tbuckley/cabot-search huggingface dataset:
Homogeneous tumor targeting with a single dose of HER2-targeted albumin-binding domain-fused nanobody-drug conjugates results in long-lasting tumor remission in mice
Authors: Katerina T Xenaki, Bram Dorresteijn, Joey A Muns, Kevin Adamzek, Sofia Doulkeridou, HendrikJan Houthoff, Sabrina Oliveira, Paul MP van Bergen en Henegouwen
Journal: Theranostics (2021)

Background:The non-homogenous distribution of antibody-drug conjugates (ADCs) within solid tumors is a major limiting factor for their wide clinical application.Nanobodies have been shown to rapidly penetrate into xenografts, achieving more homogeneous tumor targeting.However, their rapid renal clearance can hamper their application as nanobody drug conjugates (NDCs).Here, we evaluate whether half-life extension via non-covalent interaction with albumin can benefit the efficacy of a HER2-targeted NDC.Methods: HER2-targeted nanobody 11A4 and the irrelevant nanobody R2 were genetically fused to an albumin-binding domain (ABD) at their C-terminus.Binding to both albumin and tumor cells was determined by ELISA-based assays.The internalization potential as well as the in vitro efficacy of NDCs were tested on HER2 expressing cells.Serum half-life of iodinated R2 and R2-ABD was studied in tumor-free mice.The distribution of fluorescently labelled 11A4 and 11A4-ABD was assessed in vitro in 3D spheroids.Subsequently, the in vivo distribution was evaluated by optical molecular imaging and ex vivo by tissue biodistribution and tumor immunohistochemical analysis after intravenous injection of IRDye800-conjugated nanobodies in mice bearing HER2-positive subcutaneous xenografts.Finally, efficacy studies were performed in HER2-positive NCI-N87 xenograft-bearing mice intravenously injected with a single dose (250 nmol/kg) of nanobodies conjugated to auristatin F (AF) either via a maleimide or the organic Pt(II)-based linker, coined Lx ® .Results: 11A4-ABD was able to bind albumin and HER2 and was internalized by HER2 expressing cells, irrespective of albumin presence.Interaction with albumin did not alter its distribution through 3D spheroids.Fusion to ABD resulted in a 14.8-fold increase in the serum half-life, as illustrated with the irrelevant nanobody.Furthermore, ABD fusion prolonged the accumulation of 11A4-ABD in HER2-expressing xenografts without affecting the expected homogenous intratumoral distribution.Next to that, reduced kidney retention of ABD-fused nanobodies was observed.Finally, a single dose administration of either 11A4-ABD-maleimide-AF or 11A4-ABD-Lx-AF led to long-lasting tumor remission in HER2-positive NCI-N87 xenograft-bearing mice. Conclusion:Our results demonstrate that genetic fusion of a nanobody to ABD can significantly extend serum half-life, resulting in prolonged and homogenous tumor accumulation.Most importantly, as supported by the impressive anti-tumor efficacy observed after a single dose administration of 11A4-ABD-AF, our data reveal that monovalent internalizing ABD-fused nanobodies have potential for the development of highly effective NDCs.
P07.02 Detection of Molecular Residual Disease (MRD) using ctDNA in NSCLC: A Systematic Review and Meta-Analysis
Authors: A. Galvano, V. Gristina, L. Insalaco, M. La Mantia, A. Perez, N. Barraco, L. Castellana, M. Bono, S. Cusenza, M. Castiglia, C. Lisanti, S. Cutaia, M. Ricciardi, D. Sardo, S. Inguglia, S. Rizzo, V. Bazan, A. Russo
Journal: Journal of Thoracic Oncology (2021)
P09.09 Overall Survival in Elderly Metastatic Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Blockade
Authors: M.F. Simões, M.F. Medeiros, D. Maciel Santana, C.I. De Andrade Souza, L.B. Mendes Gomes, H. De Freitas, M. Petrocchi Corassa, M.D. Spina Donadio, V.C. De Lima
Journal: Journal of Thoracic Oncology (2021)
Engineering T Cells to Express Tumoricidal MDA-7/IL24 Enhances Cancer Immunotherapy
Authors: Zheng Liu, Chunqing Guo, Swadesh K. Das, Xiaofei Yu, Anjan K. Pradhan, Xia Li, Yanxia Ning, Shixian Chen, Wenjie Liu, Jolene J. Windle, Harry D. Bear, Masoud H. Manjili, Paul B. Fisher, Xiang-Yang Wang
Journal: Cancer Research (2021)

