bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure 1 from Molecular Clusters and Tumor-Immune Drivers of IgM Monoclonal Gammopathies
Authors: Mondello Patrizia , Paludo Jonas , Novak Joseph P. , Wenzl Kerstin , Yang Zhi-Zhang , Jalali Shahrzad , Krull Jordan E. , Braggio Esteban , Dasari Surendra , Manske Michelle K. , Abeykoon Jithma A. , Sarangi Vivekananda , Kapoor Prashant , Paulus Aneel , Reeder Craig B. , Ailawadhi Sikander , Chanan-Khan Asher A. , Kyle Robert A. , Gertz Morie A. , Novak Anne J. , Ansell Stephen M.
Published: April 2023

Supplemental Fig. 1. Estimation of the NMF rank.
Supplementary Table S1 from Preoperative Neutrophil-to-Lymphocyte Ratio and a New Inflammatory Biomarkers Prognostic Index for Primary Retroperitoneal Sarcomas: Retrospective Monocentric Study
Authors: Fiore Marco , Ljevar Silva , Pasquali Sandro , Morelli Daniele , Callegaro Dario , Sanfilippo Roberta , Barisella Marta , Sangalli Claudia , Miceli Rosalba , Gronchi Alessandro
Published: April 2023

Supplemental Table 1. NLR changes after neoadjuvant treatments*
Supplementary Tables S1-7 from Clinical Features Associated with Outcomes and Biomarker Analysis of Dabrafenib plus Trametinib Treatment in Patients with BRAF-Mutant Melanoma Brain Metastases
Authors: Wilmott James S. , Tawbi Hussein , Engh Johnathan A. , Amankulor Nduka M. , Shivalingam Brindha , Banerjee Hiya , Vergara Ismael A. , Lee Hansol , Johansson Peter A. , Ferguson Peter M. , Saiag Philippe , Robert Caroline , Grob Jean-Jacques , Butterfield Lisa H. , Scolyer Richard A. , Kirkwood John M. , Long Georgina V. , Davies Michael A.
Published: April 2023

Supplementary Table S1. Representativeness of study participants
Supplementary Table S2. Analysis of the intracranial response duration in the COMBI-MB trial.
Supplementary Table S3. Analysis of overall survival in the COMBI-MB trial.
Supplementary Table S4. Baseline clinical features of the COMBI-BRV trial.
Supplementary Table S5. Gene expression score (SingScore) and multiplex immunohistochemical results.
Supplementary Table S6. Summary statistics of the linear mixed models utilized to assess the association between protein/pathway expression/score and biopsy sites.
Supplementary Table S7. Mutation annotated file of exome sequencing from melanoma biopsies.
Supplementary Data DS1 from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study
Authors: Tan Lavinia , Tran Ben , Tie Jeanne , Markman Ben , Ananda Sumi , Tebbutt Niall C. , Michael Michael , Link Emma , Wong Stephen Q. , Chandrashekar Sushma , Guinto Jerick , Ritchie David , Koldej Rachel , Solomon Benjamin J. , McArthur Grant A. , Hicks Rodney J. , Gibbs Peter , Dawson Sarah-Jane , Desai Jayesh
Published: April 2023

Supplementary material
Supplementary Table S1 from Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial
Authors: Elía Andrés , Saldain Leo , Vanzulli Silvia I. , Helguero Luisa A. , Lamb Caroline A. , Fabris Victoria , Pataccini Gabriela , Martínez-Vazquez Paula , Burruchaga Javier , Caillet-Bois Ines , Spengler Eunice , Acosta Haab Gabriela , Liguori Marcos , Castets Alejandra , Lovisi Silvia , Abascal María F. , Novaro Virginia , Sánchez Jana , Muñoz Javier , Belizán José M. , Abba Martín C. , Gass Hugo , Rojas Paola , Lanari Claudia
Published: April 2023

Representativeness of Study Participants
Supplementary Data S3 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: April 2023

GSEA_RNAseq (GOBP)
Supplementary Data Table 5 from Bolus versus Continuous Intravenous Delivery of Doxorubicin in Soft-Tissue Sarcomas: Post Hoc Analysis of a Prospective Randomized Trial (SARC021/TH CR-406)
Authors: Cranmer Lee D. , Lu Yao , Heise Rachel S. , Ballman Karla V. , Loggers Elizabeth T. , Pollack Seth M. , Wagner Michael J. , Reinke Denise K. , Schöffski Patrick , Tap William D.
Published: April 2023

Univariable Cox regression of overall survival.
Supplementary Data Table 2 from Bolus versus Continuous Intravenous Delivery of Doxorubicin in Soft-Tissue Sarcomas: Post Hoc Analysis of a Prospective Randomized Trial (SARC021/TH CR-406)
Authors: Cranmer Lee D. , Lu Yao , Heise Rachel S. , Ballman Karla V. , Loggers Elizabeth T. , Pollack Seth M. , Wagner Michael J. , Reinke Denise K. , Schöffski Patrick , Tap William D.
Published: April 2023

Univariable logistic regression of grade 3-5 non-Hematologic adverse events.
Supplementary fig 2 from Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases
Authors: Wijetunga N. Ari , Goglia Alexander G. , Weinhold Nils , Berger Michael F. , Cislo Michael , Higginson Daniel S. , Chabot Kiana , Osman Ahmed M. , Schaff Lauren , Pentsova Elena , Miller Alexandra M. , Powell Simon N. , Boire Adrienne , Yang Jonathan T.
Published: April 2023

