bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary methods from Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors
Authors: Leal Mariana Ferreira , Haynes Ben P. , Schuster Eugene , Yeo Belinda , Afentakis Maria , Zabaglo Lila , Martins Vera , Buus Richard , Dodson Andrew , Cheang Maggie C.U. , Smith Ian E. , Martin Lesley-Ann , Dowsett Mitch
Published: April 2023

E2F activation metagene & Fluorescence activated cell sorting
Supplementary Tables from Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors
Authors: Leal Mariana Ferreira , Haynes Ben P. , Schuster Eugene , Yeo Belinda , Afentakis Maria , Zabaglo Lila , Martins Vera , Buus Richard , Dodson Andrew , Cheang Maggie C.U. , Smith Ian E. , Martin Lesley-Ann , Dowsett Mitch
Published: April 2023

Supplementary Table S1-S12
Supplementary Data from An Integrative Approach to Inform Optimal Administration of OX40 Agonist Antibodies in Patients with Advanced Solid Tumors
Authors: Wang Rui , Gao Chan , Raymond Megan , Dito Gennaro , Kabbabe Dominic , Shao Xiao , Hilt Ed , Sun Yongliang , Pak Irene , Gutierrez Martin , Melero Ignacio , Spreafico Anna , Carvajal Richard D. , Ong Michael , Olszanski Anthony J. , Milburn Christina , Thudium Kent , Yang Zheng , Feng Yan , Fracasso Paula M. , Korman Alan J. , Aanur Praveen , Huang Shih-Min A. , Quigley Michael
Published: April 2023

Supplementary Figure 12
Supplementary Data Tables from A Clinically Applicable Gene-Expression Classifier Reveals Intrinsic and Extrinsic Contributions to Consensus Molecular Subtypes in Primary and Metastatic Colon Cancer
Authors: Piskol Robert , Huw Ling , Sergin Ismail , Kljin Christiaan , Modrusan Zora , Kim Doris , Kljavin Noelyn , Tam Rachel , Patel Rajesh , Burton Jeremy , Penuel Elicia , Qu Xueping , Koeppen Hartmut , Sumiyoshi Teiko , de Sauvage Frederic , Lackner Mark R. , de Sousa e Melo Felipe , Kabbarah Omar
Published: April 2023

Supplementary Data Tables S1 - S14
Supplementary Data Figures from A Clinically Applicable Gene-Expression Classifier Reveals Intrinsic and Extrinsic Contributions to Consensus Molecular Subtypes in Primary and Metastatic Colon Cancer
Authors: Piskol Robert , Huw Ling , Sergin Ismail , Kljin Christiaan , Modrusan Zora , Kim Doris , Kljavin Noelyn , Tam Rachel , Patel Rajesh , Burton Jeremy , Penuel Elicia , Qu Xueping , Koeppen Hartmut , Sumiyoshi Teiko , de Sauvage Frederic , Lackner Mark R. , de Sousa e Melo Felipe , Kabbarah Omar
Published: April 2023

Supplementary Figures S1 - S7. Figure S1, Development and validation of a CRC-focused Nanostring panel and CMS classifier. Figure S2, Comparison of CRC Nanostring- and whole transcriptome-based classification of FFPE samples. Figure S3, Survival after relapse in non-metastatic patient cohorts. Figures S4, Genes significantly differentially expressed between the CMS groups are highly overlapping in both primary CRCs and metastases. Figure S5, Single nucleotide variants in matched sample pairs. Figure S6, Characterization of the procured cohort of matched primary and met samples. Figure S7, Characterization of orthotopically and HTV implanted CRC cell lines.
Table S10 from Interaction between Molecular Subtypes and Stromal Immune Infiltration before and after Treatment in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy
Authors: Hamy Anne-Sophie , Bonsang-Kitzis Hélène , De Croze Diane , Laas Enora , Darrigues Lauren , Topciu Lucian , Menet Emmanuelle , Vincent-Salomon Anne , Lerebours Florence , Pierga Jean-Yves , Brain Etienne , Feron Jean-Guillaume , Benchimol Gabriel , Lam Giang-Thanh , Laé Marick , Reyal Fabien
Published: April 2023

Table S10
Figure S2 from A T-cell–engaging B7-H4/CD3-bispecific Fab-scFv Antibody Targets Human Breast Cancer
Authors: Iizuka Akira , Nonomura Chizu , Ashizawa Tadashi , Kondou Ryota , Ohshima Keiichi , Sugino Takashi , Mitsuya Koichi , Hayashi Nakamasa , Nakasu Yoko , Maruyama Kouji , Yamaguchi Ken , Akiyama Yasuto
Published: April 2023

B7-H4 expression in various cancer cell lines
Supplementary Table 7 from Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade
Authors: Georgiadis Andrew , Durham Jennifer N. , Keefer Laurel A. , Bartlett Bjarne R. , Zielonka Magdalena , Murphy Derek , White James R. , Lu Steve , Verner Ellen L. , Ruan Finey , Riley David , Anders Robert A. , Gedvilaite Erika , Angiuoli Sam , Jones Siân , Velculescu Victor E. , Le Dung T. , Diaz Luis A. , Sausen Mark
Published: April 2023

Summary of Clinical Information for 16 Patients Evaluated for Response to Immune Checkpoint Blockade
Supplementary Table 5 from Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade
Authors: Georgiadis Andrew , Durham Jennifer N. , Keefer Laurel A. , Bartlett Bjarne R. , Zielonka Magdalena , Murphy Derek , White James R. , Lu Steve , Verner Ellen L. , Ruan Finey , Riley David , Anders Robert A. , Gedvilaite Erika , Angiuoli Sam , Jones Siân , Velculescu Victor E. , Le Dung T. , Diaz Luis A. , Sausen Mark
Published: April 2023

