bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Reconstruction of Transcriptional Networks Reveals Critical Genes with Implications for Clinical Outcome of Multiple Myeloma
Authors: Agnelli Luca , Forcato Mattia , Ferrari Francesco , Tuana Giacomo , Todoerti Katia , Walker Brian A. , Morgan Gareth J. , Lombardi Luigia , Bicciato Silvio , Neri Antonino
Published: April 2023

Abstract
Purpose: The combined use of microarray technologies and bioinformatics analysis has improved our understanding of biological complexity of multiple myeloma (MM). In contrast, the application of the same technology in the attempt to predict clinical outcome has been less successful with the identification of heterogeneous molecular signatures. Herein, we have reconstructed gene regulatory networks in a panel of 1,883 samples from MM patients derived from publicly available gene expression sets, to allow the identification of robust and reproducible signatures associated with poor prognosis across independent data sets.

Experimental Design: Gene regulatory networks were reconstructed by using Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) and microarray data from seven MM data sets. Critical analysis of network components was applied to identify genes playing an essential role in transcriptional networks, which are conserved between data sets.

Results: Network critical analysis revealed that (i) CCND1 and CCND2 were the most critical genes; (ii) CCND2, AIF1, and BLNK had the largest number of connections shared among the data sets; (iii) robust gene signatures with prognostic power were derived from the most critical transcripts and from shared primary neighbors of the most connected nodes. Specifically, a critical-gene model, comprising FAM53B, KIF21B, WHSC1, and TMPO, and a neighbor-gene model, comprising BLNK shared neighbors CSGALNACT1 and SLC7A7, predicted survival in all data sets with follow-up information.

Conclusions: The reconstruction of gene regulatory networks in a large panel of MM tumors defined robust and reproducible signatures with prognostic importance, and may lead to identify novel molecular mechanisms central to MM biology. Clin Cancer Res; 17(23); 7402–12. ©2011 AACR.
Data from KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer
Authors: Tie Jeanne , Lipton Lara , Desai Jayesh , Gibbs Peter , Jorissen Robert N. , Christie Michael , Drummond Katharine J. , Thomson Benjamin N.J. , Usatoff Valery , Evans Peter M. , Pick Adrian W. , Knight Simon , Carne Peter W.G. , Berry Roger , Polglase Adrian , McMurrick Paul , Zhao Qi , Busam Dana , Strausberg Robert L. , Domingo Enric , Tomlinson Ian P.M. , Midgley Rachel , Kerr David , Sieber Oliver M.
Published: April 2023

Abstract
Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse.

Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial.

Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1; 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial.

Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies. Clin Cancer Res; 17(5); 1122–30. ©2011 AACR.
Data from Molecular Pathways: Targeting P21-Activated Kinase 1 Signaling in Cancer—Opportunities, Challenges, and Limitations
Authors: Eswaran Jeyanthy , Li Da-Qiang , Shah Anil , Kumar Rakesh
Published: April 2023

Abstract
The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a variety of new functions for this kinase in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely upregulated in several human cancers, such as hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. Structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the possibility to develop PAK1-targeted cancer therapeutic approaches. In addition, emerging reports suggest the potential of PAK1 and its specific phosphorylated substrates as cancer prognostic markers. Here, we summarize recent findings about the PAK1 molecular pathways in human cancer and discuss the current status of PAK1-targeted anticancer therapies. Clin Cancer Res; 18(14); 3743–9. ©2012 AACR.
Data from 14-3-3ζ, a Novel Androgen-Responsive Gene, Is Upregulated in Prostate Cancer and Promotes Prostate Cancer Cell Proliferation and Survival
Authors: Murata Taro , Takayama Ken-ichi , Urano Tomohiko , Fujimura Tetsuya , Ashikari Daisaku , Obinata Daisuke , Horie-Inoue Kuniko , Takahashi Satoru , Ouchi Yasuyoshi , Homma Yukio , Inoue Satoshi
Published: April 2023

Abstract
Purpose: Androgen receptor is an essential transcriptional factor that contributes to the development and progression of prostate cancer. In this study, we investigated the androgen regulation and functional analysis of 14-3-3ζ in prostate cancer.