Supplemental Figure 2. Compartment analysis comparing altered genes in solid tumors, plasma ctDNA, and CSF ctDNA, pre and post-pCSI.
Supplementary Table S1 from Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR− Trial
Authors: Graeser Monika , Gluz Oleg , Biehl Claudia , Ulbrich-Gebauer Daniel , Christgen Matthias , Palatty Jenci , Kuemmel Sherko , Grischke Eva-Maria , Augustin Doris , Braun Michael , Potenberg Jochem , Wuerstlein Rachel , Krauss Katja , Schumacher Claudia , Forstbauer Helmut , Reimer Toralf , Stefek Andrea , Fischer Hans Holger , Pelz Enrico , zu Eulenburg Christine , Kates Ronald , Ni Hua , Kolberg-Liedtke Cornelia , Feuerhake Friedrich , Kreipe Hans Heinrich , Nitz Ulrike , Harbeck Nadia
Published: April 2023

Supplementary Table 1 lists genes comprising the RNA expression signatures measured with the BC360 panel
"Supplementary Table S5 from Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR− Trial
Authors: Graeser Monika , Gluz Oleg , Biehl Claudia , Ulbrich-Gebauer Daniel , Christgen Matthias , Palatty Jenci , Kuemmel Sherko , Grischke Eva-Maria , Augustin Doris , Braun Michael , Potenberg Jochem , Wuerstlein Rachel , Krauss Katja , Schumacher Claudia , Forstbauer Helmut , Reimer Toralf , Stefek Andrea , Fischer Hans Holger , Pelz Enrico , zu Eulenburg Christine , Kates Ronald , Ni Hua , Kolberg-Liedtke Cornelia , Feuerhake Friedrich , Kreipe Hans Heinrich , Nitz Ulrike , Harbeck Nadia
Published: April 2023

Supplementary Table 5 shows association between median sTIL levels and pCR, iDFS and OS
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: April 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 4 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: April 2023

Supplementary Figure 4: Characterization of the lung cancer recurrent DCTN1-ALK fusion identified in cGBM (case ALK.232). A. Integrative Genomic Viewer (IGV) screenshot of the DCTN1-ALK variant.B. Predicted sequence of DCTN1-ALK fusion (DCTN1 exon 1-26, ALK exon 20-29 conserved).C. PDX DCTN1-ALK sub-renal capsule engraftment confimed by IHC.C. Relative viability of the ALK wild-type GBM line (BT164) and BT1857 ceritinib-treated cells versus DMSO control.D. Relative viability of BT164 and BT1857 lorlatinib-treated cells versus DMSO control.E. Relative viability of BT164 and BT1857 cells treated with an EGFR tyrosine kinase inhibitor neratinib.F. PDX DCTN1-ALK sub-renal capsule engraftment confirmed by IHC.
Supplementary Table S1 from Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics
Authors: Lozano-Rabella Maria , Garcia-Garijo Andrea , Palomero Jara , Yuste-Estevanez Anna , Erhard Florian , Farriol-Duran Roc , Martín-Liberal Juan , Ochoa-de-Olza Maria , Matos Ignacio , Gartner Jared J. , Ghosh Michael , Canals Francesc , Vidal August , Piulats Josep Maria , Matías-Guiu Xavier , Brana Irene , Muñoz-Couselo Eva , Garralda Elena , Schlosser Andreas , Gros Alena
Published: April 2023

Show patient characteristics and relevant experimental information
Supplementary Figure S1 from Loss of CDKN2A Cooperates with WWTR1(TAZ)–CAMTA1 Gene Fusion to Promote Tumor Progression in Epithelioid Hemangioendothelioma
Authors: Seavey Caleb N. , Hallett Andrea , Li Shuo , Che Kepeng , Pobbati Ajaybabu V. , Ma Shuang , Burtscher Ashley , Kanai Ryan , Lamar John M. , Rubin Brian P.
Published: April 2023

Gross and microscopic pathology of lymphoma samples
Supplementary Figures1 from Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms
Authors: Gurska Lindsay M. , Okabe Rachel , Schurer Alexandra , Tong Meng Maxine , Soto Mark , Choi Daniel , Ames Kristina , Glushakow-Smith Shira , Montoya Allison , Tein Ellen , Miles Linde A. , Cheng Haiying , Hankey-Giblin Pamela , Levine Ross L. , Goel Swati , Halmos Balazs , Gritsman Kira
Published: April 2023

Supplementary Figures and figure legends
Supplementary Table S1 from Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial
Authors: Matikas Alexios , Johansson Hemming , Grybäck Per , Bjöhle Judith , Acs Balazs , Boyaci Ceren , Lekberg Tobias , Fredholm Hanna , Elinder Ellinor , Margolin Sara , Isaksson-Friman Erika , Bosch Ana , Lindman Henrik , Adra Jamila , Andersson Anne , Agartz Susanne , Hellström Mats , Zerdes Ioannis , Hartman Johan , Bergh Jonas , Hatschek Thomas , Foukakis Theodoros
Published: April 2023

Supplementary Table S1. Representativeness of Study Participants
Supplementary Figure S1 from Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial
Authors: Matikas Alexios , Johansson Hemming , Grybäck Per , Bjöhle Judith , Acs Balazs , Boyaci Ceren , Lekberg Tobias , Fredholm Hanna , Elinder Ellinor , Margolin Sara , Isaksson-Friman Erika , Bosch Ana , Lindman Henrik , Adra Jamila , Andersson Anne , Agartz Susanne , Hellström Mats , Zerdes Ioannis , Hartman Johan , Bergh Jonas , Hatschek Thomas , Foukakis Theodoros
Published: April 2023

