bluuebunny/crossref_metadata_2025 huggingface dataset:
Inverted Pedicled Internal Limiting Membrane Flap Attached to an Optic Disc with Autologous Blood Clot for Large Macular Holes
Authors: Zhang Lishuai , Xi Huiyu , Chen Jiayu , Sheng Aiqin , Fan Wei , Li Suyan , Liu Haiyang
Published: July 2023

Purpose. An inverted ILM flap might be accidentally separated from the retina or sucked away during surgery for large macular holes (MHs). This article is to determine the efficacy of a new inverted pedicled internal limiting membrane (ILM) flap attached to an optic disc with an autologous blood clot (ABC) technique for the treatment of large MHs. Methods. An inverted pedicled ILM flap connected to the optic disc with ABC was used to treat 12 consecutive patients with significant macular holes (>600 m). The ILM was first peeled off around MH as a semidiameter of about 1.5 diameters of the optic disc. The superior residual ILM was used to produce a pedicled ILM flap that was connected to the optic disc and was later inverted to cover the MH. The macular hole was covered with a repositioned flap larger than 2 MH diameters in an inverted way. ABC was used to fasten the flap, followed by fluid‐air exchange with air or C3F8 as tamponade. Spectral domain‐optical coherence tomography (SD‐OCT) and best‐corrected visual acuity (BCVA) were performed at each postoperative follow‐up. Results. The mean aperture and base macular hole diameters were 737.9 ± 109.6 µm (range, 607–982 µm) and 1244.3 ± 227.4 µm (range, 975–1658 µm). All macular holes (100%) were closed after a single surgery without intraoperative or postoperative complications related to the ILM transposition technique. At the last postoperative visit, we found one eye with a U‐shaped closure, three eyes with W‐shaped closures, and eight eyes with V‐shaped closures. No postoperative flap closures were noted in all cases. The preoperative mean BCVA was 1.5 ± 0.3 (range, 1.1–2.0). After a mean follow‐up of 5.3 ± 4.8 (range, 3–16) months, the postoperative mean BCVA was 0.8 ± 0.2 (range, 0.6–1.1), and the difference was statistically significant (p < 0.05). Conclusion. This novel technique is safe and suitable for large MHs and can be an alternative option for accidental ILM flap loss during other inverted ILM flap operations.
Supplementary Figure 5 from Retinol Saturase Mediates Retinoid Metabolism to Impair a Ferroptosis Defense System in Cancer Cells
Authors: Bi Guoshu , Liang Jiaqi , Shan Guangyao , Bian Yunyi , Chen Zhencong , Huang Yiwei , Lu Tao , Li Ming , Besskaya Valeria , Zhao Mengnan , Fan Hong , Wang Qun , Gan Boyi , Zhan Cheng
Published: July 2023

RETSAT mediates ferroptosis by activating the retinoic acid receptor pathway.
Supplementary Figures from PTTG1 Reprograms Asparagine Metabolism to Promote Hepatocellular Carcinoma Progression
Authors: Zhou Qi , Li Leijia , Sha Feifei , Lei Yiming , Tian Xuan , Chen Lingjun , Chen Yan , Liu Huiling , Guo Yunwei
Published: July 2023

Supplementary Figures
Data from ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma
Authors: Jackson Evangeline R. , Duchatel Ryan J. , Staudt Dilana E. , Persson Mika L. , Mannan Abdul , Yadavilli Sridevi , Parackal Sarah , Game Shaye , Chong Wai Chin , Jayasekara W. Samantha N. , Grand Marion Le , Kearney Padraic S. , Douglas Alicia M. , Findlay Izac J. , Germon Zacary P. , McEwen Holly P. , Beitaki Tyrone S. , Patabendige Adjanie , Skerrett-Byrne David A. , Nixon Brett , Smith Nathan D. , Day Bryan , Manoharan Neevika , Nagabushan Sumanth , Hansford Jordan R. , Govender Dinisha , McCowage Geoff B. , Firestein Ron , Howlett Meegan , Endersby Raelene , Gottardo Nicholas G. , Alvaro Frank , Waszak Sebastian M. , Larsen Martin R. , Colino-Sanguino Yolanda , Valdes-Mora Fatima , Rakotomalala Andria , Meignan Samuel , Pasquier Eddy , André Nicolas , Hulleman Esther , Eisenstat David D. , Vitanza Nicholas A. , Nazarian Javad , Koschmann Carl , Mueller Sabine , Cain Jason E. , Dun Matthew D.
Published: July 2023

Abstract
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.
Significance:
PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.
Data from PTTG1 Reprograms Asparagine Metabolism to Promote Hepatocellular Carcinoma Progression
Authors: Zhou Qi , Li Leijia , Sha Feifei , Lei Yiming , Tian Xuan , Chen Lingjun , Chen Yan , Liu Huiling , Guo Yunwei
Published: July 2023

Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a poor prognosis. Pituitary tumor transforming gene 1 (PTTG1) is highly expressed in HCC, suggesting it could play an important role in hepatocellular carcinogenesis. Here, we evaluated the impact of PTTG1 deficiency on HCC development using a diethylnitrosamine (DEN)-induced HCC mouse model and a hepatitis B virus (HBV) regulatory X protein (HBx)–induced spontaneous HCC mouse model. PTTG1 deficiency significantly suppressed DEN- and HBx-induced hepatocellular carcinogenesis. Mechanistically, PTTG1 promoted asparagine synthetase (ASNS) transcription by binding to its promoter, and asparagine (Asn) levels were correspondingly increased. The elevated levels of Asn subsequently activated the mTOR pathway to facilitate HCC progression. In addition, asparaginase treatment reversed the proliferation induced by PTTG1 overexpression. Furthermore, HBx promoted ASNS and Asn metabolism by upregulating PTTG1 expression. Overall, PTTG1 is involved in the reprogramming of Asn metabolism to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.
Significance:
PTTG1 is upregulated in hepatocellular carcinoma and increases asparagine production to stimulate mTOR activity and promote tumor progression.
Data from The HDAC2-SP1 axis orchestrates pro-tumor macrophage polarization
Authors: Zheng Xiang , Sarode Poonam , Weigert Andreas , Turkowski Kati , Chelladurai Prakash , Günther Stefan , Kuenne Carsten , Winter Hauke , Stenzinger Albrecht , Reu Simone , Grimminger Friedrich , Stiewe Thorsten , Seeger Werner , Pullamsetti Soni Savai. , Savai Rajkumar
Published: July 2023

Abstract
Tumor-associated macrophages (TAMs), including anti-tumor M1-like TAMs and pro-tumor M2-like TAMs, are transcriptionally dynamic innate immune cells with diverse roles in lung cancer development. Epigenetic regulators are key in controlling macrophage fate in the heterogeneous tumor microenvironment. Here, we demonstrate that the spatial proximity of HDAC2–overexpressing M2-like TAMs to tumor cells significantly correlates with poor overall survival of lung cancer patients. Suppression of HDAC2 in TAMs altered macrophage phenotype, migration, and signaling pathways related to interleukins, chemokines, cytokines, and T cell activation. In co-culture systems of TAMs and cancer cells, suppressing HDAC2 in TAMs resulted in reduced proliferation and migration, increased apoptosis of cancer cell lines and primary lung cancer cells, and attenuated endothelial cell tube formation. HDAC2 regulated the M2-like TAM phenotype via acetylation of histone H3 and transcription factor SP1. Myeloid cell–specific deletion of Hdac2 and pharmacological inhibition of class I HDACs in four different murine lung cancer models induced the switch from M2-like to M1-like TAMs, altered infiltration of CD4+ and CD8+ T cells, and reduced tumor growth and angiogenesis. TAM-specific HDAC2 expression may provide a biomarker for lung cancer stratification and a target for developing improved therapeutic approaches.
Data from The HDAC2-SP1 Axis Orchestrates Protumor Macrophage Polarization
Authors: Zheng Xiang , Sarode Poonam , Weigert Andreas , Turkowski Kati , Chelladurai Prakash , Günther Stefan , Kuenne Carsten , Winter Hauke , Stenzinger Albrecht , Reu Simone , Grimminger Friedrich , Stiewe Thorsten , Seeger Werner , Pullamsetti Soni Savai , Savai Rajkumar
Published: July 2023

Abstract
Tumor-associated macrophages (TAM), including antitumor M1-like TAMs and protumor M2-like TAMs, are transcriptionally dynamic innate immune cells with diverse roles in lung cancer development. Epigenetic regulators are key in controlling macrophage fate in the heterogeneous tumor microenvironment. Here, we demonstrate that the spatial proximity of HDAC2-overexpressing M2-like TAMs to tumor cells significantly correlates with poor overall survival of lung cancer patients. Suppression of HDAC2 in TAMs altered macrophage phenotype, migration, and signaling pathways related to interleukins, chemokines, cytokines, and T-cell activation. In coculture systems of TAMs and cancer cells, suppressing HDAC2 in TAMs resulted in reduced proliferation and migration, increased apoptosis of cancer cell lines and primary lung cancer cells, and attenuated endothelial cell tube formation. HDAC2 regulated the M2-like TAM phenotype via acetylation of histone H3 and transcription factor SP1. Myeloid cell–specific deletion of Hdac2 and pharmacologic inhibition of class I HDACs in four different murine lung cancer models induced the switch from M2-like to M1-like TAMs, altered infiltration of CD4+ and CD8+ T cells, and reduced tumor growth and angiogenesis. TAM-specific HDAC2 expression may provide a biomarker for lung cancer stratification and a target for developing improved therapeutic approaches.
Significance:
HDAC2 inhibition reverses the protumor phenotype of macrophages mediated by epigenetic modulation induced by the HDAC2–SP1 axis, indicating a therapeutic option to modify the immunosuppressive tumor microenvironment.
Data from Targeting CD44 variant 5 with an antibody-drug conjugate is an effective therapeutic strategy for intrahepatic cholangiocarcinoma
Authors: Bei Yuncheng , He Jian , Dong Xuhui , Wang Yuxin , Wang Sijie , Guo Wan , Cai Chengjie , Xu Zhiye , Wei Jia , Liu Baorui , Zhang Nan , Shen Pingping
Published: July 2023

Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most frequent type of primary liver cancer. ICC is among the deadliest malignancies, highlighting that novel treatments are urgently needed. Studies have shown that CD44 variant isoforms, rather than the CD44 standard isoform, are selectively expressed in ICC cells, providing an opportunity for the development of an antibody–drug conjugate (ADC)-based targeted therapeutic strategy. In this study, we observed the specific expression of CD44 variant 5 (CD44v5) in ICC tumors. CD44v5 protein was expressed on the surface of most ICC tumors (103 of 155). A CD44v5-targeted ADC, H1D8-DC, was developed that comprises a humanized anti-CD44v5 monoclonal antibody (mAb) conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE) via a cleavable valine-citrulline-based linker. H1D8-DC exhibited efficient antigen binding and internalization in cells expressing CD44v5 on the cell surface. Due to the high expression of cathepsin B in ICC cells, the drug was preferentially released in cancer cells but not in normal cells, thus inducing potent cytotoxicity at picomolar concentrations. In vivo studies showed that H1D8-DC was effective against CD44v5-positive ICC cells and induced tumor regression in patient-derived xenograft models, while no significant adverse toxicities were observed. These data demonstrate that CD44v5 is a bona fide target in ICC and provide a rationale for the clinical investigation of a CD44v5-targeted ADC-based approach.
Data from Metformin reprograms tryptophan metabolism to stimulate CD8+ T cell function in colorectal cancer
Authors: Huang Xiaowen , Sun Tiantian , Wang Jilin , Hong Xialu , Chen Huimin , Yan Tingting , Zhou Chengbei , Sun Danfeng , Yang Chen , Yu TaChung , Su Wenyu , Du Wan , Xiong Hua
Published: July 2023

Abstract
Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating anti-tumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer (CRC). Herein, using single-cell RNA sequencing, we showed that metformin remodels the immune landscape of CRC. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the CRC tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in CRC cells and increased in CD8+ T cells. Untreated CRC cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T cell function. Metformin in turn reduced tryptophan uptake by CRC cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in CRC cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating CRC.
Data from Metformin Reprograms Tryptophan Metabolism to Stimulate CD8+ T-cell Function in Colorectal Cancer
Authors: Huang Xiaowen , Sun Tiantian , Wang Jilin , Hong Xialu , Chen Huimin , Yan Tingting , Zhou Chengbei , Sun Danfeng , Yang Chen , Yu TaChung , Su Wenyu , Du Wan , Xiong Hua
Published: July 2023

Abstract
Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating antitumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer. Herein, using single-cell RNA sequencing (scRNA-seq), we showed that metformin remodels the immune landscape of colorectal cancer. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the colorectal cancer tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in colorectal cancer cells and increased in CD8+ T cells. Untreated colorectal cancer cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T-cell function. Metformin in turn reduced tryptophan uptake by colorectal cancer cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in colorectal cancer cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating colorectal cancer.
Significance:
Analysis of the impact of metformin on the colorectal cancer immunometabolic landscape at a single-cell resolution shows that metformin alters cancer cell tryptophan metabolism to stimulate CD8+ T-cell antitumor activity.
Data from Immune Checkpoint Inhibitors and the Exposome: Host-Extrinsic Factors Determine Response, Survival, and Toxicity
Authors: Pizzutilo Elio Gregory. , Romanò Rebecca , Roazzi Laura , Agostara Alberto Giuseppe. , Oresti Sara , Zeppellini Annalisa , Giannetta Laura , Cerea Giulio , Signorelli Diego , Siena Salvatore , Sartore-Bianchi Andrea
Published: July 2023

Abstract
Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICIs), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, which could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.
Data from Unique transcriptional profiles underlie osteosarcomagenesis driven by different p53 mutants
Authors: Chachad Dhruv , Patel Lalit R. , Recio Carlos Vera. , Pourebrahim Rasoul , Whitley Elizabeth M. , Wang Wenyi , Su Xiaoping , Xu An , Lee Dung-Fang , Lozano Guillermina
Published: July 2023

Abstract
Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function activities, such as promoting increased metastatic incidence compared to p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. In order to understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma tumor development. Survival significantly decreased and metastatic incidence increased in mice expressing p53 mutants compared to p53-null mice, suggesting gain of function. RNA-sequencing of primary osteosarcomas revealed vastly different gene expression profiles between tumors expressing the missense mutants and p53-null tumors. Further, p53R172H and p53R245W each regulated unique transcriptomes and pathways through interactions with a distinct repertoire of transcription factors. Validation assays showed that p53R245W, but not p53R172H, interacts with KLF15 to drive migration and invasion in osteosarcoma cell lines and promotes metastasis in allogeneic transplantation models. Additionally, analyses of p53R248W ChIP peaks showed enrichment of KLF15 motifs in human osteoblasts. Taken together, these data identify unique mechanisms of action of the structural and contact mutants of p53.
Data from Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants
Authors: Chachad Dhruv , Patel Lalit R. , Recio Carlos Vera , Pourebrahim Rasoul , Whitley Elizabeth M. , Wang Wenyi , Su Xiaoping , Xu An , Lee Dung-Fang , Lozano Guillermina
Published: July 2023

Abstract
Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma tumor development. Survival significantly decreased and metastatic incidence increased in mice expressing p53 mutants compared with p53-null mice, suggesting GOF. RNA sequencing of primary osteosarcomas revealed vastly different gene expression profiles between tumors expressing the missense mutants and p53-null tumors. Further, p53R172H and p53R245W each regulated unique transcriptomes and pathways through interactions with a distinct repertoire of transcription factors. Validation assays showed that p53R245W, but not p53R172H, interacts with KLF15 to drive migration and invasion in osteosarcoma cell lines and promotes metastasis in allogeneic transplantation models. In addition, analyses of p53R248W chromatin immunoprecipitation peaks showed enrichment of KLF15 motifs in human osteoblasts. Taken together, these data identify unique mechanisms of action of the structural and contact mutants of p53.
Significance:
The p53 DNA binding domain contact mutant p53R245W, but not the structural mutant p53R172H, interacts with KLF15 to drive metastasis in somatic osteosarcoma, providing a potential vulnerability in tumors expressing p53R245W mutation.
Data from Ccr2+ monocyte-derived macrophages influence trajectories of acquired therapy resistance in Braf-mutant melanoma
Authors: Kim Dahihm , An Luye , Moon Jiwon , Maymi Viviana I. , McGurk Alexander I. , Rudd Brian D. , Fowell Deborah , White Andrew C.
Published: July 2023

