tbuckley/cabot-search huggingface dataset:
Neutrophil dynamics in the tumor microenvironment
Authors: Amanda J. McFarlane, Frédéric Fercoq, Seth B. Coffelt, Leo M. Carlin
Journal: Journal of Clinical Investigation (2021)

The tumor microenvironment profoundly influences the behavior of recruited leukocytes and tissue-resident immune cells. These immune cells, which inherently have environmentally driven plasticity necessary for their roles in tissue homeostasis, dynamically interact with tumor cells and the tumor stroma and play critical roles in determining the course of disease. Among these immune cells, neutrophils were once considered much more static within the tumor microenvironment; however, some of these earlier assumptions were the product of the notorious difficulty in manipulating neutrophils in vitro. Technological advances that allow us to study neutrophils in context are now revealing the true roles of neutrophils in the tumor microenvironment. Here we discuss recent data generated by some of these tools and how these data might be synthesized into more elegant ways of targeting these powerful and abundant effector immune cells in the clinic.
P46.01 Intronic Noncoding RNA Expression of DCN is Related to Cancer-Associated Fibroblasts and NSCLC Patients’ Prognosis
Authors: J. Zhou, T. Cheng, X. Li, J. Pineda, X. Wang, H. Si, P. Shi, R. Shen, N. Zhou, C. Bai
Journal: Journal of Thoracic Oncology (2021)
Application of Value Frameworks to the Design of Clinical Trials: The Canadian Cancer Trials Group Experience
Authors: Joseph C Del Paggio, Adam M Fundytus, Wilma M Hopman, Joseph L Pater, Bingshu E Chen, Michael D Brundage, Annette E Hay, Christopher M Booth
Journal: JNCI Journal of the National Cancer Institute (2021)

Use of value framework thresholds in the design of clinical trials may increase the proportion of randomized controlled trials that identify clinically meaningful advances for patients. Existing frameworks have not been applied to the research output of a cooperative cancer trials group. We apply value frameworks to the randomized controlled trial output of the Canadian Cancer Trials Group (CCTG).Statistical design, study characteristics, and results of all published phase III trials of CCTG were abstracted. We applied the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and American Society of Clinical Oncology Net Health Benefit to study results and the statistical power calculations to identify the proportion of all trials that were designed to detect a substantial clinical benefit.During 1979 to 2017, CCTG published 113 phase III trials; 52.2% (59 of 113) of these trials were positive. One-half (50.4%, 57 of 113) of the trials were conducted in the palliative setting. In 37.2% (42 of 113) of trials, the primary endpoint was overall survival; disease-free survival or progression-free survival was used in 38.9% (44 of 113) of trials. The ESMO-MCBS could be applied to the power calculation for 69 trials; 73.9% (51 of 69) of these trials were designed to detect an effect size that could meet ESMO-MCBS thresholds for substantial benefit. Among the 51 positive trials for which the ESMO-MCBS could be applied, 41.1% (21 of 51) met thresholds for substantial benefit.Most CCTG phase III trials were designed to detect clinically meaningful differences in outcome, although less than one-half of positive trials met the threshold for substantial benefit. Application of value frameworks to the design of clinical trials is practical and may improve research efficiency and treatment options for patients.
P21.02 Incidence and Outcomes of Brain Metastases in Unresectable Stage III Patients with NSCLC Treated with Durvalumab after Chemoradiation
Authors: S. Patel, S. Zhao, L. Wei, M. Li, E. Bertino, C. Presley, M. Welliver, K. Haglund, J. Palmer, A. Arnett, S. Beyer, E. Mende, J. Elder, D. Hardesty, P. Shields, D. Carbone, G. Otterson, T. Williams, D. Owen
Journal: Journal of Thoracic Oncology (2021)
Nurses at the frontline of public health emergency preparedness and response: lessons learned from the HIV/AIDS pandemic and emerging infectious disease outbreaks
Authors: Vincent Guilamo-Ramos, Marco Thimm-Kaiser, Adam Benzekri, Andrew Hidalgo, Yzette Lanier, Sheila Tlou, María de Lourdes Rosas López, Asha B Soletti, Holly Hagan
Journal: The Lancet Infectious Diseases (2021)