Supplementary Figure S1: Bland-Altman plot depicting correlation between tumor infiltrating lymphocytes assessed manually and using digital image analysis
Supplementary Table S4 from Intratumoral CD16+ Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy
Authors: Lee Hansol , Ferguson Angela L. , Quek Camelia , Vergara Ismael A. , Pires daSilva Ines , Allen Ruth , Gide Tuba Nur , Conway Jordan W. , Koufariotis Lambros T. , Hayward Nicholas K. , Waddell Nicola , Carlino Matteo S. , Menzies Alexander M. , Saw Robyn P.M. , Shklovskaya Elena , Rizos Helen , Lo Serigne , Scolyer Richard A. , Long Georgina V. , Palendira Umaimainthan , Wilmott James S.
Published: April 2023

Clinical and mIHC data generated within the study.
Supplementary Tables S1-S6 from Selectively Targeting STAT3 Using a Small Molecule Inhibitor is a Potential Therapeutic Strategy for Pancreatic Cancer
Authors: Chen Huang , Zhou Wenbo , Bian Aiwu , Zhang Qiansen , Miao Ying , Yin Xuan , Ye Jiangnan , Xu Shifen , Ti Chaowen , Sun Zhenliang , Zheng Jianghua , Chen Yihua , Liu Mingyao , Yi Zhengfang
Published: April 2023

Table S1. List of antibodies used and their technical information Table S2. The sequence of Real-time PCR primersTable S3. The sequence of shRNAs for silencing STAT3 Table S4. The sequence of ChromatinImmunoprecipitation (Ch-IP) PCRTable S5. The binding affinities of WB436B towards STAT member protein in SPR assay Table S6. Selectivity profiling of WB436B in a kinase panel
Supplementary Figures S1-S13 from Selectively Targeting STAT3 Using a Small Molecule Inhibitor is a Potential Therapeutic Strategy for Pancreatic Cancer
Authors: Chen Huang , Zhou Wenbo , Bian Aiwu , Zhang Qiansen , Miao Ying , Yin Xuan , Ye Jiangnan , Xu Shifen , Ti Chaowen , Sun Zhenliang , Zheng Jianghua , Chen Yihua , Liu Mingyao , Yi Zhengfang
Published: April 2023

Fig. S1. Structure-based ligand discovery of STAT3 inhibitorsFig. S2. Surface plasmon resonance analysis of interactions between WB436B to STATfamily proteinsFig. S3. The biology evaluation of WB436B inactive analogue WB345Fig. S4. The mutation in STAT3 SH2 domain directly inhibited STAT3 transcriptionalactivitiesFig. S5. WB436B induced pancreatic cancer cells apoptosisFig. S6. STAT3 knockdown reduced PDAC cells growth and colony formationFig. S7. WB436B displayed little cytotoxicity to STAT3 stable knockdown PDAC cells.Fig. S8. STAT3 depletion inhibited the growth of PDAC cellsFig. S9. WB436B suppressed STAT3 nuclear translocation and the binding to the targetgenes in pancreatic cancer cellsFig. S10. WB436B was well-tolerated in vivoFig. S11. WB436B was well-tolerated in pancreatic cancer metastatic mouse model.Fig. S12. WB436B inhibited PDAC tumor metastasis in vivoFig. S13. WB436B decreased PDAC tumors angiogenesis, inhibited tumor-associatedmacrophage infiltration and induced apoptosis in vivo
Supplementary Data1 from A Phase I/II Open-Label Study of Molibresib for the Treatment of Relapsed/Refractory Hematologic Malignancies
Authors: Dawson Mark A. , Borthakur Gautam , Huntly Brian J.P. , Karadimitris Anastasios , Alegre Adrian , Chaidos Aristeidis , Vogl Dan T. , Pollyea Daniel A. , Davies Faith E. , Morgan Gareth J. , Glass Jacob L. , Kamdar Manali , Mateos Maria-Victoria , Tovar Natalia , Yeh Paul , Delgado Regina García , Basheer Faisal , Marando Ludovica , Gallipoli Paolo , Wyce Anastasia , Krishnatry Anu Shilpa , Barbash Olena , Bakirtzi Evi , Ferron-Brady Geraldine , Karpinich Natalie O. , McCabe Michael T. , Foley Shawn W. , Horner Thierry , Dhar Arindam , Kremer Brandon E. , Dickinson Michael
Published: April 2023

Supplementary Tables
Supplementary Table S2 from Longer versus Shorter Schedules of Vincristine, Irinotecan, and Temozolomide (VIT) for Relapsed or Refractory Ewing Sarcoma: A Randomized Controlled Phase 2 Trial
Authors: Xu Jie , Xie Lu , Sun Xin , Liu Kuisheng , Liang Xin , Cai Zhenyu , Tang Xiaodong , Guo Wei
Published: April 2023

Representativeness of Study Participants
Supplementary Data FS1 from Mesenchymal Stem Cell–mediated Image-guided Sodium Iodide Symporter (NIS) Gene Therapy Improves Survival of Glioblastoma-bearing Mice
Authors: Kitzberger Carolin , Spellerberg Rebekka , Han Yang , Schmohl Kathrin A. , Stauss Christina , Zach Christian , Kälin Roland E. , Multhoff Gabriele , Eiber Matthias , Schilling Franz , Glass Rainer , Weber Wolfgang A. , Wagner Ernst , Nelson Peter J. , Spitzweg Christine
Published: April 2023