Abstract Antigen-specific immunotherapy can be limited by induced tumor immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Melanoma differentiation–associated gene-7/IL24 (MDA-7/IL24) has profound tumor-specific cytotoxic effects in a broad spectrum of cancers. Here we report the enhanced therapeutic impact of genetically engineering mouse tumor-reactive or antigen-specific T cells to produce human MDA-7/IL24. While mock-transduced T cells only killed antigen-expressing tumor cells, MDA-7/IL24-producing T cells destroyed both antigen-positive and negative cancer targets. MDA-7/IL24-expressing T cells were superior to their mock-engineered counterparts in suppressing mouse prostate cancer and melanoma growth as well as metastasis. This enhanced antitumor potency correlated with increased tumor infiltration and expansion of antigen-specific T cells as well as induction of a Th1-skewed immunostimulatory tumor environment. MDA-7/IL24-potentiated T-cell expansion was dependent on T-cell–intrinsic STAT3 signaling. Finally, MDA-7/IL24-modified T-cell therapy significantly inhibited progression of spontaneous prostate cancers in Hi-Myc transgenic mice. Taken together, arming T cells with tumoricidal and immune-potentiating MDA-7/IL24 confers new capabilities of eradicating antigen-negative cancer cell clones and improving T-cell expansion within tumors. This promising approach may be used to optimize cellular immunotherapy for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape. Significance: This research describes a novel strategy to overcome the antigenic heterogeneity of solid cancers and prevent tumor escape by engineering T lymphocytes to produce a broad-spectrum tumoricidal agent.
International Variation in Intubation and Extubation Practices and Adverse Events Among Critically Ill Patients Receiving Mechanical Ventilation
Authors: Hayley B. Gershengorn
Journal: JAMA (2021)

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P24.02 Rick Factors for the Occurence of Postoperative Empyema in Malignant Pleural Mesothelioma Patients Undergoing Macroscopic Complete Resection
Authors: O. Lauk, T. Neuer, R. Werner, S. Hillinger, I. Inci, K. Furrer (Contributed Equally), I. Opitz
Journal: Journal of Thoracic Oncology (2021)
Abstract P50: Ischemic Post-Conditioning Following Global Ischemia Due to Cardiac Arrest Failed to Improve Cardiac Function and Survival
Authors: Morten Pytte, Shijie Sun, Wanchun Tang, Max H Weil
Journal: Circulation (2008)

Introduction : Repetitive episodes of ischemia and reperfusion following regional myocardial and cerebral ischemia, representing ischemic post-conditioning (IPC), protect against ischemic injury. The possibility that such may have functional application for myocardial injury and survival in settings of cardiac arrest and resuscitation was examined. We hypothesized that repetitive cycles of ventricular fibrillation and reperfusion following resuscitation, representing IPC, would improve cardiovascular function and survival. Methods : Ventricular fibrillation (VF) was electrically induced in 10 SD rats weighing 536±15 g and left untreated for 8 minutes prior to 6 minutes of uninterrupted pre-cordial compressions followed by attempted defibrillation. Resuscitated animals were randomized to either IPC or control. IPC was induced at 5 minutes with electrical re-fibrillation lasting 30 sec followed by spontaneous reversion to a perfusing rhythm. The IPC was repeated 5 minutes later. Except for IPC, controls were identically treated. Frontal plane ECG, mean arterial blood pressure, left ventricular pressures and end tidal CO 2 were continuously recorded. Left ventricular ejection fraction (EF) and cardiac output (CO) were measured echocardiographically at hourly intervals together with blood gases for a total of four hours. Survival was documented at the end of 72 hours. Results : Baseline values did not differ between the IPC and control group. No statistically significant differences between the groups were demonstrated. A power calculation indicates that a minimum of 240 animals would be required to find a difference that would be potentially significant, accordingly the study was concluded. Table . Mean values with standard deviation. Conclusion : The potential value of ischemic post-conditioning represented by repetitive episodes of VF, under the conditions of global ischemia of cardiac arrest, failed to demonstrate a survival value.
FP07.03 Landscape Heterogeneity of PD-L1 Expression and Immune Cells Predicts Prognosis of Metastatic Non-Small Cell Lung Cancer
Authors: J. Wu, W. Sun, X. Yang, H. Wang, X. Liu, K. Chi, L. Zhou, X. Huang, S. Zhao, T. Ding, B. Meng, D. Lin
Journal: Journal of Thoracic Oncology (2021)
Abstract 13632: Increase in Long-Term Major Adverse Cardiovascular Events in Patients “Appropriately” Tested for Troponin Assays in the Emergency Department
Authors: Ahmed H Qavi, Prakash Acharya, Fariha Ilyas, Andreea-Constanta Stan, Olvas Dallaku, Stephen Jesmajian, Bernard Gitler
Journal: Circulation (2019)

