bluuebunny/crossref_metadata_2025 huggingface dataset:
Table S4 from Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis
Authors: Salem Joe-Elie , Bretagne Marie , Abbar Baptiste , Leonard-Louis Sarah , Ederhy Stéphane , Redheuil Alban , Boussouar Samia , Nguyen Lee S. , Procureur Adrien , Stein Frederic , Fenioux Charlotte , Devos Perrine , Gougis Paul , Dres Martin , Demoule Alexandre , Psimaras Dimitri , Lenglet Timothee , Maisonobe Thierry , De Chambrun Marc Pineton , Hekimian Guillaume , Straus Christian , Gonzalez-Bermejo Jesus , Klatzmann David , Rigolet Aude , Guillaume-Jugnot Perrine , Champtiaux Nicolas , Benveniste Olivier , Weiss Nicolas , Saheb Samir , Rouvier Philippe , Plu Isabelle , Gandjbakhch Estelle , Kerneis Mathieu , Hammoudi Nadjib , Zahr Noel , Llontop Claudia , Morelot-Panzini Capucine , Lehmann Lorenz , Qin Juan , Moslehi Javid J. , Rosenzwajg Michelle , Similowski Thomas , Allenbach Yves
Published: May 2023

Definitions used for adjudication and grading of the different evaluated events
Table S3 from Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis
Authors: Salem Joe-Elie , Bretagne Marie , Abbar Baptiste , Leonard-Louis Sarah , Ederhy Stéphane , Redheuil Alban , Boussouar Samia , Nguyen Lee S. , Procureur Adrien , Stein Frederic , Fenioux Charlotte , Devos Perrine , Gougis Paul , Dres Martin , Demoule Alexandre , Psimaras Dimitri , Lenglet Timothee , Maisonobe Thierry , De Chambrun Marc Pineton , Hekimian Guillaume , Straus Christian , Gonzalez-Bermejo Jesus , Klatzmann David , Rigolet Aude , Guillaume-Jugnot Perrine , Champtiaux Nicolas , Benveniste Olivier , Weiss Nicolas , Saheb Samir , Rouvier Philippe , Plu Isabelle , Gandjbakhch Estelle , Kerneis Mathieu , Hammoudi Nadjib , Zahr Noel , Llontop Claudia , Morelot-Panzini Capucine , Lehmann Lorenz , Qin Juan , Moslehi Javid J. , Rosenzwajg Michelle , Similowski Thomas , Allenbach Yves
Published: May 2023

Framework for the evaluation of global respiratory muscles and diaphragm function
Supplementary Tables S1-S11 from Integrative Pan-Cancer Genomic and Transcriptomic Analyses of Refractory Metastatic Cancer
Authors: Pradat Yoann , Viot Julien , Yurchenko Andrey A. , Gunbin Konstantin , Cerbone Luigi , Deloger Marc , Grisay Guillaume , Verlingue Loic , Scott Véronique , Padioleau Ismael , Panunzi Leonardo , Michiels Stefan , Hollebecque Antoine , Jules-Clément Gérôme , Mezquita Laura , Lainé Antoine , Loriot Yohann , Besse Benjamin , Friboulet Luc , André Fabrice , Cournède Paul-Henry , Gautheret Daniel , Nikolaev Sergey I.
Published: May 2023

These tables present clinical data, sample data, whole-exome and transcriptome sequencing results, literature references, and external data sources that were used for the analyses presented in the main text.
Table S1 from Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis
Authors: Salem Joe-Elie , Bretagne Marie , Abbar Baptiste , Leonard-Louis Sarah , Ederhy Stéphane , Redheuil Alban , Boussouar Samia , Nguyen Lee S. , Procureur Adrien , Stein Frederic , Fenioux Charlotte , Devos Perrine , Gougis Paul , Dres Martin , Demoule Alexandre , Psimaras Dimitri , Lenglet Timothee , Maisonobe Thierry , De Chambrun Marc Pineton , Hekimian Guillaume , Straus Christian , Gonzalez-Bermejo Jesus , Klatzmann David , Rigolet Aude , Guillaume-Jugnot Perrine , Champtiaux Nicolas , Benveniste Olivier , Weiss Nicolas , Saheb Samir , Rouvier Philippe , Plu Isabelle , Gandjbakhch Estelle , Kerneis Mathieu , Hammoudi Nadjib , Zahr Noel , Llontop Claudia , Morelot-Panzini Capucine , Lehmann Lorenz , Qin Juan , Moslehi Javid J. , Rosenzwajg Michelle , Similowski Thomas , Allenbach Yves
Published: May 2023