Supplementary Figure 1: Radioiodide uptake of GL261 brain tumors after systemic MSC-mediated NIS reporter gene delivery in comparison to thyroid as endogenous NIS-expressing organ assessed by 124I PET/CT imaging. Results are expressed as mean value ± SEM.Supplementary Figure 2: Ex vivo analysis of non-target organs after NIS-MSC gene delivery. NIS (A) and Neomycin (B; selection marker of NIS-MSCs) mRNA expression was detected by qPCR in liver, spleen, kidney and lung after NIS-MSC application and showed no expression above the background level of untreated tumors (which was arbitrarily set to one; NIS mRNA levels of untreated ΔΔCt = 0.0003 and Neomycin mRNA levels of untreated ΔΔCt = 0.002). Data are represented as mean-fold change ± SEM (*p<0.05).
Supplementary Movie S6 from Anticoagulants Enhance Molecular and Cellular Immunotherapy of Cancer by Improving Tumor Microcirculation Structure and Function and Redistributing Tumor Infiltrates
Authors: Wei Fang , Su Yuling , Quan Yibo , Li Xiaojia , Zou Qi , Zhang Liuxi , Li Shu , Jiang Mengmeng , Lin Guohuan , Liang Ping , He Jie , Xie Keping
Published: April 2023

Supplementary Movie S6. IVIM in vivo imaging was used to observe that heparin promoted the infiltration of transferred CD8+ T cells into Panc02 orthotopic tumors. The video corresponded to the experiment shown in Figure 6B. Representative images at 12h of heparin combined with CD8+ T adoptive transfer group were shown in Figure 6B (Blue, angiography Evans Blue; Green, CFSE-CD8+ T cells).
Supplementary Movie S4 from Anticoagulants Enhance Molecular and Cellular Immunotherapy of Cancer by Improving Tumor Microcirculation Structure and Function and Redistributing Tumor Infiltrates
Authors: Wei Fang , Su Yuling , Quan Yibo , Li Xiaojia , Zou Qi , Zhang Liuxi , Li Shu , Jiang Mengmeng , Lin Guohuan , Liang Ping , He Jie , Xie Keping
Published: April 2023

Supplementary Movie S4. IVIM in vivo imaging was used to observe that heparin promoted the infiltration of transferred CD8+ T cells into Panc02 orthotopic tumors. The video corresponded to the experiment shown in Figure 6B. Representative images at 48h of CD8+ T adoptive transfer group were shown in Figure 6B (Blue, angiography Evans Blue; Green, CFSE-CD8+ T cells).
Data from Targeting DNA Repair in Chronic Lymphocytic Leukemia Cells with a Novel Acyclic Nucleotide Analogue, GS-9219
Authors: Tsai Cheng-Yu , Ray Adrian S. , Tumas Daniel B. , Keating Michael J. , Reiser Hans , Plunkett William
Published: April 2023

Abstract
Purpose: GS-9219 is a cell-permeable prodrug of the acyclic nucleotide analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG); the incorporation of the active metabolite PMEG diphosphate (PMEGpp) into DNA results in DNA chain termination due to the lack of a 3′-hydroxyl moiety. We hypothesized that the incorporation of PMEGpp into DNA during repair resynthesis would result in the inhibition of DNA repair and the accumulation of DNA breaks in chronic lymphocytic leukemia (CLL) cells that would activate signaling pathways to cell death.

Experimental Design: To test this hypothesis, CLL cells were irradiated with UV light to stimulate nucleotide excision repair pathways, enabling the incorporation of PMEGpp into DNA. The combination effects of GS-9219 and DNA-damaging agents and the signaling mechanisms activated in response to DNA repair inhibition by GS-9219, as well as changes in CLL cell viability, were investigated.

Results: PMEGpp was incorporated into DNA in CLL cells when nucleotide excision repair was activated by UV. Following PMEGpp incorporation, DNA repair was inhibited, which led to the accumulation of DNA strand breaks. The presence of DNA strand breaks activated the phosphatidylinositol 3-kinase–like protein kinase family members ataxia-telangiectasia mutated and DNA-dependent protein kinase. P53 was phosphorylated and stabilized in response to the inhibition of DNA repair. P53 targeted proteins, Puma and Bax, were up-regulated and activated. The combination of GS-9219 and DNA-damaging agents resulted in more cell death than the sum of the single agents alone.

Conclusion: GS-9219 inhibits DNA repair in CLL cells, an action that stimulates signaling pathways for apoptosis induction.
Data from GLI2 Knockdown Using an Antisense Oligonucleotide Induces Apoptosis and Chemosensitizes Cells to Paclitaxel in Androgen-Independent Prostate Cancer
Authors: Narita Shintaro , So Alan , Ettinger Susan , Hayashi Norihiro , Muramaki Mototsugu , Fazli Ladan , Kim Youngsoo , Gleave Martin E.
Published: April 2023

Abstract
Purpose: GLI transcription factors mediate hedgehog signaling and have been implicated in several human malignancies, including prostate cancer. The objectives of this study were to characterize GLI2 expression levels in human prostate cancer cell lines and tissues to test the effect of antisense oligonucleotide (ASO) targeting GLI2 on androgen-independent (AI) prostate cancer cell lines.