Introduction: Lack of criteria for ordering troponin in the ED has led to inappropriate ordering and overdiagnosis. We developed an appropriateness criteria and examined long-term cardiovascular ou...
P05.13 Central vs Peripheral Thoracic Malignancies Treated with SBRT: Early Outcomes of a Prospective Quality of Life Study
Authors: M. Carrasquilla, R. Krochmal, E. Anderson, P. Bergquist, M. Margolis, M. Forsthoefel, B. Collins, C. Kim, S. Liu, J. Lischalk
Journal: Journal of Thoracic Oncology (2021)
P37.02 Identification of Gene Fusions and Mutations in Patients with NSCLC using two Diagnostic Approaches: Rapid qPCR and NGS
Authors: A. Tysarowski, K. Seliga, A. Nowak, M. Wagrodzki, A. Gos, R. Zub, K. Olszewska, B. Jagielska, M. Knetki-Wróblewska, A. Pluzanski, M. Krzakowski, J. Siedlecki, M. Prochorec-Sobieszek
Journal: Journal of Thoracic Oncology (2021)
Correction to: LncRNA PVT1 up-regulation is a poor prognosticator and serves as a therapeutic target in esophageal adenocarcinoma
Authors: Yan Xu, Yuan Li, Jiankang Jin, Guangchun Han, Chengcao Sun, Melissa Pool Pizzi, Longfei Huo, Ailing Scott, Ying Wang, Lang Ma, Jeffrey H. Lee, Manoop S. Bhutani, Brian Weston, Christopher Vellano, Liuqing Yang, Chunru Lin, Youngsoo Kim, A. Robert MacLeod, Linghua Wang, Zhenning Wang, Shumei Song, Jaffer A. Ajani
Journal: Molecular Cancer (2021)

An amendment to this paper has been published and can be accessed via the original article.
Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120–MF59 in Adults
Authors: Glenda E. Gray, Linda-Gail Bekker, Fatima Laher, Mookho Malahleha, Mary Allen, Zoe Moodie, Nicole Grunenberg, Yunda Huang, Doug Grove, Brittany Prigmore, Jia J. Kee, David Benkeser, John Hural, Craig Innes, Erica Lazarus, Graeme Meintjes, Nivashnee Naicker, Dishiki Kalonji, Maphoshane Nchabeleng, Modulakgotla Sebe, Nishanta Singh, Philip Kotze, Sheetal Kassim, Thozama Dubula, Vimla Naicker, William Brumskine, Cleon N. Ncayiya, Amy M. Ward, Nigel Garrett, Girisha Kistnasami, Zakir Gaffoor, Pearl Selepe, Philisiwe B. Makhoba, Matsontso P. Mathebula, Pamela Mda, Tania Adonis, Katlego S. Mapetla, Bontle Modibedi, Tricia Philip, Gladys Kobane, Carter Bentley, Shelly Ramirez, Simbarashe Takuva, Megan Jones, Mpho Sikhosana, Millicent Atujuna, Michele Andrasik, Nima S. Hejazi, Adrian Puren, Lubbe Wiesner, Sanjay Phogat, Carlos Diaz Granados, Marguerite Koutsoukos, Olivier Van Der Meeren, Susan W. Barnett, Niranjan Kanesa-Thasan, James G. Kublin, M. Juliana McElrath, Peter B. Gilbert, Holly Janes, Lawrence Corey
Journal: New England Journal of Medicine (2021)