Summary of Next Generation Sequencing Statistics for Healthy Donor Samples, Contrived Samples, and Clinical Plasma Samples
Supplementary Table 2 from Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade
Authors: Georgiadis Andrew , Durham Jennifer N. , Keefer Laurel A. , Bartlett Bjarne R. , Zielonka Magdalena , Murphy Derek , White James R. , Lu Steve , Verner Ellen L. , Ruan Finey , Riley David , Anders Robert A. , Gedvilaite Erika , Angiuoli Sam , Jones Siân , Velculescu Victor E. , Le Dung T. , Diaz Luis A. , Sausen Mark
Published: April 2023

Summary of Next Generation Sequencing Statistics for FFPE Tumor and Matched Normal Samples
Supplementary Tables from Tumor Growth Rate as a Validated Early Radiological Biomarker Able to Reflect Treatment-Induced Changes in Neuroendocrine Tumors: The GREPONET-2 Study
Authors: Lamarca Angela , Ronot Maxime , Moalla Salma , Crona Joakim , Opalinska Marta , Lopez Lopez Carlos , Pezzutti Daniela , Najran Pavan , Carvhalo Luciana , Bezerra Regis Otaviano Franca , Borg Philip , Vietti Violi Naik , Vidal Trueba Hector , de Mestier Louis , Scaefer Niklaus , Baudin Eric , Sundin Anders , Costa Frederico , Pavel Marianne , Dromain Clarisse
Published: April 2023

Supplementary Table 1: Baseline characteristics of patients for external validation (Aim-2). Supplementary Table 2: Univariate and Multivariable Cox regression for Progression-Free Survival (Aim-2).
Supplementary Table 2 from Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing in ALK-Rearranged Non–Small-Cell Lung Cancer
Authors: Pailler Emma , Faugeroux Vincent , Oulhen Marianne , Mezquita Laura , Laporte Mélanie , Honoré Aurélie , Lecluse Yann , Queffelec Pauline , NgoCamus Maud , Nicotra Claudio , Remon Jordi , Lacroix Ludovic , Planchard David , Friboulet Luc , Besse Benjamin , Farace Françoise
Published: April 2023

Supplementary Table 2
Supplementary Figure 2 from Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing in ALK-Rearranged Non–Small-Cell Lung Cancer
Authors: Pailler Emma , Faugeroux Vincent , Oulhen Marianne , Mezquita Laura , Laporte Mélanie , Honoré Aurélie , Lecluse Yann , Queffelec Pauline , NgoCamus Maud , Nicotra Claudio , Remon Jordi , Lacroix Ludovic , Planchard David , Friboulet Luc , Besse Benjamin , Farace Françoise
Published: April 2023

Supplementary Figure 2
Supplementary Data from Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma
Authors: Ramchandren Radhakrishnan , Advani Ranjana H. , Ansell Stephen M. , Bartlett Nancy L. , Chen Robert , Connors Joseph M. , Feldman Tatyana , Forero-Torres Andres , Friedberg Jonathan W. , Gopal Ajay K. , Gordon Leo I. , Kuruvilla John , Savage Kerry J. , Younes Anas , Engley Gerald , Manley Thomas J. , Fenton Keenan , Straus David J.
Published: April 2023

Seven supplemental tables referenced in the body of the manuscript. Supplemental Table 1: Progression free survival outcomes by region Supplemental Table 2 Summary of response rates to frontline therapy in North America Supplemental Table 3 Summary of dose modification for brentuximab vedotin and bleomycin in North America, Europe, and Asia Supplemental Table 4 Summary of TEAEs Supplemental Table 5 Most common (>15%) TEAEs in either treatment arm Supplemental Table 6 Rates of peripheral neuropathy in North America, Europe, and Asia Supplemental Table 7 CTCAE Definition and staging of peripheral neuropathy and brentuximab vedotin dose modification guidance
Supplementary Data from Synchronous Detection of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow Predicts Adverse Outcome in Early Breast Cancer
Authors: Magbanua Mark Jesus M. , Yau Christina , Wolf Denise M. , Lee Jin Sun , Chattopadhyay Aheli , Scott Janet H. , Bowlby-Yoder Erin , Hwang E. Shelley , Alvarado Michael , Ewing Cheryl A. , Delson Amy L. , van't Veer Laura J. , Esserman Laura , Park John W.
Published: April 2023

Supplementary Table 7
Supplementary Legend from Long-Term Survival Analysis of Adjuvant Chemotherapy with or without Trastuzumab in Patients with T1, Node-Negative HER2-Positive Breast Cancer
Authors: He Xuexin , Ji Jiali , Tian Mei , Esteva Francisco J. , Hortobagyi Gabriel N. , Yeung Sai-Ching Jim
Published: April 2023

Supplementary Legend
Supplementary Table Legends from Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non–small Cell Lung Cancer
Authors: Leighl Natasha B. , Page Ray D. , Raymond Victoria M. , Daniel Davey B. , Divers Stephen G. , Reckamp Karen L. , Villalona-Calero Miguel A. , Dix Daniel , Odegaard Justin I. , Lanman Richard B. , Papadimitrakopoulou Vassiliki A.
Published: April 2023

Supplementary Table Legends
Supplementary Table 1 from Epigenetic EGFR Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas
Authors: Capdevila Jaume , Arqués Oriol , Hernández Mora Jose Ramón , Matito Judit , Caratù Ginevra , Mancuso Francesco M. , Landolfi Stefania , Barriuso Jorge , Jimenez-Fonseca Paula , Lopez Lopez Carlos , Garcia-Carbonero Rocio , Hernando Jorge , Matos Ignacio , Paolo Nuciforo , Hernández-Losa Javier , Esteller Manel , Martínez-Cardús Anna , Tabernero Josep , Vivancos Ana , Palmer Héctor G.
Published: April 2023