Diagnostic certainty criteria for ICI-myocarditis
Supplementary Figures S1-S24 from Integrative Pan-Cancer Genomic and Transcriptomic Analyses of Refractory Metastatic Cancer
Authors: Pradat Yoann , Viot Julien , Yurchenko Andrey A. , Gunbin Konstantin , Cerbone Luigi , Deloger Marc , Grisay Guillaume , Verlingue Loic , Scott Véronique , Padioleau Ismael , Panunzi Leonardo , Michiels Stefan , Hollebecque Antoine , Jules-Clément Gérôme , Mezquita Laura , Lainé Antoine , Loriot Yohann , Besse Benjamin , Friboulet Luc , André Fabrice , Cournède Paul-Henry , Gautheret Daniel , Nikolaev Sergey I.
Published: May 2023

These figures provide complementary information for the figures presented in the main text and illustrations of the methods section.
Figure S4 from Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis
Authors: Salem Joe-Elie , Bretagne Marie , Abbar Baptiste , Leonard-Louis Sarah , Ederhy Stéphane , Redheuil Alban , Boussouar Samia , Nguyen Lee S. , Procureur Adrien , Stein Frederic , Fenioux Charlotte , Devos Perrine , Gougis Paul , Dres Martin , Demoule Alexandre , Psimaras Dimitri , Lenglet Timothee , Maisonobe Thierry , De Chambrun Marc Pineton , Hekimian Guillaume , Straus Christian , Gonzalez-Bermejo Jesus , Klatzmann David , Rigolet Aude , Guillaume-Jugnot Perrine , Champtiaux Nicolas , Benveniste Olivier , Weiss Nicolas , Saheb Samir , Rouvier Philippe , Plu Isabelle , Gandjbakhch Estelle , Kerneis Mathieu , Hammoudi Nadjib , Zahr Noel , Llontop Claudia , Morelot-Panzini Capucine , Lehmann Lorenz , Qin Juan , Moslehi Javid J. , Rosenzwajg Michelle , Similowski Thomas , Allenbach Yves
Published: May 2023

Example of the first severe ICI-myocarditis case treated with abatacept guided by real-time immune-monitoring assessment of CD86RO (CD86 receptor occupancy) on circulating monocytes.
Figure S3 from Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis
Authors: Salem Joe-Elie , Bretagne Marie , Abbar Baptiste , Leonard-Louis Sarah , Ederhy Stéphane , Redheuil Alban , Boussouar Samia , Nguyen Lee S. , Procureur Adrien , Stein Frederic , Fenioux Charlotte , Devos Perrine , Gougis Paul , Dres Martin , Demoule Alexandre , Psimaras Dimitri , Lenglet Timothee , Maisonobe Thierry , De Chambrun Marc Pineton , Hekimian Guillaume , Straus Christian , Gonzalez-Bermejo Jesus , Klatzmann David , Rigolet Aude , Guillaume-Jugnot Perrine , Champtiaux Nicolas , Benveniste Olivier , Weiss Nicolas , Saheb Samir , Rouvier Philippe , Plu Isabelle , Gandjbakhch Estelle , Kerneis Mathieu , Hammoudi Nadjib , Zahr Noel , Llontop Claudia , Morelot-Panzini Capucine , Lehmann Lorenz , Qin Juan , Moslehi Javid J. , Rosenzwajg Michelle , Similowski Thomas , Allenbach Yves
Published: May 2023