Abstract
Therapies targeting oncogene addiction have had a tremendous impact on tumor growth and patient outcome, but drug resistance continues to be problematic. One approach to deal with the challenge of resistance entails extending anti-cancer treatments beyond targeting cancer cells by additionally altering the tumor microenvironment. Understanding how the tumor microenvironment contributes to the evolution of diverse resistance pathways could aid in the design of sequential treatments that can elicit and take advantage of a predictable resistance trajectory. Tumor associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models with fluorescent markers to track the stage-specific changes in macrophages under targeted therapy with Braf/Mek inhibitors and assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ monocyte-derived macrophage infiltration rose, suggesting that macrophage influx at this point could facilitate the onset of stable drug resistance. Comparison of melanomas that develop in a Ccr2-proficient or deficient microenvironment demonstrated that lack of melanoma infiltrating Ccr2+ macrophages delayed onset of resistance and shifted melanoma cell evolution towards unstable resistance. Unstable resistance was characterized by sensitivity to targeted therapy when factors from the microenvironment were lost. Importantly, this phenotype was reversed by co-culturing melanoma cells with Ccr2+ macrophages. Overall, this study demonstrates that the development of resistance may be directed by altering the tumor microenvironment to improve treatment timing and the probability of relapse.
Data from Ccr2+ Monocyte-Derived Macrophages Influence Trajectories of Acquired Therapy Resistance in Braf-Mutant Melanoma
Authors: Kim Dahihm , An Luye , Moon Jiwon , Maymi Viviana I. , McGurk Alexander I. , Rudd Brian D. , Fowell Deborah J. , White Andrew C.
Published: July 2023

Abstract
Therapies targeting oncogene addiction have had a tremendous impact on tumor growth and patient outcome, but drug resistance continues to be problematic. One approach to deal with the challenge of resistance entails extending anticancer treatments beyond targeting cancer cells by additionally altering the tumor microenvironment. Understanding how the tumor microenvironment contributes to the evolution of diverse resistance pathways could aid in the design of sequential treatments that can elicit and take advantage of a predictable resistance trajectory. Tumor-associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models with fluorescent markers to track the stage-specific changes in macrophages under targeted therapy with Braf/Mek inhibitors and assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ monocyte-derived macrophage infiltration rose, suggesting that macrophage influx at this point could facilitate the onset of stable drug resistance that melanoma cells show after several weeks of treatment. Comparison of melanomas that develop in a Ccr2-proficient or -deficient microenvironment demonstrated that lack of melanoma infiltrating Ccr2+ macrophages delayed onset of resistance and shifted melanoma cell evolution towards unstable resistance. Unstable resistance was characterized by sensitivity to targeted therapy when factors from the microenvironment were lost. Importantly, this phenotype was reversed by coculturing melanoma cells with Ccr2+ macrophages. Overall, this study demonstrates that the development of resistance may be directed by altering the tumor microenvironment to improve treatment timing and the probability of relapse.
Significance:
Ccr2+ melanoma macrophages that are active in tumors during the drug-tolerant persister state following targeted therapy-induced regression are key contributors directing melanoma cell reprogramming toward specific therapeutic resistance trajectories.
Supplementary Table S1 from Outcomes in Patients with High-Risk Features after Fixed-Duration Ibrutinib plus Venetoclax: Phase II CAPTIVATE Study in First-Line Chronic Lymphocytic Leukemia
Authors: Allan John N. , Flinn Ian W. , Siddiqi Tanya , Ghia Paolo , Tam Constantine S. , Kipps Thomas J. , Barr Paul M. , Elinder Camburn Anna , Tedeschi Alessandra , Badoux Xavier C. , Jacobs Ryan , Kuss Bryone J. , Trentin Livio , Zhou Cathy , Szoke Anita , Abbazio Christopher , Wierda William G.
Published: July 2023

Supplementary Table S1. Patient demographics and disease characteristics at baseline by cohort.
Supplementary Table S3 from Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer
Authors: Cortellini Alessio , D'Alessio Antonio , Cleary Siobhan , Buti Sebastiano , Bersanelli Melissa , Bordi Paola , Tonini Giuseppe , Vincenzi Bruno , Tucci Marco , Russo Alessandro , Pantano Francesco , Russano Marco , Stucci Luigia Stefania , Sergi Maria Chiara , Falconi Martina , Zarzana Maria Antonietta , Santini Daniele , Spagnolo Francesco , Tanda Enrica T. , Rastelli Francesca , Giorgi Francesca Chiara , Pergolesi Federica , Giusti Raffaele , Filetti Marco , Lo Bianco Francesca , Marchetti Paolo , Botticelli Andrea , Gelibter Alain , Siringo Marco , Ferrari Marco , Marconcini Riccardo , Vitale Maria Giuseppa , Nicolardi Linda , Chiari Rita , Ghidini Michele , Nigro Olga , Grossi Francesco , De Tursi Michele , Di Marino Pietro , Queirolo Paola , Bracarda Sergio , Macrini Serena , Inno Alessandro , Zoratto Federica , Veltri Enzo , Spoto Chiara , Vitale Maria Grazia , Cannita Katia , Gennari Alessandra , Morganstein Daniel L. , Mallardo Domenico , Nibid Lorenzo , Sabarese Giovanna , Brunetti Leonardo , Perrone Giuseppe , Ascierto Paolo A. , Ficorella Corrado , Pinato David J.
Published: July 2023