Experimental Design: Using chromatin immunoprecipitation (ChIP) combined with DNA microarray (ChIP-chip) analysis in LNCaP cells, we identified a functional androgen receptor–binding site in the downstream region of the 14-3-3ζ gene. Androgen regulation was examined by quantitative reverse transcription PCR and Western blot analysis. Prostate cancer cells stably expressing 14-3-3ζ and siRNA knockdown were used for functional analyses. We further examined 14-3-3ζ expression in clinical samples of prostate cancer by immunohistochemistry and quantitative reverse transcription PCR.

Results: Androgen-dependent upregulation of 14-3-3ζ was validated at the mRNA and protein levels. The 14-3-3ζ gene is favorable for cancer-cell survival, as its ectopic expression in LNCaP cells contributes to cell proliferation and the acquired resistance to etoposide-induced apoptosis. 14-3-3ζ expression was associated with androgen receptor transcriptional activity and prostate-specific antigen (PSA) mRNA expression. Immunoprecipitation indicated that 14-3-3ζ was associated with androgen receptor in the nucleus. Clinicopathologic studies further support the relevance of 14-3-3ζ in prostate cancers, as its higher expression is associated with malignancy and lymph node metastasis.

Conclusions: 14-3-3ζ is a novel androgen-responsive gene that activates proliferation, cell survival, and androgen receptor transcriptional activity. 14-3-3ζ may facilitate the progression of prostate cancer. Clin Cancer Res; 18(20); 5617–27. ©2012 AACR.
Data from Genomic and Molecular Characterization of Malignant Peripheral Nerve Sheath Tumor Identifies the IGF1R Pathway as a Primary Target for Treatment
Authors: Yang Jilong , Ylipää Antti , Sun Yan , Zheng Hong , Chen Kexin , Nykter Matti , Trent Jonathan , Ratner Nancy , Lev Dina C. , Zhang Wei
Published: April 2023

Abstract
Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. We gain insight into the most recurrent genetically altered pathways with the purpose of scanning possible therapeutic targets.

Experimental Design: We conducted a microarray-based comparative genomic hybridization profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. Immunohistochemistry (IHC) and cell biology detection and validation were carried out on human MPNST tissues and cell lines.

Results: Genomic characterization of 51 MPNST tissue samples identified several frequently amplified regions harboring 2,599 genes and regions of deletion including 4,901 genes. At the pathway level, we identified a significant enrichment of copy number–altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1R gene itself. To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using IHC. Two MPNST cell lines (ST88-14 and STS26T) were used to determine the effect of attenuating IGF1R. Inhibition of IGF1R in ST88-14 cells using siRNAs or an IGF1R inhibitor, MK-0646, led to significant decreases in cell proliferation, invasion, and migration accompanied by attenuation of the PI3K/AKT and mitogen-activated protein kinase pathways.

Conclusion: These integrated genomic and molecular studies provide evidence that the IGF1R pathway is a potential therapeutic target for patients with MPNST. Clin Cancer Res; 17(24); 7563–73. ©2011 AACR.
Data from EDNRB and DCC Salivary Rinse Hypermethylation Has a Similar Performance as Expert Clinical Examination in Discrimination of Oral Cancer/Dysplasia versus Benign Lesions
Authors: Schussel Juliana , Zhou Xian Chong , Zhang Zhe , Pattani Kavita , Bermudez Francisco , Jean-Charles Germain , McCaffrey Thomas , Padhya Tapan , Phelan Joan , Spivakovsky Silvia , Brait Mariana , Li Ryan , Yoo Bowne Helen , Goldberg Judith D. , Rolnitzky Linda , Robbins Miriam , Kerr A. Ross , Sirois David , Califano Joseph A.
Published: April 2023

Abstract
Purpose: Promoter hypermethylation has been recently proposed as a means for head and neck squamous cell carcinoma (HNSCC) detection in salivary rinses. In a prospective study of a high-risk population, we showed that endothelin receptor type B (EDNRB) promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy.