Experimental Design: A tissue microarray was used to characterize differences in GLI2 expression in benign prostate hyperplasia, prostate cancer treated by neoadjuvant hormonal therapy and AI prostate cancer. The effects of GLI2 ASO on PC-3 cell growth and paclitaxel chemosensitivity were assessed in vitro and in vivo. Oligonucleotide spotted microarray analysis was used to determine alteration in GLI2 coregulated genes after ASO treatment.

Results: The expression of GLI2 was significantly higher in prostate cancer than in benign prostate hyperplasia, decreased after androgen ablation in a time-dependent fashion, but became highly expressed again in AI prostate cancer. GLI2 ASO treatment of PC-3 cells reduced GLI2 mRNA and protein levels in a dose-dependent manner. GLI2 knockdown increased PC-3 cell apoptotic rates and significantly decreased cell growth and modulated levels of apoptosis-related genes, such as Bcl2, Bcl-xL, and clusterin. GLI2 knockdown also changed levels of several cell cycle regulators, such as cyclin D1, p27, and PKC-η. Systematic administration of GLI2 ASO in athymic mice significantly delayed PC-3 tumor progression and enhanced paclitaxel chemosensitivity.

Conclusions: These findings suggest that increased levels of GLI2 correlates with AI progression and that GLI2 may be a therapeutic target in castrate-resistant prostate cancer.
Data from Relapse-Free Survival in Breast Cancer Patients Is Associated with a Gene Expression Signature Characteristic for Inflammatory Breast Cancer
Authors: Van Laere Steven , Beissbarth Tim , Van der Auwera Ilse , Van den Eynden Gert , Trinh Xuan Bich , Elst Hilde , Van Hummelen Paul , van Dam Peter , Van Marck Eric , Vermeulen Peter , Dirix Luc
Published: April 2023

Abstract
Purpose: We hypothesize that a gene expression profile characteristic for inflammatory breast cancer (IBC), an aggressive form of breast cancer associated with rapid cancer dissemination and poor survival, might be related to tumor aggressiveness in non-IBC (nIBC).

Experimental Design: RNA from 17 IBC samples and 40 nIBC samples was hybridized onto Affymetrix chips. A gene signature predictive of IBC was identified and applied onto 1,157 nIBC samples with survival data of 881 nIBC samples. Samples were classified as IBC-like or nIBC-like. The IBC signature classification was compared with the classifications according to other prognostically relevant gene signatures and clinicopathologic variables. In addition, relapse-free survival (RFS) was compared by the Kaplan-Meyer method.

Results: Classification according to the IBC signature is significantly (P < 0.05) associated with the cell-of-origin subtypes, the wound healing response, the invasive gene signature, the genomic grade index, the fibroblastic neoplasm signature, and the 70-gene prognostic signature. Significant associations (P < 0.01) were found between the IBC signature and tumor grade, estrogen receptor status, ErbB2 status, and patient age at diagnosis. Patients with an IBC-like phenotype show a significantly shorter RFS interval (P < 0.05). Oncomine analysis identified cell motility as an important concept linked with the IBC signature.

Conclusions: We show that nIBC carcinomas having an IBC-like phenotype have a reduced RFS interval. This suggests that IBC and nIBC show comparable phenotypic traits, for example augmented cell motility, with respect to aggressive tumor cell behavior. This observation lends credit to the use of IBC to study aggressive tumor cell behavior.
Data from A Pilot Study of Consolidative Immunotherapy in Patients with High-Risk Pediatric Sarcomas
Authors: Mackall Crystal L. , Rhee Eunice H. , Read Elizabeth J. , Khuu Hanh M. , Leitman Susan F. , Bernstein Donna , Tesso Merertu , Long Lauren M. , Grindler David , Merino Margret , Kopp William , Tsokos Maria , Berzofsky Jay A. , Helman Lee J.
Published: April 2023

Abstract
Purpose: Patients with metastatic or recurrent Ewing’s sarcoma family of tumors and alveolar rhabdomyosarcoma have <25% 5-year survival in most studies. This study administered a novel immunotherapy regimen aimed at consolidating remission in these patients.

Experimental Design: Fifty-two patients with translocation positive, recurrent, or metastatic Ewing’s sarcoma family of tumors or alveolar rhabdomyosarcoma underwent prechemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts received autologous T cells, influenza vaccinations, and dendritic cells pulsed with peptides derived from tumor-specific translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate-dose recombinant human interleukin-2 (rhIL-2), cohort 2 received low-dose rhIL-2, and cohort 3 did not receive rhIL-2.

Results: All immunotherapy recipients generated influenza-specific immune responses, whereas immune responses to the translocation breakpoint peptides occurred in 39%, and only 25% of HLA-A2+ patients developed E7-specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year overall survival for all patients apheresed (median potential follow-up 7.3 years) with a 43% 5-year overall survival for patients initiating immunotherapy.

Conclusions: Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable survival. The robust influenza immune responses observed suggest that postchemotherapy immune incompetence will not fundamentally limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent dendritic cells.
Data from Novel Molecular Subtypes of Serous and Endometrioid Ovarian Cancer Linked to Clinical Outcome
Authors: Tothill Richard W. , Tinker Anna V. , George Joshy , Brown Robert , Fox Stephen B. , Lade Stephen , Johnson Daryl S. , Trivett Melanie K. , Etemadmoghadam Dariush , Locandro Bianca , Traficante Nadia , Fereday Sian , Hung Jillian A. , Chiew Yoke-Eng , Haviv Izhak , Gertig Dorota , deFazio Anna , Bowtell David D.L.
Published: April 2023

Abstract
Purpose: The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features.

