bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Cells Cue the p53 Response of Cancer-Associated Fibroblasts to Cisplatin
Authors: Schmid Jens O. , Dong Meng , Haubeiss Silke , Friedel Godehard , Bode Sabine , Grabner Andreas , Ott German , Mürdter Thomas E. , Oren Moshe , Aulitzky Walter E. , van der Kuip Heiko 
Published: September 2012

Abstract
Current understanding of the p53 response is based mainly upon in vitro studies of homogeneous cell populations. However, there is little information on whether the same principles operate within heterogeneous tumor tissues that are comprised of cancer cells and other cell types, including cancer-associated fibroblasts (CAF). Using ex-vivo tissue cultures, we investigated p53 status and responses to cisplatin in tumor cells and CAFs from tissue specimens isolated from 32 lung cancer patients. By comparing cultivated tissue slices with the corresponding tumor tissues fixed immediately after surgery, we found that morphology, proliferation, and p53 staining pattern were preserved during cultivation. Unexpectedly, when CAFs were analyzed, p53 accumulation and induction of p21 was observed only in tumors with constitutively low p53 protein and accumulation upon cisplatin treatment. In contrast, in tumors with no p53 accumulation in cancer cells there was also no p53 accumulation or p21 induction in adjacent CAFs. Furthermore, induction of cisplatin-induced apoptosis in CAFs was selectively observed in tumors characterized by a parallel induction of cancer cell death. Our findings reveal an interdependence of the p53 response in cancer cells and adjacent CAFs within tumor tissues, arguing that cancer cells control the response of their microenvironment to DNA damage. Cancer Res; 72(22); 5824–32. ©2012 AACR.
Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells
Authors: Cui Jiajun , Germer Katherine , Wu Tianying , Wang Jiang , Luo Jia , Wang Shao-chun , Wang Qianben , Zhang Xiaoting 
Published: September 2012

Abstract
Despite the fact that most breast cancer patients have estrogen receptor (ER) α-positive tumors, up to 50% of the patients are or soon develop resistance to endocrine therapy. It is recognized that HER2 activation is one of the major mechanisms contributing to endocrine resistance. In this study, we report that the ER coactivator MED1 is a novel cross-talk point for the HER2 and ERα pathways. Tissue microarray analysis of human breast cancers revealed that MED1 expression positively correlates most strongly with HER2 status of the tumors. MED1 was highly phosphorylated, in a HER2-dependent manner, at the site known to be critical for its activation. Importantly, RNAi-mediated attenuation of MED1 sensitized HER2-overexpressing cells to tamoxifen treatment. MED1 and its phosphorylated form, but not the corepressors N-CoR and SMRT, were recruited to the ERα target gene promoter by tamoxifen in HER2-overexpressing cells. Significantly, MED1 attenuation or mutation of MED1 phosphorylation sites was sufficient to restore the promoter recruitment of N-CoR and SMRT. Notably, we found that MED1 is required for the expression of not only traditional E2-ERα target genes but also the newly described EGF-ERα target genes. Our results additionally indicated that MED1 is recruited to the HER2 gene and required for its expression. Taken together, these findings support a key role for MED1 in HER2-mediated tamoxifen resistance and suggest its potential usage as a therapeutic target to simultaneously block both ERα and HER2 pathways for the treatment of this type of endocrine resistant breast cancer. Cancer Res; 72(21); 5625–34. ©2012 AACR.
Microdistribution and Long-term Retention of 239Pu (NO3)4 in the Respiratory Tracts of an Acutely Exposed Plutonium Worker and Experimental Beagle Dogs
Authors: Nielsen Christopher E. , Wilson Dulaney A. , Brooks Antone L. , McCord Stacey L. , Dagle Gerald E. , James Anthony C. , Tolmachev Sergei Y. , Thrall Brian D. , Morgan William F. 
Published: September 2012