The years 2020–21, designated by WHO as the International Year of the Nurse and Midwife, are characterised by unprecedented global efforts to contain and mitigate the COVID-19 pandemic. Lessons learned from successful pandemic response efforts in the past and present have implications for future efforts to leverage the global health-care workforce in response to outbreaks of emerging infectious diseases such as COVID-19. Given its scale, reach, and effectiveness, the response to the HIV/AIDS pandemic provides one such valuable example, particularly with respect to the pivotal, although largely overlooked, contributions of nurses and midwives. This Personal View argues that impressive achievements in the global fight against HIV/AIDS would not have been attained without the contributions of nurses. We discuss how these contributions uniquely position nurses to improve the scale, reach, and effectiveness of response efforts to emerging infectious diseases with pandemic potential; provide examples from the responses to COVID-19, Zika virus disease, and Ebola virus disease; and discuss implications for current and future efforts to strengthen pandemic preparedness and response.
Resident memory T cells form during persistent antigen exposure leading to allograft rejection
Authors: Khodor I. Abou-Daya, Roger Tieu, Daqiang Zhao, Rayan Rammal, Faruk Sacirbegovic, Amanda L. Williams, Warren D. Shlomchik, Martin H. Oberbarnscheidt, Fadi G. Lakkis
Journal: Science Immunology (2021)

Recipient effector T cells differentiate into functional tissue-resident memory T cells, causing graft rejection after kidney transplantation.
HSR21-062: Real-World Study of BRCA1/2 Mutation (BRCA1/2mut) Testing Among Adult Patients (pts) With HER2− Advanced Breast Cancer (ABC) in the US
Authors: Reshma Mahtani, Alex Niyazov, MPH; Katie Lewis, Lucy Massey, Alex Rider, Bhakti Arondekar, Michael Lux
Journal: Journal of the National Comprehensive Cancer Network (2021)

"HSR21-062: Real-World Study of BRCA1/2 Mutation (BRCA1/2mut) Testing Among Adult Patients (pts) With HER2− Advanced Breast Cancer (ABC) in the US" published on 17 Mar 2021 by National Comprehensive Cancer Network.
Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis
Authors: Victor Sapena, Marco Enea, Ferran Torres, Ciro Celsa, Jose Rios, Giacomo Emanuele Maria Rizzo, Pierre Nahon, Zoe Mariño, Ryosuke Tateishi, Tatsuya Minami, Angelo Sangiovanni, Xavier Forns, Hidenori Toyoda, Stefano Brillanti, Fabio Conti, Elisabetta Degasperi, Ming-Lung Yu, Pei-Chien Tsai, Kevin Jean, Mohamed El Kassas, Hend Ibrahim Shousha, Ashraf Omar, Claudio Zavaglia, Hiroko Nagata, Mina Nakagawa, Yasuhiro Asahina, Amit G Singal, Caitlin Murphy, Mohamed Kohla, Chiara Masetti, Jean-François Dufour, Nicolas Merchante, Luisa Cavalletto, liliana LC chemello, Stanislas POL, Javier Crespo, Jose Luis Calleja, Rosanna Villani, Gaetano Serviddio, Alberto Zanetto, Sarah Shalaby, Francesco Paolo Russo, Rob Bielen, Franco Trevisani, Calogero Cammà, Jordi Bruix, Giuseppe Cabibbo, Maria Reig
Journal: Gut (2021)

Objective The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. Design We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. Results Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I 2 =74.6%) and 5.7 (2.5 to 15.3, I 2 =54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p&lt;0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p&lt;0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). Conclusion Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.
EOMES is essential for antitumor activity of CD8+ T cells in chronic lymphocytic leukemia
Authors: Laura Llaó-Cid, Philipp M. Roessner, Vicente Chapaprieta, Selcen Öztürk, Tobias Roider, Marie Bordas, Ana Izcue, Dolors Colomer, Sascha Dietrich, Stephan Stilgenbauer, Bola Hanna, José Ignacio Martín-Subero, Martina Seiffert
Journal: Leukemia (2021)