A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox–protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1–2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa.
P76.90 Molecular Characteristics of BRAF Mutations in EGFR Mutant NSCLC after Progression on EGFR TKIs and Response to Combination Targeted Therapy
Authors: W. Fang, J. Hu, Y. Huang, C. Xu, W. Wang, G. Yao, Y.W. Shao, L. Zhang
Journal: Journal of Thoracic Oncology (2021)
EPR21-035: Immune Checkpoint Inhibitor-Related Hemophagocytic Lymphohistiocytosis: A Food and Drug Association Adverse Event Reporting System (FAERS) Analysis
Authors: Udhayvir Singh Grewal, Sahith Reddy Thotamgari, Shiva Jashwanth Gaddam, Jasmeen Kaur Uppal, Parth Rajeshbhai Shah, Cesar Davila-Chapa
Journal: Journal of the National Comprehensive Cancer Network (2021)

"EPR21-035: Immune Checkpoint Inhibitor-Related Hemophagocytic Lymphohistiocytosis: A Food and Drug Association Adverse Event Reporting System (FAERS) Analysis" published on 17 Mar 2021 by National Comprehensive Cancer Network.
Dual‐Cues Laden Scaffold Facilitates Neurovascular Regeneration and Motor Functional Recovery After Complete Spinal Cord Injury
Authors: Dingyang Liu, He Shen, Yeyu Shen, Ge Long, Xinghui He, Yannan Zhao, Zhiquan Yang, Jianwu Dai, Xing Li
Journal: Advanced Healthcare Materials (2021)

Complete transection spinal cord injury (SCI) severely disrupts the integrity of both neural circuits and the microvasculature system. Hence, fabricating a functional bio-scaffold that could coordinate axonal regeneration and vascular reconstruction in the lesion area may emerge as a new paradigm for complete SCI repair. In this study, a photosensitive hydrogel scaffold loaded with collagen-binding stromal cell-derived factor-1a and Taxol liposomes is capable of inducing migration of endothelial cells and promoting neurite outgrowth of neurons in vitro. In addition, when implanted into a rat T8 complete transection SCI model, the above dual-cues laden scaffold exhibits a synergistic effect on facilitating axon and vessel regeneration in the lesion area within 10 days after injury. Moreover, long-term therapeutic effects are also observed after dual-cues laden scaffold implantation, including revascularization, descending and propriospinal axonal regeneration, fibrotic scar reduction, electrophysiological recovery, and motor function improvement. In summary, the dual-cues laden scaffold has good clinical application potential for patients with severe SCI.
Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization
Authors: Nian Liu, JiangLin Zhang, Mingzhu Yin, Hong Liu, Xu Zhang, Jiaoduan Li, Bei Yan, Yeye Guo, Jianda Zhou, Juan Tao, Shuo Hu, Xiang Chen, Cong Peng
Journal: Molecular Therapy (2021)

Tumor cells increase glutamate release through the cystine/glutamate transporter cystine-glutamate exchange (xCT) to balance oxidative homeostasis in tumor cells and promote tumor progression. Although clinical studies have shown the potential of targeting programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling in melanoma, response rates are low. However, it remains unclear how glutamate metabolism affects anti-PD-1/PD-L1 treatment efficacy in melanoma. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine [SAS]), approved by US Food and Drug Administration (FDA) for inflammatory diseases, or genetic knockdown induced reactive oxygen species (ROS)-related death in melanoma cells, inhibition of xCT significantly reduced the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade through upregulating PD-L1 expression via the transcription factors IRF4/EGR1, as a consequence, exosomes carrying relatively large amounts of PD-L1 secreted from melanoma cells resulted in M2 macrophage polarization and reduced the efficacy of anti-PD-1/PD-L1 therapy in melanoma. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma; on the other hand, SAS treatment blunted the efficacy of anti-PD-1/PD-L1 via exosomal PD-L1-induced macrophage M2 polarization and eventually induced anti-PD-1/PD-L1 therapy resistance.
Severity of COVID-19 in patients with lung cancer: evidence and challenges
Authors: Antonio Passaro, Christine Bestvina, Maria Velez Velez, Marina Chiara Garassino, Edward Garon, Solange Peters
Journal: Journal for ImmunoTherapy of Cancer (2021)