Abstract
The long-term retention of inhaled soluble forms of plutonium raises concerns as to the potential health effects in persons working in nuclear energy or the nuclear weapons program. The distributions of long-term retained inhaled plutonium-nitrate [239Pu (NO3)4] deposited in the lungs of an accidentally exposed nuclear worker (Human Case 0269) and in the lungs of experimentally exposed beagle dogs with varying initial lung depositions were determined via autoradiographs of selected histologic lung, lymph node, trachea, and nasal turbinate tissue sections. These studies showed that both the human and dogs had a nonuniform distribution of plutonium throughout the lung tissue. Fibrotic scar tissue effectively encapsulated a portion of the plutonium and prevented its clearance from the body or translocation to other tissues and diminished dose to organ parenchyma. Alpha radiation activity from deposited plutonium in Human Case 0269 was observed primarily along the subpleural regions while no alpha activity was seen in the tracheobronchial lymph nodes of this individual. However, relatively high activity levels in the tracheobronchial lymph nodes of the beagles indicated the lymphatic system was effective in clearing deposited plutonium from the lung tissues. In both the human case and beagle dogs, the appearance of retained plutonium within the respiratory tract was inconsistent with current biokinetic models of clearance for soluble forms of plutonium. Bound plutonium can have a marked effect on the dose to the lungs and subsequent radiation exposure has the potential to increase cancer risk. Cancer Res; 72(21); 5529–36. ©2012 AACR.
CDK1 Regulates Mediator of DNA Damage Checkpoint 1 during Mitotic DNA Damage
Authors: Yu Bing , Dalton W. Brian , Yang Vincent W. 
Published: September 2012

Abstract
Cells engage sophisticated programs of DNA damage response (DDR) and repair to guard against genetic mutations. Although there is significant knowledge concerning DDR in interphase cells, much less is known about these processes in mitosis. Direct interaction between MDC1, a master DDR organizer, and a marker of DNA damage, histone γH2AX, is required to trigger robust repair. Here we show that the DNA damage-induced interaction between MDC1 and γH2AX is attenuated in mitosis. Furthermore, inhibition in the activity of the core mitotic regulator CDK1, either by pharmacologic inhibition or siRNA attenuation, enhances MDC1–γH2AX colocalization in mitosis. Our findings offer key new insights into how DDR is controlled during mitosis. Cancer Res; 72(21); 5448–53. ©2012 AACR.
Personalized Medicine in a Phase I Clinical Trials Program: The MD Anderson Cancer Center Initiative
Authors: Tsimberidou Apostolia-Maria , Iskander Nancy G. , Hong David S. , Wheler Jennifer J. , Falchook Gerald S. , Fu Siqing , Piha-Paul Sarina , Naing Aung , Janku Filip , Luthra Rajyalakshmi , Ye Yang , Wen Sijin , Berry Donald , Kurzrock Razelle 
Published: September 2012

Abstract
Purpose: We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations.
Patient and Methods: Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA)–certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy.
Results: Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P &lt; 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P &lt; 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P = 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P &lt; 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001).
Conclusion: Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials. Clin Cancer Res; 18(22); 6373–83. ©2012 AACR.
U.S. Food and Drug Administration Approval Summary: Brentuximab Vedotin for the Treatment of Relapsed Hodgkin Lymphoma or Relapsed Systemic Anaplastic Large-Cell Lymphoma
Authors: de Claro R. Angelo , McGinn Karen , Kwitkowski Virginia , Bullock Julie , Khandelwal Aakanksha , Habtemariam Bahru , Ouyang Yanli , Saber Haleh , Lee Kyung , Koti Kallappa , Rothmann Mark , Shapiro Marjorie , Borrego Francisco , Clouse Kathleen , Chen Xiao Hong , Brown Janice , Akinsanya Lara , Kane Robert , Kaminskas Edvardas , Farrell Ann , Pazdur Richard 
Published: September 2012