Abstract Genome-wide association studies identified a single-nucleotide polymorphism (SNP) affecting the transcription factor Eomesodermin (EOMES) associated with a significantly increased risk to develop chronic lymphocytic leukemia (CLL). Epigenetic analyses, RNA sequencing, and flow cytometry revealed that EOMES is not expressed in CLL cells, but in CD8 + T cells for which EOMES is a known master regulator. We thus hypothesized that the increased CLL risk associated with the EOMES SNP might be explained by its negative impact on CD8 + T-cell-mediated immune control of CLL. Flow cytometry analyses revealed a higher EOMES expression in CD8 + T cells of CLL patients compared to healthy individuals, and an accumulation of PD-1 + EOMES + CD8 + T cells in lymph nodes rather than blood or bone marrow in CLL. This was in line with an observed expansion of EOMES + CD8 + T cells in the spleen of leukemic Eµ-TCL1 mice. As EOMES expression was highest in CD8 + T cells that express inhibitory receptors, an involvement of EOMES in T-cell exhaustion and dysfunction seems likely. Interestingly, Eomes -deficiency in CD8 + T cells resulted in their impaired expansion associated with decreased CLL control in mice. Overall, these observations suggest that EOMES is essential for CD8 + T-cell expansion and/or maintenance, and therefore involved in adaptive immune control of CLL.
Abstract 4043: Blockade of Renin-Angiotensin System (RAS) Inhibits Increased Matrix Metalloproteinase-9 Expression and Apoptosis Induced by Advanced Glycation End Products (AGE) and Attenuates Receptor for AGE (RAGE) Expression
Authors: Toshiyuki Ishibashi, Michiko Kawaguchi, Masashi Kamioka, Hironori Uekita, Koichi Sugimoto, Yukio Maruyama
Journal: Circulation (2006)

Background: Diabetes is a major risk factor of coronary artery disease (CAD). AGE accumulate and RAGE expression increases in the vascular wall of type 2 diabetes, which promotes vascular remodelin...
Mutational spectrum and precision oncology for biliary tract carcinoma
Authors: Jianzhen Lin, Yinghao Cao, Xu Yang, Guangyu Li, Yang Shi, Dongxu Wang, Junyu Long, Yang Song, Jinzhu Mao, Fucun Xie, Yi Bai, Lei Zhang, Xiaobo Yang, Xueshuai Wan, Anqiang Wang, Mei Guan, Lin Zhao, Ke Hu, Jie Pan, Li Huo, Xin Lu, Yilei Mao, Xinting Sang, Henghui Zhang, Kai Wang, Xiaoyue Wang, Haitao Zhao
Journal: Theranostics (2021)

The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients.
Most Patients Hospitalized With COVID-19 Have Lasting Symptoms
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

Reducing particulate matter and nitrogen dioxide pollution in nearly 1000 European cities to the World Health Organization (WHO) target levels could save about 50 000 lives a year, a multinational team of investigators reported.Using 2015 data on air pollution and deaths in those cities, the investigators estimated the health impact of lowering levels of particulate matter with a diameter of 2.5 μm or smaller (PM 2.5 ) and nitrogen dioxide (NO 2 ) to meet the targets in the WHO's air quality guidelines.The guidelines recommend no more than an annual mean of 10 μg/m 3 for PM 2.5 and 40 μg/m 3 for NO 2 .Meeting the WHO targets would prevent an estimated 51 213 premature deaths for PM 2.5 exposure and 900 premature deaths for NO 2 exposure each year, the authors found.Achieving even lower levels of 3.7 μg/m 3 for PM 2.5 and 3.5 μg/m 3 for NO 2 -the lowest levels measured in any European city in 2015-would prevent an estimated 124 729 premature deaths from PM 2.5 exposure and 79 435 premature deaths from NO 2 exposure annually.Pollution-related health effects varied significantly by city.Three northern European cities-Tromsø, Norway; Umeå, Sweden; and Oulu, Finland-had the lowest premature mortality burden linked with PM 2.5 and NO 2 exposure.Cities in northern Italy, southern Poland, and the eastern Czech Republic had the highest burden linked with PM 2.5 , while large cities and capitals in western and southern Europe had the highest premature deaths attributed to NO 2 ."The study proves that many cities are still not doing enough to tackle air pollution, and levels above the WHO guidelines are leading to unnecessary deaths," study coauthor Mark J.
P15.01 AMG 757, a Half-Life Extended Bispecific T-Cell Engager (HLE BiTE® Immune Therapy) Targeting DLL3, for the Treatment of Small Cell Lung Cancer
Authors: K. Cooke, J. Estrada, J. Zhan, J. Werner, J. Bailis, P. Hughes, A. Shetty, J. Canon, M. Smit
Journal: Journal of Thoracic Oncology (2021)
Abstract P32: Inequalities in the decline and recovery of pathological cancer diagnoses during the first six months of the COVID-19 pandemic: A population-based study
Authors: Ashleigh C. Hamilton, David W. Donnelly, Maurice B. Loughrey, Richard C. Turkington, Colin Fox, Deirdre Fitzpatrick, Ciaran E. O'Neill, Anna T. Gavin, Helen G. Coleman
Journal: Clinical Cancer Research (2021)