Effect of plasmapheresis on ICI circulating levels in the 10 patients receiving plasmapheresis in our cohort.
Figure S2 from Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis
Authors: Salem Joe-Elie , Bretagne Marie , Abbar Baptiste , Leonard-Louis Sarah , Ederhy Stéphane , Redheuil Alban , Boussouar Samia , Nguyen Lee S. , Procureur Adrien , Stein Frederic , Fenioux Charlotte , Devos Perrine , Gougis Paul , Dres Martin , Demoule Alexandre , Psimaras Dimitri , Lenglet Timothee , Maisonobe Thierry , De Chambrun Marc Pineton , Hekimian Guillaume , Straus Christian , Gonzalez-Bermejo Jesus , Klatzmann David , Rigolet Aude , Guillaume-Jugnot Perrine , Champtiaux Nicolas , Benveniste Olivier , Weiss Nicolas , Saheb Samir , Rouvier Philippe , Plu Isabelle , Gandjbakhch Estelle , Kerneis Mathieu , Hammoudi Nadjib , Zahr Noel , Llontop Claudia , Morelot-Panzini Capucine , Lehmann Lorenz , Qin Juan , Moslehi Javid J. , Rosenzwajg Michelle , Similowski Thomas , Allenbach Yves
Published: May 2023

Delay between presentation for ICI myocarditis, appearance of life-threatening myotoxicity criteria (severity grade 4, Supplementary Table 5 for details concerning grading) and start of the immunosuppressive treatments (with dose) in severe ICI-myocarditis patients requiring abatacept.
Figure S1 from Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis
Authors: Salem Joe-Elie , Bretagne Marie , Abbar Baptiste , Leonard-Louis Sarah , Ederhy Stéphane , Redheuil Alban , Boussouar Samia , Nguyen Lee S. , Procureur Adrien , Stein Frederic , Fenioux Charlotte , Devos Perrine , Gougis Paul , Dres Martin , Demoule Alexandre , Psimaras Dimitri , Lenglet Timothee , Maisonobe Thierry , De Chambrun Marc Pineton , Hekimian Guillaume , Straus Christian , Gonzalez-Bermejo Jesus , Klatzmann David , Rigolet Aude , Guillaume-Jugnot Perrine , Champtiaux Nicolas , Benveniste Olivier , Weiss Nicolas , Saheb Samir , Rouvier Philippe , Plu Isabelle , Gandjbakhch Estelle , Kerneis Mathieu , Hammoudi Nadjib , Zahr Noel , Llontop Claudia , Morelot-Panzini Capucine , Lehmann Lorenz , Qin Juan , Moslehi Javid J. , Rosenzwajg Michelle , Similowski Thomas , Allenbach Yves
Published: May 2023

Examples of cardiac and skeletal muscle pathology findings on autopsies of 2 patients
Supplementary Table 2 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: May 2023

Characteristics of LFS patients' fibroblasts and derivatives
Supplementary Figures from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: May 2023

Supplementary Figures 1-9 demonstrating the GOF and LOF activities of p53(A347D)
Supplementary Data 3 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: May 2023

Differentially expressed genes in osteoblasts derived from normal and LFS individuals
Supplementary Data 2 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: May 2023

Differentially expressed genes in U2OS cells varying in p53 allelic status combined from two independent RNA library preparations
Supplementary Data 1 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: May 2023

Differentially expressed genes in U2OS cells varying in p53 allelic status
Data from A View on Drug Development for Cancer Prevention
Authors: Reynolds Andrew R. , Moschetta Michele , Yohannes Alula R. , Walcott Farzana , Ashford Marianne , Szucs Zoltan , Sarbajna Tina , Hadfield James , Harrison Eden , Challis Benjamin G. , Hernandez Amaya Gasco , Schiavon Gaia , Germa Caroline , Zorenyi Gyorgy , Crean Barry , Galbraith Susan
Published: May 2023