Experimental Design: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was conducted and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by quantitative methylation-specific PCR.

Results:HOXA9, EDNRB, and deleted in colorectal cancer (DCC) methylation were associated (P = 0.012; P < 0.0001; P = 0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (P = 0.0003) or DCC (P = 0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC, and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (P = 0.008; P = 0.026; P = 0.046) and multivariate analysis (P = 0.012; P = 0.037; P = 0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with a similar area under curve [AUC; 0.61, 95% confidence interval (CI) = 0.60–0.81] when compared to EDNRB and DCC combined AUC (0.60, 95% CI = 0.51–0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC, and CRC was optimal AUC (0.67, 95% CI = 0.58–0.76).

Conclusions:EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available. Clin Cancer Res; 19(12); 3268–75. ©2013 AACR.
Data from CLIC4, ERp29, and Smac/DIABLO Derived from Metastatic Cancer Stem–like Cells Stratify Prognostic Risks of Colorectal Cancer
Authors: Deng Yong-Jian , Tang Na , Liu Chao , Zhang Jiang-Yu , An Sheng-Li , Peng Yin-Li , Ma Li-Li , Li Guang-Qiu , Jiang Qiang , Hu Chun-Ting , Wang Ya-Nan , Liang Yao-Ze , Bian Xiu-Wu , Fang Wei-Gang , Ding Yan-Qing
Published: April 2023

Abstract
Purpose: Cancer stem–like cells have been well accepted to be involved in recurrence and metastasis of cancers, but the prognostic potential of biomarkers integrating with metastasis and cancer stem–like cells for colorectal cancer is unclear.

Experimental Design: We identified three proteins, CLIC4, ERp29, and Smac/DIABLO, from metastatic cancer stem–like cells of colorectal cancer and verified the proteins' role in metastatic behaviors. The proteins were detected by IHC in colorectal cancer tumors and matched colonic mucosa from patients with colorectal cancer who underwent radical surgery in the training cohort. The associations between proteins expression levels and five-year disease-specific survival (DSS) were evaluated to predict the survival probability in the training cohort of 421 cases and the validation cohort of 228 cases.

Results: A three-protein panel including CLIC4, ERp29, and Smac/DIABLO, which was generated from multivariate analysis by excluding clinicopathologic characteristics from the training cohort, distinguished patients with colorectal cancer into very low-, low-, middle-, and high-risk groups with significant differences in five-year DSS probability (88.6%, 63.3%, 30.4%, 11.4%; P < 0.001). The panel is independent from tumor–node–metastasis staging system and histologic grading to predict prognosis, and also enables classification of validation cohort into four risk stratifications (five-year DSS probability is 98.2%, 80.2%, 25.6%, and 2.7%; P < 0.001).

Conclusions: CLIC4, ERp29, and Smac/DIABLO integrated into a novel panel based on cancer stem–like cells in association with metastasis stratify the prognostic risks of colorectal cancer. Prediction of risks with molecular markers will benefit clinicians to make decisions of individual management with postoperative colorectal cancer patients. Clin Cancer Res; 20(14); 3809–17. ©2014 AACR.
Data from Worth Adapting? Revisiting the Usefulness of Outcome-Adaptive Randomization
Authors: Lee J. Jack , Chen Nan , Yin Guosheng
Published: April 2023