Abstract Introduction: The aim of this study was to evaluate the impact of COVID-19 on pathological diagnoses of cancer in Northern Ireland, and assess potential inequalities across subgroups of the population. Methods: Data from the four Northern Ireland pathology labs were used to assess trends in pathological cancer diagnoses from 1st March to 12th September 2020 overall and by cancer site, gender and age. These trends were compared to the same timeframe from 2017-2019. Results: Between 1st March and 12th September 2020 there was a 23% reduction in cancer diagnoses compared to the same time period in the preceding three years. Although some recovery occurred in August and September 2020, this revealed inequalities across certain patient groups. Pathological diagnoses of lung, prostate and gynaecological malignancies remained well below pre-pandemic levels. Males and younger/middle-aged adults, particularly the 50-59 year old patient group, also lagged behind other population demographic groups in terms of returning to expected numbers of pathological cancer diagnoses. Conclusions: There is a critical need to protect cancer diagnostic services in the ongoing pandemic to facilitate timely investigation of potential cancer cases. Targeted public health campaigns may be needed to reduce emerging inequalities in cancer diagnoses as the COVID-19 pandemic continues. Citation Format: Ashleigh C. Hamilton, David W. Donnelly, Maurice B. Loughrey, Richard C. Turkington, Colin Fox, Deirdre Fitzpatrick, Ciaran E. O'Neill, Anna T. Gavin, Helen G. Coleman. Inequalities in the decline and recovery of pathological cancer diagnoses during the first six months of the COVID-19 pandemic: A population-based study [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P32.
Abstract 13307: An Oral Antisense Oligonucleotide for PCSK9 Inhibition in Humans
Authors: Peter Gennemark, Katrin Walter, Niclas Clemmensen, Dinko Rekic, Catarina Nilsson, Jane Knoechel, Mikko Holtta, Yanfeng Wang, Rosie Yu, stanley riney, Brett P Monia, Ulf Andersson, Rasmus Jansson-Lofmark, Cristina S Rocha, Daniel Linden, Kristina Ryden-Bergsten, Eva Hurt-Camejo, Rosanne M CROOKE, Lloyd Tillman, Bjorn Carlsson, Marie Elebring, Anna Tivesten, Nigel Davies
Journal: Circulation (2020)

Current PCSK9 inhibitors are administered via subcutaneous (SC) injection. Here, we present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier ASO chemistries and intestinal permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by tri-antennary N -acetyl galactosamine (GalNAc) conjugation make this ASO highly potent. A single SC dose of 90 mg reduces PCSK9 by &gt;90% in humans with elevated LDL-C (A), and a once monthly SC dose of 25 mg ([20, 30], 90% CI) is predicted to reduce PCKS9 by 80% at steady-state. To investigate the feasibility of oral administration, we developed an oral solid tablet wherein the ASO is co-formulated with a transient permeation enhancer. Repeated oral daily dosing of tablets to dogs resulted in a bioavailability of 7% in the liver (target organ), approximately 5-fold greater than the plasma bioavailability (B). Favourable liver uptake following oral administration is supported by similar bioavailability in plasma and kidney. Since the ASO is not active in rodents or dogs, we used a rat-specific GalNAc- Malat-1 ASO with the same chemistry to confirm target engagement. Intrajejunal administration resulted in ≥78% mRNA knockdown in the liver for single doses of 3-40 mg/kg. A monkey tolerability study of the PCSK9 ASO further supports oral feasibility with all tested doses (28-56 mg/day) significantly reducing LDL-C already after 7 days of daily oral dosing. Based on available animal and human data, and an assumption of 5% oral bioavailability in humans, a daily dose of 15 mg ([10, 20], 90% CI) in man is predicted to reduce PCSK9 in plasma by 80% at steady-state. This supports the development of the compound for subcutaneous and oral administration to treat dyslipidemia.
Virtual optimization of guideline‐directed medical therapy in hospitalized patients with heart failure with reduced ejection fraction: the IMPLEMENT‐HF pilot study
Authors: Ankeet S. Bhatt, Anubodh S. Varshney, Mahan Nekoui, Alea Moscone, Jonathan W. Cunningham, Karola S. Jering, Parth N. Patel, Lauren E. Sinnenberg, Thomas D. Bernier, Leo F. Buckley, Bryan M. Cook, Jillian Dempsey, Julie Kelly, Danielle M. Knowles, Kenneth Lupi, Rhynn Malloy, Lina S. Matta, Megan N. Rhoten, Krishan Sharma, Caroline A. Snyder, Clara Ting, Erin E. McElrath, Mary G. Amato, Maryam Alobaidly, Catherine E. Ulbricht, Niteesh K. Choudhry, Dale S. Adler, Muthiah Vaduganathan
Journal: European Journal of Heart Failure (2021)
Peter Dunn: coined the term “perinatal medicine”
Authors: Andrew Whitelaw, Alan Craft
Journal: BMJ (2021)