Summary of baseline characteristics’ distribution after the propensity score matching procedure between patients on diabetes medications and those who were not receiving diabetes medications (ratio 1:2, caliper 0.1).
Figure S2 from A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2–Bispecific Antibody for Combination Cancer Therapy
Authors: El Zawily Amr , Vizeacoumar Frederick S. , Dahiya Renuka , Banerjee Sara L. , Bhanumathy Kalpana K. , Elhasasna Hussain , Hanover Glinton , Sharpe Jessica C. , Sanchez Malkon G. , Greidanus Paul , Stacey R. Greg , Moon Kyung-Mee , Alexandrov Ilya , Himanen Juha P. , Nikolov Dimitar B. , Fonge Humphrey , White Aaron P. , Foster Leonard J. , Wang Bingcheng , Toosi Behzad M. , Bisson Nicolas , Mirzabekov Tajib A. , Vizeacoumar Franco J. , Freywald Andrew
Published: July 2023

Fig. S2. A. Heatmap of the differentially expressed phosphorylated proteins that are enriched inthe top 15 gene ontology (GO) processes generated using GSEA software. B. Gene SetEnrichment Analysis plots of the top 15 GO processes for the differentially expressedphosphorylated proteins data produced by GSEA software used to generate the heatmap in A.
Supplementary Table S1 from Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer
Authors: Cortellini Alessio , D'Alessio Antonio , Cleary Siobhan , Buti Sebastiano , Bersanelli Melissa , Bordi Paola , Tonini Giuseppe , Vincenzi Bruno , Tucci Marco , Russo Alessandro , Pantano Francesco , Russano Marco , Stucci Luigia Stefania , Sergi Maria Chiara , Falconi Martina , Zarzana Maria Antonietta , Santini Daniele , Spagnolo Francesco , Tanda Enrica T. , Rastelli Francesca , Giorgi Francesca Chiara , Pergolesi Federica , Giusti Raffaele , Filetti Marco , Lo Bianco Francesca , Marchetti Paolo , Botticelli Andrea , Gelibter Alain , Siringo Marco , Ferrari Marco , Marconcini Riccardo , Vitale Maria Giuseppa , Nicolardi Linda , Chiari Rita , Ghidini Michele , Nigro Olga , Grossi Francesco , De Tursi Michele , Di Marino Pietro , Queirolo Paola , Bracarda Sergio , Macrini Serena , Inno Alessandro , Zoratto Federica , Veltri Enzo , Spoto Chiara , Vitale Maria Grazia , Cannita Katia , Gennari Alessandra , Morganstein Daniel L. , Mallardo Domenico , Nibid Lorenzo , Sabarese Giovanna , Brunetti Leonardo , Perrone Giuseppe , Ascierto Paolo A. , Ficorella Corrado , Pinato David J.
Published: July 2023

Participating centres’ list.
Figure S1 from A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2–Bispecific Antibody for Combination Cancer Therapy
Authors: El Zawily Amr , Vizeacoumar Frederick S. , Dahiya Renuka , Banerjee Sara L. , Bhanumathy Kalpana K. , Elhasasna Hussain , Hanover Glinton , Sharpe Jessica C. , Sanchez Malkon G. , Greidanus Paul , Stacey R. Greg , Moon Kyung-Mee , Alexandrov Ilya , Himanen Juha P. , Nikolov Dimitar B. , Fonge Humphrey , White Aaron P. , Foster Leonard J. , Wang Bingcheng , Toosi Behzad M. , Bisson Nicolas , Mirzabekov Tajib A. , Vizeacoumar Franco J. , Freywald Andrew
Published: July 2023

Fig. S1. The amino acid sequence of EPHA2 extracellular portion composed of ligand bindingdomain followed by sushi-like domain and two sequential fibronectin-like domains is highlyconserved among mammals.
Supplementary Table S3 from The Impact of Germline Alterations in Appendiceal Adenocarcinoma
Authors: Foote Michael B. , Walch Henry , Kemel Yelena , Vakiani Efsevia , Johannet Paul , Sheehan Margaret , Chatila Walid , Chung Sebastian , Nash Garrett M. , Maio Anna , Shia Jinru , Mandelker Diana , Berger Michael , Schultz Nikolaus , Diaz Luis A. , Cercek Andrea , Stadler Zsofia K.
Published: July 2023

Clinicopathologic Features of the Appendix-Specific Survival Analysis Cohort
Supplementary Table S1 from The Impact of Germline Alterations in Appendiceal Adenocarcinoma
Authors: Foote Michael B. , Walch Henry , Kemel Yelena , Vakiani Efsevia , Johannet Paul , Sheehan Margaret , Chatila Walid , Chung Sebastian , Nash Garrett M. , Maio Anna , Shia Jinru , Mandelker Diana , Berger Michael , Schultz Nikolaus , Diaz Luis A. , Cercek Andrea , Stadler Zsofia K.
Published: July 2023