Abstract
Outcome-adaptive randomization allocates more patients to the better treatments as the information accumulates in the trial. Is it worth it to apply outcome-adaptive randomization in clinical trials? Different views permeate the medical and statistical communities. We provide additional insights to the question by conducting extensive simulation studies. Trials are designed to maintain the type I error rate, achieve a specified power, and provide better treatment to patients. Generally speaking, equal randomization requires a smaller sample size and yields a smaller number of nonresponders than adaptive randomization by controlling type I and type II errors. Conversely, adaptive randomization produces a higher overall response rate than equal randomization with or without expanding the trial to the same maximum sample size. When there are substantial treatment differences, adaptive randomization can yield a higher overall response rate as well as a lower average sample size and a smaller number of nonresponders. Similar results are found for the survival endpoint. The differences between adaptive randomization and equal randomization quickly diminish with early stopping of a trial due to efficacy or futility. In summary, equal randomization maintains balanced allocation throughout the trial and reaches the specified statistical power with a smaller number of patients in the trial. If the trial's results are positive, equal randomization may lead to early approval of the treatment. Adaptive randomization focuses on treating patients best in the trial. Adaptive randomization may be preferred when the difference in efficacy between treatments is large or when the number of patients available is limited. Clin Cancer Res; 18(17); 4498–507. ©2012 AACR.
Data from Improved Statistical Modeling of Tumor Growth and Treatment Effect in Preclinical Animal Studies with Highly Heterogeneous Responses In Vivo
Authors: Laajala Teemu D. , Corander Jukka , Saarinen Niina M. , Mäkelä Katja , Savolainen Saija , Suominen Mari I. , Alhoniemi Esa , Mäkelä Sari , Poutanen Matti , Aittokallio Tero
Published: April 2023

Abstract
Purpose: Preclinical tumor growth experiments often result in heterogeneous datasets that include growing, regressing, or stable growth profiles in the treatment and control groups. Such confounding intertumor variability may mask the true treatment effects especially when less aggressive treatment alternatives are being evaluated.

Experimental design: We developed a statistical modeling approach in which the growing and poorly growing tumor categories were automatically detected by means of an expectation-maximization algorithm coupled within a mixed-effects modeling framework. The framework is implemented and distributed as an R package, which enables model estimation and statistical inference, as well as statistical power and precision analyses.

Results: When applied to four tumor growth experiments, the modeling framework was shown to (i) improve the detection of subtle treatment effects in the presence of high within-group tumor variability; (ii) reveal hidden tumor subgroups associated with established or novel biomarkers, such as ERβ expression in a MCF-7 breast cancer model, which remained undetected with standard statistical analysis; (iii) provide guidance on the selection of sufficient sample sizes and most informative treatment periods; and (iv) offer flexibility to various cancer models, experimental designs, and treatment options. Model-based testing of treatment effect on the tumor growth rate (or slope) was shown as particularly informative in the preclinical assessment of treatment alternatives based on dietary interventions.

Conclusions: In general, the modeling framework enables identification of such biologically significant differences in tumor growth profiles that would have gone undetected or had required considerably higher number of animals when using traditional statistical methods. Clin Cancer Res; 18(16); 4385–96. ©2012 AACR.
Data from Polycomb Repressor Complex-2 Is a Novel Target for Mesothelioma Therapy
Authors: Kemp Clinton D. , Rao Mahadev , Xi Sichuan , Inchauste Suzanne , Mani Haresh , Fetsch Patricia , Filie Armando , Zhang Mary , Hong Julie A. , Walker Robert L. , Zhu Yuelin J. , Ripley R. Taylor , Mathur Aarti , Liu Fang , Yang Maocheng , Meltzer Paul A. , Marquez Victor E. , De Rienzo Assunta , Bueno Raphael , Schrump David S.
Published: April 2023

Abstract
Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM).

Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep.

Results:EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment.

Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy. Clin Cancer Res; 18(1); 77–90. ©2011 AACR.
Data from Decreased Selenium-Binding Protein 1 Enhances Glutathione Peroxidase 1 Activity and Downregulates HIF-1α to Promote Hepatocellular Carcinoma Invasiveness
Authors: Huang Cheng , Ding Guangyu , Gu Chengyu , Zhou Jian , Kuang Ming , Ji Yuan , He Yifeng , Kondo Tadashi , Fan Jia
Published: April 2023

Abstract
Purpose: We aimed to characterize the role of selenium-binding protein 1 (SBP1) in hepatocellular carcinoma (HCC) invasiveness and underlying clinical significance.

Experimental Design: SBP1 expression was measured in stepwise metastatic HCC cell lines by Western blotting. The role of SBP1 in HCC was investigated using siRNA. Immunofluorescence analyses were used to detect the interaction between SBP1 and glutathione peroxidase 1 (GPX1). Nineteen fresh tumor tissues and 323 paraffin-embedded samples were used to validate in vitro findings and to detect the prognostic significance of SBP1, respectively.