Supplementary Table 1
Supplementary Table S1 from IL15 by Continuous Intravenous Infusion to Adult Patients with Solid Tumors in a Phase I Trial Induced Dramatic NK-Cell Subset Expansion
Authors: Conlon Kevin C. , Potter E. Lake , Pittaluga Stefania , Lee Chyi-Chia Richard , Miljkovic Milos D. , Fleisher Thomas A. , Dubois Sigrid , Bryant Bonita R. , Petrus Michael , Perera Liyanage P. , Hsu Jennifer , Figg William D. , Peer Cody J. , Shih Joanna H. , Yovandich Jason L. , Creekmore Stephen P. , Roederer Mario , Waldmann Thomas A.
Published: April 2023

Supplementary Table S1
Supplementary Data from Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer
Authors: Mao Pingping , Cohen Ofir , Kowalski Kailey J. , Kusiel Justin G. , Buendia-Buendia Jorge E. , Cuoco Michael S. , Exman Pedro , Wander Seth A. , Waks Adrienne G. , Nayar Utthara , Chung Jon , Freeman Samuel , Rozenblatt-Rosen Orit , Miller Vincent A. , Piccioni Federica , Root David E. , Regev Aviv , Winer Eric P. , Lin Nancy U. , Wagle Nikhil
Published: April 2023

Supplementary Data from Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer
Supplemental Table 4 from Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer
Authors: Mao Pingping , Cohen Ofir , Kowalski Kailey J. , Kusiel Justin G. , Buendia-Buendia Jorge E. , Cuoco Michael S. , Exman Pedro , Wander Seth A. , Waks Adrienne G. , Nayar Utthara , Chung Jon , Freeman Samuel , Rozenblatt-Rosen Orit , Miller Vincent A. , Piccioni Federica , Root David E. , Regev Aviv , Winer Eric P. , Lin Nancy U. , Wagle Nikhil
Published: April 2023

Biopsy purity and ploidy
Supplemental Table 13 from Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer
Authors: Mao Pingping , Cohen Ofir , Kowalski Kailey J. , Kusiel Justin G. , Buendia-Buendia Jorge E. , Cuoco Michael S. , Exman Pedro , Wander Seth A. , Waks Adrienne G. , Nayar Utthara , Chung Jon , Freeman Samuel , Rozenblatt-Rosen Orit , Miller Vincent A. , Piccioni Federica , Root David E. , Regev Aviv , Winer Eric P. , Lin Nancy U. , Wagle Nikhil
Published: April 2023

RNA-seq under drug treatment
Supplemental Table 11 from Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer
Authors: Mao Pingping , Cohen Ofir , Kowalski Kailey J. , Kusiel Justin G. , Buendia-Buendia Jorge E. , Cuoco Michael S. , Exman Pedro , Wander Seth A. , Waks Adrienne G. , Nayar Utthara , Chung Jon , Freeman Samuel , Rozenblatt-Rosen Orit , Miller Vincent A. , Piccioni Federica , Root David E. , Regev Aviv , Winer Eric P. , Lin Nancy U. , Wagle Nikhil
Published: April 2023

Differentially expressed genes
Supplementary Figure from Anti-CD79B Antibody–Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study
Authors: Herrera Alex F. , Patel Manish R. , Burke John M. , Advani Ranjana , Cheson Bruce D. , Sharman Jeff P. , Penuel Elicia , Polson Andrew G. , Liao Chen Di , Li Chunze , Schuth Eva , Vaze Anjali , Samineni Divya , Elstrom Rebecca , Cooper James , Diefenbach Catherine
Published: April 2023

Supplementary Figure from Anti-CD79B Antibody–Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study
Supplemental Figure 3 from Novel Lymphocyte-Independent Antitumor Activity by PD-1 Blocking Antibody against PD-1+ Chemoresistant Lung Cancer Cells
Authors: Rotolo Ramona , Leuci Valeria , Donini Chiara , Galvagno Federica , Massa Annamaria , De Santis Maria Chiara , Peirone Serena , Medico Giovanni , Sanlorenzo Martina , Vujic Igor , Gammaitoni Loretta , Basiricò Marco , Righi Luisella , Riganti Chiara , Salaroglio Iris Chiara , Napoli Francesca , Tabbò Fabrizio , Mariniello Annapaola , Vigna Elisa , Modica Chiara , D’Ambrosio Lorenzo , Grignani Giovanni , Taulli Riccardo , Hirsch Emilio , Cereda Matteo , Aglietta Massimo , Scagliotti Giorgio Vittorio , Novello Silvia , Bironzo Paolo , Sangiolo Dario
Published: April 2023

PD-L1/2 and phospho-p38 MAPK expression in NSCLC cells.
Tumor membrane expression of PD-L1 and PD-L2 in NSCLC cell lines was intensely enhanced by treatment with Interferon γ (n=9, PD-L1 p=0.02, PD-L2 p<0.0001) (A). Western blot analysis of phosphorylated (p) and total p38 MAPK in NSCLC cells (H1975) with or without treatment by anti-PD-1 and/or PD-L1s (B).
Data from Clonal Evolution in t(14;18)-Positive Follicular Lymphoma, Evidence for Multiple Common Pathways, and Frequent Parallel Clonal Evolution
Authors: d'Amore Francesco , Chan Eric , Iqbal Javeed , Geng Huimin , Young Ken , Xiao Li , Hess Michelle M. , Sanger Warren G. , Smith Lynette , Wiuf Carsten , Hagberg Oskar , Fu Kai , Chan Wing C. , Dave Bhavana J.
Published: April 2023

Abstract
Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome.

Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed.

Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances.

Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.
Data from Epithelial and Stromal Cathepsin K and CXCL14 Expression in Breast Tumor Progression
Authors: Kleer Celina G. , Bloushtain-Qimron Noga , Chen Yu-Hui , Carrasco Daniel , Hu Min , Yao Jun , Kraeft Stine-Kathrein , Collins Laura C. , Sabel Michael S. , Argani Pedram , Gelman Rebecca , Schnitt Stuart J. , Krop Ian E. , Polyak Kornelia
Published: April 2023

Abstract
Purpose: To evaluate the expression of cathepsin K (CTSK) and CXCL14 in stromal and epithelial cells in human breast tumor progression.

Experimental Design: We did immunohistochemical analyses of CTSK and CXCL14 expression in normal breast tissue, biopsy sites, benign lesions, ductal carcinoma in situ, and invasive breast tumors of different stages. Expression patterns were related to histopathologic characteristics of the tumors and clinical outcome. The effect of CTSK+ breast stromal fibroblasts on CTSK- breast cancer cells was assessed in coculture.

Results: Epithelial expression of CTSK was rarely detected in any of the tissue samples analyzed, whereas CXCL14-positive epithelial cells were found in all tissue types. The expression of CXCL14 was not associated with any tumor or patient characteristics analyzed. Stromal CTSK expression was significantly higher in invasive compared with in situ carcinomas, and in one of the two data sets analyzed, it correlated with higher tumor stage. Among all samples examined, the highest stromal CTSK levels were detected in biopsy sites. Neither epithelial nor stromal expression of CTSK was significantly associated with recurrence-free or overall survival. Coculture of CTSK+ fibroblasts enhanced the invasion of CTSK- breast tumor epithelial cells and this was blocked by CTSK inhibitors.

Conclusions: CTSK may function as a paracrine factor in breast tumorigenesis. CTSK+ fibroblasts may play a role in tumor progression by promoting the invasiveness of tumor epithelial cells. The possibility that CTSK inhibitors may have a clinical role in decreasing the risk of tumor progression merits further investigation.
Data from Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma
Authors: Voorhees Peter M. , Chen Qing , Kuhn Deborah J. , Small George W. , Hunsucker Sally A. , Strader John S. , Corringham Robert E. , Zaki Mohamed H. , Nemeth Jeffrey A. , Orlowski Robert Z.
Published: April 2023

Abstract
Purpose: Inhibition of the proteasome leads to the activation of survival pathways in addition to those that promote cell death. We hypothesized that down-regulation of interleukin-6 (IL-6) signaling using the monoclonal antibody CNTO 328 would enhance the antitumor activity of the proteasome inhibitor bortezomib in multiple myeloma by attenuating inducible chemoresistance.

Experimental Design: The cytotoxicity of bortezomib, CNTO 328, and the combination, along with the associated molecular changes, was assessed in IL-6–dependent and IL-6–independent multiple myeloma cell lines, both in suspension and in the presence of bone marrow stromal cells and in patient-derived myeloma samples.

Results: Treatment of IL-6–dependent and IL-6–independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib in a sequence-dependent fashion. This effect was additive to synergistic and was preserved in the presence of bone marrow stromal cells and in CD138+ myeloma samples derived from patients with relative clinical resistance to bortezomib. CNTO 328 potentiated bortezomib-mediated activation of caspase-8 and caspase-9 and the common downstream effector caspase-3; attenuated bortezomib-mediated induction of antiapoptotic heat shock protein-70, which correlated with down-regulation of phosphorylated signal transducer and activator of transcription-1; and inhibited bortezomib-mediated accumulation of myeloid cell leukemia-1, an effect that was associated with down-regulation of phosphorylated signal transducer and activator of transcription-3.

Conclusions: Taken together, our results provide a strong preclinical rationale for the clinical development of the bortezomib/CNTO 328 combination for patients with myeloma.
Data from Chromosomal Instability and Copy Number Alterations in Barrett's Esophagus and Esophageal Adenocarcinoma
Authors: Paulson Thomas G. , Maley Carlo C. , Li Xiaohong , Li Hongzhe , Sanchez Carissa A. , Chao Dennis L. , Odze Robert D. , Vaughan Thomas L. , Blount Patricia L. , Reid Brian J.
Published: April 2023

Abstract
Purpose: Chromosomal instability, as assessed by many techniques, including DNA content aneuploidy, loss of heterozygosity, and comparative genomic hybridization, has consistently been reported to be common in cancer and rare in normal tissues. Recently, a panel of chromosome instability biomarkers, including loss of heterozygosity and DNA content, has been reported to identify patients at high and low risk of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA), but required multiple platforms for implementation. Although chromosomal instability involving amplifications and deletions of chromosome regions have been observed in nearly all cancers, copy number alterations (CNA) in premalignant tissues have not been well characterized or evaluated in cohort studies as biomarkers of cancer risk.

Experimental Design: We examined CNAs in 98 patients having either BE or EA using Bacterial Artificial Chromosome (BAC) array comparative genomic hybridization to characterize CNAs at different stages of progression ranging from early BE to advanced EA.

Results: CNAs were rare in early stages (less than high-grade dysplasia) but were progressively more frequent and larger in later stages (high-grade dysplasia and EA), including high-level amplifications. The number of CNAs correlated highly with DNA content aneuploidy. Patients whose biopsies contained CNAs involving >70 Mbp were at increased risk of progression to DNA content abnormalities or EA (hazards ratio, 4.9; 95% confidence interval, 1.6-14.8; P = 0.0047), and the risk increased as more of the genome was affected.