Peter Dunn was a big man with an immense presence who contributed massively to the better care of newborn babies. When he qualified, 40 of every 1000 babies born alive died within seven days. In 2020 this had reduced to eight. Although the word “perinatal” had been used in “perinatal mortality” since 1944, Dunn coined the term “perinatal medicine.” He brought together obstetricians, midwives, and paediatricians and ensured that they worked together for the benefit of the baby. He was instrumental in forming the British Association of Perinatal Medicine (BAPM) and was its first president. One of the first things he did was to campaign for the NHS status of newborn babies to be recognised. When the NHS was founded in 1948, babies had a separate status only if they were sick enough to require special care. He pointed out that although the newborn infant is 10 times more likely to die than its mother, only the 10% of babies …
Transient Competitive Inhibition Bypasses the Binding Site Barrier to Improve Tumor Penetration of Trastuzumab and Enhance T-DM1 Efficacy
Authors: Brandon M. Bordeau, Yujie Yang, Joseph P. Balthasar
Journal: Cancer Research (2021)

Abstract Poor penetration of mAbs in solid tumors is explained, in part, by the binding site barrier hypothesis. Following extravasation, mAbs rapidly bind cellular antigens, leading to the observation that, at subsaturating doses, therapeutic antibody in solid tumors localizes around tumor vasculature. Here we report a unique strategy to overcome the binding site barrier through transient competitive inhibition of antibody–antigen binding. The anti-trastuzumab single domain antibody 1HE was identified through in vitro binding assays as a model inhibitor. Coadministration of 1HE did not alter the plasma pharmacokinetics of trastuzumab or ado-trastuzumab emtansine (T-DM1) in vivo. Administration of 1HE alone was rapidly eliminated with a terminal plasma half-life of 1.2 hours, while coadministrations of 1HE with trastuzumab had a terminal half-life of 56 hours. In mice harboring SKOV3 xenografts, coadministration of 1HE with trastuzumab led to significant increases in both penetration of trastuzumab from vasculature and the percentage of tumor area that stained positive for trastuzumab. 1HE coadministered with a single dose of T-DM1 to NCI-N87 xenograft–bearing mice significantly enhanced T-DM1 efficacy, increasing median survival. These results support the hypothesis that transient competitive inhibition can improve therapeutic antibody distribution in solid tumors and enhance antibody efficacy. Significance: This study describes the development of a transient competitive inhibition strategy that enhances the tumor penetration and efficacy of anticancer antibodies. See related commentary by van Dongen, p. 3956
Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health
Authors: Joji Kusuyama, Ana Barbara Alves-Wagner, Royce H. Conlin, Nathan S. Makarewicz, Brent G. Albertson, Noah B. Prince, Shio Kobayashi, Chisayo Kozuka, Magnus Møller, Mette Bjerre, Jens Fuglsang, Emily Miele, Roeland J.W. Middelbeek, Yang Xiudong, Yang Xia, Léa Garneau, Jayonta Bhattacharjee, Céline Aguer, Mary Elizabeth Patti, Michael F. Hirshman, Niels Jessen, Toshihisa Hatta, Per Glud Ovesen, Kristi B. Adamo, Eva Nozik-Grayck, Laurie J. Goodyear
Journal: Cell Metabolism (2021)
Audio Interview: Efficacy of Current Covid-19 Vaccines against Variant Viruses
Authors: Eric J. Rubin, Lindsey R. Baden, Stephen Morrissey
Journal: New England Journal of Medicine (2021)

Efficacy of Current Covid-19 Vaccines against Variant Viruses In this audio interview conducted on March 16, 2021, the editors discuss in vitro and clinical results of SARS-CoV-2 vaccination in the...
P86.03 A Phase 2 Study of Erdafitinib in Patients with Advanced Solid Tumors and Fibroblast Growth Factor Receptor Gene Alterations
Authors: S. Pant, J. Tabernero, C. Massard, D.M. Hyman, O. Witt, T. Doi, S. Qin, C. Lu-Emerson, D. Hargrave, J. Garcia-Corbacho, S. Little, J. Tolbert, A. Santiago-Walker, C. Moy, C. Hammond, Y.Y. Lau, H. Sweiti, M. Schuler
Journal: Journal of Thoracic Oncology (2021)