Results: Inhibition of SBP1 effectively increased cell motility, promoted cell proliferation, and inhibited apoptosis only under oxidative stress; it also greatly enhanced GPX1 activity without altering GPX1 expression and downregulated hypoxia-inducible factor-1α (HIF-1α) expression. SBP1 and GPX1 formed nuclear bodies and colocalized under oxidative stress. In freshly isolated clinical HCC tissues, decreased SBP1 was linked with increased GPX1 activity and correlated with vascular invasion. Tumor tissue microarrays indicated that SBP1 was an independent risk factor for overall survival and disease recurrence; patients with lower SBP1 expression experienced shorter overall survival periods and higher rates of disease recurrence (P < 0.001). Further analyses indicated that the predictive power of SBP1 was more significant for patients beyond the Milan criteria than patients within the Milan criteria.

Conclusions: Decreased expression of SBP1 could promote tumor invasiveness by increasing GPX1 activity and diminishing HIF-1α expression in HCC; SBP1 could be a novel biomarker for predicting prognosis and guiding personalized therapeutic strategies, especially in patients with advanced HCC. Clin Cancer Res; 18(11); 3042–53. ©2012 AACR.
Data from Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents
Authors: Mao Muling , Tian Feng , Mariadason John M. , Tsao Chun C. , Lemos Robert , Dayyani Farshid , Gopal Y.N. Vashisht , Jiang Zhi-Qin , Wistuba Ignacio I. , Tang Xi M. , Bornman William G. , Bollag Gideon , Mills Gordon B. , Powis Garth , Desai Jayesh , Gallick Gary E. , Davies Michael A. , Kopetz Scott
Published: April 2023

Abstract
Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies.

Experimental Design: We conducted comparative proteomic analysis of BRAFV600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models.

Results: Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification.

Conclusions: We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAFV600E CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients. Clin Cancer Res; 19(3); 657–67. ©2012 AACR.
Data from The Effects of Chemotherapy on Cognitive Function in a Mouse Model: A Prospective Study
Authors: Winocur Gordon , Henkelman Mark , Wojtowicz J. Martin , Zhang Haibo , Binns Malcolm A. , Tannock Ian F.
Published: April 2023

Abstract
Purpose: Clinical studies indicate that up to 70% of patients with cancer who receive chemotherapy experience cognitive impairment. The present study used a prospective longitudinal design to assess short- and long-term effects of commonly used anticancer drugs on cognitive performance in a mouse model.

Experimental Design: Normal mice received three weekly injections of a combination of methotrexate + 5-fluorouracil (CHEMO group) or an equal volume of saline (SAL group). Cognitive tests, measuring different aspects of learning and memory, were administered before treatment, immediately after treatment, and three months later. Structural MRI scanning was conducted at each stage of cognitive testing.

Results: The CHEMO group exhibited deficits on cognitive tasks acquired pretreatment [spatial memory, nonmatching-to-sample (NMTS) learning, and delayed NMTS], as well as impaired new learning on two tasks (conditional associative learning, discrimination learning) introduced posttreatment. Consistent with clinical evidence, cognitive deficits were pronounced on tests that are sensitive to hippocampal and frontal lobe dysfunction, but the CHEMO group's poor performance on the discrimination learning problem suggests that impairment is more widespread than previously thought. Cognitive deficits persisted for at least three months after treatment but some recovery was noted, particularly on tests thought to be under frontal lobe control. The MRI tests did not detect brain changes that could be attributed to treatment.