Conclusions: Genome-wide analysis of CNAs provides a common platform for the evaluation of chromosome instability for cancer risk assessment as well as for the identification of common regions of alteration that can be further studied for biomarker discovery.
Data from Autocrine Production of Amphiregulin Predicts Sensitivity to Both Gefitinib and Cetuximab in EGFR Wild-type Cancers
Authors: Yonesaka Kimio , Zejnullahu Kreshnik , Lindeman Neal , Homes Alison J. , Jackman David M. , Zhao Feng , Rogers Andrew M. , Johnson Bruce E. , Jänne Pasi A.
Published: April 2023

Abstract
Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, lead to significant tumor regressions in 10% to 15% of non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, 30% to 40% of NSCLC patients, majority of whom are EGFR wild-type, develop stable disease following EGFR tyrosine kinase inhibitor therapy. EGFR-directed antibodies (cetuximab) are effective treatments for head and neck squamous cell carcinomas, which seldom contain EGFR mutations. The determinant(s) of efficacy of EGFR-targeted therapies in EGFR wild-type cancers is not well defined.

Experimental Design: We examined the relationship of EGFR ligands, EGF, transforming growth factor-α,and amphiregulin and the efficacy of gefitinib and cetuximab in EGFR wild-type NSCLC (n = 10) and head and neck squamous cell carcinoma (n = 4) cell lines. We compared amphiregulin expression using immunohistochemistry in EGFR wild-type NSCLC patients (n = 24) that developed either stable or progressive disease following erlotinib or gefitinib treatment.

Results: Cell lines which produced ≥20 pmol/L amphiregulin, as detected by an ELISA, were significantly more likely to be growth inhibited by both gefitinib and cetuximab than those that produced minimal or no amphiregulin. In these cell lines, both cetuximab and gefitinib led to cell cycle arrest at the G1-S boundary and was associated with preferential inhibition of extracellular signal-regulated kinase 1/2 but not Akt signaling. Amphiregulin expression was significantly higher in NSCLC patients that developed stable disease compared with those that developed disease progression following gefitinib or erlotinib treatment.

Conclusions: Amphiregulin expression may help select EGFR wild-type patients who are likely to develop stable disease from EGFR-targeted therapies.
Data from Intracellular Clusterin Inhibits Mitochondrial Apoptosis by Suppressing p53-Activating Stress Signals and Stabilizing the Cytosolic Ku70-Bax Protein Complex
Authors: Trougakos Ioannis P. , Lourda Magda , Antonelou Marianna H. , Kletsas Dimitris , Gorgoulis Vassilis G. , Papassideri Issidora S. , Zou Yonglong , Margaritis Lukas H. , Boothman David A. , Gonos Efstathios S.
Published: April 2023

Abstract
Purpose: Secretory clusterin (sCLU)/apolipoprotein J is an extracellular chaperone that has been functionally implicated in DNA repair, cell cycle regulation, apoptotic cell death, and tumorigenesis. It exerts a prosurvival function against most therapeutic treatments for cancer and is currently an antisense target in clinical trials for tumor therapy. However, the molecular mechanisms underlying its function remained largely unknown.

Experimental Design: The molecular effects of small interfering RNA-mediated sCLU depletion in nonstressed human cancer cells were examined by focusing entirely on the endogenously expressed sCLU protein molecules and combining molecular, biochemical, and microscopic approaches.

Results: We report here that sCLU depletion in nonstressed human cancer cells signals stress that induces p53-dependent growth retardation and high rates of endogenous apoptosis. We discovered that increased apoptosis in sCLU-depleted cells correlates to altered ratios of proapoptotic to antiapoptotic Bcl-2 protein family members, is amplified by p53, and is executed by mitochondrial dysfunction. sCLU depletion-related stress signals originate from several sites, because sCLU is an integral component of not only the secretory pathway but also the nucleocytosolic continuum and mitochondria. In the cytoplasm, sCLU depletion disrupts the Ku70-Bax complex and triggers Bax activation and relocation to mitochondria. We show that sCLU binds and thereby stabilizes the Ku70-Bax protein complex serving as a cytosol retention factor for Bax.

Conclusions: We suggest that elevated sCLU levels may enhance tumorigenesis by interfering with Bax proapoptotic activities and contribute to one of the major characteristics of cancer cells, that is, resistance to apoptosis.
Data from Deficient TP53 Expression, Function, and Cisplatin Sensitivity Are Restored by Quinacrine in Head and Neck Cancer
Authors: Friedman Jay , Nottingham Liesl , Duggal Praveen , Pernas Francisco G. , Yan Bin , Yang Xin Ping , Chen Zhong , Van Waes Carter
Published: April 2023

Abstract
Purpose: To determine the nature and potential pharmacologic reversibility of deficient TP53 expression and function in head and neck squamous cell carcinomas (HNSCC) with wild-type TP53, previously associated with decreased sensitivity to cisplatin therapy.

Experimental Design:TP53 genotype, mRNA and protein expression, TP53-induced p21 expression, and TP53 DNA–binding and reporter gene function were determined in a panel of nine previously characterized HNSCC cell lines from the University of Michigan squamous cell carcinoma (UM-SCC) series. The genotoxic drug doxorubicin and the anti-inflammatory and antimalarial drug quinacrine, previously identified as inducers of TP53, were used to examine the nature and potential reversibility of deficient TP53 expression and function. The specific role of inducible TP53 on function and cellular proliferation was confirmed using selective TP53 inhibitor pifithrin-α or short hairpin RNA knockdown. The capability of quinacrine to sensitize HNSCC to the cytotoxic effects of cisplatin was assessed.