Genes evaluated by the MSK IMPACT germline sequencing panel
Supplementary Figure S3 from Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer
Authors: Cortellini Alessio , D'Alessio Antonio , Cleary Siobhan , Buti Sebastiano , Bersanelli Melissa , Bordi Paola , Tonini Giuseppe , Vincenzi Bruno , Tucci Marco , Russo Alessandro , Pantano Francesco , Russano Marco , Stucci Luigia Stefania , Sergi Maria Chiara , Falconi Martina , Zarzana Maria Antonietta , Santini Daniele , Spagnolo Francesco , Tanda Enrica T. , Rastelli Francesca , Giorgi Francesca Chiara , Pergolesi Federica , Giusti Raffaele , Filetti Marco , Lo Bianco Francesca , Marchetti Paolo , Botticelli Andrea , Gelibter Alain , Siringo Marco , Ferrari Marco , Marconcini Riccardo , Vitale Maria Giuseppa , Nicolardi Linda , Chiari Rita , Ghidini Michele , Nigro Olga , Grossi Francesco , De Tursi Michele , Di Marino Pietro , Queirolo Paola , Bracarda Sergio , Macrini Serena , Inno Alessandro , Zoratto Federica , Veltri Enzo , Spoto Chiara , Vitale Maria Grazia , Cannita Katia , Gennari Alessandra , Morganstein Daniel L. , Mallardo Domenico , Nibid Lorenzo , Sabarese Giovanna , Brunetti Leonardo , Perrone Giuseppe , Ascierto Paolo A. , Ficorella Corrado , Pinato David J.
Published: July 2023

Kaplan-Meier survival estimates according to the receipt of metformin. A) Overall Survival whole cohort; patients on metformin: 12.4 months (95%CI: 10.5-16.3; 100 events), patients not receiving metformin: 19.0 months (95%CI: 16.4 – 21.1; 732 events). B) Progression Free Survival whole cohort; patients on metformin: 7.9 months (95%CI: 5.3-10.1; 124 events), patients not receiving metformin: 8.3 months (95%CI: 7.3 – 9.5; 933 events).
Supplementary Figure 5 from ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma
Authors: Blandin Anne-Florence , Giglio Ross , Graham Maya Srikanth , Garcia Guadalupe , Malinowski Seth , Woods Jared K. , Ramkissoon Shakti , Ramkissoon Lori , Dubois Frank , Schoolcraft Kathleen , Tsai Jessica , Wang Dayle , Jones Robert , Vogelzang Jayne , Pelton Kristine , Becker Sarah , Watkinson Fiona , Sinai Claire , Cohen Elizabeth F. , Booker Matthew A. , Tolstorukov Michael Y. , Haemels Veerle , Goumnerova Liliana , Wright Karen , Kieran Mark , Fehnel Katie , Reardon David , Tauziede-Espariat Arnault , Lulla Rishi , Carcamo Benjamin , Chaleff Stanley , Charest Alain , De Smet Frederik , Ligon Azra H. , Dubuc Adrian , Pages Melanie , Varlet Pascale , Wen Patrick Y. , Alexander Brian M. , Chi Susan , Alexandrescu Sanda , Kittler Ralf , Bachoo Robert , Bandopadhayay Pratiti , Beroukhim Rameen , Ligon Keith L.
Published: July 2023

Supplementary Figure 5: Single-cell RNA Sequencing and IHC examination of ALK in human neural development and immature neural cells. A. 2D representation of human brain cell subtypes (48 samples) during cortex development using a single cell RNA-seq atlas (cortex-dev.cells.ucsc.edu) shows that ALK transcript appears to be enriched in a certain cell type. Color-coded by ALK gene expression (beige to red) and age in weeks (rainbow).B. ALK-stained sagittal section of normal human cerebellum at 15 postconceptional weeks (pcw).C. ALK-stained sagittal section of human fetal neural stem cell pellets at 13 postconceptional weeks (pcw).D. ALK-stained sagittal section of human fetal neural stem cell pellets at 15 postconceptional weeks (pcw).
Supplementary Figure 2 from ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma
Authors: Blandin Anne-Florence , Giglio Ross , Graham Maya Srikanth , Garcia Guadalupe , Malinowski Seth , Woods Jared K. , Ramkissoon Shakti , Ramkissoon Lori , Dubois Frank , Schoolcraft Kathleen , Tsai Jessica , Wang Dayle , Jones Robert , Vogelzang Jayne , Pelton Kristine , Becker Sarah , Watkinson Fiona , Sinai Claire , Cohen Elizabeth F. , Booker Matthew A. , Tolstorukov Michael Y. , Haemels Veerle , Goumnerova Liliana , Wright Karen , Kieran Mark , Fehnel Katie , Reardon David , Tauziede-Espariat Arnault , Lulla Rishi , Carcamo Benjamin , Chaleff Stanley , Charest Alain , De Smet Frederik , Ligon Azra H. , Dubuc Adrian , Pages Melanie , Varlet Pascale , Wen Patrick Y. , Alexander Brian M. , Chi Susan , Alexandrescu Sanda , Kittler Ralf , Bachoo Robert , Bandopadhayay Pratiti , Beroukhim Rameen , Ligon Keith L.
Published: July 2023