Conclusions: Chemotherapeutic agents can have adverse effects on information acquired pretreatment as well as new learning and memory and, despite some recovery, impairment is long lasting. Clin Cancer Res; 18(11); 3112–21. ©2012 AACR.
Data from Large-scale Analysis of PDGFRA Mutations in Melanomas and Evaluation of Their Sensitivity to Tyrosine Kinase Inhibitors Imatinib and Crenolanib
Authors: Dai Jie , Kong Yan , Si Lu , Chi Zhihong , Cui Chuanliang , Sheng Xinan , Mao Lili , Li Siming , Lian Bin , Yang Ruifeng , Liu Shujing , Xu Xiaowei , Guo Jun
Published: April 2023

Abstract
Purpose: Platelet-derived growth factor receptor α (PDGFRA) is a target for tyrosine kinase inhibitor (TKI)-based targeted therapy. Dysregulation of PDGFRA has been reported in many cancers. However, PDGFRA mutations in melanomas have not been well studied. We analyzed the genetic mutations of PDGFRA in Chinese patients with melanoma and determined the inhibitory potency of TKIs, such as imatinib and crenolanib, on mutant PDGFRA.

Experimental Design: Of note, 351 melanoma tissue samples were examined for genetic mutations in exons 12, 14, and 18 of PDGFRA. Activities of mutations in response to imatinib and crenolanib were analyzed by Western blotting of tyrosine-phosphorylated PDGFRA and cell proliferation assays.

Results:PDGFRA mutations were observed in 4.6% (16 of 351) of melanomas, and these mutations were mainly detected in acral and mucosal melanomas. PDGFRA mutations seem to be mutually exclusive with KIT mutations, but may coexist with BRAF and NRAS mutations. The genetic mutations of PDGFRA were unrelated to the age, thickness, and ulceration status of primary melanomas. Thirteen mutations were not reported before, and five (P577S, V658A, R841K, H845Y, and G853D) of them resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except that V658A mutation was imatinib-resistant, all the other mutations were sensitive to both imatinib and crenolanib.

Conclusions:PDGFRA mutations are detected in a small population of melanoma patients. Our study suggests that patients with melanoma harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment. Clin Cancer Res; 19(24); 6935–42. ©2013 AACR.
Data from Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors
Authors: Shames David S. , Elkins Kristi , Walter Kimberly , Holcomb Thomas , Du Pan , Mohl Dane , Xiao Yang , Pham Thinh , Haverty Peter M. , Liederer Bianca , Liang Xiaorong , Yauch Robert L. , O'Brien Thomas , Bourgon Richard , Koeppen Hartmut , Belmont Lisa D.
Published: April 2023

Abstract
Purpose: We sought to identify predictive biomarkers for a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor.

Experimental Design: We use a NAMPT inhibitor, GNE-617, to evaluate nicotinic acid rescue status in a panel of more than 400 cancer cell lines. Using correlative analysis and RNA interference (RNAi), we identify a specific biomarker for nicotinic acid rescue status. We next determine the mechanism of regulation of expression of the biomarker. Finally, we develop immunohistochemical (IHC) and DNA methylation assays and evaluate cancer tissue for prevalence of the biomarker across indications.

Results: Nicotinate phosphoribosyltransferase (NAPRT1) is necessary for nicotinic acid rescue and its expression is the major determinant of rescue status. We demonstrate that NAPRT1 promoter methylation accounts for NAPRT1 deficiency in cancer cells, and NAPRT1 methylation is predictive of rescue status in cancer cell lines. Bisulfite next-generation sequencing mapping of the NAPRT1 promoter identified tumor-specific sites of NAPRT1 DNA methylation and enabled the development of a quantitative methylation-specific PCR (QMSP) assay suitable for use on archival formalin-fixed paraffin-embedded tumor tissue.

Conclusions: Tumor-specific promoter hypermethylation of NAPRT1 inactivates one of two NAD salvage pathways, resulting in synthetic lethality with the coadministration of a NAMPT inhibitor. NAPRT1 expression is lost due to promoter hypermethylation in most cancer types evaluated at frequencies ranging from 5% to 65%. NAPRT1-specific immunohistochemical or DNA methylation assays can be used on archival formalin paraffin-embedded cancer tissue to identify patients likely to benefit from coadministration of a Nampt inhibitor and nicotinic acid. Clin Cancer Res; 19(24); 6912–23. ©2013 AACR.
Data from Development and Preclinical Characterization of a Humanized Antibody Targeting CXCL12
Authors: Zhong Cuiling , Wang Jianyong , Li Bing , Xiang Hong , Ultsch Mark , Coons Mary , Wong Terence , Chiang Nancy Y. , Clark Suzy , Clark Robyn , Quintana Leah , Gribling Peter , Suto Eric , Barck Kai , Corpuz Racquel , Yao Jenny , Takkar Rashi , Lee Wyne P. , Damico-Beyer Lisa A. , Carano Richard D. , Adams Camellia , Kelley Robert F. , Wang Weiru , Ferrara Napoleone
Published: April 2023

Abstract
Purpose: Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities.