Results: UM-SCC cell lines with wild-type TP53 genotype underexpressed TP53 mRNA and protein when compared with normal human keratinocytes or UM-SCC with mutant TP53. Although doxorubicin failed to induce TP53 expression or functional activity, quinacrine induced TP53 mRNA and protein expression, increased TP53 reporter activity and p21 protein expression, and induced growth inhibition in these wild-type TP53 cell lines. Quinacrine-induced TP53 reporter activity and growth suppression were attenuated by pifithrin-α and TP53 short hairpin RNA knockdown. Furthermore, quinacrine sensitized UM-SCC to cisplatin in vitro.

Conclusions: Deficient TP53 mRNA and protein expression underlies decreased function in a subset of HNSCC with wild-type TP53 and can be restored together with cisplatin sensitization by quinacrine.
Data from Delineation of TMPRSS2-ERG Splice Variants in Prostate Cancer
Authors: Hu Ying , Dobi Albert , Sreenath Taduru , Cook Christopher , Tadase Atekelt Y. , Ravindranath Lakshmi , Cullen Jennifer , Furusato Bungo , Chen Yongmei , Thangapazham Rajesh L. , Mohamed Ahmed , Sun Chen , Sesterhenn Isabell A. , McLeod David G. , Petrovics Gyorgy , Srivastava Shiv
Published: April 2023

Abstract
Purpose: The expression of the ETS-related gene (ERG) is low or undetectable in benign prostate epithelial cells. High prevalence of ERG overexpression in prostate cancer cells due to TMPRSS2-ERG fusions suggest for causal roles of ERG protein in the neoplastic process. TMPRSS2-ERG fusion junctions have been extensively studied in prostate cancer. However, virtually nothing is known about the nature of full-length transcripts and encoded proteins. This study focuses on qualitative and quantitative features of full-length TMPRSS2-ERG transcripts in prostate cancer.

Experimental Design: Full-length TMPRSS2-ERG transcripts were cloned and sequenced from a cDNA library generated from pooled RNA of six TMPRSS2-ERG fusion–positive prostate tumors. The encoded ERG proteins were analyzed in HEK293 cells. Copy numbers of TMPRSS2-ERG splice variants were determined by quantitative reverse transcription-PCR in laser capture microdissected prostate cancer cells.

Results: Two types of TMPRSS2-ERG cDNAs were identified: type I, which encodes full-length prototypical ERG protein (ERG1, ERG2, ERG3), and type II, encoding truncated ERG proteins lacking the ETS domain (ERG8 and a new variant, TEPC). In microdissected prostate tumor cells from 122 patients, relative abundance of these variants was in the following order: ERG8 > TEPC > ERG 3 > ERG1/2 with combined overexpression rate of 62.3% in prostate cancer. Increased ratio of type I over type II splice forms showed a trend of correlation with less favorable pathology and outcome.

Conclusions: Qualitative and quantitative features of specific ERG splice variants defined here promise to enhance the utility of ERG as a biomarker and therapeutic target in prostate cancer.
Data from Characterization of Functional Excision Repair Cross-Complementation Group 1 Variants and Their Association with Lung Cancer Risk and Prognosis
Authors: Yu Dianke , Zhang Xuemei , Liu Ju , Yuan Peng , Tan Wen , Guo Yongli , Sun Tong , Zhao Dan , Yang Ming , Liu Junniao , Xu Binghe , Lin Dongxin
Published: April 2023

Abstract
Purpose: The excision repair cross-complementation group 1 (ERCC1) plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to platinum-based anticancer drugs. We tested whether genetic variants in the ERCC1 gene are associated with susceptibility to lung cancer and efficacy of platinum-chemotherapy in patients with small cell lung cancer (SCLC).

Experimental Design: Thirty individual DNA samples were sequenced to search for single-nucleotide polymorphisms, and the functions of the variants were investigated by a series of biochemical assays. A case-control study was done in 988 patients with lung cancer and 986 control subjects. According to the genotypes, a comparison of chemotherapy outcome in 162 SCLC patients was executed. Overall survival was computed by Cox model adjusted for clinical factors.

Results: We identified two functional variants in the ERCC1 5′-flanking region, −433T>C and 262G>T, which cooperatively influence transcriptional regulation of ERCC1. The 262G allele had significantly lower affinity to bind nuclear protein(s) and was associated with decreased ERCC1 RNA expression. The case-control analysis showed that the −433C and 262G alleles are associated with an increased susceptibility to lung cancer, alone and in a gene-smoking joint effect manner. In contrast, the analysis of chemotherapy outcome of SCLC patients revealed that the 262G allele is associated with better drug response and longer survival time compared with the 262T allele.

Conclusions: These findings are consistent with the notion that DNA repair is a double-edged sword in cancer and suggest that functional single-nucleotide polymorphisms in ERCC1 might serve as simple and less invasive biomarkers for personalized chemotherapy of platinum-based anticancer drugs.
Data from Antiapoptotic Activity of Autocrine Interleukin-22 and Therapeutic Effects of Interleukin-22-Small Interfering RNA on Human Lung Cancer Xenografts
Authors: Zhang Weici , Chen Yongyan , Wei Haiming , Zheng Chaogu , Sun Rui , Zhang Jian , Tian Zhigang
Published: April 2023

Abstract
Purpose: Non–small cell lung carcinoma (NSCLC) is one of most common malignant diseases and usually is resistant against apoptosis-inducing chemotherapy. This study is to explore the antiapoptotic mechanisms of interleukin (IL)-22 in human lung cancer.

Experimental Design: Nineteen cases with stage I to III NSCLC were collected to determine the expression of IL-22. Stable transfection of human IL-22 cDNA into A549 and PG cells and transfection of IL-22-RNA interference (RNAi) into these cancer cell lines were done to reveal the molecular mechanisms of IL-22.