Supplementary Figure 2: T1 post-contrast axial and sagittal images of ALK-fused and non ALK-altered GBMs and ALK staining in ALK-fused congenital GBMs. A. Example images from patients with ALK aberrations (76, 89, 116, 197)B. In contrast to those without ALK aberrations (right columns). Contrast is gadolinium for those where applicable and show enhancement within both the tumor categories.C. Representative H&E and ALK IHCs of congenital GBM harboring an ALK fusion.
Supplementary Methods S1 from Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance)
Authors: Wang Qiao-Li , Ma Chao , Yuan Chen , Shi Qian , Wolpin Brian M. , Zhang Yin , Fuchs Charles S. , Meyer Jeffrey , Zemla Tyler , Cheng En , Kumthekar Priya , Guthrie Katherine A. , Couture Felix , Kuebler Philip , Kumar Pankaj , Tan Benjamin , Krishnamurthi Smitha , Goldberg Richard M. , Venook Alan , Blanke Charles , Shields Anthony F. , O'Reilly Eileen M. , Meyerhardt Jeffrey A. , Ng Kimmie
Published: July 2023

Supplementary Methods
Supplementary Methodology 1 from Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial
Authors: Morgan Robert D. , Clamp Andrew R. , White Daniel J. , Price Marcus , Burghel George J. , Ryder W. David J. , Mahmood Reem D. , Murphy Alexander D. , Hasan Jurjees , Mitchell Claire L. , Salih Zena , Wheeler Chelsey , Buckley Emma , Truelove Joanna , King Georgia , Ainaoui Yasmina , Bhaskar Sanjeev S. , Shaw Joseph , Evans D. Gareth R. , Kilerci Bedirhan , Pearce Simon P. , Brady Gerard , Dive Caroline , O'Connor James P.B. , Wallace Andrew J. , Rothwell Dominic G. , Edmondson Richard J. , Jayson Gordon C.
Published: July 2023

Supplementary Methodology.
Supplementary Figure S1 from Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance)
Authors: Wang Qiao-Li , Ma Chao , Yuan Chen , Shi Qian , Wolpin Brian M. , Zhang Yin , Fuchs Charles S. , Meyer Jeffrey , Zemla Tyler , Cheng En , Kumthekar Priya , Guthrie Katherine A. , Couture Felix , Kuebler Philip , Kumar Pankaj , Tan Benjamin , Krishnamurthi Smitha , Goldberg Richard M. , Venook Alan , Blanke Charles , Shields Anthony F. , O'Reilly Eileen M. , Meyerhardt Jeffrey A. , Ng Kimmie
Published: July 2023

Figure S1. Diagram for study cohort derivation
Table S3 from Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution
Authors: Rastegar Bahar , Andersson Natalie , Petersson Alexandra , Karlsson Jenny , Chattopadhyay Subhayan , Valind Anders , Jansson Caroline , Durand Geoffroy , Romerius Patrik , Jirström Karin , Holmquist Mengelbier Linda , Gisselsson David
Published: July 2023

Supplementary Table 3. Table. Sample list with TP53 status. All 20 WT cases and their corresponding samples are listed. ‘Sample position’ refers to the individual sample and its position in a certain paraffin block (see Figure 1 for details.) IR= intermediate risk, BT= blastemal type, DA= diffuse anaplasia. Headings marked in grey show TP53 sequencing results; wt=wild type, mut=mutation, NA= not annotated (i.e. not sequenced), aa= amino acid, REF= reference nucleotide, ALT= alternative nucleotide, TP53 ref= number of wild type TP53 alleles, TP53 mut=number of TP53 mutated alleles. Genomic positions according to hg19. In all columns with grey headings (except column ‘TP53’), semicolons (;) denote when more than one unique TP53 mutation is present in the same tumor sample.
Supplementary Table 3 from Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes
Authors: Hwang Justin , Shi Xiaolei , Elliott Andrew , Arnoff Taylor E. , McGrath Julie , Xiu Joanne , Walker Phillip , Bergom Hannah E. , Day Abderrahman , Ahmed Shihab , Tape Sydney , Makovec Allison , Ali Atef , Shaker Rami M. , Toye Eamon , Passow Rachel , Lozada John R. , Wang Jinhua , Lou Emil , Mouw Kent W. , Carneiro Benedito A. , Heath Elisabeth I. , McKay Rana R. , Korn W. Michael , Nabhan Chadi , Ryan Charles J. , Antonarakis Emmanuel S.
Published: July 2023

Comparisons of WTS profiles between ATMm and BRCA2m to the HRP group.
Supplementary Figure S8 from TIGIT Expression Delineates T-cell Populations with Distinct Functional and Prognostic Impact in Pancreatic Cancer
Authors: Heiduk Max , Klimova Anna , Reiche Charlotte , Digomann David , Beer Carolin , Aust Daniela E. , Distler Marius , Weitz Jürgen , Seifert Adrian M. , Seifert Lena
Published: July 2023

General CD39 and CD103 expression and expression as a function of PD-1 and TIGIT in blood.
Supplementary Figure S7 from TIGIT Expression Delineates T-cell Populations with Distinct Functional and Prognostic Impact in Pancreatic Cancer
Authors: Heiduk Max , Klimova Anna , Reiche Charlotte , Digomann David , Beer Carolin , Aust Daniela E. , Distler Marius , Weitz Jürgen , Seifert Adrian M. , Seifert Lena
Published: July 2023

Cytokine expression as a function of PD-1 and TIGIT expression in blood.
Supplementary Figure S4 from TIGIT Expression Delineates T-cell Populations with Distinct Functional and Prognostic Impact in Pancreatic Cancer
Authors: Heiduk Max , Klimova Anna , Reiche Charlotte , Digomann David , Beer Carolin , Aust Daniela E. , Distler Marius , Weitz Jürgen , Seifert Adrian M. , Seifert Lena
Published: July 2023

