &lt; 0,001) the production of IL-1 RA in a dose dependent manner with a plateau effect beyond 80 μM. Leflunomide decreased significantly (p &lt; 0,001) the IL-6 production by 70 to 75% in a dose dependent manner. On the other hand, leflunomide did not have a significant effect on sTNF RI production. Dexamethasone decreased all the cytokine productions. <h3>Conclusion</h3> Leflunomide could have an immunomodulatory action in the cytokine network involved in the pathogenesis of RA with a decrease production of the proinflammatory cytokine IL-6 and increase synthesis of the antiinflammatory cytokine IL-1 RA. This work has been supported by Aventis Pharma laboratory.
18295 Mandelic acid, a lipophilic alpha hydroxy acid, reduces lipid production, enhances exfoliation and provides clinical and patient perceivable benefits to oily and photodamaged skin
Authors: Brenda L. Edison, Heather A. Smith, Wen-Hwa Li, Ramine Parsa, Barbara A. Green, Peter Konish, Marisa Dufort, Neena K. Tierney
Journal: Journal of the American Academy of Dermatology (2020)
Effect of early application of social distancing interventions on COVID-19 mortality over the first pandemic wave: An analysis of longitudinal data from 37 countries
Authors: Daniele Piovani, Maria Nefeli Christodoulou, Andreas Hadjidemetriou, Katerina Pantavou, Paraskevi Zaza, Pantelis G. Bagos, Stefanos Bonovas, Georgios K. Nikolopoulos
Journal: Journal of Infection (2020)

ObjectivesTo estimate the effect of early application of social distancing interventions on Covid-19 cumulative mortality during the first pandemic wave.MethodsEcological longitudinal study using multivariable negative binomial regression for panel data. Daily numbers of Covid-19 cases and deaths, and data on social distancing interventions, for the 37 member countries of the Organization for Economic Cooperation and Development (OECD) were analysed.ResultsCovid-19 cumulative mortality over the first pandemic wave varied widely across countries (range, 4.16 to 855 deaths per million population). On average, one-day delay in application of mass gatherings ban was associated with an adjusted increase in Covid-19 cumulative mortality by 6.97% (95% CI, 3.45 to 10.5), whilst a one-day delay in school closures was associated with an increase of 4.37% (95% CI, 1.58 to 7.17) over the study period. We estimated that if each country had enacted both interventions one week earlier, Covid-19 cumulative mortality could have been reduced by an average of 44.1% (95% CI, 20.2 to 67.9).ConclusionsEarly application of mass gatherings ban and school closures in outbreak epicentres was associated with an important reduction in Covid-19 cumulative mortality during the first pandemic wave. These findings may support policy decision making.
The Reception of William Beaumont's Discovery in Europe
Journal: JAMA (1942)

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170P Sintilimab plus anlotinib as first-line therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC)
Authors: X. Chen, W. Li, X. Wu, F. Zhao, H. Wu, Y. Gu, X. Li, X. Qian, J. Hu, C. Li, Y. Xia, A. Yao, P.K. Seesaha, Q. Shao, X. Dong, X. Li, Y. Shu
Journal: Annals of Oncology (2020)