Results: It was found that IL-22 was highly expressed in primary tumor tissue, malignant pleural effusion, and serum of patients with NSCLC. IL-22R1 mRNA was also detected in lung cancer tissues as well as lung cancer cell lines. Overexpression of IL-22 protected lung cancer cell lines from serum starvation-induced and chemotherapeutic drug-induced apoptosis via activation of STAT3 and its downstream antiapoptotic proteins such as Bcl-2 and Bcl-xL and inactivation of extracellular signal-regulated kinase 1/2. Exposure to blocking antibodies against IL-22R1 or transfection with the IL-22-RNAi plasmid in vitro resulted in apoptosis of these lung cancer cells via STAT3 and extracellular signal-regulated kinase 1/2 pathways. Furthermore, an in vivo xenograft study showed that administration of IL-22-RNAi plasmids significantly inhibited the human tumor cell growth in BALB/c nude mice.

Conclusions: Our study indicates that autocrine production of IL-22 contributes to human lung cancer cell survival and resistance to chemotherapy through the up-regulation of antiapoptotic proteins.
Data from Characterization of Genetically Modified T-Cell Receptors that Recognize the CEA:691-699 Peptide in the Context of HLA-A2.1 on Human Colorectal Cancer Cells
Authors: Parkhurst Maria R. , Joo Jayne , Riley John P. , Yu Zhiya , Li Yong , Robbins Paul F. , Rosenberg Steven A.
Published: April 2023

Abstract
Purpose: Carcinoembryonic antigen (CEA) is a tumor-associated protein expressed on a variety of adenocarcinomas. To develop an immunotherapy for patients with cancers that overexpress CEA, we isolated and genetically modified a T-cell receptors (TCRs) that specifically bound a CEA peptide on human cancer cells.

Experimental Design: HLA-A2.1 transgenic mice were immunized with CEA:691-699. A CEA-reactive TCR was isolated from splenocytes of these mice and was genetically introduced into human peripheral blood lymphocytes via RNA electroporation or retroviral transduction. Amino acid substitutions were introduced throughout the complementarity determining regions (CDR1, CDR2, and CDR3) of both TCR α and β chains to improve recognition of CEA.

Results: Murine lymphocytes bearing the CEA-reactive TCR specifically recognized peptide-loaded T2 cells and HLA-A2.1+ CEA+ human colon cancer cells. Both CD8+ and CD4+ human lymphocytes expressing the murine TCR specifically recognized peptide-loaded T2 cells. However, only gene-modified CD8+ lymphocytes specifically recognized HLA-A2.1+ CEA+ colon cancer cell lines, and tumor cell recognition was weak and variable. We identified two substitutions in the CDR3 of the α chain that significantly influenced tumor cell recognition by human peripheral blood lymphocytes. One substitution, T for S at position 112 (S112T), enhanced tumor cell recognition by CD8+ lymphocytes, and a second dually substituted receptor (S112T L110F) enhanced tumor cell recognition by CD4+ T cells.

Conclusions: The modified CEA-reactive TCRs are good candidates for future gene therapy clinical trials and show the power of selected amino acid substitutions in the antigen-binding regions of the TCR to enhance desired reactivities.
Data from Identification of PMF1 Methylation in Association with Bladder Cancer Progression
Authors: Aleman Ainel , Cebrian Virginia , Alvarez Miguel , Lopez Virginia , Orenes Esteban , Lopez-Serra Lidia , Algaba Ferran , Bellmunt Joaquin , López-Beltrán Antonio , Gonzalez-Peramato Pilar , Cordon-Cardo Carlos , García Javier , del Muro Javier García , Esteller Manel , Sánchez-Carbayo Marta
Published: April 2023

Abstract
Purpose: Polyamines are important regulators of cell growth and death. The polyamine modulated factor-1 (PMF-1) is involved in polyamine homeostasis. After identifying an enriched CpG island encompassing the PMF1 promoter, we aimed at evaluating the clinical relevance of PMF1 methylation in bladder cancer.

Experimental Design: The epigenetic silencing of PMF1 by hypermethylation was tested in bladder cancer cells (n = 11) after azacytidine treatment. PMF1 methylation status was evaluated in 507 bladder tumors and 118 urinary specimens of bladder cancer patients and controls. PMF1 protein expression was analyzed by immunohistochemistry on tissue arrays containing bladder tumors for which PMF1 methylation was assessed (n = 218).

Results: PMF1 hypermethylation was associated with gene expression loss, being restored in vitro by a demethylating agent. An initial set of 101 primary frozen bladder tumors served to identify PMF1 hypermethylation in 88.1% of the cases. An independent set of 406 paraffin-embedded tumors also revealed a high PMF1 methylation rate (77.6%). PMF1 methylation was significantly associated with increasing stage (P = 0.025). Immunohistochemical analyses revealed that PMF1 methylation was associated with cytoplasmic PMF1 expression loss (P = 0.032). PMF1 protein expression patterns were significantly associated with stage (P < 0.001), grade (P < 0.001), and poor overall survival using univariate (P < 0.001) and multivariate (P = 0.011) analyses. Moreover, PMF1 methylation in urinary specimens distinguished bladder cancer patients from controls (area under the curve = 0.800).

Conclusion: PMF1 was identified to be epigenetically modified in bladder cancer. The association of PMF1 methylation with tumor progression and its diagnostic ability using urinary specimens support including PMF1 assessment for the clinical management of bladder cancer patients.
Data from Bringing DNA Repair in Tumors into Focus
Authors: Lord Christopher J. , Ashworth Alan
Published: April 2023

Abstract
Biomarkers are of crucial importance in optimizing cancer therapies. In this edition of Clinical Cancer Research, Bañuelos and colleagues assess H2AX phosphorylation as a predictive biomarker of response to DNA damaging agents. We discuss these results as well as the impact that double strand break repair biomarkers may have in cancer therapy.
Data from Regulation of CD151 by Hypoxia Controls Cell Adhesion and Metastasis in Colorectal Cancer
Authors: Chien Chun-Wei , Lin Shih-Chieh , Lai Yen-Yu , Lin Bo-Wen , Lin Shao-Chieh , Lee Jenq-Chang , Tsai Shaw-Jenq
Published: April 2023

Abstract
Purpose: The first step of metastasis is the detachment of cancer cells from the surrounding matrix and neighboring cells; however, how cancer cells accomplish this process remains unclear. Thus, we aimed to investigate the underlying mechanism that controls the early event of metastasis.