Abstract
Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention.
Significance:
The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.
Data from Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program
Authors: Gencel-Augusto Jovanka , Su Xiaoping , Qi Yuan , Whitley Elizabeth M. , Pant Vinod , Xiong Shunbin , Shah Vrutant , Lin Jerome , Perez Encarnacion , Fiorotto Marta L. , Mahmud Iqbal , Jain Abhinav K. , Lorenzi Philip L. , Navin Nicholas E. , Richie Ellen R. , Lozano Guillermina
Published: May 2023

Abstract
Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li–Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence of thymic lymphomas and increased CD8+ T-cell differentiation. Lymphomas derived from dimeric p53 mice show cooperating alterations in the PPAR pathway, further implicating a role for these activities in tumor suppression. Our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as therapies.
Significance:
New mouse models with TP53R342P (monomer) or TP53A347D (dimer) mutations mimic Li–Fraumeni syndrome. Although p53 monomers lack function, p53 dimers conferred noncanonical tumor-suppressive activities. We describe novel activities for p53 dimers facilitated by PPARs and propose these are “basal” p53 activities.

See related commentary by Stieg et al., p. 1046.

See related article by Choe et al., p. 1250.

This article is highlighted in the In This Issue feature, p. 1027
Data from Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma
Authors: Hoppe Michal Marek , Jaynes Patrick , Shuangyi Fan , Peng Yanfen , Sridhar Shruti , Hoang Phuong Mai , Liu Clementine Xin , De Mel Sanjay , Poon Limei , Chan Esther Hian Li , Lee Joanne , Ong Choon Kiat , Tang Tiffany , Lim Soon Thye , Nagarajan Chandramouli , Grigoropoulos Nicholas F. , Tan Soo-Yong , Hue Susan Swee-Shan , Chang Sheng-Tsung , Chuang Shih-Sung , Li Shaoying , Khoury Joseph D. , Choi Hyungwon , Harris Carl , Bottos Alessia , Gay Laura J. , Runge Hendrik F.P. , Moutsopoulos Ilias , Mohorianu Irina , Hodson Daniel J. , Farinha Pedro , Mottok Anja , Scott David W. , Pitt Jason J. , Chen Jinmiao , Kumar Gayatri , Kannan Kasthuri , Chng Wee Joo , Chee Yen Lin , Ng Siok-Bian , Tripodo Claudio , Jeyasekharan Anand D.
Published: May 2023

Abstract
Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6− (M+2+6−) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6− percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6− unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance.
Significance:
Using single-cell–resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer.

This article is highlighted in the In This Issue feature, p. 1027
Weighing Antitumor Immunity against Life-threatening Myocarditis from Immune-Checkpoint Inhibitors
Authors: Dougan Michael
Published: May 2023

In this issue of Cancer Discovery, Salem and colleagues report a combination therapy for immune-checkpoint inhibitor (ICI) myocarditis using high-dose glucocorticoids, abatacept, and the JAK inhibitor ruxolitinib. The apparent efficacy of their strategy and an accompanying animal model provide further evidence for common immune mechanisms underlying ICI toxicities.

See related article by Salem et al., p. 1100 (2).
Supplementary Video S1 UT from Breast Cancer Stem Cell–Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands
Authors: Raute Katrin , Strietz Juliane , Parigiani Maria Alejandra , Andrieux Geoffroy , Thomas Oliver S. , Kistner Klaus M. , Zintchenko Marina , Aichele Peter , Hofmann Maike , Zhou Houjiang , Weber Wilfried , Boerries Melanie , Swamy Mahima , Maurer Jochen , Minguet Susana
Published: May 2023

Supplementary Video S1 UT
Supplementary Table S1 from Breast Cancer Stem Cell–Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands
Authors: Raute Katrin , Strietz Juliane , Parigiani Maria Alejandra , Andrieux Geoffroy , Thomas Oliver S. , Kistner Klaus M. , Zintchenko Marina , Aichele Peter , Hofmann Maike , Zhou Houjiang , Weber Wilfried , Boerries Melanie , Swamy Mahima , Maurer Jochen , Minguet Susana
Published: May 2023