Experimental Design: Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results.

Results: Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends.

Conclusion: Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.
Data from Serum Peptidome Profiling Revealed Platelet Factor 4 as a Potential Discriminating Peptide Associated with Pancreatic Cancer
Authors: Fiedler Georg Martin , Leichtle Alexander Benedikt , Kase Julia , Baumann Sven , Ceglarek Uta , Felix Klaus , Conrad Tim , Witzigmann Helmut , Weimann Arved , Schütte Christof , Hauss Johann , Büchler Markus , Thiery Joachim
Published: April 2023

Abstract
Purpose: Mass spectrometry–based serum peptidome profiling is a promising tool to identify novel disease-associated biomarkers, but is limited by preanalytic factors and the intricacies of complex data processing. Therefore, we investigated whether standardized sample protocols and new bioinformatic tools combined with external data validation improve the validity of peptidome profiling for the discovery of pancreatic cancer–associated serum markers.

Experimental Design: For the discovery study, two sets of sera from patients with pancreatic cancer (n = 40) and healthy controls (n = 40) were obtained from two different clinical centers. For external data validation, we collected an independent set of samples from patients (n = 20) and healthy controls (n = 20). Magnetic beads with different surface functionalities were used for peptidome fractionation followed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). Data evaluation was carried out by comparing two different bioinformatic strategies. Following proteome database search, the matching candidate peptide was verified by MALDI-TOF MS after specific antibody-based immunoaffinity chromatography and independently confirmed by an ELISA assay.

Results: Two significant peaks (m/z 3884; 5959) achieved a sensitivity of 86.3% and a specificity of 97.6% for the discrimination of patients and healthy controls in the external validation set. Adding peak m/z 3884 to conventional clinical tumor markers (CA 19-9 and CEA) improved sensitivity and specificity, as shown by receiver operator characteristics curve analysis (AUROCcombined = 1.00). Mass spectrometry–based m/z 3884 peak identification and following immunologic quantitation revealed platelet factor 4 as the corresponding peptide.

Conclusions: MALDI-TOF MS-based serum peptidome profiling allowed the discovery and validation of platelet factor 4 as a new discriminating marker in pancreatic cancer.
Data from A Multigene Assay Is Prognostic of Survival in Patients with Early-Stage Lung Adenocarcinoma
Authors: Raz Dan J. , Ray M. Roshni , Kim Jae Y. , He Biao , Taron Miquel , Skrzypski Marcin , Segal Mark , Gandara David R. , Rosell Rafael , Jablons David M.
Published: April 2023

Abstract
Purpose: Clinical staging does not adequately risk stratify patients with early stage non–small cell lung cancer. We sought to generate a real-time PCR (RT-PCR)–based prognostic model in patients with early stage lung adenocarcinoma, the dominant histology of lung cancer in the United States.

Experimental Design: We studied gene expression of 61 candidate genes in 107 patients with completely surgically resected lung adenocarcinoma using RT-PCR. We used crossvalidation methods to select and validate a prognostic model based on the expression of a limited number of genes. A risk score was generated based on model coefficients, and survival of patients with high- and low-risk scores were analyzed.

Results: We generated a four-gene model based on expression of WNT3a, ERBB3, LCK, and RND3. Risk score predicted mortality better than clinical stage or tumor size (adjusted hazard ratio, 6.7; 95% confidence interval, 1.6-28.9; P = 0.001). Among 70 patients with stage I disease, 5-year overall survival was 87% among patients with low-risk scores, and 38% among patients with high-risk scores (P = 0.0002). Among all patients, 5-year overall survival was 62% and 41%, respectively (P = 0.0054). Disease-free survival was also significantly different among low- and high-risk score patients.

Conclusions: This multigene assay predicts overall and disease-free survival significantly better than clinical stage and tumor size in patients with early stage lung adenocarcinoma and performs especially well in patients with stage I disease. Prospective clinical trials are needed to determine whether high-risk patients with stage I disease benefit from adjuvant chemotherapy.
Data from Epithelial-Mesenchymal Transition in Cervical Cancer: Correlation with Tumor Progression, Epidermal Growth Factor Receptor Overexpression, and Snail Up-Regulation
Authors: Lee Mei-Yi , Chou Cheng-Yang , Tang Ming-Jer , Shen Meng-Ru
Published: April 2023

Abstract
Purpose: Acquisition of epithelial-mesenchymal transition (EMT) by primary carcinoma cells is associated with disrupted epithelial integrity, local invasion, and ultimately metastasis. Little is known about the existence and function of EMT in cervical cancer. This study aims to investigate the regulation of EMT in cervical squamous cell carcinoma.

Experimental Design: We investigated the molecular events of EMT in surgical specimens, which present the progression of cervical carcinoma. Two cervical cancer cell lines and the primary culture of normal cervical epithelia were used to study the regulatory mechanisms of EMT.

Results: The chronic epidermal growth factor (EGF) treatment induces the elongation of cell shape, increases cell scattering, and enhances cell invasion. EGF treatment down-regulates E-cadherin and up-regulates vimentin in cervical cancer cells. These characteristics are consistent with the morphologic changes, molecular events, and functional significance of EMT. EGF receptor (EGFR) signaling inactivates glycogen synthase kinase-3β, which results in the nuclear accumulation of up-regulated Snail and then leads to EMT program. α5β1 integrin signaling and extracellular matrix fibronectin can modulate EGF-induced EMT. Importantly, the immunofluorescent stainings of surgical specimens indicate that cervical carcinoma progression is accompanied by EGFR overexpression, which is in parallel with decreased E-cadherin and increased vimentin. Up-regulation and nuclear accumulation of Snail correlate with EMT program in tumor tissues.