Experimental Design: One hundred and thirty-seven paired colorectal carcinoma and normal colon tissues were examined by immunohistochemical staining and Western blot for the expression of CD151, a member of the tetraspanin family that plays important roles in cell adhesion and motility. The effect of CD151 on cancer cell adhesion was investigated under normoxia and hypoxia conditions.

Results: The level of CD151 was down-regulated in colon cancer compared with the paired normal counterparts. Expression of CD151 was negatively regulated by hypoxia inducible factor-1–dependent hypoxic stress. Suppression of CD151 by hypoxia caused the detachment of cancer cells from the surrounding matrix and neighboring cells whereas restoration of CD151 expression during reoxygenation facilitated the adhesion capacity. Clinical examination further showed that metastasized cancer cells expressed a greater level of CD151 compared with that of primary tumor.

Conclusion: Regulation of CD151 by oxygen tension may play an important role in cancer metastasis by regulating the detachment from the primary site and homing in the secondary site.
Data from An Imaging-Based Rapid Evaluation Method for Complement-Dependent Cytotoxicity Discriminated Clinical Response to Rituximab-Containing Chemotherapy
Authors: Mishima Yuji , Sugimura Natsuhiko , Matsumoto-Mishima Yuko , Terui Yasuhito , Takeuchi Kengo , Asai Suzuka , Ennishi Daisuke , Asai Hiroaki , Yokoyama Masahiro , Kojima Kiyotsugu , Hatake Kiyohiko
Published: April 2023

Abstract
Purpose: Rituximab has greatly improved the efficacy of chemotherapy regimens for CD20-positive non-Hodgkin's lymphoma. However, although several mechanisms of action of rituximab have been identified, the exact therapeutic functions of these mechanisms remains to be clarified. In addition, there is no established prognostic marker to predict an individual response. This study verified the validity of ex vivo complement-dependent cytotoxicity (CDC) susceptibility as a predictor of pathologic tumor regression in patients undergoing rituximab-containing chemotherapy and examined whether CDC contributes to the mechanism of action of rituximab.

Experimental Design: A rapid assay system was established to evaluate the tumoricidal activity of rituximab using a living cell–imaging technique. We analyzed lymph node biopsies obtained from 234 patients with suspected lymphomas and estimated the association between CDC susceptibility and the response to rituximab-containing chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma.

Results: This study revealed that CDC susceptibility of lymphoma cells freshly obtained from patients was strongly associated with response to rituximab-containing chemotherapy in both diffuse large B-cell lymphoma and follicular lymphoma. This correlation was not apparent in cases that received chemotherapy without rituximab.

Conclusions: The system that we have established allows a successful assessment of rituximab-induced CDC and can distinguish cases refractory to rituximab-containing chemotherapy. The association between CDC susceptibility and therapy response suggests that CDC is pivotal in the ability of chemotherapy including rituximab to induce remission.
Data from CpG Island Methylator Phenotype Associates with Low-Degree Chromosomal Abnormalities in Colorectal Cancer
Authors: Cheng Yu-Wei , Pincas Hanna , Bacolod Manny D. , Schemmann Gunter , Giardina Sarah F. , Huang Jianmin , Barral Sandra , Idrees Kamran , Khan Sajid A. , Zeng Zhaoshi , Rosenberg Shoshana , Notterman Daniel A. , Ott Jurg , Paty Philip , Barany Francis
Published: April 2023

Abstract
Purpose: Aberrant promoter methylation and genomic instability occur frequently during colorectal cancer development. CpG island methylator phenotype (CIMP) has been shown to associate with microsatellite instability, and BRAF mutation and is often found in the right-side colon. Nevertheless, the relative importance of CIMP and chromosomal instability (CIN) for tumorigenesis has yet to be thoroughly investigated in sporadic colorectal cancers.

Experimental Design: We determined CIMP in 161 primary colorectal cancers and 66 matched normal mucosae using a quantitative bisulfite/PCR/ligase detection reaction (LDR)/Universal Array assay. The validity of CIMP was confirmed in a subset of 60 primary tumors using MethyLight assay and five independent markers. In parallel, CIN was analyzed in the same study cohort using Affymetrix 50K Human Mapping arrays.

Results: The identified CIMP-positive cancers correlate with microsatellite instability (P = 0.075) and the BRAF mutation V600E (P = 0.00005). The array-based high-resolution analysis of chromosomal aberrations indicated that the degree of aneuploidy is spread over a wide spectrum among analyzed colorectal cancers. Whether CIN was defined by copy number variations in selected microsatellite loci (criterion 1) or considered as a continuous variable (criterion 2), CIMP-positive samples showed a strong correlation with low-degree chromosomal aberrations (P = 0.075 and P = 0.012, respectively). Similar correlations were observed when CIMP was determined by MethyLight assay (P = 0.001 and P = 0.013, respectively).

Conclusion: CIMP-positive tumors generally possess lower chromosomal aberrations, which may only be revealed using a genome-wide approach. The significant difference in the degree of chromosomal aberrations between CIMP-positive and the remainder of samples suggests that epigenetic (CIMP) and genetic (CIN) abnormalities may arise from independent molecular mechanisms of tumor progression.