Supplementary Table S1
Data from Breast Cancer Stem Cell–Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands
Authors: Raute Katrin , Strietz Juliane , Parigiani Maria Alejandra , Andrieux Geoffroy , Thomas Oliver S. , Kistner Klaus M. , Zintchenko Marina , Aichele Peter , Hofmann Maike , Zhou Houjiang , Weber Wilfried , Boerries Melanie , Swamy Mahima , Maurer Jochen , Minguet Susana
Published: May 2023

Abstract
There are no targeted therapies for patients with triple-negative breast cancer (TNBC). TNBC is enriched in breast cancer stem cells (BCSC), which play a key role in metastasis, chemoresistance, relapse, and mortality. γδ T cells hold great potential in immunotherapy against cancer and might provide an approach to therapeutically target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor-sensing mechanisms, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. Herein, we show that patient-derived triple-negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T-cell immunotherapy. We unraveled concerted differentiation and immune escape mechanisms: xenografted BCSCs lost stemness, expression of γδ T-cell ligands, adhesion molecules, and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither promigratory engineered γδ T cells, nor anti–PD-1 checkpoint blockade, significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells and could be pharmacologically reverted by zoledronate or IFNα treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.
Supplementary Table S8 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Supplementary Table S8. Hypoxia-Immune classification of Schmitz et al., window-of-opportunity trial (GSE109756)
Supplementary Table S7 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Supplementary Table S7. Core enriched genes in the TGF-β signaling
Supplementary Table S6 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Supplementary Table S6. Core enriched genes within the Hypoxia signature
Supplementary Table S5 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Supplementary Table S5. Immune profile of the primary and recurrent tumors in Moffitt HNSCC cohort
Supplementary Table S4 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Supplementary Table S4. TME across the Immune, Mixture and Hypoxia subgroups
Supplementary Table S3 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Supplementary Table S3. 49-gene hypoxia-immune signature
Supplementary Table S2 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Supplementary Table S2. CPTAC Cohort
Supplementary Table S1 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Supplementary Table S1. TCGA Cohort
Supplementary Figure S6 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

TIMEx scores for the Immune gene signature among the 15 patients classified into the Hypoxia, Mixture and Immune subgroups.
Supplementary Figure S5 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Protein network analysis of core-enriched genes within the hypoxia signature and TGF-β signaling from GSEA analysis. Clustering was performed using the STRING database. Three main clusters are depicted: hypoxia (blue color), TGF-β (green color), and EGFR (red color).
Supplementary Figure S4 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

(A-C) Clinical Proteomic Tumor Analysis Consortium head and neck squamous cell carcinoma cohort. The gene expressions were compared for pathways enriched in: (A) Immune vs Hypoxia. Red: enriched in Immune, Blue: enriched in Hypoxia. (B) Immune vs Mixture. Red: enriched in Immune, Blue: enriched in Mixture. (C) Hypoxia vs Mixture. Red: enriched in Hypoxia, Blue: enriched in Mixture. Indicated are the top 10 most differentially expressed pathways in Cancer Hallmarks gene sets. NES: Normalized Enrichment Score
Supplementary Figure S3 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

Heatmap of molecular subgroups in MCC18754 (n=48). RNA expression data was z-normalized, each row represents a single gene in the Hypoxia-Immune signature gene list, each column represents a patient sample. Samples were reordered according to its molecular subgroup: Immune (blue), Mixture (black) and Hypoxia (red).
Supplementary Figure S1 from Epidermal growth factor receptor inhibition by cetuximab modulates hypoxia and interferon response genes in head and neck squamous cell carcinoma
Authors: Chaudhary Ritu , Slebos Robbert J.C. , Noel Leenil C. , Song Feifei , Poole Maria I. , Hoening Dirk S , Hernandez-Prera Juan C. , Conejo-Garcia Jose R , Guevara Jose Alejandro , Wang Xuefeng , Xie Mengyu , Tan Aik Choon , Chung Christine H.
Published: May 2023