Distribution of PD-1 and TIGIT co-expression and expression as a function of the differentiation status in blood.
Supplementary Data 1 from Investigation of PARP Inhibitor Resistance Based on Serially Collected Circulating Tumor DNA in Patients With BRCA-Mutated Ovarian Cancer
Authors: Kim Yoo-Na , Shim Yeeun , Seo Jieun , Choi Zisun , Lee Yong Jae , Shin Saeam , Kim Sang Wun , Kim Sunghoon , Choi Jong Rak , Lee Jung-Yun , Lee Seung-Tae
Published: July 2023

Supplementary MethodsSupplementary Figure 1-5Supplementary Table 1-2
Supplemental Table 4 from The GENIE BPC NSCLC Cohort: A Real-World Repository Integrating Standardized Clinical and Genomic Data for 1,846 Patients with Non–Small Cell Lung Cancer
Authors: Choudhury Noura J. , Lavery Jessica A. , Brown Samantha , de Bruijn Ino , Jee Justin , Tran Thinh Ngoc , Rizvi Hira , Arbour Kathryn C. , Whiting Karissa , Shen Ronglai , Hellmann Matthew , Bedard Philippe L. , Yu Celeste , Leighl Natasha , LeNoue-Newton Michele , Micheel Christine , Warner Jeremy L. , Ginsberg Michelle S. , Plodkowski Andrew , Girshman Jeffrey , Sawan Peter , Pillai Shirin , Sweeney Shawn M. , Kehl Kenneth L. , Panageas Katherine S. , Schultz Nikolaus , Schrag Deborah , Riely Gregory J.
Published: July 2023

Supplemental Table 4
Supplemental Table 3 from The GENIE BPC NSCLC Cohort: A Real-World Repository Integrating Standardized Clinical and Genomic Data for 1,846 Patients with Non–Small Cell Lung Cancer
Authors: Choudhury Noura J. , Lavery Jessica A. , Brown Samantha , de Bruijn Ino , Jee Justin , Tran Thinh Ngoc , Rizvi Hira , Arbour Kathryn C. , Whiting Karissa , Shen Ronglai , Hellmann Matthew , Bedard Philippe L. , Yu Celeste , Leighl Natasha , LeNoue-Newton Michele , Micheel Christine , Warner Jeremy L. , Ginsberg Michelle S. , Plodkowski Andrew , Girshman Jeffrey , Sawan Peter , Pillai Shirin , Sweeney Shawn M. , Kehl Kenneth L. , Panageas Katherine S. , Schultz Nikolaus , Schrag Deborah , Riely Gregory J.
Published: July 2023

Supplemental Table 3
Supplementary figures 1-9 from Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia
Authors: Saygin Caner , Giordano Giorgia , Shimamoto Kathryn , Eisfelder Bart , Thomas-Toth Anika , Venkataraman Girish , Ananthanarayanan Vijayalakshmi , Vincent Tiffaney L. , DuVall Adam , Patel Anand A. , Chen Yi , Tan Fenlai , Anthony Stephen P. , Chen Yu , Shen Yue , Odenike Olatoyosi , Teachey David T. , Kee Barbara L. , LaBelle James , Stock Wendy
Published: July 2023

Supplementary Figures 1-9
Data from A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2–Bispecific Antibody for Combination Cancer Therapy
Authors: El Zawily Amr , Vizeacoumar Frederick S. , Dahiya Renuka , Banerjee Sara L. , Bhanumathy Kalpana K. , Elhasasna Hussain , Hanover Glinton , Sharpe Jessica C. , Sanchez Malkon G. , Greidanus Paul , Stacey R. Greg , Moon Kyung-Mee , Alexandrov Ilya , Himanen Juha P. , Nikolov Dimitar B. , Fonge Humphrey , White Aaron P. , Foster Leonard J. , Wang Bingcheng , Toosi Behzad M. , Bisson Nicolas , Mirzabekov Tajib A. , Vizeacoumar Franco J. , Freywald Andrew
Published: July 2023

AbstractPurpose:
Accumulating analyses of pro-oncogenic molecular mechanisms triggered a rapid development of targeted cancer therapies. Although many of these treatments produce impressive initial responses, eventual resistance onset is practically unavoidable. One of the main approaches for preventing this refractory condition relies on the implementation of combination therapies. This includes dual-specificity reagents that affect both of their targets with a high level of selectivity. Unfortunately, selection of target combinations for these treatments is often confounded by limitations in our understanding of tumor biology. Here, we describe and validate a multipronged unbiased strategy for predicting optimal co-targets for bispecific therapeutics.
Experimental Design:
Our strategy integrates ex vivo genome-wide loss-of-function screening, BioID interactome profiling, and gene expression analysis of patient data to identify the best fit co-targets. Final validation of selected target combinations is done in tumorsphere cultures and xenograft models.
Results:
Integration of our experimental approaches unambiguously pointed toward EGFR and EPHA2 tyrosine kinase receptors as molecules of choice for co-targeting in multiple tumor types. Following this lead, we generated a human bispecific anti-EGFR/EPHA2 antibody that, as predicted, very effectively suppresses tumor growth compared with its prototype anti-EGFR therapeutic antibody, cetuximab.
Conclusions:
Our work not only presents a new bispecific antibody with a high potential for being developed into clinically relevant biologics, but more importantly, successfully validates a novel unbiased strategy for selecting biologically optimal target combinations. This is of a significant translational relevance, as such multifaceted unbiased approaches are likely to augment the development of effective combination therapies for cancer treatment.

See related commentary by Kumar, p. 2570