Conclusion: EGF cooperates with α5β1 integrin signaling to induce EMT in cervical cancer cells via up-regulated Snail. Blockade of EGFR activity or expression may provide a potential target for the treatment of cervical cancer progression.
Data from Interleukin 13 Mediates Signal Transduction through Interleukin 13 Receptor α2 in Pancreatic Ductal Adenocarcinoma: Role of IL-13 Pseudomonas Exotoxin in Pancreatic Cancer Therapy
Authors: Shimamura Takeshi , Fujisawa Toshio , Husain Syed R. , Joshi Bharat , Puri Raj K.
Published: April 2023

Abstract
Purpose: Interleukin-13 receptor α2 (IL-13Rα2) is a tumor antigen that is overexpressed in certain human tumors. However, its significance and expression in pancreatic cancer is not known. It is also not known whether IL-13 can signal through IL-13Rα2 in cancer.

Experimental Design: The expression of IL-13Rα2 was assessed in pancreatic cancer samples by immunohistochemistry and in cell lines by flow cytometry and reverse transcription-PCR. The role of IL-13Rα2 was examined by IL-13–induced signaling in pancreatic cancer cell lines. IL-13Rα2–positive tumors were targeted by IL-13PE cytotoxin in vitro and in vivo in an orthotopic murine model of human pancreatic cancer.

Results: Of the pancreatic tumor samples 71% overexpressed moderate to high-density IL-13Rα2 chain compared with normal pancreatic samples. IL-13 induced transforming growth factor-β1 promoter activity in IL-13Rα2–positive tumor cells and in cells engineered to express IL-13Rα2 but not in IL-13Rα2–negative or RNA interference knockdown cells. c-Jun and c-Fos of the AP-1 family of nuclear factors were activated by IL-13 only in IL-13Rα2–positive cells. In the orthotopic mouse model, IL13-PE significantly decreased tumor growth when assessed by whole-body imaging and prolonged the mean survival time. Similar results were observed in mice xenografted with a surgically resected human pancreatic tumor sample.

Conclusions: These results indicate that IL-13Rα2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes transforming growth factor-β activation via AP-1 pathway, which may cause tumor induced immunosuppression in the host. In addition, IL13-PE cytotoxin may be an effective therapeutic agent for the treatment of pancreatic cancer. Clin Cancer Res; 16(2); 577–86
Data from Heterogeneity for Stem Cell–Related Markers According to Tumor Subtype and Histologic Stage in Breast Cancer
Authors: Park So Yeon , Lee Hee Eun , Li Hailun , Shipitsin Michail , Gelman Rebecca , Polyak Kornelia
Published: April 2023

Abstract
Purpose: To evaluate the expression of stem cell–related markers at the cellular level in human breast tumors of different subtypes and histologic stage.

Experimental Design: We performed immunohistochemical analyses of 12 proteins [CD44, CD24, ALDH1, vimentin, osteonectin, EPCR, caveolin 1, connexin 43, cytokeratin 18 (CK18), MUC1, claudin 7, and GATA3] selected based on their differential expression in breast cancer cells with more differentiated and stem cell–like characteristics in 47 cases of invasive ductal carcinoma (IDC) only, 135 cases of IDC with ductal carcinoma in situ (DCIS), 35 cases of DCIS with microinvasion, and 58 cases of pure DCIS. We also analyzed 73 IDCs with adjacent DCIS to determine the differences in the expression of markers by histology within individual tumors. CD44+/CD24− and CD24−/CD24+ cells were detected using double immunohistochemistry.

Results: CD44 and EPCR expression was different among the four histologic groups and was lower in invasive compared with in situ tumors, especially in luminal A subtype. The expression of vimentin, osteonectin, connexin 43, ALDH1, CK18, GATA3, and MUC1 differed by tumor subtype in some histologic groups. ALDH1-positive cells were more frequent in basal-like and HER2+ than in luminal tumors. CD44+/CD24− cells were detected in 69% of all tumors with 100% of the basal-like and 52% of HER2+ tumors having some of these cells.

Conclusions: Our findings suggest that in breast cancer, the frequency of tumor cells positive for stem cell–like and more differentiated cell markers varies according to tumor subtype and histologic stage. Clin Cancer Res; 16(3); 876–87
Data from Gene Expression Patterns in Mismatch Repair-Deficient Colorectal Cancers Highlight the Potential Therapeutic Role of Inhibitors of the Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway
Authors: Vilar Eduardo , Mukherjee Bhramar , Kuick Rork , Raskin Leon , Misek David E. , Taylor Jeremy M.G. , Giordano Thomas J. , Hanash Samir M. , Fearon Eric R. , Rennert Gad , Gruber Stephen B.
Published: April 2023

Abstract
Purpose: High-frequency microsatellite-instable (MSI-H) tumors account for ∼15% of colorectal cancers. Therapeutic decisions for colorectal cancer are empirically based and currently do not emphasize molecular subclassification despite an increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI colorectal cancers using combined gene expression data sets.