(A, B) Heatmap of molecular subgroups in two different HNSCC datasets (A) TCGA and (B) CPTAC. RNA expression data was z-normalized, each row represents a single gene in the hypoxia-immune signature gene list, each column represents a patient sample. Samples were reordered according to its molecular subgroup: Immune (blue), Mixture (black) and Hypoxia (red). (C) Kaplan–Meier survival plots for overall survival stratified according to the hypoxia-immune signature for TCGA (n = 518) HNSCC patient cohorts.
Table S6 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

94 Putative synthetic lethal genes identified in the screen
Table S5 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Gene_scoreMageckComparison
Table S3 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

sgRNAcounts
Table S2 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

QCsummary
Table S1 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

library preparation primers
Supplementary Figure 8 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Determination of RAB10 localization
Supplementary Figure 7 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Proteins level assessment by western blotting
Supplementary Figure 6 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Validation of RAB10 susceptibility in two additional cell lines.
Supplementary Figure 5 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Short validation screen in plate to validate the top 4 synthetic lethal gene candidates
Supplementary Figure 4 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

RAB10 essentiality in cells having altered SMAD4 is confirmed by the in vitro CRISPR screen database DepMap
Supplementary Figure 3 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Behavior of sgRNAs targeting essential and nonessential genes in the screen samples.
Supplementary Figure 2 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

S2. Quality check of the CRISPR screen samples.
Supplementary Figure 1 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Map of the plasmids to express inducible SMAD4 and Cas9
FIGURE 7 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

RAB10 is crucial for the proliferation of the SMAD4-negative SW620 and HT29 cell lines. A, Design of the ND HA-tagged RAB10 allele (HA-RAB10 ND), with seven mutations, including one mutation in the PAM sequence. B, Plasmid used to transfect SW620-pCM3586 C4 and HT29-pCM3586 C4. The plasmid pCM3675 contains EGFP, the plasmid pCM4942 contains the exogenous HA-RAB10 ND allele. Plasmid pMCS5 (not represented) is an empty counterpart. RAB10 expression assessed with Western blot analysis in the HT29_C4 (C) and in the SW620_C4 (D) clones expressing Cas9 under doxycycline treatment, infected with sgRNA against RAB10 (sgRNA #14), and transfected either with the empty plasmid pMCS5, EGFP (pCM3675), or with the HA-RAB10 ND allele (pCM4942). Colony formation assay performed on the inducible Cas9-expressing clones SW620-pCM3586 C4 (E) and HT29-pCM3586 C4 (F) that were infected with lentivirus-carrying sgRNAs targeting RAB10 (sgRNA #14), and transfected either with the empty plasmid pMCS5, EGFP (pCM3675), or with the HA-RAB10 ND allele (pCM4942). Cells were seeded at 5,000 cells per well in 6-well plates. They were treated with doxycycline (0.3 μg/mL) at day 1 to induce the KO and allowed to grow for 3 weeks before being washed with PBS and stained with crystal violet dye.
FIGURE 5 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Association of the expression level of Rab10 with the CNA of SMAD4 in pancreatic and colorectal tumors. Violin plot showing the expression level of Rab10 relative to SMAD4 CNAs in colorectal cancer (TCGA, PanCancer Atlas, 524 patients, *, P < 0.05; A) and in pancreas cancers (pancreatic adenocarcinoma; TCGA, PanCancer Atlas, 168 patients; B). For both panels, we performed a Kruskal–Wallis one-way ANOVA, followed by a post hoc Dunnett test to compare each group versus the “SMAD4 deep deletion” group.
FIGURE 4 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Identification of genes required for SMAD4-deficient cells viability via CRISPR/Cas9 viability screen. A, Identification of top candidates. Top 1,000 hits ranked by MAGeCK for each PD0 versus PD15 comparison were compared trough cell lines, as well to an essential list of genes published by Hart and colleagues (2017). A total of 94 genes that were not core-essential genes were found to be essential for the two SMAD4-negative cell lines. B, Heatmap of negative Mageck scores of the four selected top synthetic lethal genes. C, Depleted genes in MIAPaCa-2, DLD1, HT29, and SW620, ranked by their FDR from the MAGeCK analysis. The four top candidate genes are indicated with colored dots.
FIGURE 3 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