Abstract
The U.S. Food and Drug Administration (FDA) describes the accelerated approval of brentuximab vedotin for patients with relapsed Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma (sALCL). FDA analyzed the results of two single-arm trials, enrolling 102 patients with Hodgkin lymphoma and 58 patients with sALCL. Both trials had primary endpoints of objective response rate (ORR) and key secondary endpoints of response duration and complete response (CR) rate. For patients with Hodgkin lymphoma, ORR was 73% (95% CI, 65–83%); median response duration was 6.7 months, and CR was 32% (95% CI, 23–42%). For patients with sALCL, ORR was 86% (95% CI, 77–95%), median response duration was 12.6 months, and CR was 57% (95% CI, 44–70%). The most common adverse reactions were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. FDA granted accelerated approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with sALCL after failure of at least one prior multiagent chemotherapy regimen. Clin Cancer Res; 18(21); 5845–9. ©2012 AACR.
Inhibition of Monocarboxylate Transporter 2 Induces Senescence-Associated Mitochondrial Dysfunction and Suppresses Progression of Colorectal Malignancies In Vivo
Authors: Lee Inkyoung , Lee Sook-Ja , Kang Won Ki , Park Chaehwa 
Published: September 2012

Abstract
Senescence, an inherent tumor suppressive mechanism, is a critical determinant for chemotherapy. In the present study, we show that the monocarboxylate transporter 2 (MCT2) protein was tumor-selectively expressed in human colorectal malignancies and knockdown of MCT2 induces mitochondrial dysfunction, cell-cycle arrest, and senescence without additional cellular stress in colorectal cancer cell lines. Moreover, the reactive oxygen species (ROS) scavenger, N-acetylcysteine, blocked MCT2 knockdown-induced growth arrest and cellular senescence, indicating a pivotal role of ROS in this pathway. Dramatic induction of mitochondrial superoxide generation and decrease in ATP production was observed, indicating that mitochondrial dysfunction is the major mechanism underlying MCT2 knockdown-induced ROS generation. Senescence-associated DNA damage was also evident from the increase in promyelocytic leukemia bodies, γH2AX foci, and SAHF. Conversely, overexpression of MCT2 prevented doxorubicin-induced ROS accumulation (P = 0.0002) and cell growth inhibition (P = 0.001). MCT2 knockdown suppressed KRAS mutant colorectal tumor growth in vivo. In addition, MCT2 knockdown and cytostatic drug combination further enhanced the antitumor effect. These findings support the use of MCT2 as a promising target for inhibition of colorectal cancer. Mol Cancer Ther; 11(11); 2342–51. ©2012 AACR.
Roles of Estrogen Receptor and p21Waf1 in Bortezomib-Induced Growth Inhibition in Human Breast Cancer Cells
Authors: Maynadier Marie , Shi Jingxue , Vaillant Ophélie , Gary-Bobo Magali , Basile Ilaria , Gleizes Michel , Cathiard Anne-Marie , Wah Jonathan Lee Tin , Sheikh M. Saeed , Garcia Marcel 
Published: September 2012

Abstract
Proteasome inhibitors such as bortezomib constitute novel therapeutic agents that are currently in clinical use and in clinical trials. In some neoplasms, cyclin-dependent kinase inhibitors (CKI) such as p21WAF1 have been proposed as key targets of proteasome inhibitors. p21WAF1 expression can be modulated by p53, a tumor suppressor, and especially in breast cancer cells, by estrogen receptor alpha (ERα), which is highly relevant to cancer growth. We investigated the effects of bortezomib using a panel of six cancer cell lines with variable status of ERα or p53 and found that bortezomib inhibited the growth of all cell lines in the same concentration range irrespective of the ERα expression or the mutational status of p53. Bortezomib treatment significantly enhanced p21WAF1 protein levels in all cell lines but with different mechanisms according to ERα status. In ERα-positive cells, bortezomib treatment caused a strong increase in p21WAF1 mRNA, whereas in ERα-negative cells it predominantly enhanced p21WAF1 protein levels suggesting a posttranslational mechanism of p21WAF1 regulation in the ERα-negative cells. Moreover, the antiproliferative activity of bortezomib was prevented by ERα silencing or p21WAF1 knockdown in ERα-positive cells. Collectively, our results highlight the potential roles of ERα and p21WAF1 in growth inhibition of cancer cells mediated by proteasome inhibitors, such as bortezomib. Mol Cancer Res; 10(11); 1473–81. ©2012 AACR.
SUZ12 Promotes Human Epithelial Ovarian Cancer by Suppressing Apoptosis via Silencing HRK
Authors: Li Hua , Cai Qi , Wu Hong , Vathipadiekal Vinod , Dobbin Zachary C. , Li Tianyu , Hua Xiang , Landen Charles N. , Birrer Michael J. , Sánchez-Beato Margarita , Zhang Rugang 
Published: September 2012