Experimental Design: Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities.

Results: 30D8, a hamster antibody against mouse and human CXCL12α, CXCL12β, and CXCL12γ, was shown to dose-dependently block CXCL12α binding to CXCR4 and CXCR7, and CXCL12α-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-α antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12α complex in combination with mutational analysis revealed a “hot spot” around residues Asn44/Asn45 of CXCL12α and part of the RFFESH region required for CXCL12α binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats.

Conclusion: CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans. Clin Cancer Res; 19(16); 4433–45. ©2013 AACR.
Data from Differential Response to Neoadjuvant Chemotherapy Among 7 Triple-Negative Breast Cancer Molecular Subtypes
Authors: Masuda Hiroko , Baggerly Keith A. , Wang Ying , Zhang Ya , Gonzalez-Angulo Ana Maria , Meric-Bernstam Funda , Valero Vicente , Lehmann Brian D. , Pietenpol Jennifer A. , Hortobagyi Gabriel N. , Symmans W. Fraser , Ueno Naoto T.
Published: April 2023

Abstract
Purpose: The clinical relevancy of the 7-subtype classification of triple-negative breast cancer (TNBC) reported by Lehmann and colleagues is unknown. We investigated the clinical relevancy of TNBC heterogeneity by determining pathologic complete response (pCR) rates after neoadjuvant chemotherapy, based on TNBC subtypes.

Experimental Design: We revalidated the Lehmann and colleagues experiments using Affymetrix CEL files from public datasets. We applied these methods to 146 patients with TNBC with gene expression microarrays obtained from June 2000 to March 2010 at our institution. Of those, 130 had received standard neoadjuvant chemotherapy and had evaluable pathologic response data. We classified the TNBC samples by subtype and then correlated subtype and pCR status using Fisher exact test and a logistic regression model. We also assessed survival and compared the subtypes with PAM50 intrinsic subtypes and residual cancer burden (RCB) index.

Results: TNBC subtype and pCR status were significantly associated (P = 0.04379). The basal-like 1 (BL1) subtype had the highest pCR rate (52%); basal-like 2 (BL2) and luminal androgen receptor had the lowest (0% and 10%, respectively). TNBC subtype was an independent predictor of pCR status (P = 0.022) by a likelihood ratio test. The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes (basal-like vs. non basal-like).

Conclusions: Classifying TNBC by 7 subtypes predicts high versus low pCR rate. We confirm the clinical relevancy of the 7 subtypes of TNBC. We need to prospectively validate whether the pCR rate differences translate into long-term outcome differences. The 7-subtype classification may spur innovative personalized medicine strategies for patients with TNBC. Clin Cancer Res; 19(19); 5533–40. ©2013 AACR.
Data from Increased miR-708 Expression in NSCLC and Its Association with Poor Survival in Lung Adenocarcinoma from Never Smokers
Authors: Jang Jin Sung , Jeon Hyo-Sung , Sun Zhifu , Aubry Marie Christine , Tang Hui , Park Cheol-Hong , Rakhshan Fariborz , Schultz Debra A. , Kolbert Christopher P. , Lupu Ruth , Park Jae Yong , Harris Curtis C. , Yang Ping , Jen Jin
Published: April 2023

Abstract
Purpose: miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non–small cell lung cancer.

Experimental Design: We conducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells.

Results: Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08–3.35; P = 0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02–3.63; P = 0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 3′ UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture.