Construction and isolation of Cas9-expressing clones and workflow of our CRISPR screens. A, Levels of SMAD4 protein detected by the Sally Sue Simple Western system in the four cell lines HT29, SW620, DLD1, and MIAPaCa-2. B, Levels of Cas9 protein detected by the Sally Sue Simple Western system, in response to doxycycline treatment (exposure at 1 μg/mL for 3 days) in the four clones HT29, SW620, DLD1, and MIAPaCa-2 used in this study. C, Schematic representation of genome-wide CRISPR viability screens performed in HT29, SW620, DLD1, and MIAPaCa-2. Cells were infected at low MOI with a genome-wide library of sgRNAs. After selection, doxycycline was added to induce Cas9 and the KOs. Cells were regularly split and harvested, while keeping at least 200 million cells in culture to ensure a 1,000x library coverage. Cell growth curves of transduced cell lines following puromycin selection are plotted over time, for both replicates (circle and square). Arrows indicate samples that were harvested for sequencing at PD0 and PD15. sgRNA sequences were amplified and identified by NGS (NovaSeq). Enrichment/depletion of sgRNAS were assessed by comparing sgRNA counts at PD15 and PD0 using the Mageck analysis tool and by removing published core essential genes (Hart et al. 2017). PD, population doublings.
FIGURE 2 from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

SMAD4-inducible restoration restores the TGFβ-induced growth inhibition of colorectal cancer cells in vivo.A,In vivo tumorigenicity assay. To assess the effects of SMAD4 restoration in SMAD4-deficient cell lines on tumorigenicity, parental cell line as well as clones stably expressing a doxycycline-inducible Smad4 were injected subcutaneously into the flank region of female SCID mice. Tumor volume over time is plotted. Square: no treatment; Triangle: Glucose treatment; Circle: Doxycycline treatment. Mean with SD (ns, P > 0.05; *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001). B, At the end of the experiment, SMAD4-reexpressing HT29 tumors were harvested, frozen and a protein extraction was performed to assess the level of SMAD4 by Western blot analysis.
Data from Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss
Authors: Erasimus Hélène , Kolnik Vanessa , Lacroix Frédéric , Sidhu Sukhvinder , D'Agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Thill Gilbert , Didier Michel , Debussche Laurent , Marcireau Christophe
Published: May 2023

The TGFβ signaling mediator SMAD4 is frequently mutated or deleted in colorectal and pancreatic cancers. SMAD4 acts as a tumor suppressor and its loss is associated with poorer patient outcomes. The purpose of this study was to find synthetic lethal interactions with SMAD4 deficiency to find novel therapeutic strategies for the treatment of patients with SMAD4-deficient colorectal or pancreatic cancers. Using pooled lentiviral single-guide RNA libraries, we conducted genome-wide loss-of-function screens in Cas9-expressing colorectal and pancreatic cancer cells harboring altered or wild-type SMAD4. The small GTPase protein RAB10 was identified and validated as a susceptibility gene in SMAD4-altered colorectal and pancreatic cancer cells. Rescue assays showed that RAB10 reintroduction reversed the antiproliferative effects of RAB10 knockout in SMAD4-negative cell lines. Further investigation is necessary to shed light on the mechanism by which RAB10 inhibition decreases cell proliferation of SMAD4-negative cells.
Significance:
This study identified and validated RAB10 as new synthetic lethal gene with SMAD4. This was achieved by conducting a whole-genome CRISPR screens in different colorectal and pancreatic cell lines. A future RAB10 inhibitors could correspond to a new therapeutic solution for patients with cancer with SMAD4 deletion.
Updates in the Incidence, Pathogenesis, and Management of Cancer and Venous Thromboembolism
Authors: Girardi Laura , Wang Tzu-Fei , Ageno Walter , Carrier Marc
Published: May 2023