Cancer patients are highly vulnerable to SARS-CoV-2 infections due to frequent contacts with the healthcare system, immunocompromised state from cancer or its therapies, supportive medications such as steroids and most importantly their advanced age and comorbidities. Patients with lung cancer have consistently been reported to suffer from an increased risk of death compared with other cancers. This is possibly due to the combination of specific pathophysiological aspects, including underlying pulmonary compromise due to smoking history and the increased specific pressures on respiratory healthcare services caused by the related pandemic. Rationally and safely treating patients with lung cancer during the pandemic has become a continuous challenge over the last year. Deciding whether to offer, modify, postpone or even cancel treatments for this particular patient’s population has become the crucial recurrent dilemma for lung cancer professionals. Chemotherapy, immunotherapy and targeted agents represent distinct risks factors in the context of COVID-19 that should be balanced with the short-term and long-term consequences of delaying cancer care. Despite the rapid and persistent trend of the pandemic, declared by WHO on March 11, 2020, and still ongoing at the time of writing (January 2021), various efforts were made by oncologists worldwide to understand the impact of COVID-19 on patients with cancer. Adapted recommendations of our evidence-based practice guidelines have been developed for all stakeholders. Different small and large-scale registries, such as the COVID-19 and Cancer Consortium (CCC19) and Thoracic Cancers International COVID-19 Collaboration quickly collected data, supporting cancer care decisions under the challenging circumstance created by the COVID-19 pandemic. Several recommendations were developed as guidance for prioritizing the various aspects of lung cancer care in order to mitigate the adverse effects of the COVID-19 healthcare crisis, potentially reducing the morbidity and mortality of our patients from COVID-19 and from cancer. These recommendations helped inform decisions about treatment of established disease, continuation of clinical research and lung cancer screening. In this review, we summarize available evidence regarding the direct and indirect impact of the COVID-19 pandemic on lung cancer care and patients.
Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress
Authors: Wen Chen, Chenzhou Wu, Yafei Chen, Yuhao Guo, Ling Qiu, Zhe Liu, Haibin Sun, Siyu Chen, Zijian An, Zhuoyuan Zhang, Yi Li, Longjiang Li
Journal: International Journal of Oral Science (2021)

Abstract C18 ceramide plays an important role in the occurrence and development of oral squamous cell carcinoma. However, the function of ceramide synthase 1, a key enzyme in C18 ceramide synthesis, in oral squamous cell carcinoma is still unclear. The aim of our study was to investigate the relationship between ceramide synthase 1 and oral cancer. In this study, we found that the expression of ceramide synthase 1 was downregulated in oral cancer tissues and cell lines. In a mouse oral squamous cell carcinoma model induced by 4-nitroquinolin-1-oxide, ceramide synthase 1 knockout was associated with the severity of oral malignant transformation. Immunohistochemical studies showed significant upregulation of PCNA, MMP2, MMP9, and BCL2 expression and downregulation of BAX expression in the pathological hyperplastic area. In addition, ceramide synthase 1 knockdown promoted cell proliferation, migration, and invasion in vitro. Overexpression of CERS1 obtained the opposite effect. Ceramide synthase 1 knockdown caused endoplasmic reticulum stress and induced the VEGFA upregulation. Activating transcription factor 4 is responsible for ceramide synthase 1 knockdown caused VEGFA transcriptional upregulation. In addition, mild endoplasmic reticulum stress caused by ceramide synthase 1 knockdown could induce cisplatin resistance. Taken together, our study suggests that ceramide synthase 1 is downregulated in oral cancer and promotes the aggressiveness of oral squamous cell carcinoma and chemotherapeutic drug resistance.
P03.03 MERMAID-1: A Phase III Study of Adjuvant Durvalumab plus Chemotherapy in Resected NSCLC Patients with MRD+ Post-Surgery
Authors: S. Peters, D. Spigel, M. Ahn, M. Tsuboi, J. Chaft, D. Harpole, G. Goss, F. Barlesi, C. Abbosh, L. Poole, R. May, P.A. Dennis, C. Swanton
Journal: Journal of Thoracic Oncology (2021)
HSR21-051: Treatment Outcomes Among HR+/HER2- Advanced/Metastatic Breast Cancer Patients Receiving CDK 4 &amp; 6 Inhibitors in a United States Clinical Practice Setting
Authors: Yu-Jing Huang, Paula D. Ryan, Gregory L. Price, Gebra Cuyun Carter, Kristin M. Sheffield, Emily Nash Smyth, Claudia Morato Guimaraes, Sarah Rybowski, Jonathan Rajkumar, Lavanya Sudharshan
Journal: Journal of the National Comprehensive Cancer Network (2021)

"HSR21-051: Treatment Outcomes Among HR+/HER2- Advanced/Metastatic Breast Cancer Patients Receiving CDK 4 & 6 Inhibitors in a United States Clinical Practice Setting" published on 17 Mar 2021 by National Comprehensive Cancer Network.