Conclusions: miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer. Clin Cancer Res; 18(13); 3658–67. ©2012 AACR.
Data from Interleukin 15 Provides Relief to CTLs from Regulatory T Cell–Mediated Inhibition: Implications for Adoptive T Cell–Based Therapies for Lymphoma
Authors: Perna Serena K. , De Angelis Biagio , Pagliara Daria , Hasan Sayyeda T. , Zhang Lan , Mahendravada Aruna , Heslop Helen E. , Brenner Malcolm K. , Rooney Cliona M. , Dotti Gianpietro , Savoldo Barbara
Published: April 2023

Abstract
Purpose: Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs. We used the model of adoptive transfer of Epstein–Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients.

Experimental Design: Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored.

Results: We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs.

Conclusions: IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies. Clin Cancer Res; 19(1); 106–17. ©2012 AACR.
Data from The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis
Authors: Li Dawei , Wei Ping , Peng Zhihai , Huang Chen , Tang Huamei , Jia Zhiliang , Cui Jiujie , Le Xiangdong , Huang Suyun , Xie Keping
Published: April 2023

Abstract
Purpose: The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer pathogenesis remains unknown.

Experimental Design: We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer.

Results: We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by siRNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase-type plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis.

Conclusions: Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis. Clin Cancer Res; 19(1); 62–72. ©2012 AACR.
Data from Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study
Authors: Ang Joo Ern , Gourley Charlie , Powell C. Bethan , High Hilda , Shapira-Frommer Ronnie , Castonguay Vincent , De Greve Jacques , Atkinson Tina , Yap Timothy A. , Sandhu Shahneen , Banerjee Susana , Chen Lee-May , Friedlander Michael L. , Kaufman Bella , Oza Amit M. , Matulonis Ursula , Barber Louise J. , Kozarewa Iwanka , Fenwick Kerry , Assiotis Ioannis , Campbell James , Chen Lina , de Bono Johann S. , Gore Martin E. , Lord Christopher J. , Ashworth Alan , Kaye Stan B.
Published: April 2023

Abstract
Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.

Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.

Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)].

Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.
Data from Epigenetic Inactivation of microRNA-34b/c Predicts Poor Disease-Free Survival in Early-Stage Lung Adenocarcinoma
Authors: Nadal Ernest , Chen Guoan , Gallegos Marc , Lin Lin , Ferrer-Torres Daysha , Truini Anna , Wang Zhuwen , Lin Jules , Reddy Rishindra M. , Llatjos Roger , Escobar Ignacio , Moya Juan , Chang Andrew C. , Cardenal Felipe , Capellà Gabriel , Beer David G.
Published: April 2023

Abstract
Purpose: The microRNA-34b/c (miR-34b/c) is considered a tumor suppressor in different tumor types and a transcriptional target of TP53. The main objectives of this study were to investigate the clinical implications of miR-34b/c methylation in patients with early-stage lung adenocarcinoma and to determine the functional role of miR-34b/c re-expression in lung adenocarcinoma cell lines.

Experimental Design: Aberrant methylation and expression of miR-34b/c were assessed in 15 lung adenocarcinoma cell lines and a cohort of 140 early-stage lung adenocarcinoma. Lung adenocarcinoma cell lines were transfected with miR-34b/c and the effects upon cell proliferation, migration, invasion, and apoptosis were investigated.

Results: Aberrant methylation of miR-34b/c was detected in 6 (40%) of 15 lung adenocarcinoma cell lines and 64 of 140 (46%) primary lung adenocarcinoma. Expression of miR-34b/c was significantly reduced in all methylated cell lines and primary tumors, especially with TP53 mutations. Patients with increased miR-34b/c methylation had significantly shorter disease-free and overall survival as compared to patients with unmethylated or low level of miR-34b/c methylation. Ectopic expression of miR-34b/c in lung adenocarcinoma cell lines decreased cell proliferation, migration, and invasion.

Conclusions: Epigenetic inactivation of miR-34b/c by DNA methylation has independent prognostic value in patients with early-stage lung adenocarcinoma. Reexpression of miR-34b/c leads to a less aggressive phenotype in lung adenocarcinoma cell lines. Clin Cancer Res; 19(24); 6842–52. ©2013 AACR.