Abstract
Epithelial ovarian cancer (EOC) ranks first as the cause of death for gynecological cancers in the United States. SUZ12 is a component of the polycomb repressive complex 2 (PRC2) and is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). The role of SUZ12 in EOC has never been investigated. Here, we show that SUZ12 is expressed at significantly higher levels in human EOC (n = 117) compared with either normal human ovarian surface epithelium (n = 35, P &lt; 0.001) or fallopian tube epithelium (n = 15, P &lt; 0.001). There is a positive correlation between expression of SUZ12 and EZH2 in human EOC (P &lt; 0.001). In addition, expression of SUZ12 positively correlates with Ki67, a marker of cell proliferation (P &lt; 0.001), and predicts shorter overall survival (P = 0.0078). Notably, knockdown of SUZ12 suppresses the growth of human EOC cells in vitro and in vivo in both orthotopic and subcutaneous xenograft EOC models. In addition, SUZ12 knockdown decreases the levels of H3K27Me3 and triggers apoptosis of human EOC cells. Mechanistically, we identified Harakiri (HRK), a proapoptotic gene, as a novel SUZ12 target gene, and showed that HRK upregulation mediates apoptosis induced by SUZ12 knockdown in human EOC cells. In summary, we show that SUZ12 promotes the proliferation of human EOC cells by inhibiting apoptosis and HRK is a novel SUZ12 target gene whose upregulation contributes to apoptosis induced by SUZ12 knockdown. Mol Cancer Res; 10(11); 1462–72. ©2012 AACR.
The Lymphotactin Receptor Is Expressed in Epithelial Ovarian Carcinoma and Contributes to Cell Migration and Proliferation
Authors: Kim Mijung , Rooper Lisa , Xie Jia , Rayahin Jamie , Burdette Joanna E. , Kajdacsy-Balla Andre A. , Barbolina Maria V. 
Published: September 2012

Abstract
Chemokine receptor-ligand interactions are important to support functioning of both normal and pathologic cells. The expression and function of chemokine receptors in epithelial ovarian carcinoma (EOC) is largely unknown. Here, we report that the lymphotactin receptor (XCR1) was expressed in primary and metastatic human epithelial ovarian carcinoma (EOC) specimens and cell lines. In contrast, expression of XCR1 was not detected in the normal ovary or in human normal ovarian surface epithelial cells. Our data indicate that XCL1 and XCL2 are either present in the malignant ascites or expressed by the ovarian carcinoma cells. The addition of lymphotactin (XCL1 and XCL2) stimulated migration and proliferation of XCR1-positive cells. Reduction of XCR1 expression in ovarian carcinoma cell line SKOV-3 resulted in abrogated diaphragm and peritoneal wall tumor formation and in reduced frequency of colonic, splenetic, and liver nodules in an in vivo xenograft mouse model. Taken together, our data suggest that XCR1 is expressed early during the course of tumorigenic transformation and contributes towards increased cell migration and proliferation, which can facilitate the prometastatic behavior of EOC cells. Mol Cancer Res; 10(11); 1419–29. ©2012 AACR.
Multiphoton Tomographic Imaging: A Potential Optical Biopsy Tool for Detecting Gastrointestinal Inflammation and Neoplasia
Authors: Makino Tomoki , Jain Manu , Montrose David C. , Aggarwal Amit , Sterling Joshua , Bosworth Brian P. , Milsom Jeffrey W. , Robinson Brian D. , Shevchuk Maria M. , Kawaguchi Kathy , Zhang Ning , Brown Christopher M. , Rivera David R. , Williams Wendy O. , Xu Chris , Dannenberg Andrew J. , Mukherjee Sushmita 
Published: September 2012