Patients with cancer are at higher risk of developing venous thromboembolism (VTE) compared with the general population. This elevated risk is due to several risk factors and multiple, overlapping thrombotic and hemostatic pathophysiological pathways that are specific to this patient population. Hence, the management of cancer-associated VTE can be challenging for clinicians. Patients with cancer-associated VTE are at higher risk of both recurrent events despite anticoagulation and bleeding complications due to the anticoagulant regimens. Direct oral anticoagulants have recently been shown to be effective, safe, and more convenient than parenteral low-molecular-weight heparin for the management of cancer-associated VTE. Despite these recent advances in anticoagulant therapy, many unmet needs remain in these patients (increased risk of bleeding with specific cancer types, drug-drug interactions, liver dysfunction). Factor XI inhibitors are currently being assessed for the management of cancer-associated VTE and may help clinicians address these important knowledge gaps.
Prevalence and Procedural Risk of Intracranial Atherosclerotic Stenosis Coexisting With Unruptured Intracranial Aneurysm
Authors: Yin Zihan , Zhang Qihang , Zhao Yahui , Lu Junlin , Ge Peicong , Xie Hutao , Wu Delong , Yu Shaochen , Kang Shuai , Zhang Qian , Zhang Yan , Zhang Dong , Zhao Jizong , Liu Xingju
Published: May 2023

Background:

Coexistence of intracranial atherosclerotic stenosis (ICAS) and unruptured intracranial aneurysms (UIAs) is increasingly encountered in clinical practice. This study aims to determine the prevalence of ICAS in patients with UIAs and procedural ischemic risk associated with ICAS when treating UIAs.

Methods:

Based on the CAIASA study (Coexistence of Atherosclerotic Intracranial Arterial Stenosis With Intracranial Aneurysms), we prospectively included patients undergoing treatment procedures for UIAs from October 2015 to December 2020 at Beijing Tiantan Hospital, China. We used computed tomography angiography or digital subtraction angiography to diagnose ICAS (stenosis≥50%). Multivariable logistic regression and propensity-score matching were performed to evaluate the risk of procedure-related ischemic stroke and unfavorable outcome associated with ICAS. The ICAS score was used to explore the association between different burden of ICAS and procedure-related ischemic risk.

Results:

Among 3949 patients who underwent endovascular or open surgical procedures for UIAs, 245 (6.2%) had ICAS. After exclusion, 15.7% (32/204) of patients with ICAS experienced procedure-related ischemic stroke compared with 5.0% (141/2825) of patients without ICAS. From the unmatched and matched cohort, ICAS was significantly associated with increased risk of procedure-related ischemic stroke (unmatched: adjusted odds ratio=3.11 [1.89–5.11]; and matched: adjusted odds ratio=2.99 [1.38–6.48]). This association became more evident among patients not receiving antiplatelet therapy (
P
interaction
=0.022). For patients undergoing different treatment modalities, similar increased risks were observed (clipping: adjusted odds ratio=3.43 [1.73–6.79]; and coiling: adjusted odds ratio=3.59 [1.94–6.65]). Higher ICAS score was correlated with higher procedural ischemic risk (
P
trend
<0.001).

Conclusions:

The occurrence of ICAS is not infrequent in patients with UIAs. ICAS confers an ~2-fold increased procedural ischemic risk, irrespective of clipping or coiling. Previous antiplatelet therapy may decrease the risk.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02795078.
Dimensions of Explanatory Value in NLP Models
Authors: Deemter Kees van
Published: May 2023

Performance on a dataset is often regarded as the key criterion for assessing NLP models. I argue for a broader perspective, which emphasizes scientific explanation. I draw on a long tradition in the philosophy of science, and on the Bayesian approach to assessing scientific theories, to argue for a plurality of criteria for assessing NLP models. To illustrate these ideas, I compare some recent models of language production with each other. I conclude by asking what it would mean for institutional policies if the NLP community took these ideas onboard.