Experimental Design: Three expression/query signatures (discovery data set) characterizing MSI-H colorectal cancer were matched with information derived from changes induced in cell lines by 164 compounds using the systems biology tool “Connectivity Map.” A series of sequential filtering and ranking algorithms were used to select the candidate compounds. Compounds were validated using two additional expression/query signatures (validation data set). Cytotoxic, cell cycle, and apoptosis effects of validated compounds were evaluated in a panel of cell lines.

Results: Fourteen of the 164 compounds were validated as targeting MSI-H cell lines using the bioinformatics approach; rapamycin, LY-294002, 17-(allylamino)-17-demethoxygeldanamycin, and trichostatin A were the most robust candidate compounds. In vitro results showed that MSI-H cell lines due to hypermethylation of MLH1 are preferentially targeted by rapamycin (18.3 versus 4.4 μmol/L; P = 0.0824) and LY-294002 (15.02 versus 10.37 μmol/L; P = 0.0385) when compared with microsatellite-stable cells. Preferential activity was also observed in MSH2 and MSH6 mutant cells.

Conclusion: Our study shows that the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway is of special relevance in mismatch repair-deficient colorectal cancer. In addition, we show that amalgamation of gene expression information across studies provides a robust approach for selection of potential therapies corresponding to specific groups of patients.
Data from Histone Deacetylase Inhibitors and 15-Deoxy-Δ12,14-Prostaglandin J2 Synergistically Induce Apoptosis
Authors: Koyama Makoto , Izutani Yasuyuki , Goda Ahmed E. , Matsui Taka-aki , Horinaka Mano , Tomosugi Mitsuhiro , Fujiwara Jun , Nakamura Yoshitaka , Wakada Miki , Yogosawa Shingo , Sowa Yoshihiro , Sakai Toshiyuki
Published: April 2023

Abstract
Purpose: The clinically relevant histone deacetylase inhibitors (HDI) valproic acid (VPA) and suberoylanilide hydroxamic acid exert variable antitumor activities but increase therapeutic efficacy when combined with other agents. The natural endogenous ligand of peroxisome proliferator–activated receptor γ 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a potent antineoplastic agent. Therefore, we investigated whether these HDIs in combination with 15d-PGJ2 could show synergistic antitumor activity in colon cancer DLD-1 cells.

Experimental Design: Cell viability was determined using a Cell Counting Kit-8 assay. Apoptosis and reactive oxygen species (ROS) generation were determined using flow cytometry analysis. Western blotting and real-time reverse transcription-PCR analysis were carried out to investigate the expression of apoptosis-related molecules. Mice bearing DLD-1 xenograft were divided into four groups (n = 5) and injected everyday (i.p.) with diluent, VPA (100 mg/kg), 15d-PGJ2 (5 mg/kg), or a combination for 25 days.

Results: HDI/15d-PGJ2 cotreatments synergistically induced cell death through caspase-dependent apoptosis in DLD-1 cells. Moreover, HDIs/15d-PGJ2 caused histone deacetylase inhibition, leading to subsequent ROS generation and endoplasmic reticulum stress to decrease the expression of antiapoptotic molecules Bcl-XL and XIAP and to increase that of proapoptotic molecules CAAT/enhancer binding protein homologous protein and death receptor 5. Additionally, VPA/15d-PGJ2 cotreatment induced ROS-dependent apoptosis in other malignant tumor cells and was more effective than a VPA or 15d-PGJ2 monotherapy in vivo.

Conclusions: Cotreatments with the clinically relevant HDIs and the endogenous peroxisome proliferator–activated receptor γ ligand 15d-PGJ2 are promising for the treatment of a broad spectrum of malignant tumors. Clin Cancer Res; 16(8); 2320–32. ©2010 AACR.
Data from Phosphorylation of the src Epithelial Substrate Trask Is Tightly Regulated in Normal Epithelia but Widespread in Many Human Epithelial Cancers
Authors: Wong Ching Hang , Baehner Frederick L. , Spassov Danislav S. , Ahuja Deepika , Wang Donghui , Hann Byron , Blair Jimmy , Shokat Kevan , Welm Alana L. , Moasser Mark M.
Published: April 2023

Abstract
Purpose: The frequently elevated activities of the c-src and c-yes products in human epithelial tumors suggest that these activated tyrosine kinases have tumorigenic functions analogous to the v-src and v-yes oncogene products. Studies of v-src–transformed fibroblasts have identified many of the effectors of this potent oncogene; however, because c-src and c-yes lack the mutational and promiscuous activities of their retroviral oncogene homologues, their presumptive tumorigenic functions in human epithelial tumors are more subtle, less well-defined, and await identification of possible effectors more directly relevant to epithelial cells.

Experimental Design: We recently identified a transmembrane glycoprotein named Trask that is expressed in epithelial tissues but not fibroblasts and is phosphorylated by SRC kinases in mitotic epithelial cells. In this study, we have surveyed the expression and phosphorylation of Trask in many human epithelial cancer cell lines and surgical tissues and tumors.

Results: Trask is widely expressed in human epithelial tissues, but its phosphorylation is tightly regulated and restricted to detached mitotic cells or cells undergoing physiologic shedding. However, abberant Trask phosphorylation is seen in many epithelial tumors from all stages including preinvasive, invasive, and metastatic tumors. Trask phosphorylation requires SRC kinases, and is also aberrantly hyperphosphorylated in the SRC-activated PyMT mouse epithelial tumors and dephosphorylated by the SRC inhibitor treatment of these tumors.

Conclusions: The widespread phosphorylation of Trask in many human epithlelial cancers identifies a new potential effector of SRC kinases in human epithelial tumorigenesis.