Abstract
Endoscopy is widely used to detect and remove premalignant lesions with the goal of preventing gastrointestinal (GI) cancers. Because current endoscopes do not provide cellular resolution, all suspicious lesions are biopsied and subjected to histologic evaluation. Technologies that facilitate directed biopsies should decrease both procedure-related morbidity and cost. Here we explore the use of multiphoton microscopy (MPM), an optical biopsy tool that relies on intrinsic tissue emissions, to evaluate pathology in both experimental and human GI specimens, using hematoxylin and eosin (H&E)-stained sections from these tissues for comparison. After evaluating the entire normal mouse GI tract, MPM was used to investigate disease progression in mouse models of colitis and colorectal carcinogenesis. MPM provided sufficient histologic detail to identify all relevant substructures in ex vivo normal GI tissue, visualize both acute and resolving stages of colitis, and show the progression of colorectal carcinogenesis. Next, ex vivo specimens from human subjects with celiac sprue, inflammatory bowel disease, and colorectal neoplasia were imaged by MPM. Finally, colonic mucosa in live anesthetized rats was imaged in vivo using a flexible endoscope prototype. In both animal models and human specimens, MPM images showed a striking similarity to the results of H&E staining, as shown by the 100% concordance achieved by the study pathologists' diagnoses. In summary, MPM is a promising technique that accurately visualizes histology in fresh, unstained tissues. Our findings support the continued development of MPM as a technology to enhance the early detection of GI pathologies including premalignant lesions. Cancer Prev Res; 5(11); 1280–90. ©2012 AACR.
Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Authors: Byers Lauren Averett , Wang Jing , Nilsson Monique B. , Fujimoto Junya , Saintigny Pierre , Yordy John , Giri Uma , Peyton Michael , Fan You Hong , Diao Lixia , Masrorpour Fatemeh , Shen Li , Liu Wenbin , Duchemann Boris , Tumula Praveen , Bhardwaj Vikas , Welsh James , Weber Stephanie , Glisson Bonnie S. , Kalhor Neda , Wistuba Ignacio I. , Girard Luc , Lippman Scott M. , Mills Gordon B. , Coombes Kevin R. , Weinstein John N. , Minna John D. , Heymach John V. 
Published: September 2012

Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.
Significance: SCLC is a highly lethal cancer with a 5-year survival rate of less than 10%. To date, no molecularly targeted agents have prolonged survival in patients with SCLCs. As a step toward identifying new targets, we systematically profiled SCLCs with a focus on therapeutically relevant signaling pathways. Our data reveal fundamental differences in the patterns of pathway activation in SCLCs and NSCLCs and identify several potential therapeutic targets for SCLCs, including PARP1 and EZH2. On the basis of these results, clinical studies evaluating PARP and EZH2 inhibition, together with chemotherapy or other agents, warrant further investigation. Cancer Discov; 2(9); 798–811. ©2012 AACR.
Read the Commentary on this article by Rosell and Wannesson, p. 769.
This article is highlighted in the In This Issue feature, p. 753.
Paracrine Signaling between Carcinoma Cells and Mesenchymal Stem Cells Generates Cancer Stem Cell Niche via Epithelial–Mesenchymal Transition
Authors: Räsänen Kati , Herlyn Meenhard 
Published: September 2012

Abstract
Summary: Li and colleagues present data that cancer cell–derived interleukin-1 induces prostaglandin E2 and cytokine secretion in mesenchymal stem cells (MSC) to activate β-catenin signaling in the cancer cell. This paracrine signaling between carcinoma cells and MSC leads to the creation of a cancer stem cell niche via epithelial–mesenchymal transition. Cancer Discov; 2(9); 775–7. ©2012 AACR.
Commentary on Li et al., p. 840.